| Pulsed electric field has been widely used in biomedical application field;especially,the application of non-thermal irreversible electroporation(IRE)in tissue ablation attracts lots of scholars’ attention.IRE employs the external pulsed electric field to act on the cell membrane,destroying the structure of the membrane,striking the extracellular and intercellular balance,leading to the cell death.Cell killing and tissue ablation of IRE is realized by the action of field with the advantages of non-thermal,faster,controllable,selectivity and so on.IRE has been introduced into tumor therapy because of its advantages;especially for the tumors that are difficuilt for thermal ablation,and already has some clinical trials in multiple kinds of tumor.Recently,a new type of irreversible electroporation,called composite pulse irreversible electroporation,was proposed to solve the problems of muscle contraction and the blind ablation area caused by the tissue heterogeneity when using conventional irreversible electroporation,which can promote the clinical application of IRE.However,as a new type of pulses,there are several problems need to be solved for its tumor therapy application.Firstly,the characteristic of the pulse is different from traditional pulses,resulting in the change of the tissue dielectric property is different,then this will further affect the distribution of the electric field inside the tissue,making it is a little different in pulse parameter determination from traditional IRE pulse.On the other hand,there is a time period for the ablation zone to develop after treating by pulsed electric field.Therefore,it is a little difficult to evaluate the ablation outcome right after the treatment,leading to the determination of optimized pulse dosage,the perfect time to stop pulsing more empirical.To solve those two critical problems,from angle of the high voltage engineering and electrical theory,we get that the essential problem of the determination of the pulse protocol for treatment is to study the dynamic coupling process between the change of the tissue dielectric property and the distribution of the electric field inside the tissue under different pulse parameters.Secondly,the in-time assessment of the abltion outcome after treatment is a kind of evaluating of the tissue status after treatment.Then,the problem can be transferred into the evaluation of the tissue property after pulsing.As conclusion,the mechanism of the tissue dielectric property variation caused by composite pulsed pulses and the dynamic process of irreversible electroporation were studied in this dissertation,guiding the determination of the pulse parameters.On the other hand,the change of the tissue property during electroporation gives the chance to assess the ablation outcome.This study supported by Scientific Foundation for Outstanding Young Scientist of Chongqing(cstc2014jcyjjq90001),the Fundamental Research Funds for the Central Universities(106112015CDJZR158804)and the Key Industrial Generic Technology Innovation Special Project of CQ CSTC(cstc2015zdcy-ztzxX0003)investigated the key scientific problems of tissue dielectric property variation machenism when treated by composite pulse,the relationship between the impedance change information and the ablation outcome,and finally the first clinical trials of prostate tumor ablation by composite pulse in the world were conducted.The main achievements of this dissertation are:(1)The killing effect of the composite pulse on cells were studied by simulation and experiments.When the pulse width is wider than the cell membrane time constant,the duty cycle inner the burst of composite pulse has little effect on the killing effect of composite pulse,however the longer the interval time between positive and negative pulse,the better the induced electroporation effect when the pulse width is narrower than cell membrane time constant.The wider the pulse width,the more significant dielectric response of the tissue has when treated by composite pulse with the same pulse dosage.The dielectric response study showed that the DC conductivity of the tissue has the pronounced variation when treated by pulses and this was a good indication for dynamic electroporation process study.(2)The dynamic conductivity model was built for New Zealand rabbit liver when treated by composite pulse,and the ablation area can be well predicted when using this model.At the same time,the cumulative effect on conductivity change of multiple pulses was also studied,finally the conductivity as a function of electric field and pulse number was given which can be used to explain some phenomenon in electroporation experiments.The recovery of the conductivity during the interval of the pulses was pre-studied and a model was build to describe the process,also the stable value of the conductivity after the recovery process can be obtained,which was an important indicator for evaluating the tissue status.(3)The change of the impedance spectrum,which is related to the change of the conductivity,was chosen to reflect the ablation outcome of irreversible electroporation,considering the convenience of the measurement.By measuring the tissue impedance with the pulsing electrodes before and after treatment,it was found that the impedance had a significant change.When quanlified the change of the impedance by fitting the impedance data to an equivalent circuit model,it was found that the change of the impedance caused by composite pulse was less than conventional IRE pulse,and there is a function relationship between the relative change of the impedance and the ablation area.With the increasing of the burst number of composite pulse,the ablation area increase gradually while there is a satuation of the change of the impedance meaused by the treatment electrodes.Therefore,a new evaluation method needs to be proposed while the ablation area is relatively large.(4)Considering oftentimes multiple electrodes are employed in IRE treatment,the impedance measured by different electrode pairs to evaluate the ablation area from different directions was proposed in this study which can avoiding the satuation of the impedance change measured only by the treatment electrodes.The optimal impedance measurement sequence,which means its coverage area is bigger while times of measurement is less,was given by the simulation on impedance sensitivity analysis.According to the measured impedance from different electrode pairs,the relationship between the relative change of impedance and the positions of the ablation boundary at different directions was proposed by which we can predict the ablation area based on the change of impedance,and this method was also verified in rabbit liver ablation by composite pulse.The cycled pulsing by multi-electrode system was conducted in a perfused organ model,and the relationship between the change of impedance and the ablation size was also studied.The results show that the manner of the impedance measurement optimized by the impedance sensitivity analysis worked well for four electrodes experiments.(5)The real 3D normal tissue and tumoe models were reconstructed according to the patient’s CT image,and the electric and thermal field inside the tissue was calculated by finite element calculation to analyze the its effect on the normal tissue and vessels.The first clinical trial of composite pulse IRE on human prostate tumor ablation was conducted,and the results showed that this new type of pulse can effectivily and safely ablate human prostate tumor.The impedance of the prostate tumor was measured for one patient;the results showed that the dispersion of the equvilaent extracellular resistance decreased,and the there is a relationship between the relative change of the impedance and the ablation range detected by MRI.The larger of the impedance change,the bigger of the ablation zoom around the specific electrode.In conclusion,the effect of the composite pulse parameters on the cell killing effect and the dielectric response of tissue were studied.The dynamic process of IRE caused by composite pulse was studied and also the cumulative effect of multiple pulses and the recovery process during the interval of the pulse,revealing the mechanism of electroporation treated by multiple pulsed electric field pulses.Based on the understanding of the dynamic change of the tissue dielctric property,the relationship between the change of impedance and the ablation area under two-electrode and multi-electrode systems was studied,and a mathematic model used to describing this relationship was built which can be used to predict the ablation size based on the change of the impedance;The real 3D tumor model of patient was built and the electric-thermal field inside the tissue caused by composite pulsed electric field was simulated.Finally,the first clinical trial of human prostate tumor abltion was carried out,and the safty and the effectiveness of composite pulsed electric field in tumor ablation were verified.The basic theoretical research and the clinical research laid the theoretical foundation and provided valuable experience for investigating the basic mechanism of composite pulsed electric field in electroporation and promoting the clinical application in other tumors. |
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