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纳秒级高压脉冲电场的生物医学应用是近年来新兴的交叉学科研究领域, 相比于微秒和毫秒级脉冲电场, 高压纳秒脉冲电场不仅能够导致细胞膜结构极化和介电击穿, 产生膜电穿孔, 还可以穿透至细胞内部, 引发诸如细胞骨架解聚、胞内钙离子释放及线粒体膜电位耗散等细胞器生物电效应, 吸引了学术界的广泛关注. 本文首先介绍高压纳秒脉冲电场及其细胞器生物电作用的物理模型; 然后对高压纳秒脉冲电场与细胞骨架、线粒体、内质网、细胞核等亚细胞结构的相互作用研究进行综述和总结; 强调高压纳秒脉冲电场的细胞器作用与细胞死亡、细胞间通信等生物效应之间的联系; 最后, 凝练当前高压纳秒脉冲电场在生物医学研究中的关键技术问题, 并对未来潜在的研究方向进行展望.The biomedical application of high-voltage nanosecond pulsed electric fields (nsPEFs) has become an emerging interdisciplinary research field in recent years. Compared with microsecond and millisecond pulsed electric fields, high-voltage nsPEFs can not only lead the cell membrane structure to polarize and dielectric break down the cell membrane structure, i.e. membrane electroporation, but also penetrate into the cell, triggering off organelle bioelectrical effects such as cytoskeleton depolymerization, intracellular calcium ion release, and mitochondrial membrane potential dissipation. Extensive attention has been attracted from related academic communities. In this article, the following aspects are involved. First, the physical model of high-voltage nsPEFs and its bioelectrical effects on cellular organelles are introduced. Then, the existing researches of the interactions of high-voltage nsPEFs with cytoskeleton, mitochondria, endoplasmic reticulum, cell nucleus and other subcellular structure are reviewed and summarized; the relationship between the influence on cellular organelles by high-voltage nsPEFs and the biological effects such as cell death and intercellular communication is highlighted. Finally, the key technical challenges to high-voltage nsPEFs in biomedical research are condensed, followed by the prospects of future research directions.
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细胞器 细胞类型 脉冲宽度/ns 电场强度/(kV·cm–1) 主要结果概述 细胞骨架 GH3, HeLa[47] 60 12 肌动蛋白丝变短、变细、碎片化、解聚、收缩、分离, 细胞弹性降低;
微管屈曲、解聚、破碎;
微管聚合速率和聚合数量发生变化;
中间丝破坏;
细胞通透性改变;
细胞肿胀、起泡、细胞质颗粒化;
细胞间通讯受抑制;
细胞骨架的破坏受钙离子调控: 1)高钙离子浓度溶液中, nsPEFs处理会使微管解聚, 破坏肌动蛋白丝; 2) 低钙离子浓度溶液中, nsPEFs处理后微管显示正常结构BY-2[48] 10 33 Jurkat, HeLa, SV40[49] 60 15, 60 CHO-K1[50] 600 19.2 Jurkat, U937, CHO-K1[51] 10 150 WB-F344[52] 100 5—35 U87-MG[53] 10, 100 44 CHO[54] 600 16.2 GUV[55] 3—10 tubulin[56] 10 20 U2OS[57] CHO-K1[58] 10, 60 27.7, 150 HepG2[59] 450 8 B16-F10[60] 300 12, 18, 26, 40, 60 WB-F344, WB-Ras[61] 100 20 U-937[62] 60 10 线粒体 Jurkat[63] 60 0—60 线粒体膜通透性改变, 线粒体的通透性转换孔(MPTP)不可逆过度开放;
线粒体膜电位损失;
线粒体肿胀;
线粒体膜蛋白受影响, 线粒体膜间隙蛋白 Cyt-C, AIF 释放入胞浆;
调控线粒体凋亡途径, Caspase-3表达量增加, Bax 表达量增加;
线粒体释放细胞色素C;
影响线粒体信号传导途径;
ATP消耗;
胞内ROS水平升高N1-S1[36] 600 0—80 Jurkat, U-937[46] 10 50, 150 Jurkat[64] 600 0—60 HeLa S3[65] 80 20 HCT116, NCM460[66] 10, 600, 800 3, 4, 5 Jurkat, B10-2[67] 10—300 ≤ 300 Jurkat, HL-60[68] 10, 60, 300 150, 60, 25 Jurkat, HL-60[34] 10—300 15—60 Hela[69] 10, 20, 30, 50 40, 45 CT-26 tumor cells[70] 10 22 MCA205, McA-RH7777,
JurkatE6-1[71]100 6—25 4T1[72] 100 46—54 内质网 Jurkat[73] 7, 10, 30 25 内质网穿孔、损伤;
钙离子释放, 引发胞内钙离子浓度升高;
内质网应激响应;
免疫原性细胞死亡;
肿瘤细胞内与内质网凋亡相关蛋白Caspase-3的释放量增加;
内质网凋亡信号通路起作用Jurkat, HL-60[74] 60, 300 15—60 Jurkat, HL-60[75] 10, 60, 300 26, 40, 60, 150, 300 (10 ns); 16, 26, 40, 60 (60 ns); 40 (300 ns) Newly outdated platelet[76] 300 0—30 Cardiac cells from rats[77] 4 10—80 Jurkat[15] 60 25, 50, 100 NG108-15[78] 4 16.2 CHO-K1[79] 60 3.7—30 U937, CHO-K1, BPAE[80] 300 HeLa, HEK293T, C2C12[40] 7, 10, 20 10—50 HeLa, HEK293, MEF[81] 14 10, 20, 25, 30, 40, 50 MG63[82] 60 6.7, 13.3, 16.7, 20,
26.7, 33.3HeLa, MEF[83] 14, 70 80, 100 (14 ns), 30, 50, 70, 75 (70 ns) Bovine chromaffin cells[84] 5 170 B16 F10, EL-4[39] 200 7 Hela[85] 20, 500 100, 20 Murine secondary oocytes[86] 10 4—10 MEF[87] 60—300 30, 60 CHO-K1, NG108[88] 300, 600 3.7, 7.4, 11, 1 细胞核 HL-60[89] 10, 60 65 (10 ns), 25 (60 ns) 核膜穿孔;
DNA双链破坏、DNA片段化;
选择性降低DNA甲基化;
核蛋白复合物改变, 抑制snRNA的生成, 改变亚核结构B16 F10[18,90,91] 300 40 Jurkat[92] 10 150 Jurkat, U-937[93] 10, 300 2.25, 4.5, 150, 290 B16F10[60] 300 0—60 E4 squamous cell[94] 300 0—60 Jurkat[16] 60 10, 15, 25 N1-S1[17] 600 0—80 N1-S1[95] 100 50 CHO[58] 10, 600 18.2, 27.7, 16.7 HEK 293[96] 300 25.5 HL-60[36] 80 20 K562, CT26. WT[97] 600 50 HL60, Jurkat, ALL[98] 10, 60, 300 26, 60, 150, 300 B10-2, HL-60[99] 10, 50, 60, 300 26, 60, 75, 150 溶酶体 CHO-K1[41] 1, 20, 600 16.2 溶酶体去膜化、溶酶体损伤;
溶酶体运动受影响, 高钙离子浓度溶液下, 溶酶体迁移停止;CHO-K1[42] 600 16.2 囊泡 Human eosinophils[100] 60 36, 53 囊泡穿孔;
诱导细胞外囊泡的释放COS-7[101] 50 20—300 
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