集成介电电泳检测芯片系统关键技术研究
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摘要
微流控芯片是生化微分析系统（Bio-MEMS，Bio-Micro-electromechanicalSystem）技术发展的重要方向之一。由于介电电泳芯片可实现对细胞的非侵入式操控、能最大限度地保持被测样品的生理活性，从而成为人们进行微环境中细胞、细菌等操控、分析研究的热点与前沿。
本论文在研究分析介电电泳芯片技术研究现状的基础上，针对介电电泳芯片存在的细胞富集、分离、检测一体化集成加工技术等问题，提出了实现介电电泳富集电极、微通道网络、在线检测系统等一体化集成的介电电泳芯片系统新思想与新方法；研究分析了介电电泳富集、流体力与介电电泳力联用的连续细胞分离的机理和方法；建立了基于叉指式阵列电极和水力聚焦原理的介电电泳芯片的电场和流场模型，通过相应的模拟分析，确定了介电电泳芯片系统的整体结构；提出了在芯片系统上集成LED诱导透射式荧光检测系统和阻抗检测器两种不同检测原理互补的在线双检测系统的新思想与新方法；基于实验室MEMS加工技术平台，完成了芯片加工工艺流程、芯片版图、外围电路、检测电路、应用软件等设计，成功研制出集成介电电泳检测芯片系统原理样机。以红细胞和肝癌细胞的混合细胞液为样品体系，进行了介电电泳原位富集、连续分离、光/电在线检测等实验，验证了集成介电电泳检测芯片系统的主要功能。
论文的主要研究工作包括：
①在研究介电电泳芯片及其检测技术的国内外研究现状和发展趋势基础上，分析了介电电泳芯片分析系统存在的主要不足，提出了本论文的研究目标和主要研究内容；
②分析研究了介电电泳富集机理及其主要影响因素，探讨了流体力与介电电泳力联用的连续细胞分离的方法，创新性地提出在介电电泳芯片系统上集成LED诱导透射式荧光检测系统和阻抗检测器的在线双检测系统的新思想；
③建立了基于叉指式阵列电极和水力聚焦原理的介电电泳芯片的电场和流场模型，通过相应的模拟分析，确定了介电电泳芯片系统的结构参数；完成了LED诱导透射式荧光检测系统的构建和阻抗检测器的设计；
④基于实验室MEMS加工技术平台，完成了芯片加工工艺流程和版图设计，成功研制出满足设计指标要求的集成介电电泳检测芯片；通过集成介电电泳检测芯片、光/电在线双检测系统、外围电路、检测电路等模块的集成设计，成功研制出集成介电电泳检测芯片系统原理样机；
⑤开展了基于本论文研制的集成介电电泳检测芯片系统的应用实验研究。分别以肝癌细胞和人体小梁网细胞为实验样品，验证了小型LED诱导透射式荧光检测系统对单细胞的响应能力以及阻抗检测器对细胞生理状态的监测能力。以红细胞和肝癌细胞的混合细胞液为样品体系，进行了介电电泳原位富集、连续分离、光/电在线检测等实验研究。实验结果表明，集成介电电泳检测芯片系统对肝癌细胞的nDEP原位富集效率达到87.5%，对连续分离后的肝癌细胞的捕获率大于85%，小型荧光检测系统和阻抗检测器分别实现了细胞计数检测功能和生理状态的在线检测和识别功能，验证了集成介电电泳检测芯片系统的可行性和有效性。
Microfluidic chip is one of the most important development directions among theBio-MEMS (Bio-Micro-electromechanical System). Dielectrophoresis Chip (DC),which is based on invasive cell operation and has the advantage of keeping cellphysiological activity, is always the research hotspot and fronts for studying andmanipulating cells and bacteriain in the micro environment.
Based on study the background of the DC technology, this dissertation aiming atthe problem of integrating the cell enrich, separation, detection analysis, and chipsystem, proposed a novel plan and new method of developing DC system that integratsdielectrophoresis enrich microelectrodes, microchannel network, on-line detectionsystem together; it was studied the factors that effect the dielectrophoresis enrichprocess, and the continuous separation condition for dielectrophoresis force and fluidforce coupling technique; it was also established the electric model and fluid model forDC based on interdigitated microelectrodes array and hydrodynamic focusing principle,respectively, and the overall design for the DC was determined by solving these models;it was proposed a new idea of integrating on-line dual detection system that LEDinduced transmitted fluorescence detection system and impedance sensor together onthe DC system; based on the MEMS fabrication platform in the lab, by finishing layoutand fabrication process design, and by combining the peripheral control circuit,detection circuit together, it was successfully developed a prototype of integrateddielectrophoresis chip detection system. Using the mixed red blood cells andHepatocarcinoma cells as experiment sample, the main function of the integrateddielectrophoresis chip detection system was verified.
The main contributions of this work are listed as follows:
①Based on reviewing literature and references on DC and its detectiontechnology, the main problems on the current DC analysis system were pointed out.Motivated by the above observation, the research objectives and contents of this workwere developed, respectively;
②It was studied the dielectrophoresis enrich mechanism and the effect factors,and the continuous separation condition for dielectrophoresis force and fluid forcecoupling technique was discussed; it was innovatively proposed a new idea ofintegrating on-line dual detection system which includes LED induced transmitted fluorescence detection system and impedance sensor together on the DC system;
③It was established the electric model and fluid model for DC based oninterdigitated microelectrodes array and hydrodynamic focusing principle, respectively,and the overall design for the DC system was determined by solving these models; Itwas set up the LED induced transmitted fluorescence detection system and impedancesensor was designed.
④Based on the MEMS fabrication platform in the lab, by finishing fabricationprocess and layout design, the integrated dielectrophoresis detection chip wassuccessfully developed, which was satisfied with the design index. It was accomplishedthe integrated dielectrophoresis detection chip, optical/electric on-line dual detectionsystem, control circuit and other modules integrated together, and successfullydeveloped a prototype of integrated dielectrophoresis detection chip system.
⑤The application experiments based on the developed integrateddielectrophoresis detection chip system were studied. Using the Hepatocarcinoma cellsand human trabecular meshwork endothelium cells as experiment sample respectively, itis verified the single cell response ability for LED induced transmitted fluorescencedetection system, and the ability which can monitor cell physiological status by theintegrated impedance sensor. Using the suspension that mixed red blood cells andHepatocarcinoma cells together as experiment sample, the dielectrophoresis in situenrich, continuous separation, online dual detection experiments were done. The resultsshowed that the nDEP in situ enrich efficiency for Hepatocarcinoma cells can reach to87.5%, and the capture efficiency for Hepatocarcinoma cells in the mixed cellsuspension is greater than85%. The compact fluorescence detector and the integratedimpedance detector accomplished the functions of cell number counting detection andcell physiological state online identification, respectively, which demonstrated thefeasibility and validity of the developed integrated dielectrophoresis detection chipsystem.
本论文在研究分析介电电泳芯片技术研究现状的基础上，针对介电电泳芯片存在的细胞富集、分离、检测一体化集成加工技术等问题，提出了实现介电电泳富集电极、微通道网络、在线检测系统等一体化集成的介电电泳芯片系统新思想与新方法；研究分析了介电电泳富集、流体力与介电电泳力联用的连续细胞分离的机理和方法；建立了基于叉指式阵列电极和水力聚焦原理的介电电泳芯片的电场和流场模型，通过相应的模拟分析，确定了介电电泳芯片系统的整体结构；提出了在芯片系统上集成LED诱导透射式荧光检测系统和阻抗检测器两种不同检测原理互补的在线双检测系统的新思想与新方法；基于实验室MEMS加工技术平台，完成了芯片加工工艺流程、芯片版图、外围电路、检测电路、应用软件等设计，成功研制出集成介电电泳检测芯片系统原理样机。以红细胞和肝癌细胞的混合细胞液为样品体系，进行了介电电泳原位富集、连续分离、光/电在线检测等实验，验证了集成介电电泳检测芯片系统的主要功能。
论文的主要研究工作包括：
①在研究介电电泳芯片及其检测技术的国内外研究现状和发展趋势基础上，分析了介电电泳芯片分析系统存在的主要不足，提出了本论文的研究目标和主要研究内容；
②分析研究了介电电泳富集机理及其主要影响因素，探讨了流体力与介电电泳力联用的连续细胞分离的方法，创新性地提出在介电电泳芯片系统上集成LED诱导透射式荧光检测系统和阻抗检测器的在线双检测系统的新思想；
③建立了基于叉指式阵列电极和水力聚焦原理的介电电泳芯片的电场和流场模型，通过相应的模拟分析，确定了介电电泳芯片系统的结构参数；完成了LED诱导透射式荧光检测系统的构建和阻抗检测器的设计；
④基于实验室MEMS加工技术平台，完成了芯片加工工艺流程和版图设计，成功研制出满足设计指标要求的集成介电电泳检测芯片；通过集成介电电泳检测芯片、光/电在线双检测系统、外围电路、检测电路等模块的集成设计，成功研制出集成介电电泳检测芯片系统原理样机；
⑤开展了基于本论文研制的集成介电电泳检测芯片系统的应用实验研究。分别以肝癌细胞和人体小梁网细胞为实验样品，验证了小型LED诱导透射式荧光检测系统对单细胞的响应能力以及阻抗检测器对细胞生理状态的监测能力。以红细胞和肝癌细胞的混合细胞液为样品体系，进行了介电电泳原位富集、连续分离、光/电在线检测等实验研究。实验结果表明，集成介电电泳检测芯片系统对肝癌细胞的nDEP原位富集效率达到87.5%，对连续分离后的肝癌细胞的捕获率大于85%，小型荧光检测系统和阻抗检测器分别实现了细胞计数检测功能和生理状态的在线检测和识别功能，验证了集成介电电泳检测芯片系统的可行性和有效性。
Microfluidic chip is one of the most important development directions among theBio-MEMS (Bio-Micro-electromechanical System). Dielectrophoresis Chip (DC),which is based on invasive cell operation and has the advantage of keeping cellphysiological activity, is always the research hotspot and fronts for studying andmanipulating cells and bacteriain in the micro environment.
Based on study the background of the DC technology, this dissertation aiming atthe problem of integrating the cell enrich, separation, detection analysis, and chipsystem, proposed a novel plan and new method of developing DC system that integratsdielectrophoresis enrich microelectrodes, microchannel network, on-line detectionsystem together; it was studied the factors that effect the dielectrophoresis enrichprocess, and the continuous separation condition for dielectrophoresis force and fluidforce coupling technique; it was also established the electric model and fluid model forDC based on interdigitated microelectrodes array and hydrodynamic focusing principle,respectively, and the overall design for the DC was determined by solving these models;it was proposed a new idea of integrating on-line dual detection system that LEDinduced transmitted fluorescence detection system and impedance sensor together onthe DC system; based on the MEMS fabrication platform in the lab, by finishing layoutand fabrication process design, and by combining the peripheral control circuit,detection circuit together, it was successfully developed a prototype of integrateddielectrophoresis chip detection system. Using the mixed red blood cells andHepatocarcinoma cells as experiment sample, the main function of the integrateddielectrophoresis chip detection system was verified.
The main contributions of this work are listed as follows:
①Based on reviewing literature and references on DC and its detectiontechnology, the main problems on the current DC analysis system were pointed out.Motivated by the above observation, the research objectives and contents of this workwere developed, respectively;
②It was studied the dielectrophoresis enrich mechanism and the effect factors,and the continuous separation condition for dielectrophoresis force and fluid forcecoupling technique was discussed; it was innovatively proposed a new idea ofintegrating on-line dual detection system which includes LED induced transmitted fluorescence detection system and impedance sensor together on the DC system;
③It was established the electric model and fluid model for DC based oninterdigitated microelectrodes array and hydrodynamic focusing principle, respectively,and the overall design for the DC system was determined by solving these models; Itwas set up the LED induced transmitted fluorescence detection system and impedancesensor was designed.
④Based on the MEMS fabrication platform in the lab, by finishing fabricationprocess and layout design, the integrated dielectrophoresis detection chip wassuccessfully developed, which was satisfied with the design index. It was accomplishedthe integrated dielectrophoresis detection chip, optical/electric on-line dual detectionsystem, control circuit and other modules integrated together, and successfullydeveloped a prototype of integrated dielectrophoresis detection chip system.
⑤The application experiments based on the developed integrateddielectrophoresis detection chip system were studied. Using the Hepatocarcinoma cellsand human trabecular meshwork endothelium cells as experiment sample respectively, itis verified the single cell response ability for LED induced transmitted fluorescencedetection system, and the ability which can monitor cell physiological status by theintegrated impedance sensor. Using the suspension that mixed red blood cells andHepatocarcinoma cells together as experiment sample, the dielectrophoresis in situenrich, continuous separation, online dual detection experiments were done. The resultsshowed that the nDEP in situ enrich efficiency for Hepatocarcinoma cells can reach to87.5%, and the capture efficiency for Hepatocarcinoma cells in the mixed cellsuspension is greater than85%. The compact fluorescence detector and the integratedimpedance detector accomplished the functions of cell number counting detection andcell physiological state online identification, respectively, which demonstrated thefeasibility and validity of the developed integrated dielectrophoresis detection chipsystem.
引文
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