低电压毛细管电泳芯片集成系统研究
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摘要
毛细管电泳芯片是一种微量分离分析装置,它具有高效、高速、高通量、低消耗等优点,已成为蛋白质组学、临床医学、药物筛选等研究的重要手段之一。但是,通常意义上的毛细管电泳芯片系统的进样和分离过程往往需要高电压才能完成,且毛细管电泳芯片检测器的体积往往远大于芯片本身体积,使整个分析系统微型化面临诸多困难。为此,本文以低压、微型化、集成化为目标,开展低电压毛细管电泳芯片集成系统相关技术的研究工作。
在分析毛细管电泳芯片非接触电导检测器结构、检测原理基础上,采用VHDL-AMS语言,建立平面四电极非接触电导检测器的VHDL-AMS模型,研究了待测溶液介电常数、绝缘层厚度、检测电极宽度、微沟道深度以及交流电压幅度等参数对非接触电导检测器输出信号频率响应的影响。在此基础上,对适合芯片电泳信号的检测方法进行分析,重点探讨了正交矢量锁定放大器以及互相关-Duffing混沌振子检测相结合的检测方法在电泳芯片非接触电导检测中的应用。并结合电泳芯片非接触电导检测特点,研究了小波消噪对电泳芯片非接触电导检测信号的降噪处理,并基于短时能量差函数对芯片电泳色谱的提取进行了探讨。
研究了ITO微阵列电极、微沟道模具以及PDMS微沟道的制备工艺,并以ITO导电玻璃为基底制备了用于实验的低电压毛细管电泳芯片原型样品。
基于SOPC嵌入式技术搭建了低电压毛细管电泳芯片集成系统。结合低电压毛细管电泳芯片微阵列电极特点以及阵列电极控制电路,提出了低压移动控制算法。并基于VHDL语言编制了低电压毛细管电泳芯片微阵列电极移动控制IP核,通过对8片MAX306多路选择开关构成的阵列电极控制电路的控制,使芯片微沟道内能产生驱动待测各组分定向迁移的电场；同时,为满足微阵列电极的驱动以及检测器激励的需要,采用模拟与数字两种方法设计了低电压毛细管电泳芯片微阵列电极控制、非接触电导检测所需的四相位信号源,一是基于MAX038信号发生器设计；一是基于DDS技术设计；结合非接触电导检测信号特点,设计了双差分阻抗／电压变换电路实现阻抗到电压转换以及信号放大,同时,采用模拟式锁定放大器实现检测器输出交流信号到直流信号的转换；采用SOPC Builder定制了以NIOSⅡ软核处理器为核心的SOPC系统,用于协调控制各功能模块,并基于C++Builder设计了低电压毛细管电泳芯片上位机电泳检测程序。在此基础上,进行低电压毛细管电泳芯片集成系统的初步实验,并提出了后续工作需解决的相关问题。
Capillary electrophoresis microchip is a microdosage separate and analysis instrument, which has many advantages of high-efficiency, high-speed, high-throughput, low-consumption, etc. It has become one important means for proteomics, clinical medicine, drug screening and others. However, the injection and separation processes of capillary electrophoresis microchip often require high voltage to drive, and the detector volume of capillary electrophoresis micochip is often much larger than the size of microchip itself, so that, the miniaturization of entire analysis system is facing many difficulties. In this dissertation, the integration system of capillary electrophoresis microchip has been studied, and aiming to the integration system characteristic which include the low-voltage, miniaturization and integration.
The VHDL-AMS model of in-plane four-electrode contactless conductivity detector of electrophoresis microchip is built using VHDL-AMS language, and the effect parameters of output frequency response for contactless conductivity detector is investigated, such as the dielectric constant of electrolyte solution, insulation materials, the thickness of insulation materials, the distance of any two adjacent electrodes, the width of detection electrode and so on. On this basis, the detection methods suitable for chip electrophoresis are discussed. Especially, the orthogonal vector lock-in amplifier and cross-correlation-chaos detection methods are studied. According to the detection characteristics of contactless conductivity detector, the wavelet de-noising method is selected to reduce noise. And the extraction of electrophoresis chromatography of microchip based on short-time energy difference function is studied.
The preparation technologies of ITO array-electrode, micro-channel mold and PDMS micro-channel are studied. Simultaneously, the experimental low-voltage capillary electrophoresis separation chips with ITO array-electrode is developed and fabricated based on ITO glass substrate.
For satisfying the research of low-voltage capillary electrophoresis separation chip integrated system, a detection and control system based on SOPC embedded technology is present. According to the micro-array electrode distribution features and the circuit structure, a moving control algorithm suitable for low-voltage control strategy is proposed. The moving control IP core for micro-array-electrode of low-voltage capillary electrophoresis chip is developed using VHDL language. By eight chips multiplexers, MAX306, ordered arrangement, the directional moving electric field, which can drive the components to be determined directional migration, can be formed. At the same time, for satisfying the requirements of driving micro-array-electrode of low-voltage capillary electrophoresis microchip and excitating the contactless conductivity detector, two kinds of four-phase signal sources are designed. One is based on MAX038 function generator, another is based on DDS technology. According to the features of contactless conductivity detector, the corresponding dual differential impedance to voltage converter circuits are designed for impedance to voltage conversion and signal amplification, and the detection circuits based on analog lock-in amplifier are designed to realize detector output's AC signal to DC signal conversion. The SOPC system with NIOSⅡsoft-core processor, which is customized using SOPC Builder, is used to control coordinated functional modules. The PC detection program based on C++Builder is designed for low-voltage electrophoresis separation chip conductivity weak signal detection demand. On this basis, the preliminary experiments of low-voltage electrophoresis separation chip integration system were tested, and the related issues of future work are proposed.
在分析毛细管电泳芯片非接触电导检测器结构、检测原理基础上,采用VHDL-AMS语言,建立平面四电极非接触电导检测器的VHDL-AMS模型,研究了待测溶液介电常数、绝缘层厚度、检测电极宽度、微沟道深度以及交流电压幅度等参数对非接触电导检测器输出信号频率响应的影响。在此基础上,对适合芯片电泳信号的检测方法进行分析,重点探讨了正交矢量锁定放大器以及互相关-Duffing混沌振子检测相结合的检测方法在电泳芯片非接触电导检测中的应用。并结合电泳芯片非接触电导检测特点,研究了小波消噪对电泳芯片非接触电导检测信号的降噪处理,并基于短时能量差函数对芯片电泳色谱的提取进行了探讨。
研究了ITO微阵列电极、微沟道模具以及PDMS微沟道的制备工艺,并以ITO导电玻璃为基底制备了用于实验的低电压毛细管电泳芯片原型样品。
基于SOPC嵌入式技术搭建了低电压毛细管电泳芯片集成系统。结合低电压毛细管电泳芯片微阵列电极特点以及阵列电极控制电路,提出了低压移动控制算法。并基于VHDL语言编制了低电压毛细管电泳芯片微阵列电极移动控制IP核,通过对8片MAX306多路选择开关构成的阵列电极控制电路的控制,使芯片微沟道内能产生驱动待测各组分定向迁移的电场；同时,为满足微阵列电极的驱动以及检测器激励的需要,采用模拟与数字两种方法设计了低电压毛细管电泳芯片微阵列电极控制、非接触电导检测所需的四相位信号源,一是基于MAX038信号发生器设计；一是基于DDS技术设计；结合非接触电导检测信号特点,设计了双差分阻抗／电压变换电路实现阻抗到电压转换以及信号放大,同时,采用模拟式锁定放大器实现检测器输出交流信号到直流信号的转换；采用SOPC Builder定制了以NIOSⅡ软核处理器为核心的SOPC系统,用于协调控制各功能模块,并基于C++Builder设计了低电压毛细管电泳芯片上位机电泳检测程序。在此基础上,进行低电压毛细管电泳芯片集成系统的初步实验,并提出了后续工作需解决的相关问题。
Capillary electrophoresis microchip is a microdosage separate and analysis instrument, which has many advantages of high-efficiency, high-speed, high-throughput, low-consumption, etc. It has become one important means for proteomics, clinical medicine, drug screening and others. However, the injection and separation processes of capillary electrophoresis microchip often require high voltage to drive, and the detector volume of capillary electrophoresis micochip is often much larger than the size of microchip itself, so that, the miniaturization of entire analysis system is facing many difficulties. In this dissertation, the integration system of capillary electrophoresis microchip has been studied, and aiming to the integration system characteristic which include the low-voltage, miniaturization and integration.
The VHDL-AMS model of in-plane four-electrode contactless conductivity detector of electrophoresis microchip is built using VHDL-AMS language, and the effect parameters of output frequency response for contactless conductivity detector is investigated, such as the dielectric constant of electrolyte solution, insulation materials, the thickness of insulation materials, the distance of any two adjacent electrodes, the width of detection electrode and so on. On this basis, the detection methods suitable for chip electrophoresis are discussed. Especially, the orthogonal vector lock-in amplifier and cross-correlation-chaos detection methods are studied. According to the detection characteristics of contactless conductivity detector, the wavelet de-noising method is selected to reduce noise. And the extraction of electrophoresis chromatography of microchip based on short-time energy difference function is studied.
The preparation technologies of ITO array-electrode, micro-channel mold and PDMS micro-channel are studied. Simultaneously, the experimental low-voltage capillary electrophoresis separation chips with ITO array-electrode is developed and fabricated based on ITO glass substrate.
For satisfying the research of low-voltage capillary electrophoresis separation chip integrated system, a detection and control system based on SOPC embedded technology is present. According to the micro-array electrode distribution features and the circuit structure, a moving control algorithm suitable for low-voltage control strategy is proposed. The moving control IP core for micro-array-electrode of low-voltage capillary electrophoresis chip is developed using VHDL language. By eight chips multiplexers, MAX306, ordered arrangement, the directional moving electric field, which can drive the components to be determined directional migration, can be formed. At the same time, for satisfying the requirements of driving micro-array-electrode of low-voltage capillary electrophoresis microchip and excitating the contactless conductivity detector, two kinds of four-phase signal sources are designed. One is based on MAX038 function generator, another is based on DDS technology. According to the features of contactless conductivity detector, the corresponding dual differential impedance to voltage converter circuits are designed for impedance to voltage conversion and signal amplification, and the detection circuits based on analog lock-in amplifier are designed to realize detector output's AC signal to DC signal conversion. The SOPC system with NIOSⅡsoft-core processor, which is customized using SOPC Builder, is used to control coordinated functional modules. The PC detection program based on C++Builder is designed for low-voltage electrophoresis separation chip conductivity weak signal detection demand. On this basis, the preliminary experiments of low-voltage electrophoresis separation chip integration system were tested, and the related issues of future work are proposed.
引文
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