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WO2023065645A1 - Electrowetting-based concentration homogenization microfluidic chip and concentration homogenization method - Google Patents

Electrowetting-based concentration homogenization microfluidic chip and concentration homogenization method Download PDF

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Publication number
WO2023065645A1
WO2023065645A1 PCT/CN2022/091636 CN2022091636W WO2023065645A1 WO 2023065645 A1 WO2023065645 A1 WO 2023065645A1 CN 2022091636 W CN2022091636 W CN 2022091636W WO 2023065645 A1 WO2023065645 A1 WO 2023065645A1
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area
concentration
sample
homogenization
dilution
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French (fr)
Chinese (zh)
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杨柳青
张东锋
吴玥
王超
刘聪
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Autobio Labtec Instruments Zhengzhou Co Ltd
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Autobio Labtec Instruments Zhengzhou Co Ltd
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/50273—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the means or forces applied to move the fluids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502769—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by multiphase flow arrangements
    • B01L3/502784—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by multiphase flow arrangements specially adapted for droplet or plug flow, e.g. digital microfluidics
    • B01L3/502792—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by multiphase flow arrangements specially adapted for droplet or plug flow, e.g. digital microfluidics for moving individual droplets on a plate, e.g. by locally altering surface tension
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0605—Metering of fluids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0694—Creating chemical gradients in a fluid
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/16—Reagents, handling or storing thereof
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/16—Surface properties and coatings
    • B01L2300/161—Control and use of surface tension forces, e.g. hydrophobic, hydrophilic
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0415—Moving fluids with specific forces or mechanical means specific forces electrical forces, e.g. electrokinetic
    • B01L2400/0427—Electrowetting

Definitions

  • the invention relates to a microfluidic chip based on electrowetting, in particular to a microfluidic chip and a concentration uniformization method based on electrowetting.
  • Mixed detection of multiple samples has the advantages of saving time, reducing costs, and improving efficiency. It is a commonly used detection method in the fields of gene sequencing, pharmaceutical synthesis, biochemical analysis and diagnosis. Before the mixed sample detection, due to the inconsistent initial concentration of each sample, the concentration of some samples in the same mixed system will be too high after mixing, and the concentration of some samples will be too low. The signal of low concentration samples is easily covered and lost, and the signal of high concentration samples is easy to exceed the detection range, resulting in inaccurate overall detection. Concentration homogenization is a sample mixing method that mixes samples of different concentrations according to a certain ratio to keep the quality or concentration of each sample consistent in the same mixing system. This method can effectively solve the above problems.
  • the concentration homogenization workflow mainly includes three steps: concentration quantification, calculation and comparison, and accurate sample mixing: 1) Concentration quantification: use quantitative detection instruments to detect the initial concentration of different samples; 2) Calculation and comparison: quantify according to the concentration Calculate the volume required for different samples based on the result and the required value of the homogenized concentration; 3) Accurate sample mixing: According to the calculation result, accurately pipette the required volume from each sample, and then mix.
  • Microfluidic systems are widely used in chemical analysis, biomedicine, food hygiene and the environment because of their advantages such as less sample consumption, fast response, high detection efficiency, good heat and mass transfer effects, no cross-contamination, and easy integration with other technical equipment. monitoring and other fields.
  • electrowetting English Electrowetting, abbreviated as EW
  • pipetting technology is a new droplet manipulation method for electrically controlling the surface tension change of the droplet, that is, by changing the voltage between the droplet and the insulating substrate.
  • To change the wettability of the droplet on the substrate that is, to change the contact angle, to promote the deformation and displacement of the droplet.
  • Electrowetting pipetting technology breaks through the pipetting system's dependence on traditional robotic arms, pump valve pipelines and complex flow channels, and can achieve highly flexible and precise control of reagents through digital programming. Therefore, how to use the microfluidic chip to control the concentration of the sample in the microchannel of the microfluidic chip through the electrowetting pipetting technology has not yet been reported.
  • the purpose of the present invention is to provide a microfluidic chip for uniform concentration based on electrowetting. Another purpose of the present invention is to provide a method for using the microfluidic chip to uniformize the concentration, so as to solve the problem that the current manual pipetting is limited by personnel. Operating proficiency, as well as the problems of large pipetting deviation, low accuracy and low efficiency caused by the inherent deviation of the pipette.
  • the present invention takes the following technical solutions:
  • the electrowetting-based concentration uniform microfluidic chip of the present invention includes a microfluidic chip body provided with a microchannel, and the microchannel is used to transport the liquid in it along the microchannel by using electrowetting liquid transfer technology.
  • the microfluidic chip body is also provided with a sample area, a reagent storage area, a dilution area, a concentration quantification area, an accurate sampling area and a homogenization area; the sample area, reagent storage area, dilution area, concentration quantification area, The precise sampling area and the homogenization area communicate through microchannels; where:
  • the sample area is used to store the original sample
  • the reagent storage area is used to store reagents, and the reagents are used to dilute the original sample according to the set gradient;
  • the dilution zone is used to mix the reagent and the original sample entering this zone through the microchannel to prepare a diluted sample;
  • the concentration quantification area is used for concentration determination of the diluted sample entering this area through the microchannel;
  • the total volume and concentration required for homogenization according to the set concentration, and according to the detected or calculated concentration of the original sample and the diluted sample select the appropriate original sample or diluted sample as the mother solution, and calculate the concentration for normalization
  • For the required volume of mother liquor use electrowetting pipetting technology to pipette a set volume of mother liquor to this area to complete concentration homogenization.
  • the microfluidic chip body includes an upper substrate and a lower substrate arranged at an interval between the upper and lower substrates, the microchannel through which the liquid moves is formed between the upper and lower substrates; the structure of the upper substrate from top to bottom is The upper insulating substrate, the common electrode, and the upper hydrophobic layer; the structure of the lower substrate is, from bottom to top, the lower insulating substrate, the driving electrode array, the dielectric layer, and the lower hydrophobic layer.
  • the concentration uniformization method of the concentration uniformization microfluidic chip of the present invention comprises the following steps:
  • Step 1 adding multiple original samples to respective sample areas
  • Step 2 adding the reagent to the reagent storage area
  • Step 3 using electrowetting pipetting technology, moving the reagents to each dilution area according to the set volume, and moving each original sample to the respective dilution area through the microchannel according to the set volume, mixing Prepare diluted samples evenly, and complete the set gradient dilution in sequence;
  • Step 4 using electrowetting pipetting technology, sequentially manipulate the diluted samples in each dilution area, move to the concentration quantification area according to the set volume for electrochemical or fluorescence detection, and directly obtain or calculate the final sample according to the test results.
  • Step 5 according to the total volume and concentration required for homogenization, select the original sample or diluted sample of appropriate concentration as the mother liquor, and calculate the required mother liquor volume;
  • Step 6 Use electrowetting pipetting technology to accurately separate the required volume from each mother liquor through the precise sampling area, and move to the homogenization area for mixing to complete the concentration homogenization.
  • the method of the invention has simple operation and high degree of automation, reduces human operation errors, and the homogenization process can be completed within one hour, which saves time and greatly improves detection efficiency.
  • Electrowetting pipetting technology is used to achieve precise pipetting, and the volume deviation is less than 3%, which solves the problem of inaccurate pipetting results caused by the proficiency of the operator or the inherent deviation of the pipette in traditional pipetting.
  • Fig. 1 is a schematic structural view of the microfluidic chip body of the present invention.
  • Fig. 2 is a schematic diagram of the layout of the sample area, reagent storage area, dilution area, concentration quantification area, precise sampling area, homogenization area and microchannels of the present invention.
  • the electrowetting-based concentration uniform microfluidic chip of the present invention includes a microfluidic chip body provided with a microchannel 1, and the microchannel 1 is used to transport its The droplet 2 inside moves along the microchannel 1.
  • the body of the microfluidic chip includes an upper substrate and a lower substrate arranged at intervals between the upper and lower substrates, and a microchannel 1 through which droplets 2 move is formed between the upper and lower substrates;
  • the structure of the upper substrate is an upper insulating substrate 3, a common The electrode 4, the upper hydrophobic layer 5;
  • the lower substrate structure is the lower insulating substrate 6, the driving electrode array 7, the dielectric layer 8, and the lower hydrophobic layer 9 from bottom to top.
  • the microfluidic chip body is also provided with a sample area, a reagent storage area, a dilution area, a concentration quantification area, an accurate sampling area and a homogenization area; a sample area, a reagent storage area, a dilution area, a concentration quantification area, an accurate sampling area and a homogenization area Areas communicate through microchannel 1; where:
  • the sample area is used to store the original sample; the present embodiment sets four sample areas 10.1, 10.2, 10.3, 10.4;
  • the reagent storage area 11 is used for storing reagents, and the reagents are used to dilute the original sample according to the set gradient;
  • the dilution area is used to mix the reagent and the original sample entering this area through the microchannel 1 to prepare a diluted sample; this embodiment takes two gradient dilutions as an example, and each sample area corresponds to two dilution areas, namely: the first The first dilution zone 12.1 and the second dilution zone 12.2; of course, three gradient dilutions or more gradient dilutions can also be selected according to needs;
  • the concentration quantification area 13 is used to measure the concentration of the diluted sample entering this area through the microchannel 1 by electrochemical or fluorescence detection method;
  • the precise sampling area 14 is used to obtain the original sample or/and the diluted sample according to the set volume
  • Homogenization zone 15 the total volume and concentration required for homogenization according to the set concentration, and according to the detected or calculated concentration of the original sample and the diluted sample, select the appropriate original sample or diluted sample as the mother solution, and calculate the concentration uniformity Use electrowetting pipetting technology to pipette the set volume of mother liquor to this area to complete the concentration homogenization.
  • the concentration uniformization method of the concentration uniform microfluidic chip of the present invention comprises the following steps:
  • Step 1 adding four original samples to the sample areas 10.1, 10.2, 10.3, and 10.4 in advance;
  • Step 2 adding the reagent to the reagent storage area 11 in advance;
  • Step 3 use electrowetting pipetting technology to manipulate the original samples in each sample area 10.1, 10.2, 10.3, and 10.4, move them to the respective first dilution areas 12.1 through the microchannel 1 according to the set volume, and then move them to the respective first dilution areas 12.1 according to the set volume.
  • the reagents are moved to the first dilution area 12.1 with a predetermined volume, and mixed to prepare the first diluted sample; then, the electrowetting pipetting technology is used to control the first diluted sample to move to the second diluted sample through the microchannel 1 according to the set volume.
  • Step 4 using electrowetting pipetting technology, sequentially manipulate the second diluted samples in each second dilution zone 12.2, move to the concentration quantification zone 13 according to the set volume for electrochemical or fluorescence detection, and directly obtain or calculate the concentration of the second diluted sample, and calculate the corresponding concentration of the first diluted sample and the original sample according to the dilution factor of the second diluted sample in each second dilution zone;
  • Step 5 according to the total volume and concentration required for homogenization, select the original sample or diluted sample of appropriate concentration as the mother liquor, and calculate the required mother liquor volume;
  • Step 6 using electrowetting pipetting technology, through the precise sampling area 14, accurately separate the required volume from each mother liquor, and move to the homogenization area 15 for mixing to complete the concentration homogenization.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Dispersion Chemistry (AREA)
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  • General Health & Medical Sciences (AREA)
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Abstract

An electrowetting-based concentration homogenization microfluidic chip and a concentration homogenization method, the chip comprising a microfluidic chip body provided with a microchannel; the microchannel is used to transport, by using electrowetting pipetting technology, liquid to move along the microchannel; the microfluidic chip body is provided with a sample region, a reagent storage region, a dilution region, a concentration quantification region, an accurate sampling region and a homogenization region; and the sample region, the reagent storage region, the dilution region, the concentration quantification region, the accurate sampling region and the homogenization region communicate with one another by means of the microchannel. The method comprises: 1. adding a plurality of original samples to respective sample regions; 2. adding a reagent to a reagent storage region; 3. using electrowetting pipetting technology to move the reagent to a dilution region, and moving the original samples to the dilution region to complete set gradient dilution; 4. manipulating the diluted sample to move to a concentration quantification region for measuring; 5. selecting, according to homogenization, an original sample as a mother liquor; and 6. separating a required volume by means of an accurate sampling region and moving same to a homogenization region to complete concentration homogenization.

Description

基于电润湿的浓度均一化微流控芯片及浓度均一化方法Concentration uniformization microfluidic chip and concentration uniformization method based on electrowetting

本申请要求于2021年10月19日提交中国专利局、申请号为202111217576.X、发明名称为“基于电润湿的浓度均一化微流控芯片及浓度均一化方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。This application claims the priority of the Chinese patent application submitted to the China Patent Office on October 19, 2021, with the application number 202111217576.X, and the title of the invention is "a microfluidic chip with uniform concentration based on electrowetting and a method for uniform concentration" rights, the entire contents of which are incorporated in this application by reference.

技术领域technical field

本发明涉及基于电润湿的微流控芯片，尤其是涉及基于电润湿的浓度均一化微流控芯片及浓度均一化方法。The invention relates to a microfluidic chip based on electrowetting, in particular to a microfluidic chip and a concentration uniformization method based on electrowetting.

背景技术Background technique

多个样本混合检测(以下简称混样检测)具有节省时间、降低成本、提升效率等优势，是基因测序、医药合成、生物化学分析及诊断等领域常用的检测手段。混样检测前由于各样本起始浓度不一致，混合后会导致在同一混合体系中有些样本浓度过高，有些样本浓度过低，低浓度样本的信号容易被掩盖而丢失，高浓度样本容易超出检测范围，从而造成整体检测不准确。浓度均一化是一种将不同浓度的样本按照一定的比例混合，使各样本在同一混合体系中质量或浓度保持一致的混样方法，该方法可以有效解决上述问题。Mixed detection of multiple samples (hereinafter referred to as mixed detection) has the advantages of saving time, reducing costs, and improving efficiency. It is a commonly used detection method in the fields of gene sequencing, pharmaceutical synthesis, biochemical analysis and diagnosis. Before the mixed sample detection, due to the inconsistent initial concentration of each sample, the concentration of some samples in the same mixed system will be too high after mixing, and the concentration of some samples will be too low. The signal of low concentration samples is easily covered and lost, and the signal of high concentration samples is easy to exceed the detection range, resulting in inaccurate overall detection. Concentration homogenization is a sample mixing method that mixes samples of different concentrations according to a certain ratio to keep the quality or concentration of each sample consistent in the same mixing system. This method can effectively solve the above problems.

浓度均一化工作流程主要包含浓度定量、计算比对、精确混样三个步骤：1)浓度定量：采用定量检测仪器，对不同的样本进行起始浓度检测；2)计算比对：根据浓度定量结果及均一化浓度需求值，计算不同样本所需体积；3)精确混样：依据计算结果，从每个样本中精确移取所需体积，然后进行混合。The concentration homogenization workflow mainly includes three steps: concentration quantification, calculation and comparison, and accurate sample mixing: 1) Concentration quantification: use quantitative detection instruments to detect the initial concentration of different samples; 2) Calculation and comparison: quantify according to the concentration Calculate the volume required for different samples based on the result and the required value of the homogenized concentration; 3) Accurate sample mixing: According to the calculation result, accurately pipette the required volume from each sample, and then mix.

上述现有的浓度均一化方法，通常基于定量检测仪器完成浓度检测，采用手工方法进行样本的移取及混合，存在自动化程度低、操作复杂等不足，严重降低了混样检测的效率。同时受限于移液工具的固有偏差及操作人员的熟练度，手工方法往往会导致移液体积偏差较大、准确度较低的情 况。例如，采用传统移液器移液时经常会发生挂液或试剂残留。The above-mentioned existing concentration homogenization methods are usually based on quantitative detection instruments to complete concentration detection, and manual methods are used for pipetting and mixing of samples, which have disadvantages such as low degree of automation and complicated operation, which seriously reduces the efficiency of mixed sample detection. At the same time, limited by the inherent deviation of pipetting tools and the proficiency of operators, manual methods often lead to large deviations in pipetting volume and low accuracy. For example, hang-up or reagent carryover often occurs when pipetting with traditional pipettes.

微流控系统因具有样品消耗少、反应快、检测效率高、传热传质效果好、无交叉污染、易于和其他技术设备集成等优点，广泛应用于化学分析、生物医疗、食品卫生及环境监测等领域。在微流控系统中，电润湿(英文Electrowetting，缩写EW)移液技术是一种对液滴进行电控表面张力变化的新型液滴操控方式，即通过改变液滴与绝缘基板之间电压来改变液滴在基板上的润湿性，即改变接触角，促使液滴发生形变、位移。电润湿移液技术突破了移液系统对传统机械臂、泵阀管路及复杂流道的依赖，通过数字化编程即可实现试剂的高灵活、高精准的操控。由此，如何采用微流控芯片，通过电润湿移液技术操控微流控芯片微通道中的样品进行浓度均一化，目前还未见诸有关报道。Microfluidic systems are widely used in chemical analysis, biomedicine, food hygiene and the environment because of their advantages such as less sample consumption, fast response, high detection efficiency, good heat and mass transfer effects, no cross-contamination, and easy integration with other technical equipment. monitoring and other fields. In the microfluidic system, electrowetting (English Electrowetting, abbreviated as EW) pipetting technology is a new droplet manipulation method for electrically controlling the surface tension change of the droplet, that is, by changing the voltage between the droplet and the insulating substrate. To change the wettability of the droplet on the substrate, that is, to change the contact angle, to promote the deformation and displacement of the droplet. Electrowetting pipetting technology breaks through the pipetting system's dependence on traditional robotic arms, pump valve pipelines and complex flow channels, and can achieve highly flexible and precise control of reagents through digital programming. Therefore, how to use the microfluidic chip to control the concentration of the sample in the microchannel of the microfluidic chip through the electrowetting pipetting technology has not yet been reported.

发明内容Contents of the invention

本发明目的在于提供一种基于电润湿的浓度均一化微流控芯片，本发明另一目的在于提供利用该微流控芯片进行浓度均一化的方法，达到解决当前手工移液受限于人员操作熟练度，以及移液器固有偏差而导致的移液偏差大、准确度和效率低的问题。The purpose of the present invention is to provide a microfluidic chip for uniform concentration based on electrowetting. Another purpose of the present invention is to provide a method for using the microfluidic chip to uniformize the concentration, so as to solve the problem that the current manual pipetting is limited by personnel. Operating proficiency, as well as the problems of large pipetting deviation, low accuracy and low efficiency caused by the inherent deviation of the pipette.

为实现上述目的，本发明采取下述技术方案：To achieve the above object, the present invention takes the following technical solutions:

本发明所述基于电润湿的浓度均一化微流控芯片，包括设置有微通道的微流控芯片本体，所述微通道用于采用电润湿移液技术输送其内的液体沿微通道移动，所述微流控芯片本体还设置有样本区、试剂储存区、稀释区、浓度定量区、精确取样区和均一化区；所述样本区、试剂储存区、稀释区、浓度定量区、精确取样区和均一化区通过微通道互通；其中：The electrowetting-based concentration uniform microfluidic chip of the present invention includes a microfluidic chip body provided with a microchannel, and the microchannel is used to transport the liquid in it along the microchannel by using electrowetting liquid transfer technology. Moving, the microfluidic chip body is also provided with a sample area, a reagent storage area, a dilution area, a concentration quantification area, an accurate sampling area and a homogenization area; the sample area, reagent storage area, dilution area, concentration quantification area, The precise sampling area and the homogenization area communicate through microchannels; where:

样本区，用于储存原始样本；The sample area is used to store the original sample;

试剂储存区，用于存储试剂，所述试剂用于按照设定的梯度稀释所述原始样本；The reagent storage area is used to store reagents, and the reagents are used to dilute the original sample according to the set gradient;

稀释区，用于将通过微通道进入本区的所述试剂和原始样本进行混匀 制备成稀释样本；The dilution zone is used to mix the reagent and the original sample entering this zone through the microchannel to prepare a diluted sample;

浓度定量区，用于对通过微通道进入本区的所述稀释样本进行浓度测定；The concentration quantification area is used for concentration determination of the diluted sample entering this area through the microchannel;

精确取样区，用于按照设定的体积，获取原始样本或/和稀释样本；Accurate sampling area, used to obtain the original sample or/and diluted sample according to the set volume;

均一化区，根据设定的浓度均一化所需的总体积和浓度，并根据检测或计算得到的原始样本和稀释样本的浓度，选择合适的原始样本或稀释样本作为母液，并计算浓度均一化所需的母液体积，采用电润湿移液技术移取设定体积的母液至本区，完成浓度均一化。In the homogenization area, the total volume and concentration required for homogenization according to the set concentration, and according to the detected or calculated concentration of the original sample and the diluted sample, select the appropriate original sample or diluted sample as the mother solution, and calculate the concentration for normalization For the required volume of mother liquor, use electrowetting pipetting technology to pipette a set volume of mother liquor to this area to complete concentration homogenization.

优选地，所述微流控芯片本体包括上、下间隔设置的上基板和下基板，所述上、下两基板之间形成液体移动的所述微通道；上基板结构自上至下依次为上绝缘基板、公共电极、上疏水层；下基板结构自下至上依次为下绝缘基板、驱动电极阵列、介质层、下疏水层。Preferably, the microfluidic chip body includes an upper substrate and a lower substrate arranged at an interval between the upper and lower substrates, the microchannel through which the liquid moves is formed between the upper and lower substrates; the structure of the upper substrate from top to bottom is The upper insulating substrate, the common electrode, and the upper hydrophobic layer; the structure of the lower substrate is, from bottom to top, the lower insulating substrate, the driving electrode array, the dielectric layer, and the lower hydrophobic layer.

本发明所述浓度均一化微流控芯片的浓度均一化方法，包括下述步骤：The concentration uniformization method of the concentration uniformization microfluidic chip of the present invention comprises the following steps:

步骤1，将多个原始样本分别加入至各自的样本区；Step 1, adding multiple original samples to respective sample areas;

步骤2，将试剂加入至试剂储存区；Step 2, adding the reagent to the reagent storage area;

步骤3，采用电润湿移液技术，按照设定的体积将试剂分别移动至每个稀释区，并按照设定的体积通过所述微通道将各原始样本分别移动至各自的稀释区，混匀制备成稀释样本，并依次完成设定的梯度稀释；Step 3, using electrowetting pipetting technology, moving the reagents to each dilution area according to the set volume, and moving each original sample to the respective dilution area through the microchannel according to the set volume, mixing Prepare diluted samples evenly, and complete the set gradient dilution in sequence;

步骤4，采用电润湿移液技术，分别依次操控各稀释区内的所述稀释样本，按照设定的体积移动至浓度定量区进行电化学或荧光检测，根据测试结果直接得到或计算出最终的稀释样本的浓度，并根据各稀释区的稀释样本的稀释倍数，计算出对应的稀释样本和原始样本的浓度；Step 4, using electrowetting pipetting technology, sequentially manipulate the diluted samples in each dilution area, move to the concentration quantification area according to the set volume for electrochemical or fluorescence detection, and directly obtain or calculate the final sample according to the test results. The concentration of the diluted sample, and according to the dilution factor of the diluted sample in each dilution area, calculate the concentration of the corresponding diluted sample and the original sample;

步骤5，根据均一化所需的总体积及浓度，选择合适浓度的原始样本或稀释样本作为母液，并计算所需母液体积；Step 5, according to the total volume and concentration required for homogenization, select the original sample or diluted sample of appropriate concentration as the mother liquor, and calculate the required mother liquor volume;

步骤6，采用电润湿移液技术，通过精确取样区，从各母液中精确分 离出所需的体积，并移动至均一化区进行混匀，完成浓度均一化。Step 6: Use electrowetting pipetting technology to accurately separate the required volume from each mother liquor through the precise sampling area, and move to the homogenization area for mixing to complete the concentration homogenization.

本发明方法操作简单、自动化程度高，减少了人为操作误差，且均一化过程在1小时内即可完成，节省了时间，大大提高了检测效率。采用电润湿移液技术实现精确移液，体积偏差小于3％，解决了传统移液因操作人员的熟练度或移液器的固有偏差引起的移液结果不准确问题。The method of the invention has simple operation and high degree of automation, reduces human operation errors, and the homogenization process can be completed within one hour, which saves time and greatly improves detection efficiency. Electrowetting pipetting technology is used to achieve precise pipetting, and the volume deviation is less than 3%, which solves the problem of inaccurate pipetting results caused by the proficiency of the operator or the inherent deviation of the pipette in traditional pipetting.

附图说明Description of drawings

图1是本发明所述微流控芯片本体的结构示意图。Fig. 1 is a schematic structural view of the microfluidic chip body of the present invention.

图2是本发明所述样本区、试剂储存区、稀释区、浓度定量区、精确取样区、均一化区和微通道的布置示意图。Fig. 2 is a schematic diagram of the layout of the sample area, reagent storage area, dilution area, concentration quantification area, precise sampling area, homogenization area and microchannels of the present invention.

具体实施方式Detailed ways

下面结合附图对本发明的实施例作详细说明，本实施例在以本发明技术方案为前提下进行实施，给出了详细的实施方式和具体的操作过程，但本发明的保护范围不限于下述实施例。The embodiments of the present invention will be described in detail below in conjunction with the accompanying drawings. This embodiment is implemented on the premise of the technical solution of the present invention, and detailed implementation methods and specific operating procedures are provided, but the scope of protection of the present invention is not limited to the following Described embodiment.

如图1所示，本发明所述基于电润湿的浓度均一化微流控芯片，包括设置有微通道1的微流控芯片本体，微通道1用于采用电润湿移液技术输送其内的液滴2沿微通道1移动。As shown in Figure 1, the electrowetting-based concentration uniform microfluidic chip of the present invention includes a microfluidic chip body provided with a microchannel 1, and the microchannel 1 is used to transport its The droplet 2 inside moves along the microchannel 1.

微流控芯片本体包括上、下间隔设置的上基板和下基板，上、下两基板之间形成液滴2移动的微通道1；上基板结构自上至下依次为上绝缘基板3、公共电极4、上疏水层5；下基板结构自下至上依次为下绝缘基板6、驱动电极阵列7、介质层8、下疏水层9。The body of the microfluidic chip includes an upper substrate and a lower substrate arranged at intervals between the upper and lower substrates, and a microchannel 1 through which droplets 2 move is formed between the upper and lower substrates; the structure of the upper substrate is an upper insulating substrate 3, a common The electrode 4, the upper hydrophobic layer 5; the lower substrate structure is the lower insulating substrate 6, the driving electrode array 7, the dielectric layer 8, and the lower hydrophobic layer 9 from bottom to top.

微流控芯片本体还设置有样本区、试剂储存区、稀释区、浓度定量区、精确取样区和均一化区；样本区、试剂储存区、稀释区、浓度定量区、精确取样区和均一化区通过微通道1互通；其中：The microfluidic chip body is also provided with a sample area, a reagent storage area, a dilution area, a concentration quantification area, an accurate sampling area and a homogenization area; a sample area, a reagent storage area, a dilution area, a concentration quantification area, an accurate sampling area and a homogenization area Areas communicate through microchannel 1; where:

如图2所示，样本区，用于储存原始样本；本实施例设置四个样本区 10.1、10.2、10.3、10.4；As shown in Figure 2, the sample area is used to store the original sample; the present embodiment sets four sample areas 10.1, 10.2, 10.3, 10.4;

试剂储存区11，用于存储试剂，试剂用于按照设定的梯度稀释原始样本；The reagent storage area 11 is used for storing reagents, and the reagents are used to dilute the original sample according to the set gradient;

稀释区，用于将通过微通道1进入本区的试剂和原始样本进行混匀制备成稀释样本；本实施例以二梯度稀释为例，每个样本区分别对应两个稀释区，即：第一稀释区12.1、第二稀释区12.2；当然，根据需要，也可选择三梯度稀释或更多的梯度稀释；The dilution area is used to mix the reagent and the original sample entering this area through the microchannel 1 to prepare a diluted sample; this embodiment takes two gradient dilutions as an example, and each sample area corresponds to two dilution areas, namely: the first The first dilution zone 12.1 and the second dilution zone 12.2; of course, three gradient dilutions or more gradient dilutions can also be selected according to needs;

浓度定量区13，用于将通过微通道1进入本区的稀释样本，采用电化学或荧光检测方法进行浓度测定；The concentration quantification area 13 is used to measure the concentration of the diluted sample entering this area through the microchannel 1 by electrochemical or fluorescence detection method;

精确取样区14，用于按照设定的体积，获取原始样本或/和稀释样本；The precise sampling area 14 is used to obtain the original sample or/and the diluted sample according to the set volume;

均一化区15，根据设定的浓度均一化所需的总体积和浓度，并根据检测或计算得到的原始样本和稀释样本的浓度，选择合适的原始样本或稀释样本作为母液，并计算浓度均一化所需的母液体积，采用电润湿移液技术移取设定体积的母液至本区，完成浓度均一化。Homogenization zone 15, the total volume and concentration required for homogenization according to the set concentration, and according to the detected or calculated concentration of the original sample and the diluted sample, select the appropriate original sample or diluted sample as the mother solution, and calculate the concentration uniformity Use electrowetting pipetting technology to pipette the set volume of mother liquor to this area to complete the concentration homogenization.

本发明浓度均一化微流控芯片的浓度均一化方法，包括下述步骤：The concentration uniformization method of the concentration uniform microfluidic chip of the present invention comprises the following steps:

步骤1，将四个原始样本分别预先加入到样本区10.1、10.2、10.3、10.4；Step 1, adding four original samples to the sample areas 10.1, 10.2, 10.3, and 10.4 in advance;

步骤2，将试剂预先加入至试剂储存区11；Step 2, adding the reagent to the reagent storage area 11 in advance;

步骤3，采用电润湿移液技术，操控各样本区10.1、10.2、10.3、10.4内的原始样本，按照设定的体积通过微通道1分别移动至各自的第一稀释区12.1，并按照设定的体积将试剂分别移动至第一稀释区12.1，混匀制备成第一稀释样本；然后，采用电润湿移液技术，按照设定的体积通过微通道1操控第一稀释样本移动至第二稀释区12.2，并按照设定的体积将试剂移动至第二稀释区12.2，混匀制备成第二稀释样本，完成各原始样本的二梯度稀释；Step 3, use electrowetting pipetting technology to manipulate the original samples in each sample area 10.1, 10.2, 10.3, and 10.4, move them to the respective first dilution areas 12.1 through the microchannel 1 according to the set volume, and then move them to the respective first dilution areas 12.1 according to the set volume. The reagents are moved to the first dilution area 12.1 with a predetermined volume, and mixed to prepare the first diluted sample; then, the electrowetting pipetting technology is used to control the first diluted sample to move to the second diluted sample through the microchannel 1 according to the set volume. The second dilution area 12.2, and move the reagent to the second dilution area 12.2 according to the set volume, mix and prepare the second dilution sample, and complete the second gradient dilution of each original sample;

步骤4，采用电润湿移液技术，分别依次操控各第二稀释区12.2内的第二稀释样本，按照设定的体积移动至浓度定量区13进行电化学或荧光检 测，根据测试结果直接得到或计算出第二稀释样本的浓度，并根据各第二稀释区的第二稀释样本的稀释倍数，计算出对应的第一稀释样本和原始样本的浓度；Step 4, using electrowetting pipetting technology, sequentially manipulate the second diluted samples in each second dilution zone 12.2, move to the concentration quantification zone 13 according to the set volume for electrochemical or fluorescence detection, and directly obtain or calculate the concentration of the second diluted sample, and calculate the corresponding concentration of the first diluted sample and the original sample according to the dilution factor of the second diluted sample in each second dilution zone;

步骤5，根据均一化所需的总体积及浓度，选择合适浓度的原始样本或稀释样本作为母液，并计算所需母液体积；Step 5, according to the total volume and concentration required for homogenization, select the original sample or diluted sample of appropriate concentration as the mother liquor, and calculate the required mother liquor volume;

步骤6，采用电润湿移液技术，通过精确取样区14，从各母液中精确分离出所需的体积，并移动至均一化区15进行混匀，完成浓度均一化。Step 6, using electrowetting pipetting technology, through the precise sampling area 14, accurately separate the required volume from each mother liquor, and move to the homogenization area 15 for mixing to complete the concentration homogenization.

Claims (3)

一种基于电润湿的浓度均一化微流控芯片，包括设置有微通道的微流控芯片本体，所述微通道用于采用电润湿移液技术输送其内的液体沿微通道移动，其特征是，所述微流控芯片本体还设置有样本区、试剂储存区、稀释区、浓度定量区、精确取样区和均一化区；所述样本区、试剂储存区、稀释区、浓度定量区、精确取样区和均一化区通过微通道互通；其中：A microfluidic chip for uniform concentration based on electrowetting, comprising a microfluidic chip body provided with a microchannel, the microchannel is used to transport the liquid in it to move along the microchannel by using electrowetting liquid transfer technology, It is characterized in that the microfluidic chip body is also provided with a sample area, a reagent storage area, a dilution area, a concentration quantification area, an accurate sampling area and a homogenization area; the sample area, reagent storage area, dilution area, concentration quantification The area, the precise sampling area and the homogenization area communicate with each other through microchannels; where: 样本区，用于储存原始样本；The sample area is used to store the original sample; 试剂储存区，用于存储试剂，所述试剂用于按照设定的梯度稀释所述原始样本；The reagent storage area is used to store reagents, and the reagents are used to dilute the original sample according to the set gradient; 稀释区，用于将通过微通道进入本区的所述试剂和原始样本进行混匀制备成稀释样本；The dilution area is used to mix the reagent and the original sample entering this area through the microchannel to prepare a diluted sample; 浓度定量区，用于对通过微通道进入本区的所述稀释样本进行浓度测定；The concentration quantification area is used for concentration determination of the diluted sample entering this area through the microchannel; 精确取样区，用于按照设定的体积，获取原始样本或/和稀释样本；Accurate sampling area, used to obtain the original sample or/and diluted sample according to the set volume; 均一化区，根据设定的浓度均一化所需的总体积和浓度，并根据检测或计算得到的原始样本和稀释样本的浓度，选择原始样本或稀释样本作为母液，并计算浓度均一化所需的母液体积，采用电润湿移液技术移取设定体积的母液至本区，完成浓度均一化。In the homogenization area, the total volume and concentration required for homogenization according to the set concentration, and according to the detected or calculated concentration of the original sample and the diluted sample, select the original sample or the diluted sample as the mother solution, and calculate the concentration required for homogenization. The volume of the mother liquor is transferred to this area by electrowetting pipetting technology to complete the concentration homogenization. 根据权利要求1所述基于电润湿的浓度均一化微流控芯片，其特征是，所述微流控芯片本体包括上、下间隔设置的上基板和下基板，所述上、下两基板之间形成液体移动的所述微通道；上基板结构自上至下依次为上绝缘基板、公共电极、上疏水层；下基板结构自下至上依次为下绝缘基板、驱动电极阵列、介质层、下疏水层。According to the microfluidic chip with uniform concentration based on electrowetting according to claim 1, it is characterized in that, the microfluidic chip body includes an upper substrate and a lower substrate arranged at intervals above and below, and the upper and lower substrates are The microchannel through which the liquid moves is formed between them; the structure of the upper substrate is an upper insulating substrate, a common electrode, and an upper hydrophobic layer from top to bottom; the structure of the lower substrate is a lower insulating substrate, a drive electrode array, a dielectric layer, and Lower hydrophobic layer. 根据权利要求1所述浓度均一化微流控芯片的浓度均一化方法，其特征是，包括下述步骤：According to the concentration uniformization method of the concentration uniformization microfluidic chip described in claim 1, it is characterized in that, comprising the following steps: 步骤1，将多个原始样本分别加入至各自的样本区；Step 1, adding multiple original samples to respective sample areas; 步骤2，将试剂加入至试剂储存区；Step 2, adding the reagent to the reagent storage area; 步骤3，采用电润湿移液技术，按照设定的体积将试剂分别移动至每个稀释区，并按照设定的体积通过所述微通道将各原始样本分别移动至各自的稀释区，混匀制备成稀释样本，并依次完成设定的梯度稀释；Step 3, using electrowetting pipetting technology, moving the reagents to each dilution area according to the set volume, and moving each original sample to the respective dilution area through the microchannel according to the set volume, mixing Prepare diluted samples evenly, and complete the set gradient dilution in sequence; 步骤4，采用电润湿移液技术，分别依次操控各稀释区内的所述稀释样本，按照设定的体积移动至浓度定量区进行浓度检测，根据测试结果直接得到或计算出的稀释样本的浓度，并根据各稀释区的稀释样本的稀释倍数，计算出对应的稀释样本和原始样本的浓度；Step 4, using electrowetting pipetting technology, sequentially manipulate the diluted samples in each dilution area, move to the concentration quantitative area according to the set volume for concentration detection, and directly obtain or calculate the concentration of the diluted sample according to the test results Concentration, and according to the dilution factor of the diluted sample in each dilution area, calculate the concentration of the corresponding diluted sample and the original sample; 步骤5，根据均一化所需的总体积及浓度，选择原始样本或稀释样本作为母液，并计算所需母液体积；Step 5, according to the total volume and concentration required for homogenization, select the original sample or diluted sample as the mother solution, and calculate the required mother solution volume; 步骤6，采用电润湿移液技术，通过精确取样区，从各母液中精确分离出所需的体积，并移动至均一化区进行混匀，完成浓度均一化。Step 6: Use electrowetting pipetting technology to accurately separate the required volume from each mother liquor through the precise sampling area, and move to the homogenization area for mixing to complete the concentration homogenization.
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