基于数字信号处理器的陡脉冲肿瘤治疗系统的设计与实现方法研究
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摘要
实验和理论研究初步证实,细胞膜的电穿孔程度(包含穿孔可逆或不可逆)与施加电脉冲的多个特征参数相关。为了更深入地研究电脉冲作用于细胞膜的内部机制,满足目前临床试验和应用的要求,有必要研制一套参数调节灵活、输出稳定、监测方便并能用于肿瘤细胞发生不可逆电穿孔试验研究的高压陡脉冲肿瘤治疗系统。
本论文在交流一直流功率转换电路的基础上,提出一种基于数字信号处理器的电脉冲参数控制和测量一体化方案。结合现场可编程门阵列和其他电子元器件,设计并实现的高压陡脉冲肿瘤治疗系统不仅能对系统输出的电压幅值、上升时间、下降时间、重复频率和脉冲宽度等参数进行在线监测,而且可对上述部分参数进行闭环控制,保持输出的稳定性。文中详细介绍了功率转换电路PWM控制的基本原理和频率差值倍增技术的具体方法,简要阐述了液晶显示电路、日历时钟模块和电容切换电路的控制策略,重点探讨了电压幅值测量模块、上升时间和下降时间测量模块、电压幅值控制模块及键盘接口电路、RS-232通信等电路的设计依据、结构和功能。此外,还介绍了对电压幅值测量模块、上升时间和下降时间测量模块进行仿真的过程和结果。本论文采用了典型的前后台模式的软件组织形式,以主程序作为后台任务,中断服务程序作为前台任务,通过对前后台任务的快速切换和优先级排序,达到及时响应测量、控制和显示等一系列任务的目的。
本论文对设计完成的高压陡脉冲肿瘤治疗系统进行了测试和校正,通过对测量模块、控制模块和显示模块等的检验和调试,以及系统整机联调和带负载测试,对测试结果进行了分析,表明本论文提出的设计方案和实现方法能够满足使肿瘤细胞不可逆电击穿机理研究及临床试验和应用的需要,达到了预期设计目标。
It has been validated that cell membrane electroporation, including reversible and irreversible electropermeabilization occurred, when it was exposed to high intensity electric pulse. And the electroporation degree has relation to many pulse characteristic parameters. For deeper research on the inner inter-mechanism of electric pulse and cell membrane, it's essentially to develope a set of high voltage steep pulse tumor treatment system, whose parameters can be set agilely, exported stably, monitored conveniently.This paper brings forward a pulse parameters controlling and measuring integrative scheme based on Digital Signal Processor. The high voltage steep pulse tumor treatment system, designed and realized combining Complex Programmable Logic Device and other electrical components, not only can on-line monitor the parameters of pulse rise time, fall time, repeat frequencies and pulse durations, et al, but also can close-loop control partial parameters fore mentioned. The paper detailedly introduces the primary principles of PWM controlling and the concretes method of frequency difference multiply, briefly illustrates the control strategy of Liquid Crystal Display module, real time clock module and the capacitor switching circuit, particularly discusses the scheme and the function of the voltage measurement module, the rise time and fall time measurement module, the voltage amplitude controlling module and the keyboard interface circuit, the RS-232 communication module. Moreover, the simulation processes and results of voltage amplitude measurement module and rise time/fall time measurement are recommended in this paper. The classic foreground and background pattern is chosen as the software organizing form in this paper, in which the main program is background application and the interrupt service program is background correspondingly. By switching the foreground and background program instantly, sorting priority of applications, the soft can respond a series task of measurement, controlment and display instantly.Including the adjustment and test to measurement module, controlment module and display module, the paper accomplishes the adjustment and test to the whole high voltage steep pulse tumor treatment system. The test results indicate that the design scheme and the realization method brought forward in this paper can satisfy the requirements of tumor cell irreversible mechanism research and clinic application, obtaining the anticipated target.
本论文在交流一直流功率转换电路的基础上,提出一种基于数字信号处理器的电脉冲参数控制和测量一体化方案。结合现场可编程门阵列和其他电子元器件,设计并实现的高压陡脉冲肿瘤治疗系统不仅能对系统输出的电压幅值、上升时间、下降时间、重复频率和脉冲宽度等参数进行在线监测,而且可对上述部分参数进行闭环控制,保持输出的稳定性。文中详细介绍了功率转换电路PWM控制的基本原理和频率差值倍增技术的具体方法,简要阐述了液晶显示电路、日历时钟模块和电容切换电路的控制策略,重点探讨了电压幅值测量模块、上升时间和下降时间测量模块、电压幅值控制模块及键盘接口电路、RS-232通信等电路的设计依据、结构和功能。此外,还介绍了对电压幅值测量模块、上升时间和下降时间测量模块进行仿真的过程和结果。本论文采用了典型的前后台模式的软件组织形式,以主程序作为后台任务,中断服务程序作为前台任务,通过对前后台任务的快速切换和优先级排序,达到及时响应测量、控制和显示等一系列任务的目的。
本论文对设计完成的高压陡脉冲肿瘤治疗系统进行了测试和校正,通过对测量模块、控制模块和显示模块等的检验和调试,以及系统整机联调和带负载测试,对测试结果进行了分析,表明本论文提出的设计方案和实现方法能够满足使肿瘤细胞不可逆电击穿机理研究及临床试验和应用的需要,达到了预期设计目标。
It has been validated that cell membrane electroporation, including reversible and irreversible electropermeabilization occurred, when it was exposed to high intensity electric pulse. And the electroporation degree has relation to many pulse characteristic parameters. For deeper research on the inner inter-mechanism of electric pulse and cell membrane, it's essentially to develope a set of high voltage steep pulse tumor treatment system, whose parameters can be set agilely, exported stably, monitored conveniently.This paper brings forward a pulse parameters controlling and measuring integrative scheme based on Digital Signal Processor. The high voltage steep pulse tumor treatment system, designed and realized combining Complex Programmable Logic Device and other electrical components, not only can on-line monitor the parameters of pulse rise time, fall time, repeat frequencies and pulse durations, et al, but also can close-loop control partial parameters fore mentioned. The paper detailedly introduces the primary principles of PWM controlling and the concretes method of frequency difference multiply, briefly illustrates the control strategy of Liquid Crystal Display module, real time clock module and the capacitor switching circuit, particularly discusses the scheme and the function of the voltage measurement module, the rise time and fall time measurement module, the voltage amplitude controlling module and the keyboard interface circuit, the RS-232 communication module. Moreover, the simulation processes and results of voltage amplitude measurement module and rise time/fall time measurement are recommended in this paper. The classic foreground and background pattern is chosen as the software organizing form in this paper, in which the main program is background application and the interrupt service program is background correspondingly. By switching the foreground and background program instantly, sorting priority of applications, the soft can respond a series task of measurement, controlment and display instantly.Including the adjustment and test to measurement module, controlment module and display module, the paper accomplishes the adjustment and test to the whole high voltage steep pulse tumor treatment system. The test results indicate that the design scheme and the realization method brought forward in this paper can satisfy the requirements of tumor cell irreversible mechanism research and clinic application, obtaining the anticipated target.
引文
[1] Okino M. Optimal electric conditions in electrical impulse chemotherapy. Japanese Journal of Cancer Research. 1992. 83(10): 1095～1101.
[2] Caixin Sun, Lan Xiong, Chenguo Yao. Cytocidal and inhibitory effect of energy-controllable pulse on ovarian cancer cell line SKOV3. IEEE conference of EMBS & BMES' 2002, Houston, Texas.
[3] Marko Puc, Selma Corovie, Karel Flisar, et al. Techniques of signal generation required for electropermeabilization. Survey of electropermeabilization devices. Bioelectrochemistry 64(2004), 113-124.
[4] Lluis M. Mir. Therapeutic perspectives of in vivo cell electropermeabilization. Bioelectrochemistry 53(2000), 1-10.
[5] 王丰,陈霞芳,田毓华,等.电穿孔介导质粒DNA肿瘤内转移抑制恶性肿瘤生长与转移.生物化学与生物物理进展,2002,29(5),734—740.
[6] Corinne Ramos, Justin Teissie. Electrofusion: A biophysical modification of cell membrane and a mechanism in exocytosis. Biochimie 82(2000) 511-518.
[7] Alexander Angersbach, Volker Heinz, Dietrich Knorr. Effects of pulsed electric fields on cell membranes in real food system. Innovative Food Science & Emerging Technologies 1(2000) 135-149.
[8] 郝新保,常智杰.电穿孔技术在转基因及动物克隆中的应用.生物技术通报,2003,1,1-3.
[9] Damijan Miklavcic, Dejan Semrov, Halima Mekid, et al. A validated model of in vivo electric field distribution in tissues for electrochemotherapy and for DNA electrotransfer for gene therapy. Biochimica et Biophysica Acta, 2000, (1519), 73-83.
[10] M. -C. Vernhes, P. -A. Cabanes, J. Teissie. Chinese hamster ovary cells sensitivity to localized electrical stresses. Bioelectrochemistry and Bioenergetics, 1999, (48), 17-25.
[11] Marie-Pierre Rols, Justin Teissie. Electropermeabilization of Mammalian Cells to Macromolecules Control by Pulse Duration. Biophysical Journal, 1998, 75, 1415-1423.
[12] 姚陈果,孙才新,米彦等.陡脉冲不可逆性电击穿恶性肿瘤细胞的研究.高电压技术,2003,29(1):45-47.
[13] Anna O. Bilska, Katherine A. DeBruin, Wanda Krassowska. Theoretical modeling of the effects of shock duration, frequency, and strength on the degree of electroporation. Bioelectrochemistry, 2000, 51, 133-143.
[14] Gregor SerSa, Maja CemaZar, Dejan Semrov, et al. Changing electrode orientation improves the efficacy of electrochemotherapy of solid tumors in mice. Bioelectrochemistry and Bioenergetics, 1996, 39, 61-66.
[15] Per E. Engstrom, Bertil R. R. Persson, Leif G. Salford, et al. Studies of in vivo electropermeabilization by gamma camera measurements of ~(99m)Tc-DTPA. Biochimica et Biophysica Acta. 1999, 1473, 321-328.
[16] Julie Gehl, Thyge H. Sorensen, Kurt Nielsen, In vivo electroporation of skeletal muscle: threshold, efficacy and relation to electric field distribution. Biochimica et Biophysica Acta, 2000, (1428), 233-240.
[17] Lee RC, Canaday DJ, Hammer SM, Transient and stable ionic permeabilization of isolated skeletal muscle cells after electrical shock. J Burn Care Rehabil, 1993, 14(5), 528-540.
[18] G. Pucihar, L. M. Mir, Damijan Miklavcic. The effect of pulse repetition frequency on the uptake into electropermeabilized cells in vitro with possible applications in electrochemotherapy. Bioelectrochemistry, 2002, (57), 167-172.
[19] Sun Caixin, Yao Chenguo, Mi Yan, et al. Experimental study on irreversible electrical breakdown of tumor cell under steep pulsed electric fields. 24th Annual Conference and the Annual Fall Meeting of the Biomedical Engineering Society EMBS/BMES Conference, Houston, 2002.
[20] 牛中奇,侯建强,王海彬,等.电磁波的生物学窗效应.中国生物医学工程学报,2003,22(2):126—132.
[21] Alenka Macek Lebar, Gregory C. Troiano, Leslie Tung, et al. Inter-pulse interval between rectangular voltage pulses affects electroporation threshold of artificial lipid bilayers. 2002, 1(3), 116-120.
[22] Andreason GL, Evans GA, Introduction and expression of DNA molecules in eukaryotic cells by electroporation. Biotechniques, 1988, 6(7), 650-660.
[23] M. Bettan, M. -A. Ivanov, L. M. Mir, et al. Efficient DNA electrotransfer into tumors. Bioelectrochemistry, 2000, 52, 83-90.
[24] Takahashi M, Furukawa T, Saitoh H, Gene transfer into human leukemia cell lines by electroporation: experience with exponentially decaying and square wave pulse. Leuk Res. 1991, 15(6), 507-513.
[25] Marie-Pierre Rols, Justin Teissie. Electropermeabilization of Mammalian Cells to Macromolecules Control by Pulse Duration. Biophysical Journal, 1998, 75, 1415-1423.
[26] 包家立,胡巧红,梁文权等.电穿孔能量对药物经皮渗透速率的影响.仪器仪表学报.2000,21(5),377-379.
[27] 黄俊,王兆安.电力电子变流技术(第三版).北京:机械工业出版社,1993.
[28] 张立.现代电力电子技术基础.北京:高等教育出版社,1999.
[29] [美]Texas Instruments Incorporated.徐科军,张兴,肖本贤等.TMS320LF/LC24系列DSP的CPU与外设.北京:清华大学出版社,2004.
[30] 姜建国,曹建中,高玉明.信号与系统分析基础.北京:清华大学出版社,1994.
[31] 宋万杰,罗丰,吴顺君.CPLD技术及其应用.西安:西安电子科技大学出版社,1999.
[32] 张国雄,金篆芷.测控电路.北京:机械工业出版社,2001.
[33] 郑步生,吴渭.Multisim 2001电路设计及仿真入门与应用.北京:电子工业出版社,2002.
[34] 刘兆祥,陈海霞,利用矩形脉冲测定脉冲的上、下限频率,通化师范学院学报,2003,24(2):43—44.
[35] 宋同根,王向阳,频率计量标准装置不确定度分析与评定,计量技术,2003,(4):15—16.
[36] 朱长清,张金池.频标比对器频差倍增系数的合理选用.军械工程学院学报,1994,6(3):217—220.
[37] 王道宪.CPLD/FPGA可编程逻辑器件应用与开发.北京:国防工业出版社,2004.1.
[38] 廖裕评,陆瑞强.CPLD数字电路设计.北京:清华大学出版社,2001.
[39] 刘和平,王维俊等,TMS320LF240x DSP C语言开发应用,北京:北京航空航天大学出版社,2003.
[40] 何苏勤,王忠勇.TMS320C2000系列DSP原理及实用技术.北京:电子工业出版社,2003.
[41] 刘瑞新,胡健,高明远等.Protel DXP实用教程.北京:机械工业出版社,2003.
[42] [美]Mark I.Montrose.刘元安,李书芳,高攸纲.电磁兼容和印刷电路板理论、设计和布线.北京:人民邮电出版社,2002.
[43] 周啟海,计算机同构化程序设计原理及其应用导论.北京:清华大学出版社,1993.
[44] 刘和平,严利平,张学锋等.TMS320LF240x DSP结构、原理及应用.北京:北京航空航天大学出版社,2002.
[45] [美]Marco Cantu.王辉,谭海平等.Delphi 3从入门到精通.北京:电子工业出版社,1998.
[2] Caixin Sun, Lan Xiong, Chenguo Yao. Cytocidal and inhibitory effect of energy-controllable pulse on ovarian cancer cell line SKOV3. IEEE conference of EMBS & BMES' 2002, Houston, Texas.
[3] Marko Puc, Selma Corovie, Karel Flisar, et al. Techniques of signal generation required for electropermeabilization. Survey of electropermeabilization devices. Bioelectrochemistry 64(2004), 113-124.
[4] Lluis M. Mir. Therapeutic perspectives of in vivo cell electropermeabilization. Bioelectrochemistry 53(2000), 1-10.
[5] 王丰,陈霞芳,田毓华,等.电穿孔介导质粒DNA肿瘤内转移抑制恶性肿瘤生长与转移.生物化学与生物物理进展,2002,29(5),734—740.
[6] Corinne Ramos, Justin Teissie. Electrofusion: A biophysical modification of cell membrane and a mechanism in exocytosis. Biochimie 82(2000) 511-518.
[7] Alexander Angersbach, Volker Heinz, Dietrich Knorr. Effects of pulsed electric fields on cell membranes in real food system. Innovative Food Science & Emerging Technologies 1(2000) 135-149.
[8] 郝新保,常智杰.电穿孔技术在转基因及动物克隆中的应用.生物技术通报,2003,1,1-3.
[9] Damijan Miklavcic, Dejan Semrov, Halima Mekid, et al. A validated model of in vivo electric field distribution in tissues for electrochemotherapy and for DNA electrotransfer for gene therapy. Biochimica et Biophysica Acta, 2000, (1519), 73-83.
[10] M. -C. Vernhes, P. -A. Cabanes, J. Teissie. Chinese hamster ovary cells sensitivity to localized electrical stresses. Bioelectrochemistry and Bioenergetics, 1999, (48), 17-25.
[11] Marie-Pierre Rols, Justin Teissie. Electropermeabilization of Mammalian Cells to Macromolecules Control by Pulse Duration. Biophysical Journal, 1998, 75, 1415-1423.
[12] 姚陈果,孙才新,米彦等.陡脉冲不可逆性电击穿恶性肿瘤细胞的研究.高电压技术,2003,29(1):45-47.
[13] Anna O. Bilska, Katherine A. DeBruin, Wanda Krassowska. Theoretical modeling of the effects of shock duration, frequency, and strength on the degree of electroporation. Bioelectrochemistry, 2000, 51, 133-143.
[14] Gregor SerSa, Maja CemaZar, Dejan Semrov, et al. Changing electrode orientation improves the efficacy of electrochemotherapy of solid tumors in mice. Bioelectrochemistry and Bioenergetics, 1996, 39, 61-66.
[15] Per E. Engstrom, Bertil R. R. Persson, Leif G. Salford, et al. Studies of in vivo electropermeabilization by gamma camera measurements of ~(99m)Tc-DTPA. Biochimica et Biophysica Acta. 1999, 1473, 321-328.
[16] Julie Gehl, Thyge H. Sorensen, Kurt Nielsen, In vivo electroporation of skeletal muscle: threshold, efficacy and relation to electric field distribution. Biochimica et Biophysica Acta, 2000, (1428), 233-240.
[17] Lee RC, Canaday DJ, Hammer SM, Transient and stable ionic permeabilization of isolated skeletal muscle cells after electrical shock. J Burn Care Rehabil, 1993, 14(5), 528-540.
[18] G. Pucihar, L. M. Mir, Damijan Miklavcic. The effect of pulse repetition frequency on the uptake into electropermeabilized cells in vitro with possible applications in electrochemotherapy. Bioelectrochemistry, 2002, (57), 167-172.
[19] Sun Caixin, Yao Chenguo, Mi Yan, et al. Experimental study on irreversible electrical breakdown of tumor cell under steep pulsed electric fields. 24th Annual Conference and the Annual Fall Meeting of the Biomedical Engineering Society EMBS/BMES Conference, Houston, 2002.
[20] 牛中奇,侯建强,王海彬,等.电磁波的生物学窗效应.中国生物医学工程学报,2003,22(2):126—132.
[21] Alenka Macek Lebar, Gregory C. Troiano, Leslie Tung, et al. Inter-pulse interval between rectangular voltage pulses affects electroporation threshold of artificial lipid bilayers. 2002, 1(3), 116-120.
[22] Andreason GL, Evans GA, Introduction and expression of DNA molecules in eukaryotic cells by electroporation. Biotechniques, 1988, 6(7), 650-660.
[23] M. Bettan, M. -A. Ivanov, L. M. Mir, et al. Efficient DNA electrotransfer into tumors. Bioelectrochemistry, 2000, 52, 83-90.
[24] Takahashi M, Furukawa T, Saitoh H, Gene transfer into human leukemia cell lines by electroporation: experience with exponentially decaying and square wave pulse. Leuk Res. 1991, 15(6), 507-513.
[25] Marie-Pierre Rols, Justin Teissie. Electropermeabilization of Mammalian Cells to Macromolecules Control by Pulse Duration. Biophysical Journal, 1998, 75, 1415-1423.
[26] 包家立,胡巧红,梁文权等.电穿孔能量对药物经皮渗透速率的影响.仪器仪表学报.2000,21(5),377-379.
[27] 黄俊,王兆安.电力电子变流技术(第三版).北京:机械工业出版社,1993.
[28] 张立.现代电力电子技术基础.北京:高等教育出版社,1999.
[29] [美]Texas Instruments Incorporated.徐科军,张兴,肖本贤等.TMS320LF/LC24系列DSP的CPU与外设.北京:清华大学出版社,2004.
[30] 姜建国,曹建中,高玉明.信号与系统分析基础.北京:清华大学出版社,1994.
[31] 宋万杰,罗丰,吴顺君.CPLD技术及其应用.西安:西安电子科技大学出版社,1999.
[32] 张国雄,金篆芷.测控电路.北京:机械工业出版社,2001.
[33] 郑步生,吴渭.Multisim 2001电路设计及仿真入门与应用.北京:电子工业出版社,2002.
[34] 刘兆祥,陈海霞,利用矩形脉冲测定脉冲的上、下限频率,通化师范学院学报,2003,24(2):43—44.
[35] 宋同根,王向阳,频率计量标准装置不确定度分析与评定,计量技术,2003,(4):15—16.
[36] 朱长清,张金池.频标比对器频差倍增系数的合理选用.军械工程学院学报,1994,6(3):217—220.
[37] 王道宪.CPLD/FPGA可编程逻辑器件应用与开发.北京:国防工业出版社,2004.1.
[38] 廖裕评,陆瑞强.CPLD数字电路设计.北京:清华大学出版社,2001.
[39] 刘和平,王维俊等,TMS320LF240x DSP C语言开发应用,北京:北京航空航天大学出版社,2003.
[40] 何苏勤,王忠勇.TMS320C2000系列DSP原理及实用技术.北京:电子工业出版社,2003.
[41] 刘瑞新,胡健,高明远等.Protel DXP实用教程.北京:机械工业出版社,2003.
[42] [美]Mark I.Montrose.刘元安,李书芳,高攸纲.电磁兼容和印刷电路板理论、设计和布线.北京:人民邮电出版社,2002.
[43] 周啟海,计算机同构化程序设计原理及其应用导论.北京:清华大学出版社,1993.
[44] 刘和平,严利平,张学锋等.TMS320LF240x DSP结构、原理及应用.北京:北京航空航天大学出版社,2002.
[45] [美]Marco Cantu.王辉,谭海平等.Delphi 3从入门到精通.北京:电子工业出版社,1998.