摘要
论文讨论了三个方面的研究内容：为研究不同波形参数的电脉冲对肿瘤细胞的电穿孔效应，设计并研制了脉宽从ps-ns、偏压从100-101kV的高压脉冲源；为进一步探索电磁脉冲的电穿孔效应，设计了辐射瞬态电磁脉冲的超宽带聚焦天线；采用细胞均匀分层介质模型及其等效电路，结合已有实验文献的相关数据，定量分析了肿瘤细胞发生外膜、内膜电穿孔效应的波形参数条件，并对应开展了相关医学验证性实验。
采用IGBT模块，设计并研制了脉宽300-800ns、电压0-5kV连续可调、重频1-400Hz连续可调、输出脉冲为高斯波形的电脉冲源，主要用于肿瘤细胞外膜穿孔等医学实验研究；采用MOSFET开关管，设计并研制了20ns高斯上升沿、40-200ns指数下降沿、分档可调(半峰值脉宽50-250ns分档可调)、幅值0-1kV连续可调、重复频率0-5kHz连续可调的纳秒脉冲源；采用基于Blumlein形成线的光控光电导开关(Photoconductive Semiconductor Switches, PCSS)，设计并研制了脉宽1-5ns可调、电压1-10kV连续可调、重频1-1kHz连续可调的高压脉冲源；采用雪崩三极管，设计并研制了基于Marx电路的高压脉冲源，输出电脉冲宽度0.2-10ns可调、输出电压1.2kV、重频1-10kHz可调。通过上述研制的四种不同脉冲源，实现了脉冲宽度从亚纳秒到微秒量级、偏压从1-10kV的各种瞬态电脉冲输出。
在电磁脉冲的电穿孔效应的研究方面，主要开展了基于电磁波束聚焦的电磁信号源设计工作。包括采用椭球反射面的蝶形天线及天线阵的电磁脉冲信号源设计以及用龙伯透镜聚焦抛物面天线电磁波束的电磁脉冲信号源设计。
将肿瘤细胞的细胞膜、细胞质、细胞核膜、染色质分别看作不同电参数(r,)的均匀分层介质，各细胞组分在瞬态电脉冲作用下被看作为由不同电阻、电容构成的等效电路；依据电路理论，可定量分析不同电脉冲参数下电路元器件的端压，结合文献报道细胞膜、细胞核膜发生电穿孔的电压条件，得到细胞膜、细胞核膜发生电穿孔的电脉冲波形参数阈值条件。
考虑到悬浮组织液中瞬态电场分布对细胞电穿孔效应的影响，采用CST电磁仿真软件，对不同形状、容量、针状电极尺寸及相对位置等不同实验条件情形开展了系统的仿真计算，为优化实验方案提供参考数据；利用所研制的瞬态脉冲信号源，开展了电脉冲诱导HeLa细胞坏死、凋亡的相关医学实验研究；并定量分析了脉宽与细胞凋亡之间的关系。
Three subjects are discussed in this dissertation. To study the electroporationeffects of electric pulses with different waveform parameters, high voltage pulsegenerators are designed and developed, which are capable of generating ps-ns width,100-101kV amplitude pulses. For further exploration of the electroporation effects of theelectromagnetic pulses, ultra-wideband, focused aperture antennas are designed, whichare capable of radiating transient electromagnetic pulses. Adopting the multilayerdielectric model and the equivalent circuit, the waveform parameters with which electricpulses will perforate the plasma membrane or nuclear envelope are quantitativelyanalyze by using some previous experiments data. And related medical experiments arecarried out.
With IGBT module, a pulsed generator capable of producing high voltage Gaussianpulses with width300-800ns, continual adjustable amplitude0-5kV and continualadjustable repetition frequency rate1-400Hz is developed to enable research theelectroporation of plasma membrane in medical experiments. Using MOSFET, a pulsegenerator is developed, which is capable of producing high voltage pulses withGaussian rising edge20ns, step adjustable exponential falling edge40-200ns(The stepadjustable half-peak width is50-250ns), continual adjustable amplitude0-1kV, andcontinual adjustable repetition frequency rate0-5kHz. Based on Blumlein forming lineand Photoconductive Semiconductor Switches (PCSS), a high voltage pulse generator isdesigned and developed. It can produce pulses with adjustable width1-5ns, continualadjustable amplitude1-10kV and continual adjustable repetition frequency rate1-1kHz.With avalanche transistors, a pulse generator based on Marx circuit is designed anddeveloped, which can generate adjustable0.2-10ns width,1.2kV amplitude pulses of1-10kHz continual adjustable repetition frequency rate. So, transient electric pulseswith width from sub-nanosecond to microsecond, amplitude from1-10kV are obtainedby the above four pulse generators.
The electromagnetic pulse generators based on focusing electromagnetic beam aredesigned in the research aspect of electromagnetic pulses’ electroporation effect. One is developed adopting a bow-tie antenna with an elliptical reflector or bow-tie antennaarray, and the other is desiened with a parabolic antenna using a Luneberg-lens focusingelectromagnetic wave.
The cell membrane, cytoplasm, nuclear envelope and chromatin of tumor cells areconsidered as lateral homogenous layered medium with different electricparameters(r,), and each cell components is regarded as a equivalent circuit composedof different resistance and capacitance if transient electric pulses are applied. Based oncircuit theory, the voltages on circuit components can be quantitatively analyze whenelectric pulses with different waveform parameters applies on them. The threshold ofwaveform parameters with which electric pulses will perforate the plasma membrane ornuclear envelop are obtained, combined with voltage condition of electroporationreported in previous literature.
Considering the influence of transient pulsed electric field distribution onelectroporation effect in suspension, the system simulation calculation is carried outunder different experiment conditions as pulse shapes, capacity, size of needleelectrodes, and relative position, which provides reference data for optimization ofexperimental plan. The apoptosis or necrosis of HeLa induced by nanosecond electricpulses is studied. The relationship between pulse duration and apoptosis isquantitatively analyzed.
引文
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