CN101085391A - Device for inducing tumor cell apoptosis by high-voltage nanosecond pulse - Google Patents
Device for inducing tumor cell apoptosis by high-voltage nanosecond pulse Download PDFInfo
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Abstract
A device for inducing apoptosis of tumor cell with high voltage nanosecond pulse belongs to technology field of electric impulse for treatment of tumor. The inventive device mainly comprises high voltage direct current module, pulse formation system, pulse measurement system, computer system, and power system. Amplitude value of high voltage nanosecond pulse is continuously regulated or preset between 0-9.9kV, repetition frequency is continuously regulated or preset between 2-100Hz, width is continuously regulated or preset between 200ns-1 mu s by separating to 7 grades, and numbers is regulated or preset according to treatment requirement. As the inventive device can induce apoptosis of tumor cell, is an unalloyed physical method, has no requirement of medicament assistance, thus can completely avoid toxic and adverse side effect of chemotherapeutics during treatment and adverse reaction such as inflammation, pain, ulcer and stammer, therefore the inventive device can be widely used in oncotherapy and treatment of removing polypus and redundant grease and vulvopathy.
Description
Technical field
The invention belongs to point electric impulse therapeutic tumor technical field, particularly the device of high-voltage nanosecond pulse treatment tumor.
Background technology
The seventies in 20th century, it is found that in field intensity to be that 1kV/cm level, pulsewidth are under the impulse electric field effect of 100 μ s levels, the lipid bilayer of cell membrane is temporarily rearranged formation, and some are called as the hydrophilic pathway of micropore, after impulse electric field is cancelled, micropore can be closed voluntarily and can not had any impact by pair cell, this phenomenon be referred to as the reversibility electroporation (reversible electroporation, REP).In recent years, discover and increase the impulse electric field dosage (increasing pulse amplitude or pulsewidth or pulse number) of inducing the reversibility electroporation, can not heal behind the membrane perforation, integrity is damaged, the death of cell generation coagulability, this phenomenon be called the irreversibility electroporation (irreversible electroporation, IRE) or the irreversibility electrical breakdown (irreversibleelectrical breakdown, IREB).Since the irreversibility electroporation can be under the assosting effect that does not use chemotherapeutics direct cell killing, can avoid the damaging effect of chemotherapeutics to patient body, it is painful to reduce treatment, therefore people just are being devoted to the irreversibility electroporation is applied in the oncotherapy, i.e. irreversibility electroporation tumor therapy.
The application of irreversibility electroporation treatment tumor does not also have commercialization, but has been in the application process of clinical trial.Chinese patent application number is that 200710078282.7 " device and method of tumor treating steep pulse " discloses a kind of device and method that utilizes steep-sided pulse irreversibility electrical breakdown effect treatment tumor, this device is taken place and TT﹠C system by steep-sided pulse, computer system, power-supply system and bench board are formed, can produce peak value is that 0～1000V is adjustable continuously, repetition rate is that 1Hz～10kHz is adjustable continuously, pulsewidth be 100ns～100 μ s divide 6 grades adjustable, the continuously adjustable unidirectional exponential damping electric pulse of rise time 10～100ns, its Therapeutic Method is the on position and the degree of depth of determining earlier the characteristic parameter and the motor head of steep-sided pulse according to the concrete condition of patient's characteristics and tumor tissues thereof, characteristic parameter by the computer system presetter device, then electrode tip is inserted in the tumor tissues, treats by keyboard or mouse action at last.This steep-sided pulse irreversibility electroporation treatment tumor method is a kind of physical method, be under the situation of not using chemotherapeutics, to carry out, it utilizes steep-sided pulse inducing tumor cell film generation irreversibility electroporation, destroy the integrity of cell membrane and the living environment of cell, make tumor cell generation coagulation necrosis, thereby reach the purpose of treatment tumor.Though, untoward reaction such as inflammation, pain, ulcer, stammerer can occur though this method has fundamentally been avoided the toxic and side effects of chemotherapeutics to health.
Summary of the invention
The objective of the invention is deficiency, a kind of device of inducing tumor cell apoptosis by high-voltage nanosecond pulse is provided at existing irreversibility electroporation tumor therapeuticing method.The present invention is under the situation of injected chemical medicine not, applies high pressure (a few kV/cm) nanosecond (hundreds of ns) impulse electric field and acts on tumor cell, makes tumor cell generation apoptosis, thereby reaches the purpose of kill tumor cell.This method disappears tumor cell automatically, can avoid inflammation, pain, ulcer, stammerer etc., has reduced the untoward reaction in the therapeutic process.
Mechanism of the present invention: because apoptosis is a kind of with downright bad different dead mechanism, be that cell is under certain physiology or pathological conditions, follow the program of oneself, oneself finishes the process of life, last cell detachment exsomatizes or is cracked into some apoptotic bodies, is engulfed by the phagocyte in the body.Therefore, inducing tumor cell apoptosis by high-voltage nanosecond pulse is that a kind of and low pressure steep-sided pulse make the distinct mechanism of killing tumor cell of tumor cell generation coagulation necrosis by the irreversibility electrical breakdown.Simultaneously, though the peak power of high-voltage nanosecond pulse very high (reaching several megawatts), because the pulse duration (pulse width) is very short, the energy that is released on the tumor tissues is very little, heat effect can be ignored, and visible inducing tumor cell apoptosis by high-voltage nanosecond pulse is a kind of non-thermal biological effect.And traditional radio frequency, high intensity focused ultrasound, freezing etc. be to utilize electromagnetic wave, ultrasonic or cryogen etc. that tumor tissues is heated or refrigeration, change the living environment of tumor cell, thereby also make tumor tissues generation coagulation necrosis, but these traditional Therapeutic Method based on heat effect are because the heat that a part produces is taken away in the blood National Games, thereby therapeutic effect can be affected, and easily normal structure or internal organs on every side be caused the hot injury.Therefore, from the biological effect angle, the present invention is to provide a kind of with traditional radio frequency, high intensity focused ultrasound, the different oncotherapy principle of tumor therapy such as freezing.
The technical scheme that realizes the object of the invention is: a kind of device of inducing tumor cell apoptosis by high-voltage nanosecond pulse mainly comprises HVDC module, pulse shaping system, impulsive measurement system, computer system, power-supply system etc.Power-supply system is made up of power supply, power-supply filter, isolating transformer and wiring board, power supply is connected with the input of power-supply filter by lead, the outfan of power-supply filter is connected with the input of isolating transformer by lead, carries out filtering and isolation in order to the power supply to input; The outfan of isolating transformer is connected to wiring board by lead, the outfan of wiring board is connected to preheating transformer and an end of foot switch, the oscillograph of impulsive measurement system and the medical panel computer of computer system of HVDC module, pulse shaping system respectively with lead, in order to supply with its power supply.The HVDC module is commercial module, is connected by the end of lead with the charging resistor of pulse shaping system, in order to the continuously adjustable high voltage direct current of output under the control of computer system, as the charge power supply of the storage capacitor of pulse shaping system.The impulsive measurement system is made up of potentiometer, current sensor and oscillograph, and the input of potentiometer is connected with the outfan of bonding jumper with the fictitious load of pulse shaping system, and the outfan of potentiometer is connected with oscillographic input with lead; Current sensor is enclosed within on the output interface of pulse shaping system, the high-voltage nanosecond pulse electric current of pulse shaping system output is flow through from the center of current sensor, the outfan of current sensor is connected with the trigger element of oscillographic input with the pulse shaping system respectively with lead, oscillographic data output interface is connected with the medical panel computer of computer system with lead, and the high-voltage nanosecond pulse voltage and current waveform of exporting in order to paired pulses formation system detects and data acquisition in real time.Computer system is by medical panel computer, keyboard and mouse and I/O control module are formed, keyboard and mouse is connected with medical panel computer with lead, medical panel computer is connected with the input of lead with the I/O control module, the outfan of I/O control module is connected with the trigger element of HVDC module with the pulse shaping system with lead, in order to the voltage of HVDC module output is regulated or preset, being used to of the trigger element of pulse shaping system output triggers the repetition rate and the number of the trigger impulse of thyratron and regulates or preset, demonstration and the measurement of characteristic parameter and the management of patient medical record of the high-voltage nanosecond pulse voltage and current waveform of pulse shaping system output.The pulse shaping system is made up of charging resistor, storage capacitor, thyratron, preheating transformer, trigger element, foot switch and fictitious load, the other end of charging resistor is connected with an end of storage capacitor and the anode of thyratron respectively with bonding jumper, the other end of storage capacitor is connected with fictitious load with bonding jumper, the outfan of preheating transformer is with pre-thermoae be connected of lead with thyratron, in order to thyratron is carried out preheating, the outfan of trigger element is connected with the trigger electrode of thyratron with lead, with thinking that thyratron provides trigger impulse; The other end of foot switch is connected with trigger element by lead, as treating switch with handled easily.The high voltage direct current of HVDC module output charges to storage capacitor by charging resistor and equivalent load (fictitious load is in parallel with tumor cell as equivalent load), after being full of electricity, thyratron conducting rapidly under the trigger impulse effect of trigger element output through preheating, be discharged into the electric charge that stores in the storage capacitor on the equivalent load rapidly, form unidirectional negative polarity exponential damping high-voltage nanosecond pulse output, be used for inducing apoptosis of tumour cell.
The formed high-voltage nanosecond pulse of pulse shaping system of apparatus of the present invention is the pulse of unidirectional negative polarity exponential damping, by the high-voltage dc voltage that computer system is regulated or preset high pressure direct current module is exported, the high-voltage nanosecond pulse peak value is regulated continuously or is preset in 0～9.9kV scope; Regulate or presetting pulse forms the repetition rate and the number of trigger impulse that is used to trigger thyratron of the trigger element output of system by computer system, the repetition rate of high-voltage nanosecond pulse is regulated continuously or is preset in 2～100Hz scope, and number is regulated or preset according to the treatment needs; The capacitor number of the energy-storage units by manual adjustments pulse shaping system, pulse width in 200ns～1 μ s scope, divide 7 grades adjustable, the adjusting of these parameters is independent separately, be independent of each other.Apparatus of the present invention are by powerful software system, except can to output peak value of pulse, repetition rate, pulse number is regulated and preset, can also gather in real time and the real-time measurement of demonstration and characteristic parameter the nanosecond pulse waveform, and have more perfect database of patient medical records system.
Utilize apparatus of the present invention by program tumor to be treated, its concrete grammar step and the applicant's application number are that the method for 200710078282.7 " device and method of tumor treating steep pulse " is identical.
After the present invention adopts technique scheme, mainly contain following characteristics:
1, the equivalent frequency of high-voltage nanosecond pulse of the present invention is very high, can see through the cell membrane that mainly shows as capacitance characteristic in the cell, act on film inner cell organs such as nucleus, mitochondrion, endoplasmic reticulum, the antiapoptotic factors of active cell inside, inducing cell generation apoptosis, last cell detachment exsomatizes or is cracked into some apoptotic bodies, is engulfed by the phagocyte in the body.This method disappears tumor cell automatically, thus can not produce inflammation, untoward reaction such as pain, ulcer, stammerer.
Though 2, high-voltage nanosecond pulse peak power of the present invention very high (reaching several megawatts), but because the pulse duration (pulse width) is very short, the energy that is released on the tumor tissues is very little, heat effect can be ignored, be that inducing tumor cell apoptosis by high-voltage nanosecond pulse of the present invention is a kind of non-thermal biological effect, thereby therapeutic effect can not be subjected to the influence of blood fortune, can not cause the hot injury to normal surrounding tissue or internal organs yet.
3, the present invention adopts inducing tumor cell apoptosis by high-voltage nanosecond pulse, without any need for assisting of medicine, is a kind of pure physical method, can avoid the toxic and side effects of chemotherapeutics fully.
Apparatus of the present invention can be widely used in oncotherapy, also can be applied to remove treatment of conditions such as polyp, superabundant fats (fat-reducing) and pudendum pathological changes.
Description of drawings
Fig. 1 is the theory diagram of apparatus of the present invention;
Fig. 2 is the pulse shaping system of present embodiment device;
Fig. 3 is the main circuit schematic diagram of the trigger element of Fig. 2;
Fig. 4 is the IGBT drive circuit schematic diagram of the trigger element of Fig. 2;
Fig. 5 is the holding circuit schematic diagram of the trigger element of Fig. 2;
Fig. 6 is the chip operation power circuit principle figure of the trigger element of Fig. 2;
Fig. 7 is the fluorescence microscope photo of the high-voltage nanosecond pulse cell death inducing of present embodiment;
Wherein: A is matched group (amplification is 200), and B is processed group (amplification is 200).
Fig. 8 is the transmission electron microscope photo of the high-voltage nanosecond pulse cell death inducing of present embodiment;
Wherein: A is processed group (amplification is 5000), and B is matched group (amplification is 5000).
Fig. 9 is the Flow cytometry figure as a result of the high-voltage nanosecond pulse cell death inducing of present embodiment.
Wherein: A is a matched group, and B is a processed group.
Among the figure: 1 HVDC module, 2 pulse shaping systems, 3 impulsive measurement systems, 4 computer systems; 5 power-supply systems, R resistance, C electric capacity, K thyratron; the B transformator, L inductance, D diode, Q igbt (IGBT); the TK trigger element, TQ IGBT drive circuit, Ip holding circuit, IC1 digital regulation resistance; IC2, IC4 555 intervalometers, IC3 photoisolator, IC5 operational amplifier; IC6 comparator (LM3 11), IC7 nor gate, U1, U2 three terminal integrated voltage stabilizer.
The specific embodiment:
Below in conjunction with the specific embodiment, further specify the present invention.
Shown in Fig. 1～6, a kind of device of inducing tumor cell apoptosis by high-voltage nanosecond pulse mainly comprises HVDC module 1, pulse shaping system 2, impulsive measurement system 3, computer system 4 and power-supply system 5 etc.Power-supply system 5 is made up of power supply, power-supply filter, isolating transformer and wiring board, power supply is the civil power of 220V/50Hz, power supply is connected with the input of power-supply filter by power line, the outfan of power-supply filter is connected with the input of isolating transformer by power line, carries out filtering and isolation in order to the power supply to input; The outfan of isolating transformer is connected to wiring board by power line, the outfan of wiring board is connected to preheating transformer B1 and an end of foot switch, the oscillograph of impulsive measurement system 3 and the medical panel computer of computer system 4 of HVDC module 1, pulse shaping system 2 respectively with the power line line, in order to supply with its power supply.HVDC module 1 is commercial module, its model is DW-P153-20AC, be connected by the end of power line with the charging resistor R0 of pulse shaping system 2, in order to the continuously adjustable high voltage direct current of output under the control of computer system 4, as the charge power supply of the storage capacitor C0 of pulse shaping system 2.Impulsive measurement system 3 is made up of potentiometer, current sensor and oscillograph, and the input of potentiometer is connected with the outfan of bonding jumper with the fictitious load Rf of pulse shaping system 2, and the outfan of potentiometer is connected with oscillographic input with coaxial cable; Current sensor is enclosed within on the output interface of pulse shaping system 2, the high-voltage nanosecond pulse electric current of pulse shaping system 2 outputs is flow through from the center of current sensor, the outfan of current sensor is connected with the trigger element TK of oscillographic input and pulse shaping system 2 respectively with coaxial cable, oscillographic data output interface is connected with the medical panel computer of computer system 4 with data wire, and the high-voltage nanosecond pulse voltage and current waveform that forms system's 2 outputs in order to paired pulses detects and data acquisition in real time.Computer system 4 is by medical panel computer, keyboard and mouse and I/O control module are formed, keyboard and mouse is connected with medical panel computer with holding wire, medical panel computer is connected with the input of data wire with the I/O control module, the outfan of I/O control module is connected with the trigger element TK of holding wire with HVDC module 1 and pulse shaping system 2, in order to the voltage of HVDC module 1 output is regulated or preset, being used to of the trigger element TK of pulse shaping system 2 output triggers the repetition rate and the number of the trigger impulse of thyratron K and regulates or preset, demonstration and the measurement of characteristic parameter and the management of patient medical record of the high-voltage nanosecond pulse voltage and current waveform of pulse shaping system 2 outputs.Pulse shaping system 2 is mainly by charging resistor R0, storage capacitor C0, thyratron K, preheating transformer B1, trigger element TK and fictitious load Rf form, the other end of charging resistor R0 is connected with the end of storage capacitor C0 and the anode A of thyratron K respectively with bonding jumper, the other end of storage capacitor C0 is connected with the end of fictitious load Rf with bonding jumper, the other end of fictitious load Rf is connected with ground 1 (Gnd1) with bonding jumper, two lead-out terminals of preheating transformer B1 are connected with ground 1 (Gnd1) with the pre-thermoae F1 of thyratron K respectively with power line, the pre-thermoae F2 of thyratron K all uses bonding jumper to be connected with ground (Gnd1) with negative electrode KC, in order to thyratron K is carried out preheating, trigger element TK is connected with the trigger electrode G of thyratron K with coaxial cable, K provides trigger impulse for thyratron, the other end of foot switch is connected with trigger element TK by power line, as treating switch with handled easily.The high voltage direct current of HVDC module 1 output charges to storage capacitor C0 by charging resistor R0 and equivalent load (fictitious load Rf is in parallel with tumor cell as equivalent load), after being full of electricity, through 3～5 minutes thyratron K of preheating conducting rapidly under the trigger impulse effect of trigger element Tk output, be discharged into the electric charge that stores among the storage capacitor C0 on the equivalent load rapidly, form unidirectional negative polarity exponential damping high-voltage nanosecond pulse output, be used for inducing apoptosis of tumour cell.By the high-voltage dc voltage that computer system 4 is regulated or preset high pressure direct current module 1 is exported, the high-voltage nanosecond pulse amplitude is regulated continuously or is preset in 0～9.9kV scope; Regulate or presetting pulse forms the repetition rate and the number of trigger impulse that is used to trigger thyratron K of the trigger element Tk output of system 2 by computer system 4, regulate continuously or preset in repetition rate 2～100Hz scope of high-voltage nanosecond pulse, number is regulated or is preset according to the treatment needs; By the capacitor number of manual adjustments storage capacitor C0, pulse width is divided 7 grades of adjustings in 200ns～1 μ s scope.
The main circuit of the trigger element TK of pulse shaping system 2 mainly is made up of igbt (IGBT) Q, booster transformer B2, four diode D3～D6, inductance L, two Transient Suppression Diode D7 and D8, three capacitor C 11～C13, two resistance R 6 and R7.220V/50Hz power supply after passing through power-supply system 1 filtering and isolating is connected with an end of foot switch with power line, to be 1: 2 booster transformer B2 with no-load voltage ratio respectively with power line be connected with former limit winding with the step-down transformer B3 of two independent secondary windings the other end of foot switch, the secondary winding of booster transformer B2 links to each other with four diode D3～D6, constitute uncontrollable full bridge rectifier, its outfan and inductance L, two series filtering capacitor C 11 are connected with the LC filter circuit that C12 constitutes, in order to civil power is boosted, rectification and filtering obtain being about the unidirectional current of 600V.This galvanic outfan links to each other with an end of resistance R 6, and the other end of resistance R 6 links to each other with an end of capacitor C 13 and the colelctor electrode Qc of IGBT Q, and the other end of capacitor C 13 links to each other with ground (Gnd1), and this unidirectional current is by 13 chargings of 6 pairs of capacitor C of resistance R.The grid Qg of IGBT Q and emitter stage Qe link to each other with the outfan of the IGBT drive circuit TQ of trigger element TK and an end of resistance R 7 respectively, the other end of resistance R 7 links to each other with ground 1 (Gnd1), IGBT Q conducting under the driving signal effect that the IGBT of trigger element TK drive circuit TQ produces, energy stored in the capacitor C 13 is discharged on the resistance R 7, obtain amplitude at resistance R 7 two ends and be about 600V, pulse width is about the trigger impulse of 5 μ s, in order to trigger thyratron K, the repetition rate and the number of the driving signal that produces by the IGBT drive circuit TQ that regulates or preset trigger element TK, being used to of trigger element TK output triggers the repetition rate of thyratron K trigger impulse and regulates between 2～100Hz or preset, and the trigger impulse number is according to the adjusting of treatment needs or preset.Be connected in parallel on resistance R 7 two ends after the Transient Suppression Diode D7 of two rated voltage 300V and the D8 series connection, prevent that the overvoltage that produces in the thyratron K turn on process from exerting an influence to trigger element TK.The break-make of control foot switch can be controlled trigger element TK and whether export the trigger impulse that is used to trigger thyratron K, whether export high-voltage nanosecond pulse thereby control this device, thereby foot switch is the treatment switch of this device.
The IGBT drive circuit TQ of the trigger element TK of pulse shaping system 2 is that the digital regulation resistance IC1 of MAX5455, two models 555 intervalometer IC2 that are NE555P and IC4, the model photoisolator IC3 that is TLP250, nor gate IC7 and the correspondent peripheral circuit that model is MC74HC02 are formed by model mainly.Digital regulation resistance IC1,555 intervalometer IC2, resistance R 1 and R2, capacitor C 1～C5 constitute multi-resonant oscillating circuit, are the square wave control signal of 5V in order to produce amplitude, from outfan (3 foot) output of 555 intervalometer IC2.The outfan of 555 intervalometer IC2 (3 foot) links to each other with the input (2 foot) of photoisolator IC3, photoisolator IC3, resistance R 3 and capacitor C 6 constitute buffer circuit, isolate in order to the square wave control signal of 555 intervalometer IC2 output is carried out earth potential, simultaneously amplitude is amplified to 15V.The outfan of photoisolator IC3 (6 foot) links to each other with the peaker that capacitor C 7, resistance R 4 and diode D1 constitute, and peaker obtains the exponential damping pulse of pulsewidth less than 5 μ s in order to carrying out differential through the square wave control signal after isolation and the amplification.The outfan of peaker links to each other with the input (2 foot) of 555 intervalometer IC4,555 intervalometer IC4, resistance R 5 and capacitor C 8～C10 constitute monostable circuit, the outfan of 555 intervalometer IC4 (3 foot) and earth terminal (1 foot) link to each other with emitter stage Qe with the grid Qg of the IGBT Q of the main circuit of trigger element TK respectively, the exponential damping pulses switch that monostable circuit is exported peaker becomes pulsewidth to be fixed as 5 μ s, amplitude is the driving signal of 15V, in order to the IGBT Q in the main circuit that drives trigger element TK.The two ends of Zener diode D2 link to each other with ground 2 (Gnd2) with the outfan (3 foot) of operational amplifier IC5 respectively, in order to the overvoltage in the restriction IGBT Q turn on process.Digital regulation resistance IC1 increases/down control input (3 foot), control input end (12 foot) is regulated in the contact, sheet choosing end (14 foot) and earth terminal (11 foot) link to each other with the outfan of the I/O control module of computer system 4 with holding wire, regulate or preset the resistance value of digital regulation resistance IC1 output by computer system 4, the repetition rate of the square wave control signal of 555 intervalometer IC2 output is regulated between 2～100Hz or is preset, and regulates between 2～100Hz or presets thereby being used for of making that IGBT drive circuit TQ exports drives the repetition rate of driving signal of the IGBT Q of trigger element TK.The outfan (3 foot) of the Enable Pin of 555 intervalometer IC2 (4 foot) AND IC7 links to each other; and two inputs of nor gate IC7 (1 foot and 2 feet) link to each other with the outfan of the I/O control module of computer system 4 and the outfan of the holding circuit Ip of trigger element TK respectively; whether control 555 intervalometer IC2 by the output level of computer system 4 control nor gate IC7 works; the number of the square wave control signal of 555 intervalometer IC2 output is regulated or is preset according to the treatment needs, thereby makes the driving signal number of IGBT Q that is used for driving trigger element TK of IGBT drive circuit TQ output regulate or preset according to the treatment needs.
The holding circuit Ip of the trigger element TK of pulse shaping system 2 is that the operational amplifier IC5 of OP07 and comparator IC6 and correspondent peripheral circuit that model is LM311 are formed by model mainly.The outfan of current sensor links to each other with the anode of diode D9 by the heart yearn of coaxial cable, the screen layer of coaxial cable links to each other with ground (Gnd1), diode D9, resistance R 8 and capacitor C 14 constitute peak holding circuits, in order to current sensor senses to the high-voltage nanosecond pulse current signal of pulse shaping system 2 outputs carry out peak value and keep.The negative electrode of diode D9 links to each other with the in-phase input end (3 foot) of operational amplifier IC5, and operational amplifier IC5, resistance R 9, capacitor C 15 and C16 constitute voltage follower circuit, in order to the current signal through peak holding circuit is carried out voltage follow.The outfan of operational amplifier IC5 (6 foot) links to each other with the in-phase input end (2 foot) of comparator IC6, comparator IC6, adjustable resistance R10, resistance R 11 and capacitor C 17 constitute comparison circuit, the centre tap of adjustable resistance R10 links to each other with the inverting input (3 foot) of comparator IC6, two ends link to each other with ground 1 (Gnd1) with power supply 1 (VCC1) respectively in addition, for the inverting input (3 foot) of comparator IC6 provides reference potential.Resistance R 11 two ends link to each other with outfan (7 foot) with the inverting input (3 foot) of comparator IC6 respectively, as feedback branch.Comparison circuit compares the current potential of the in-phase input end (2 foot) of comparator IC6 and the reference potential of inverting input (3 foot), when the reference potential of in-phase input end (2 foot) current potential greater than inverting input (3 foot), comparator IC6 exports high level, otherwise, output low level.The input (2 foot) of the outfan of comparator IC6 (7 foot) AND IC7 links to each other, when comparator IC6 output high level, and nor gate IC7 output low level, 555 intervalometer IC2 quit work.Therefore; the high-voltage nanosecond pulse electric current of exporting when this device surpasses setting value; when being the reference potential of the in-phase input end current potential of comparator IC6 and inverting input; the high level of comparator IC6 output makes nor gate IC7 output low level; 555 intervalometer IC2 quit work; trigger element TK stops to export the trigger impulse that is used to trigger thyratron K, and apparatus of the present invention stop to export high-voltage nanosecond pulse, thereby realizes overcurrent or short-circuit protection to this device.
The chip operation power circuit of the trigger element TK of pulse shaping system 2 is that the three terminal integrated voltage stabilizer U1 of MC7805, the three terminal integrated voltage stabilizer U2 that model is MC7815, ten diode D10～D19, eight capacitor C 19～C26 form by step-down transformer B3, model mainly.After the blood pressure lowering of the power supply of 220V/50Hz through step-down transformer B3, on two secondary windings, obtain two independently virtual value be the low-voltage alternating current power supply of 15V, one of them secondary winding links to each other with four diode D10～D13, constitute uncontrollable full bridge rectifier, be used for the low-voltage alternating current power supply of this secondary winding output is carried out rectification, obtain Rectified alternating current, the outfan of rectification circuit links to each other with capacitor C 19, pulse direct current after 19 pairs of rectifications of capacitor C carries out filtering, obtain the unidirectional current that secondary value is about 21V, be connected to the capacitor C 20～C22 of three terminal integrated voltage stabilizer U1 and periphery thereof and the 5V mu balanced circuit that diode D14 constitutes again, exporting stable amplitude is the unidirectional current of 5V, the outfan of three terminal integrated voltage stabilizer U1 (3 foot) and earth terminal (2 foot) respectively with digital regulation resistance IC1,555 intervalometer IC2, operational amplifier IC5, comparator IC6, (Gnd1's power end of nor gate IC7) links to each other with accordingly, for they provide working power.Another secondary winding of step-down transformer B3 links to each other with four diode D15～D18, constitute uncontrollable full bridge rectifier, be used for the low-voltage alternating current power supply of this secondary winding output is carried out rectification, obtain Rectified alternating current, the outfan of rectification circuit links to each other with capacitor C 23, Rectified alternating current after 23 pairs of rectifications of capacitor C carries out filtering, obtain the unidirectional current that secondary value is about 21V, be connected to the capacitor C 24～C26 of three terminal integrated voltage stabilizer U2 and periphery thereof and the 15V mu balanced circuit that diode D19 constitutes again, exporting stable amplitude is the unidirectional current of 15V, the outfan of three terminal integrated voltage stabilizer U2 (3 foot) and earth terminal (2 foot) photoisolator IC3, (Gnd2's power end of 555 intervalometer IC4) links to each other with accordingly, for they provide working power.
Utilize apparatus of the present invention to induce people's ovary SKOV of artificial culture by programme-control
3Apoptosis takes place, and its concrete grammar step and the applicant's application number are that the method for 200710078282.7 " device and method of tumor treating steep pulse " is identical.
Experimental result
Adopt the device of the high-voltage nanosecond pulse cell death inducing of present embodiment, to people's ovary SKOV of artificial culture
3Cell experimentizes.The pulse parameter that experiment is applied is: peak value 8kV/cm, pulse width 200ns, repetition rate 2Hz, 300 of pulse numbers.After the test, adopt multiple medical science apoptosis detection method respectively processed group and matched group to be detected, shown in Fig. 7～9.
The AO/EB fluorescent staining microphotograph of high-voltage nanosecond pulse cell death inducing as shown in Figure 7.The only visible normal cell form rule of matched group is fusiformis, and after birth is complete, and nucleus fluorescence is even, is green hyperfluorescence, and endochylema is visible a small amount of red punctate fluorescence under the green fluorescence background.The visible viable apoptotic cell of processed group, non-viable apoptotic cell, non-viable non-apoptotic cell and normal cell.Viable apoptotic cell: cell volume dwindles, and after birth is complete, and nucleus is yellow green or fluorescent orange, and the dense graininess of gathering into is positioned at a side of cell, and kytoplasm concentrates, and is yellow-green fluorescence.Non-viable apoptotic cell: cell volume dwindles, and after birth is complete, and nucleus is fluorescent red-orange, dense poly-and deflection, and kytoplasm also concentrates, and fluorescence takes on a red color.Non-viable non-apoptotic cell: cell volume increases, and is uneven fluorescent red-orange, and profile is unclear, has disintegrated or approaching the disintegration.
The transmission electron microscope photo of high-voltage nanosecond pulse cell death inducing as shown in Figure 8.Matched group normal cell form rule has abundant microvillus, the nuclear rule, and based on autosome, kernel is clear, near a side of nuclear membrane; Endochylema is abundant, and electron density is low, mitochondrial crista structural integrity, and visible a large amount of thick endoplasmic reticulum and free ribosome.The visible apoptotic cell of processed group, volume obviously diminishes, and surperficial microvillus disappears, and cell membrane is complete, the nuclear membrane gauffer, heterochromatin increases in the nuclear, and chromatin concentrates, and the limit combines in nuclear membrane, is lobulated, the petal-shaped basilar part is close to nuclear membrane; The endochylema electron density increases, and organelle is concentrated, the mitochondrion mild swelling, and the lysosome compensatory increases; After birth goes out " bud " and is forming apoptotic body.。
The Flow cytometry of high-voltage nanosecond pulse cell death inducing as shown in Figure 9 is figure as a result.Left upper quadrant is represented the mechanical injuries that occur in the cell harvesting process or is handled the cell (Annexin-/PI+) of too intense mechanical loss; Right upper quadrant is represented apoptosis or non-viable non-apoptotic cell (Annexin+/PI+) in late period; Left lower quadrant is represented normal cell (Annexin-/PI-); Right lower quadrant is represented viable apoptotic cell (Annexin+/PI-).Processed group cell apoptosis rate in early stage and late period is respectively 39.96% and 31.28%, compares remarkable increase (P＜0.01) with matched group; Processed group apoptosis and downright bad overall rate are 74.52%, compare with matched group also to have significant difference (P＜0.05), and as seen, from statistics, apoptosis has all taken place cell major part after treatment.
From above-mentioned experimental result as can be known, no matter be angle from morphology (fluorescence microscope and electron microscope observation result), still proved all that from the angle of statistics (Flow cytometry result) high-voltage nanosecond pulse can inducing cell generation apoptosis, thereby reached the purpose of killing tumor cell.
Claims (3)
1, a kind of device of inducing tumor cell apoptosis by high-voltage nanosecond pulse, mainly comprise HVDC module (1), pulse shaping system (2), impulsive measurement system (3), computer system (4), power-supply system (5), it is characterized in that power-supply system (5) is by power supply, power-supply filter, isolating transformer and wiring board are formed, power supply is connected with the input of power-supply filter by lead, the outfan of power-supply filter is connected with the input of isolating transformer by lead, the outfan of isolating transformer is connected to wiring board by lead, the outfan of wiring board is connected to HVDC module (1) respectively with lead, the preheating transformer of pulse shaping system (2) and an end of foot switch, the medical panel computer of the oscillograph of impulsive measurement system (3) and computer system (4), HVDC module (1) is commercial module, be connected by the end of lead with the charging resistor (R0) of pulse shaping system (2), impulsive measurement system (3) is by potentiometer, current sensor and oscillograph are formed, the input of potentiometer is connected with the outfan of bonding jumper with the fictitious load (Rf) of pulse shaping system (2), the outfan of potentiometer is connected with oscillographic input with lead, current sensor is enclosed within on the output interface of pulse shaping system (2), the outfan of current sensor is connected with the trigger element (TK) of oscillographic input and pulse shaping system (2) respectively with lead, oscillographic data output interface is connected with the medical panel computer of lead with computer system (4), computer system (4) is by medical panel computer, keyboard and mouse and I/O control module are formed, keyboard and mouse is connected with medical panel computer with lead, medical panel computer is connected with the input of lead with the I/O control module, the outfan of I/O control module is connected with the trigger element (TK) of lead with HVDC module (1) and pulse shaping system (2), pulse shaping system (2) is mainly by charging resistor (R0), storage capacitor (C0), thyratron (K), preheating transformer (B1), trigger element (TK), foot switch and fictitious load (Rf) are formed, the other end of charging resistor (R0) is connected with an end of storage capacitor (C0) and the anode (A) of thyratron (K) respectively with bonding jumper, the other end of storage capacitor (C0) is connected with fictitious load (Rf) with bonding jumper, the outfan of preheating transformer (B1) thermoae in advance (F1 of lead and thyratron (K), F2) be connected, the outfan of trigger element (TK) is connected with the trigger electrode (G) of thyratron (K) with lead, and the other end of foot switch is connected with trigger element (TK) with lead.
2, according to the described inducing tumor cell apoptosis by high-voltage nanosecond pulse device of claim 1, it is characterized in that the formed high-voltage nanosecond pulse of described pulse shaping system (2) is the pulse of unidirectional negative polarity exponential damping, its pulse amplitude regulate continuously between 0～9.9kV or preset, repetition rate is being regulated between 2Hz～100Hz continuously or preset, pulse width between 200ns～1 μ s, divide 7 grades regulate or preset, pulse number regulates or presets according to the treatment needs.
3, according to the described inducing tumor cell apoptosis by high-voltage nanosecond pulse device of claim 1, it is characterized in that a kind of inducing tumor cell apoptosis by high-voltage nanosecond pulse device, mainly comprise HVDC module (1), pulse shaping system (2), impulsive measurement system (3), computer system (4) and power-supply system (5), power-supply system (5) is by power supply, power-supply filter, isolating transformer and wiring board are formed, power supply is the civil power of 220V/50Hz, power supply is connected with the input of power-supply filter by power line, the outfan of power-supply filter is connected with the input of isolating transformer by power line, the outfan of isolating transformer is connected to wiring board by power line, the outfan of wiring board is connected to HVDC module (1) respectively with the power line line, the preheating transformer (B1) of pulse shaping system (2) and an end of foot switch, the medical panel computer of the oscillograph of impulsive measurement system (3) and computer system (4), HVDC module (1) is commercial module, its model is DW-P153-20AC, be connected by the end of power line with the charging resistor (R0) of pulse shaping system (2), impulsive measurement system (3) is by potentiometer, current sensor and oscillograph are formed, the input of potentiometer is connected with the outfan of bonding jumper with the fictitious load (Rf) of pulse shaping system (2), the outfan of potentiometer is connected with oscillographic input with coaxial cable, current sensor is enclosed within on the output interface of pulse shaping system (2), the outfan of current sensor is connected with the trigger element (TK) of oscillographic input and pulse shaping system (2) respectively with coaxial cable, oscillographic data output interface is connected with the medical panel computer of data wire with computer system (4), computer system (4) is by medical panel computer, keyboard and mouse and I/O control module are formed, keyboard and mouse is connected with medical panel computer with holding wire, medical panel computer is connected with the input of data wire with the I/O control module, the outfan of I/O control module is connected with the trigger element (TK) of holding wire with HVDC module (1) and pulse shaping system (2), pulse shaping system (2) is mainly by charging resistor (R0), storage capacitor (C0), thyratron (K), preheating transformer (B1), trigger element (TK) and fictitious load (Rf) are formed, the other end of charging resistor (R0) is connected with an end of storage capacitor (C0) and the anode (A) of thyratron (K) respectively with bonding jumper, the other end of storage capacitor (C0) is connected with the end of bonding jumper with fictitious load (Rf), the other end of fictitious load (Rf) is connected with ground 1 with bonding jumper, two lead-out terminals of preheating transformer (B1) are connected with ground 1 with thermoae in advance (F1) of thyratron (K) respectively with power line, thermoae in advance (F2) of thyratron (K) all is connected with ground 1 with bonding jumper with negative electrode (KC), trigger element (TK) is connected with the trigger electrode (G) of thyratron (K) with coaxial cable, the other end of foot switch is connected with trigger element (TK) by power line, the unidirectional negative polarity exponential damping high-voltage nanosecond pulse of pulse shaping system (2) output, its pulse amplitude is regulated continuously between 0～9.9kV or is preset, repetition rate is regulated continuously between 2Hz～100Hz or is preset, pulse width in 200ns～1 μ s scope, divide 7 grades adjustable, number is regulated or is preset according to the treatment needs;
The main circuit of the trigger element (TK) of described pulse shaping system (2) is mainly by IGBT (Q), booster transformer (B2), four diodes (D3～D6), inductance (L), two Transient Suppression Diodes (D7) and (D8), three electric capacity (C11～C13) and two resistance (R6, R7) form, 220V/50Hz power supply after passing through power-supply system (1) filtering and isolating is connected with an end of foot switch with power line, to be 1: 2 booster transformer (B2) with no-load voltage ratio respectively with power line be connected with former limit winding with the step-down transformer (B3) of two independent secondary windings the other end of foot switch, the secondary winding of booster transformer (B2) and four diode (D3～D6) link to each other, constitute uncontrollable full bridge rectifier, its outfan and inductance (L) and two placed in-line filter capacitor (C11, C12) the LC filter circuit of Gou Chenging is connected, the outfan of filter circuit links to each other with an end of resistance (R6), the other end of resistance (R6) links to each other with an end of electric capacity (C13) and the colelctor electrode (Qc) of IGBT (Q), the other end of electric capacity (C13) links to each other with ground 1, the grid (Qg) of IGBT (Q) and emitter stage (Qe) link to each other with the outfan of the IGBT drive circuit (TQ) of trigger element (TK) and an end of resistance (R7) respectively, the other end of resistance (R7) links to each other with ground 1, Transient Suppression Diode (the D7 of two rated voltage 300V, D8) be connected in parallel on resistance (R7) two ends after the series connection, the trigger impulse that is used to trigger thyratron (K) is exported at two ends at resistance (R7), and its pulse amplitude is about 600V, pulse width is about 5 μ s, repetition rate is regulated continuously between 2Hz～100Hz or is preset, number is regulated or is preset according to the treatment needs;
The IGBT drive circuit (TQ) of the trigger element (TK) of described pulse shaping system (2) is main to be the digital regulation resistance (IC1) of MAX5455 by model, two models are the 555 intervalometer (IC2 of NE555P, IC4), model is the photoisolator (IC3) of TLP250, model is that nor gate (IC7) and the correspondent peripheral circuit of MC74HC02 formed, digital regulation resistance (IC1), 555 intervalometers (IC2), resistance (R1, R2), (C1～C5) constitutes multi-resonant oscillating circuit to electric capacity, the outfan of 555 intervalometers (IC2) (3 foot) links to each other with the input (3 foot) of photoisolator (IC3), photoisolator (IC3), resistance (R3) and electric capacity (C6) constitute buffer circuit, outfan of photoisolator (IC3) (6 foot) and electric capacity (C7), the peaker that resistance (R4) and diode (D1) constitute links to each other, the outfan of peaker links to each other with the input (2 foot) of 555 intervalometers (IC4), 555 intervalometers (IC4), (C8～C10) constitutes monostable circuit for resistance (R5) and electric capacity, the outfan of 555 intervalometers (IC4) (3 foot) and earth terminal (1 foot) link to each other with emitter stage (Qe) with the grid (Qg) of the IGBT (Q) of the main circuit of trigger element (TK) respectively, the two ends of Zener diode (D2) link to each other with ground 2 with the outfan (3 foot) of 555 intervalometers (IC4) respectively, increasing/down control input (3 foot) of digital regulation resistance (IC1), control input end (12 foot) is regulated in the contact, sheet choosing end (14 foot) and earth terminal (11 foot) link to each other with the outfan of the I/O control module of computer system (4) with holding wire, the outfan of the Enable Pin of 555 intervalometers (IC2) (4 foot) AND (IC7) (3 foot) links to each other, and two inputs of nor gate (IC7) (1 foot and 2 feet) link to each other with the outfan of the I/O control module of computer system (4) and the holding circuit (Ip) of trigger element (TK) respectively, the driving signal of the IGBT that is used for driving trigger element (TK) (Q) of IGBT drive circuit (TQ) output, its amplitude is 15V, pulsewidth is 5 μ s, repetition rate is regulated continuously between 2～100Hz or is preset, number is regulated or is preset according to the treatment needs;
The holding circuit (Ip) of the trigger element (TK) of described pulse shaping system (2) is that the operational amplifier (IC5) of OP07 and comparator (IC6) and correspondent peripheral circuit that model is LM311 are formed by model mainly, the outfan of current sensor links to each other with the anode of diode (D9) by the heart yearn of coaxial cable, the screen layer of coaxial cable links to each other with ground 1, diode (D9), resistance (R8) and electric capacity (C14) constitute peak holding circuit, the negative electrode of diode (D9) links to each other with the in-phase input end of operational amplifier (IC5) (3 foot), operational amplifier (IC5), resistance (R9), electric capacity (C15) and (C16) constitute voltage follower circuit, the outfan of operational amplifier (IC5) (6 foot) links to each other with the in-phase input end (2 foot) of comparator (IC6), comparator (IC6), adjustable resistance (R10), resistance (R11) and electric capacity (C17) constitute comparison circuit, the centre tap of adjustable resistance (R10) links to each other with the inverting input of comparator (IC6) (3 foot), in addition two ends respectively with power supply 1) link to each other with ground 1, resistance (R11) two ends link to each other with outfan (7 foot) with the inverting input (3 foot) of comparator (IC6) respectively, and the input of the outfan of comparator (IC6) (7 foot) AND (IC7) (2 foot) links to each other;
The chip operation power circuit of the trigger element (TK) of described pulse shaping system (2) is mainly by step-down transformer (B3), model is the three terminal integrated voltage stabilizer (U1) of MC7805, model is the three terminal integrated voltage stabilizer (U2) of MC7815, ten diodes (D10～D19), eight electric capacity (C19～C26) form, after the blood pressure lowering of the power supply of 220V/50Hz through step-down transformer (B3), on two secondary windings, obtain two independently virtual value be the low-voltage alternating current power supply of 15V, one of them secondary winding and four diode (D10～D13) link to each other, constitute uncontrollable full bridge rectifier, the outfan of rectification circuit links to each other with electric capacity (C19), be connected to three terminal integrated voltage stabilizer (U1) and peripheral electric capacity thereof (C20～C22) and the 5V mu balanced circuit of diode (D14) formation again, exporting stable amplitude is the unidirectional current of 5V, the outfan of three terminal integrated voltage stabilizer U1 (3 foot) and earth terminal (2 foot) respectively with digital regulation resistance (IC1), 555 intervalometers (IC2), operational amplifier (IC5), comparator (IC6), the power end of nor gate (IC7) with link to each other accordingly, another secondary winding of step-down transformer (B3) and four diode (D15～D18) link to each other, constitute uncontrollable full bridge rectifier, the outfan of rectification circuit links to each other with electric capacity (C23), be connected to three terminal integrated voltage stabilizer (U2) and peripheral electric capacity thereof (C24～C26) and the 15V mu balanced circuit of diode (D19) formation again, exporting stable amplitude is the unidirectional current of 15V, outfan of three terminal integrated voltage stabilizer (U2) (3 foot) and earth terminal (2 foot) respectively with photoisolator (IC3), the power end of 555 intervalometers (IC4) with link to each other accordingly.
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