微流控液滴单细胞分析系统的研究
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摘要
近年来,随着液滴微流控技术的迅速发展,其在单细胞分析中的应用引起了越来越多的关注。液滴作为单细胞微反应器,能够有效控制扩散,加速混合,提高检测灵敏度,已被成功应用于多种单细胞分析中。然而,受液滴操控能力所限,在液滴系统中在线对单细胞进行复杂操纵仍存在较大困难。本工作的目的就是发展多种液滴操纵技术,建立一个自动化多功能的微流控液滴单细胞分析平台。
第一章综述了微流控单细胞分析系统的优势及发展现状,包括基于单相流的微流控单细胞分析系统以及基于液滴的微流控单细胞分析系统两部分。其中,在第二部分,系统介绍了液滴生成、试样引入、液滴融合及多步操纵技术,综述了液滴微流控系统在单细胞包裹、分选、培养和分析中的应用。
第二章的工作中建立了一种基于毛细管取样探针和缺口管阵列的自动化微流控液滴单细胞分析系统。采用液滴组装的方式,通过顺序引入细胞悬液、分析试剂和油相间隔,完成单细胞包裹和单细胞液滴反应器的生成。实验考察了影响单细胞包裹概率的各种因素,在优化的液滴生成条件下,得到的单细胞包裹概率为46.7±2.0%,比常规系统高出约10%。将系统应用于大鼠嗜铬瘤细胞(PC12细胞)内的β-半乳糖苷酶活性分析,对单细胞内酶反应进行了长时间监测,并且实现了对两种不同细胞样品的同时分析。
第三章在第二章工作的基础上,发展了一种简单新颖的液滴融合技术。充分利用系统具有的生成不同组分液滴的能力,通过改变液滴组成,调节液滴的界面张力,产生液滴流速的差异,进而实现毛细管中无需任何外部设备和处理的多液滴顺序融合。将液滴融合技术成功应用于短时间内单细胞酶反应动力学过程的监测中。
第四章在前两章工作的基础上,改进了常用的磁力液滴操控系统,通过引入少量的磁粉粒子作为载体的方法,实现了皮升级液滴的分裂操作。进而通过液滴多步操纵技术,包括液滴产生、移动、混合和分裂,实现了基于皮升级液滴的固相萃取操作。将固相萃取技术应用于单细胞及少量细胞的DNA提取中,取得了初步结果。
In rescent years, droplet-based microfluidics has made great progress and its application in single cell analysis has attracted more and more attension. Droplets, which are used as single cell microreactors, have the advantages of limiting dispersion, accelerating mixing and improving detection sensitivity. Despite the great success of droplet-based systems in single cell analysis, a multifunctional microfluidic platform that could perform complex single cell analysis with multiple manipulations of droplets including generation, transport, combining and splitting still present challenges.
In Chapter One, the recent progress of microfluidic single cell analysis systems are reviewed, including the single phase microfluidic single cell analysis system and the droplet-based microfluidic single cell analysis system. In the latter section, various droplet manipulation techniques are comprehensively described including droplet generation, reagent introduction, droplet fusion and multi-step manipulation. The application of droplet microfluidics in single cell encapsulation, sorting, culture and analysis are also introduced.
In Chapter Two, an automated doplet-based microfluidic single cell anlysis system based on a capillary sampling probe and a slotted-vials array was developed. The single cell droplet was formed using droplet assembling technique by sequentially aspirating cell suspension, reagent solutions and oil carrier into the capillary. Various factors affecting single cell encapsulating efficiencies were investigated. Under optimized conditions, a high single cell encapsulation efficiency of 46.7±2.0% was obtained, which was 10% higher than those reported by other groups. The performance of the system was demonstrated in the intracellularβ-galactosidase activity assays of pheochromocytoma cells (PC 12 cells) at the single cell level. With the ability in generating droplets with different compositions, simultaneous analysis for different cell samples was also performed.
In Chapter Three, a novel and simple droplet fusion method was developed with the single cell analysis system described in Chapter Two, based on the use of the difference of droplet interfacial tensions. By varying the droplet interfacial tension, the velocity differences between the droplets was generated, and droplet fusion in a capillary-based system without any external devices was achieved. The droplet fusion techinique was applied in on-line monitoring of enzymatic reaction dynamic process of single cells in a short period.
In Chapter Four, multi-step magnetic droplet manipulation technique was developed with the single cell analysis system described in Chapter Two. By introducing ferromagnetic particles as carriers to assist the magnetic beads in passing through the phase interface, picoliter-scale droplet splitting was achieved. By employing multi-step droplet manipulations including droplet transferring, merging and splitting, solid phase extraction among picoliter-scale droplets was performed and applied in DNA purification for single cell or small numbers of cells.
第一章综述了微流控单细胞分析系统的优势及发展现状,包括基于单相流的微流控单细胞分析系统以及基于液滴的微流控单细胞分析系统两部分。其中,在第二部分,系统介绍了液滴生成、试样引入、液滴融合及多步操纵技术,综述了液滴微流控系统在单细胞包裹、分选、培养和分析中的应用。
第二章的工作中建立了一种基于毛细管取样探针和缺口管阵列的自动化微流控液滴单细胞分析系统。采用液滴组装的方式,通过顺序引入细胞悬液、分析试剂和油相间隔,完成单细胞包裹和单细胞液滴反应器的生成。实验考察了影响单细胞包裹概率的各种因素,在优化的液滴生成条件下,得到的单细胞包裹概率为46.7±2.0%,比常规系统高出约10%。将系统应用于大鼠嗜铬瘤细胞(PC12细胞)内的β-半乳糖苷酶活性分析,对单细胞内酶反应进行了长时间监测,并且实现了对两种不同细胞样品的同时分析。
第三章在第二章工作的基础上,发展了一种简单新颖的液滴融合技术。充分利用系统具有的生成不同组分液滴的能力,通过改变液滴组成,调节液滴的界面张力,产生液滴流速的差异,进而实现毛细管中无需任何外部设备和处理的多液滴顺序融合。将液滴融合技术成功应用于短时间内单细胞酶反应动力学过程的监测中。
第四章在前两章工作的基础上,改进了常用的磁力液滴操控系统,通过引入少量的磁粉粒子作为载体的方法,实现了皮升级液滴的分裂操作。进而通过液滴多步操纵技术,包括液滴产生、移动、混合和分裂,实现了基于皮升级液滴的固相萃取操作。将固相萃取技术应用于单细胞及少量细胞的DNA提取中,取得了初步结果。
In rescent years, droplet-based microfluidics has made great progress and its application in single cell analysis has attracted more and more attension. Droplets, which are used as single cell microreactors, have the advantages of limiting dispersion, accelerating mixing and improving detection sensitivity. Despite the great success of droplet-based systems in single cell analysis, a multifunctional microfluidic platform that could perform complex single cell analysis with multiple manipulations of droplets including generation, transport, combining and splitting still present challenges.
In Chapter One, the recent progress of microfluidic single cell analysis systems are reviewed, including the single phase microfluidic single cell analysis system and the droplet-based microfluidic single cell analysis system. In the latter section, various droplet manipulation techniques are comprehensively described including droplet generation, reagent introduction, droplet fusion and multi-step manipulation. The application of droplet microfluidics in single cell encapsulation, sorting, culture and analysis are also introduced.
In Chapter Two, an automated doplet-based microfluidic single cell anlysis system based on a capillary sampling probe and a slotted-vials array was developed. The single cell droplet was formed using droplet assembling technique by sequentially aspirating cell suspension, reagent solutions and oil carrier into the capillary. Various factors affecting single cell encapsulating efficiencies were investigated. Under optimized conditions, a high single cell encapsulation efficiency of 46.7±2.0% was obtained, which was 10% higher than those reported by other groups. The performance of the system was demonstrated in the intracellularβ-galactosidase activity assays of pheochromocytoma cells (PC 12 cells) at the single cell level. With the ability in generating droplets with different compositions, simultaneous analysis for different cell samples was also performed.
In Chapter Three, a novel and simple droplet fusion method was developed with the single cell analysis system described in Chapter Two, based on the use of the difference of droplet interfacial tensions. By varying the droplet interfacial tension, the velocity differences between the droplets was generated, and droplet fusion in a capillary-based system without any external devices was achieved. The droplet fusion techinique was applied in on-line monitoring of enzymatic reaction dynamic process of single cells in a short period.
In Chapter Four, multi-step magnetic droplet manipulation technique was developed with the single cell analysis system described in Chapter Two. By introducing ferromagnetic particles as carriers to assist the magnetic beads in passing through the phase interface, picoliter-scale droplet splitting was achieved. By employing multi-step droplet manipulations including droplet transferring, merging and splitting, solid phase extraction among picoliter-scale droplets was performed and applied in DNA purification for single cell or small numbers of cells.
引文
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