CN104007091A - High-throughput detection system for microbe based on droplet microfluidic chip - Google Patents
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- 238000012545 processing Methods 0.000 abstract description 2
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Abstract
一种基于液滴微流控芯片的高通量检测系统，主要包括液滴微流控芯片系统(1)、光路系统(2)、数据采集分析系统(3)构成；其中液滴微流控芯片系统(1)将待检测微生物包埋形成独立单液滴微反应小室，通过光路系统(2)进行单液滴微反应小室内微生物样品的激光诱导荧光检测信号传输，并由数据采集分析系统(3)通过计算机软件对采集得到的信号进行检测分析。本发明中的液滴微流控芯片能进行替换，适用于不同类型微生物的激光诱导荧光检测分析；具有系统设计简单，加工制造成本低廉，检测成本低、速度快、通量高的显著特点；实现包括大肠杆菌、谷氨酸棒杆菌和酿酒酵母不同类型工业微生物生产相关目标酶和代谢产物的高效筛选。A high-throughput detection system based on a droplet microfluidic chip, mainly composed of a droplet microfluidic chip system (1), an optical path system (2), and a data acquisition and analysis system (3); wherein the droplet microfluidic The chip system (1) embeds the microorganisms to be detected to form an independent single-droplet micro-reaction chamber, and transmits the laser-induced fluorescence detection signal of the microbial sample in the single-droplet micro-reaction chamber through the optical path system (2), and the data acquisition and analysis system (3) The collected signal is detected and analyzed by computer software. The droplet microfluidic chip in the present invention can be replaced, and is suitable for laser-induced fluorescence detection and analysis of different types of microorganisms; it has the remarkable characteristics of simple system design, low processing and manufacturing costs, low detection cost, fast speed, and high throughput; Realize efficient screening of target enzymes and metabolites related to the production of different types of industrial microorganisms including Escherichia coli, Corynebacterium glutamicum and Saccharomyces cerevisiae.
Description
所属技术领域Technical field
本发明涉及一种基于液滴微流控芯片的高通量检测系统，特别涉及一种基于液滴微流控芯片激光诱导荧光检测的微生物高通量检测系统。The invention relates to a high-throughput detection system based on a droplet microfluidic chip, in particular to a high-throughput detection system for microorganisms based on laser-induced fluorescence detection of a droplet microfluidic chip.
背景技术Background technique
微生物高通量筛选系统是指能够自动、快速、高效地针对微生物的机能与产品进行筛选的技术平台，是工业微生物资源开发和产业化的瓶颈之一。从自然界筛选并在实验室诱变进化一直是发现和创新工业微生物菌种的重要途径，是工业生物技术产业的基础，现在工业上使用的微生物菌种主要是通过诱变筛选得到的。随着现代代谢工程技术和合成生物学的快速发展，理性设计逐渐成为微生物酶和菌种优化和创新的重要手段，然而由于生物体的复杂性和人类认识的局限性，理性设计得到的微生物通常不能完全达到设计的要求，仍然需要通过诱变筛选实施进一步优化，弥补理性设计的不足。微生物高通量筛选平台是传统诱变筛选技术的现代化发展，利用先进的现代自动化技术和仪器分析技术实现传统的菌种诱变筛选过程，具有自动化、标准化、高通量化等特征，大大突破了人工筛选在速度、效率和标准化等方面的限制，是微生物菌种筛选和改造的一次技术革命。然而已经投入使用的各类高通量筛选系统主要是国外公司开发的价值昂贵、操作复杂的大型装备系统，特别是经常需要以细胞流式分选仪作为主要部件，以完成筛选高通量的要求。例如美国Caliper公司和热电公司(ThermoFisher Scientific)等公司可以提供高通量筛选平台主体部分(包括菌落挑选与培养、液体处理与分析测试系统)；BD公司和贝克曼库尔特公司(Beckman Coulter)可以提供流式细胞分析仪；沃特世公司(Waters)和安捷伦公司(Agilent Technologies)等公司可以提供辅助分析检测平台(液相色谱等)。要建成完整的高通量筛选系统一般要花费上千万人民币，尽管整个系统的性能优越，但是昂贵的成本是一般普通实验室无法承受的。因此有必要开发一种普通、低成本，操作简单的小型化高通量筛选系统，微流控芯片系统。The microbial high-throughput screening system refers to a technical platform that can automatically, quickly and efficiently screen the functions and products of microorganisms, and is one of the bottlenecks in the development and industrialization of industrial microbial resources. Screening from nature and mutation evolution in the laboratory has always been an important way to discover and innovate industrial microbial strains, and is the basis of the industrial biotechnology industry. The microbial strains used in industry are mainly obtained through mutagenesis screening. With the rapid development of modern metabolic engineering technology and synthetic biology, rational design has gradually become an important means for the optimization and innovation of microbial enzymes and strains. However, due to the complexity of organisms and the limitations of human understanding, rationally designed microorganisms are usually If the requirements of the design cannot be fully met, further optimization through mutagenesis screening is still needed to make up for the lack of rational design. The microbial high-throughput screening platform is a modern development of traditional mutagenesis screening technology. It uses advanced modern automation technology and instrument analysis technology to realize the traditional strain mutagenesis screening process. It has the characteristics of automation, standardization, and high-throughput quantification, which greatly breaks through the artificial The limitations of screening in terms of speed, efficiency, and standardization are a technological revolution in the screening and transformation of microbial strains. However, the various high-throughput screening systems that have been put into use are mainly large-scale equipment systems that are expensive and complex to operate developed by foreign companies. Require. For example, companies such as Caliper and ThermoFisher Scientific in the United States can provide the main part of the high-throughput screening platform (including colony selection and cultivation, liquid handling and analysis testing systems); BD and Beckman Coulter (Beckman Coulter) Flow cytometers can be provided; companies such as Waters and Agilent Technologies can provide auxiliary analytical detection platforms (liquid chromatography, etc.). It generally costs tens of millions of RMB to build a complete high-throughput screening system. Although the performance of the entire system is superior, the high cost is beyond the reach of ordinary laboratories. Therefore, it is necessary to develop a common, low-cost, and easy-to-operate miniaturized high-throughput screening system, a microfluidic chip system.
目前的微流控分析系统主要包括连续微流体系统和以间断液滴为基础的微流体系统。基于连续微流系统的微流控系统研究较多，已经成功应用在蛋白或者基因的电泳分析上，并有商品化的分析仪，如Agilent2100bioanalyzer等。相对连续流体系统，间断液滴的研究进展较慢，目前还没有任何相关的商品化仪器。基于液滴微流控芯片高通量检测系统，它的独特优势在于可以形成独立的单个液滴微反应小室，将待分析样品(微生物)进行单独包埋在相互分开、互不干扰的小室中进行检测分析，使得分析微生物和它的胞外分泌产物成为可能。对包含有待检测样品(微生物及其相关酶类和代谢产物)的独立液滴微反应小室进行检测分析，具有速度快，通量高，成本低等显著特点。这对开展微生物定向进化改造工程用酶，研究外微生物的代谢产物，细胞分析和药物筛选等相关研究领域中具有重要推动作用。The current microfluidic analysis systems mainly include continuous microfluidic systems and microfluidic systems based on intermittent droplets. There are many studies on microfluidic systems based on continuous microfluidic systems, which have been successfully applied to electrophoretic analysis of proteins or genes, and there are commercial analyzers, such as Agilent2100bioanalyzer, etc. Compared with the continuous fluid system, the research progress of the intermittent droplet is slow, and there is no related commercialized instrument yet. Based on the droplet microfluidic chip high-throughput detection system, its unique advantage is that it can form an independent single droplet micro-reaction chamber, and the samples (microorganisms) to be analyzed are individually embedded in separate chambers that do not interfere with each other. Perform detection assays that make it possible to analyze microorganisms and their extracellular secretion products. The detection and analysis of the independent droplet micro-reaction chamber containing the sample to be detected (microorganisms and their related enzymes and metabolites) has the remarkable characteristics of fast speed, high throughput, and low cost. This will play an important role in promoting the development of enzymes for microbial directed evolution engineering, the study of metabolites of exogenous microorganisms, cell analysis and drug screening and other related research fields.
发明内容Contents of the invention
本发明的目的在于提供一种基于液滴微流控芯片的高通量检测系统，该检测系统可以对待检测样品(微生物)进行包埋，形成独立的单液滴微反应小室，并通过激光诱导荧光检测，实现实时高通量检测分析；该检测系统的分析检测通量可以达到上千范围，并可以通过不同类型液滴微流控芯片，实现包括大肠杆菌、谷氨酸棒杆菌和酿酒酵母不同类型工业微生物生产不同类型酶和代谢产物的高效筛选。The purpose of the present invention is to provide a high-throughput detection system based on a droplet microfluidic chip, which can embed the sample (microorganism) to be detected to form an independent single droplet micro-reaction chamber, and induce Fluorescence detection realizes real-time high-throughput detection and analysis; the detection throughput of the detection system can reach thousands of ranges, and through different types of droplet microfluidic chips, including E. coli, Corynebacterium glutamicum and Saccharomyces cerevisiae can be realized Efficient screening of different types of enzymes and metabolites produced by different types of industrial microorganisms.
本发明提供了一种基于液滴微流控芯片的高通量检测系统，主要包括液滴微流控芯片系统(1)、光路系统(2)、数据采集分析系统(3)构成；其特征在于：液滴微流控芯片系统(1)可以对待检测样品(微生物)进行包埋形成独立的单液滴微反应小室，通过光路系统(2)对单液滴微反应小室内的微生物样品关联的激光诱导荧光检测信号进行传输，并由数据采集分析系统(3)对从微流控芯片上采集得到的信号进行检测分析。The invention provides a high-throughput detection system based on a droplet microfluidic chip, which mainly includes a droplet microfluidic chip system (1), an optical path system (2), and a data acquisition and analysis system (3); its features The reason is that the droplet microfluidic chip system (1) can embed the sample (microorganism) to be detected to form an independent single droplet micro-reaction chamber, and the microbial sample in the single-droplet micro-reaction chamber can be associated with each other through the optical path system (2). The laser-induced fluorescence detection signal is transmitted, and the signal collected from the microfluidic chip is detected and analyzed by the data collection and analysis system (3).
本发明液滴微流控芯片的高通量检测系统中，微流控芯片系统(1)可以生成独立的液滴微反应小室，液滴微流控芯片可以自由进行更换，芯片包括适用于，但不局限于，大肠杆菌、谷棒杆菌、酵母菌微生物。In the high-throughput detection system of the droplet microfluidic chip of the present invention, the microfluidic chip system (1) can generate an independent droplet micro-reaction chamber, and the droplet microfluidic chip can be freely replaced, and the chip includes suitable for, But not limited to, Escherichia coli, Corynebacterium glutenus, yeast microorganisms.
本发明液滴微流控芯片的高通量检测系统中，光路系统(2)可以进行激光诱导荧光检测信号的传输，包括微流芯片(201)、显微镜(202)、反射镜(203)、分光镜(204)、分光镜(205)、聚光器(206)、滤镜(207)、滤镜(208)、照相机(209)、光电倍增管(210)、激光器(211)，各个部件按照实际工作时在光路上排列的先后顺序进行放置。In the high-throughput detection system of the droplet microfluidic chip of the present invention, the optical path system (2) can transmit the detection signal of laser-induced fluorescence, including a microfluidic chip (201), a microscope (202), a mirror (203), Spectroscope (204), beam splitter (205), condenser (206), filter (207), filter (208), camera (209), photomultiplier tube (210), laser (211), each component Place them in the order they are arranged on the optical path during actual work.
本发明液滴微流控芯片的高通量检测系统的工作原理是，从激光器(211)发出的激光通过二色分光镜(204)和反色镜(203)进入到物镜(202)，照射到微流芯片平台上的微流芯片(201)检测通道；荧光激发信号一部分则通过物镜(202)，反色镜(203)和分光镜(204)，通过滤光片(207)后由高速照相系统(209)进行拍照；另一部分则进入光电倍增管(210)，将光信号转变成电信号，被采集卡采集到计算机中设计的软件进行检测分析。The working principle of the high-throughput detection system of the droplet microfluidic chip of the present invention is that the laser light emitted from the laser (211) enters the objective lens (202) through the dichromatic beam splitter (204) and the anti-color mirror (203), and irradiates to the detection channel of the microfluidic chip (201) on the microfluidic chip platform; a part of the fluorescence excitation signal passes through the objective lens (202), the reverse color mirror (203) and the spectroscopic mirror (204), and passes through the optical filter (207) and is transmitted by the high-speed The camera system (209) takes pictures; the other part enters the photomultiplier tube (210), converts the optical signal into an electrical signal, and is collected by the acquisition card into the software designed in the computer for detection and analysis.
本发明液滴微流控芯片的高通量检测系统与文献报道相比，具有的有益效果是：系统设计简单，加工制造成本低，操作简单；其中液滴微流控芯片系统能生成独立的单个液滴微反应小室，将待分析样品(微生物和它的相关目标酶类和代谢产物)单独包埋在相互分开、互不干扰的微反应小室中进行检测分析；液滴微流控芯片可以自由替换适用于不同微生物的芯片；独立微反应小室具有皮升到纳升的体积，具有检测成本低、速度快、通量高的显著特点；可以实现包括大肠杆菌、谷氨酸棒杆菌和酿酒酵母不同类型工业微生物生产目标酶和代谢产物的高效筛选。Compared with the literature reports, the high-throughput detection system of the droplet microfluidic chip of the present invention has the beneficial effects of simple system design, low processing and manufacturing costs, and simple operation; wherein the droplet microfluidic chip system can generate independent A single droplet micro-reaction chamber, the samples to be analyzed (microorganisms and its related target enzymes and metabolites) are individually embedded in micro-reaction chambers that are separated from each other and do not interfere with each other for detection and analysis; the droplet microfluidic chip can Freely replace chips suitable for different microorganisms; the independent micro-reaction chamber has a volume from picoliters to nanoliters, and has the remarkable characteristics of low detection cost, fast speed, and high throughput; it can realize the detection of Escherichia coli, Corynebacterium glutamicum, and wine Efficient screening of target enzymes and metabolites produced by different types of yeast industrial microorganisms.
附图说明Description of drawings
下面结合附图和实施例对本发明进一步说明。The present invention will be further described below in conjunction with the accompanying drawings and embodiments.
附图1是本发明的结构原理图。Accompanying drawing 1 is a structural principle diagram of the present invention.
附图2是本发明的光学结构示意图。Accompanying drawing 2 is the schematic diagram of the optical structure of the present invention.
具体实施方式Detailed ways
下边结合附图与具体实施例对本发明作进一步详细描述：Below in conjunction with accompanying drawing and specific embodiment the present invention is described in further detail:
如附图1所示本发明液滴微流控芯片的高通量检测系统，包括液滴微流控芯片系统(1)、光路系统(2)和数据采集分析系统(3)。其中液滴微流控芯片系统(1)和光路系统(2)固定在一个二维平台上；数据采集分析系统(3)与计算机连接，对从微流控芯片上采集得到的信号进行检测分析。待检测的微生物样本，在液滴微流控芯片系统(1)中被包埋形成独立的单液滴微反应小室，然后通过光路系统(2)对单液滴微反应小室内的微生物样品的激光诱导荧光检测信号进行传输，具体是由激光器(211)发出的激光通过二色分光镜(204)和反色镜(203)进入到物镜(202)，照射到微流芯片平台上的微流芯片(201)检测通道；荧光激发信号一部分则通过物镜(202)，反色镜(203)和分光镜(204)，通过滤光片(207)后由高速照相系统(209)进行拍照；另一部分则进入光电倍增管(210)，将光信号转变成电信号，通过数据采集分析系统(3)被采集卡采集，由计算机软件实现对从液滴微流控芯片(201)上采集得到的微生物关联信号的高通量检测分析。As shown in Figure 1, the high-throughput detection system of the droplet microfluidic chip of the present invention includes a droplet microfluidic chip system (1), an optical path system (2) and a data acquisition and analysis system (3). The droplet microfluidic chip system (1) and the optical path system (2) are fixed on a two-dimensional platform; the data acquisition and analysis system (3) is connected to a computer to detect and analyze the signals collected from the microfluidic chip . The microbial sample to be detected is embedded in the droplet microfluidic chip system (1) to form an independent single-droplet micro-reaction chamber, and then the microbial sample in the single-droplet micro-reaction chamber is detected by the optical path system (2). The laser-induced fluorescence detection signal is transmitted, specifically, the laser light emitted by the laser (211) enters the objective lens (202) through the dichroic beam splitter (204) and the anti-color mirror (203), and irradiates the microfluidic fluid on the microfluidic chip platform. chip (201) detection channel; a part of the fluorescence excitation signal passes through the objective lens (202), the mirror (203) and the beam splitter (204), and is taken by the high-speed camera system (209) after passing through the optical filter (207); Part of it enters the photomultiplier tube (210), converts the optical signal into an electrical signal, and is collected by the acquisition card through the data acquisition and analysis system (3), and the computer software realizes the acquisition from the droplet microfluidic chip (201). High-throughput detection and analysis of microbe-associated signals.
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Cited By (19)
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| CN104232468A (en) * | 2014-08-28 | 2014-12-24 | 中北大学 | Laser array coded and photoinduced cell separation device |
| CN106399494A (en) * | 2016-09-07 | 2017-02-15 | 泸州职业技术学院 | Method for in-situ detection and analysis of microorganism interactions in living bodies |
| CN106442443A (en) * | 2016-09-12 | 2017-02-22 | 清华大学 | Micro-droplet fluorescence detection system |
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| CN108485984A (en) * | 2018-02-08 | 2018-09-04 | 中国科学院天津工业生物技术研究所 | The high-throughput screening method of cellulase high-yield |
| CN108823092A (en) * | 2018-03-22 | 2018-11-16 | 广州市第人民医院（广州消化疾病中心、广州医科大学附属市人民医院、华南理工大学附属第二医院） | Liquid drop chip nucleic acid analysis system and analysis method thereof |
| CN108593944A (en) * | 2018-03-22 | 2018-09-28 | 广州市第人民医院（广州消化疾病中心、广州医科大学附属市人民医院、华南理工大学附属第二医院） | Liquid drop chip immunoassay system and method |
| CN108823092B (en) * | 2018-03-22 | 2021-09-28 | 广州市第一人民医院（广州消化疾病中心、广州医科大学附属市一人民医院、华南理工大学附属第二医院） | Liquid drop chip nucleic acid analysis system and analysis method thereof |
| CN108535239A (en) * | 2018-03-28 | 2018-09-14 | 上海艾瑞德生物科技有限公司 | Micro-fluidic chip based on microlayer model and detecting system |
| CN110577888B (en) * | 2018-06-07 | 2023-08-29 | 洛阳华清天木生物科技有限公司 | Microfluidic chip and system comprising same |
| WO2019233245A1 (en) | 2018-06-07 | 2019-12-12 | 洛阳华清天木生物科技有限公司 | Microdroplet treatment device and use method thereof |
| CN110577888A (en) * | 2018-06-07 | 2019-12-17 | 洛阳华清天木生物科技有限公司 | micro-fluidic chip and system comprising same |
| CN110296963A (en) * | 2019-06-13 | 2019-10-01 | 深圳先进技术研究院 | A kind of fluorescence detection device and fluorescence detection method |
| CN112403539A (en) * | 2019-08-23 | 2021-02-26 | 无锡源清天木生物科技有限公司 | Micro-fluidic chip |
| CN112657563A (en) * | 2020-12-10 | 2021-04-16 | 深圳先进技术研究院 | Micro-fluidic liquid drop platform based on BRET bioluminescence technology |
| CN114317585B (en) * | 2021-12-31 | 2023-07-04 | 南京工业大学 | Liquid drop microfluidic assisted method for screening double rhamnolipid high-yield strain |
| CN114317585A (en) * | 2021-12-31 | 2022-04-12 | 南京工业大学 | Method for screening dual rhamnolipid high-yield strains assisted by droplet microfluidics |
| CN114907960A (en) * | 2022-05-20 | 2022-08-16 | 中国科学院深圳先进技术研究院 | A system and method for label-free live cell screening based on droplet microfluidics |
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