基于取样探针的微流控试样引入系统的研究
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摘要
微流控学是在微米级通道中操控微升至飞升级流体的技术与科学,自从二十世纪九十年代提出以来,已经在分析化学中得到广泛的应用。其目的是将在常规实验室中进行的试样引入、预处理、混合、反应、分离和检测等分析操作集成到微型化、自动化的微流控系统中,最终目标是实现分析系统的便携化。微流控分析系统可以分为均相的流动分析系统和基于液滴的间隔相分析系统,也可将其分为基于芯片的和基于毛细管的微流控系统。目前,微流控系统发展的主要瓶颈之一是宏观体系与微流控系统的衔接问题,发展针对不同试样的高通量试样引入技术,对于微流控分析的发展和应用至关重要。本文对基于取样探针的微流控试样引入技术进行了研究,分别建立了基于芯片和基于毛细管的液滴分析筛选系统,以及毛细管薄层色谱系统。
第一章首先综述了基于取样探针的微流控试样引入技术的研究现状,包括耦合式及一体式的取样探针的加工方法及其应用。同时,对于目前正在兴起的微流控液滴分析系统的研究进展也进行了相应介绍,包括液滴的生成及操控、液滴的检测,以及系统的应用。
第二章搭建了基于毛细管和缺口管阵列的微流控液滴分析系统。系统由缺口型试样管阵列、毛细管和微量注射泵组成,不需要复杂的微加工技术和设备,操作完全自动化,可以通过调节进样顺序、进样组分、进样时间和流速等参数,灵活而又精确地控制每个液滴的大小和组成。将该系统初步应用于液滴内多种反应和液滴间的相间传质研究,展示了该系统在化学、生物学和医学等领域所具有的广泛的应用前景。
第三章首次建立了基于一体化取样探针和缺口管阵列的微流控芯片液滴分析系统。将试样引入、试剂加入和液滴生成等单元集成于一体化取样探针内,实现对不同试样的高通量试样引入及液滴生成。该系统集成度高,自动化程度高,可达到很高的换样通量,为目前微流控液滴分析系统提供了一种新的试样引入方法。该系统被成功应用于蛋白结晶实验中沉淀剂的筛选以及酶抑制分析中的抑制剂筛选。
第四章提出了一种基于玻璃毛细管的薄层色谱分离方法。在拉尖的毛细管内填充薄层色谱硅胶固定相,利用手工点样和缺口管技术完成进样,采用简易和缺口管阵列两种展开模式。系统具有点样方法简单,操作方便,展开剂消耗少的特点。该系统被初步应用于混合染料和中药大青叶的分离。
Microfluidics is the science and technology that manipulate small (nL～fL scale) amounts of fluids in channels with dimensions of tens to hundreds of micrometer, which have been widely applied in analytical chemistry. Its objective is to integrate all of the modules performed in routine laboratories, including sample introduction, pretreatment, transportation, mixing, reaction, separation and detection, into a compact device to achieve the miniaturization, automatization and integration of the whole analytical systems, providing advantages of high throughput, low samples and reagents consumption and low cost. Nevertheless, one of the major bottleneck in the development of microfluidic analytical systems lies in world-to-chip interface, which means sample introduction from external systems (μL～mL scale) into microfluidic systems (below nL scale) is of great significance to microfluidics.
This dissertation is dedicated to relate the development of microfluidic sample introduction techniques based on sampling probes and their applications in chip-based and capillary-based droplet analysis, as well as in thin layer chromatography (TLC).
In chapter one, the development of sample introduction techniques based on sampling probes, and the recent progress in microfluidic droplet analytical systems were detailedly reviewed.
In chapter two, a capillary-based droplet analytical system based on a capillary and a slotted-vial array (SVA) sample presenting device was built, which capable of producing multi-component droplets in the nanoliter range. The present system was applied in various droplet microreactors, to demonstrate its application potentials in chemistry, biology and medicine.
In chapter three, a microchip-based droplet analysis system with a monolithic sampling probe was developed for the first time, to achieve high-throughput sample introduction for different samples in droplet-based analysis. The sampling probe integrating functions of sample introduction, merging with reagents and generating droplet, was employed to produce diverse droplet microreactors automatically and continuously by coupling with a SVA system. The performance of the system was demonstrated in evaluating protein crystallization conditions and screening inhibitors for enzyme reaction. A possible highest sampling throughput of 10,000 samples/h for different screening reagents could be achieved by using this sample introduction technique.
In chapter four, a simple capillary based TLC system was developed. A tapered glass capillary packed with silica gel was used as sampling probe and chromatographic column for TLC. The performance of the system was demonstrated in the separation of Camag test dye mixture I and a traditional Chinese medicine-Folium Isatidis.
第一章首先综述了基于取样探针的微流控试样引入技术的研究现状,包括耦合式及一体式的取样探针的加工方法及其应用。同时,对于目前正在兴起的微流控液滴分析系统的研究进展也进行了相应介绍,包括液滴的生成及操控、液滴的检测,以及系统的应用。
第二章搭建了基于毛细管和缺口管阵列的微流控液滴分析系统。系统由缺口型试样管阵列、毛细管和微量注射泵组成,不需要复杂的微加工技术和设备,操作完全自动化,可以通过调节进样顺序、进样组分、进样时间和流速等参数,灵活而又精确地控制每个液滴的大小和组成。将该系统初步应用于液滴内多种反应和液滴间的相间传质研究,展示了该系统在化学、生物学和医学等领域所具有的广泛的应用前景。
第三章首次建立了基于一体化取样探针和缺口管阵列的微流控芯片液滴分析系统。将试样引入、试剂加入和液滴生成等单元集成于一体化取样探针内,实现对不同试样的高通量试样引入及液滴生成。该系统集成度高,自动化程度高,可达到很高的换样通量,为目前微流控液滴分析系统提供了一种新的试样引入方法。该系统被成功应用于蛋白结晶实验中沉淀剂的筛选以及酶抑制分析中的抑制剂筛选。
第四章提出了一种基于玻璃毛细管的薄层色谱分离方法。在拉尖的毛细管内填充薄层色谱硅胶固定相,利用手工点样和缺口管技术完成进样,采用简易和缺口管阵列两种展开模式。系统具有点样方法简单,操作方便,展开剂消耗少的特点。该系统被初步应用于混合染料和中药大青叶的分离。
Microfluidics is the science and technology that manipulate small (nL～fL scale) amounts of fluids in channels with dimensions of tens to hundreds of micrometer, which have been widely applied in analytical chemistry. Its objective is to integrate all of the modules performed in routine laboratories, including sample introduction, pretreatment, transportation, mixing, reaction, separation and detection, into a compact device to achieve the miniaturization, automatization and integration of the whole analytical systems, providing advantages of high throughput, low samples and reagents consumption and low cost. Nevertheless, one of the major bottleneck in the development of microfluidic analytical systems lies in world-to-chip interface, which means sample introduction from external systems (μL～mL scale) into microfluidic systems (below nL scale) is of great significance to microfluidics.
This dissertation is dedicated to relate the development of microfluidic sample introduction techniques based on sampling probes and their applications in chip-based and capillary-based droplet analysis, as well as in thin layer chromatography (TLC).
In chapter one, the development of sample introduction techniques based on sampling probes, and the recent progress in microfluidic droplet analytical systems were detailedly reviewed.
In chapter two, a capillary-based droplet analytical system based on a capillary and a slotted-vial array (SVA) sample presenting device was built, which capable of producing multi-component droplets in the nanoliter range. The present system was applied in various droplet microreactors, to demonstrate its application potentials in chemistry, biology and medicine.
In chapter three, a microchip-based droplet analysis system with a monolithic sampling probe was developed for the first time, to achieve high-throughput sample introduction for different samples in droplet-based analysis. The sampling probe integrating functions of sample introduction, merging with reagents and generating droplet, was employed to produce diverse droplet microreactors automatically and continuously by coupling with a SVA system. The performance of the system was demonstrated in evaluating protein crystallization conditions and screening inhibitors for enzyme reaction. A possible highest sampling throughput of 10,000 samples/h for different screening reagents could be achieved by using this sample introduction technique.
In chapter four, a simple capillary based TLC system was developed. A tapered glass capillary packed with silica gel was used as sampling probe and chromatographic column for TLC. The performance of the system was demonstrated in the separation of Camag test dye mixture I and a traditional Chinese medicine-Folium Isatidis.
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