WO2021208872A1 - 基于电流体动力学的微流控芯片、微量点样装置及方法 - Google Patents

基于电流体动力学的微流控芯片、微量点样装置及方法 Download PDF

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WO2021208872A1
WO2021208872A1 PCT/CN2021/086739 CN2021086739W WO2021208872A1 WO 2021208872 A1 WO2021208872 A1 WO 2021208872A1 CN 2021086739 W CN2021086739 W CN 2021086739W WO 2021208872 A1 WO2021208872 A1 WO 2021208872A1
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capillary
voltage
microfluidic chip
channel
electrohydrodynamics
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PCT/CN2021/086739
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English (en)
French (fr)
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马波
刁志钿
葛安乐
徐健
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中国科学院青岛生物能源与过程研究所
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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
    • B01L3/02—Burettes; Pipettes
    • B01L3/0241—Drop counters; Drop formers
    • 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
    • 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
    • B01L3/02—Burettes; Pipettes
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/65—Raman scattering

Definitions

  • the invention belongs to the field of microfluidic chips, and specifically relates to a microfluidic chip, a micro-spotting device and a method based on electrohydrodynamics.
  • the droplet generation technology is an important branch of the microfluidic chip technology.
  • the droplet-based microfluidic chip technology is compatible with numerous chemical and biological reagents and "electronic control", and has good programmability and constructability.
  • the microfluidic chip droplet generation platform can accurately control and quickly mix the samples in the droplets, thereby reducing the reaction time.
  • the microfluidic chip droplet technology can precisely control the occurrence and manipulation of droplets, and produce uniform monodisperse droplets, it has become a high-throughput platform for biomedical and chemical research.
  • the droplets produced are nL and pL in size, and can be used as a reactor to directly synthesize particles or to carry reagents in the field of biomedicine.
  • the droplet-based microfluidic technology has great potential in drug transportation and biosensing. In recent years, it has become more and more widely used. Its advantages are: low reagent consumption, and each microdroplet can be used as an independent microfluidic.
  • the reaction vessel is used for various biochemical reactions, which can be controlled independently, and the huge specific surface area of the droplets has a catalytic effect on many reactions.
  • Electrohydrodynamic jet printing is proposed and developed by JUPark 1 and others based on electrohydrodynamic dynamics (EHD) micro-droplet jet forming deposition technology.
  • the basic principle is that the conductive nozzle (first electrode) and the conductive substrate (second electrode) A high voltage of several thousand to several tens of thousands of volts is applied between ), and a strong electric field is formed between the two.
  • the droplet at the nozzle tip will be polarized and form a positive charge accumulation on the surface; due to Coulomb With the existence of repulsive force, the charged droplets are gradually elongated to form a Taylor cone; when the electric field force on the nozzle tip of the droplet exceeds the surface tension of the liquid, the tiny positively charged droplets are ejected from the top of the Taylor cone, forming a diameter larger than the nozzle size
  • a very thin cone jet with a size of 1 to 2 orders of magnitude; combined with the control of the motion platform, the precise deposition of droplets on the substrate is realized.
  • the electrofluidic jet printing technology was originally applied in the material field. After development, the current electrofluidic jet printing technology has also been applied to the biological field, and it is partially coupled with the microfluidic chip, but the technology currently exists. It requires sophisticated support and alignment equipment, precision-sized printing nozzles, and cumbersome conductive electrodes. Therefore, complex and sophisticated equipment is required to support this technology. Therefore, most laboratories do not have the basis for this research.
  • the present invention provides a microfluidic chip and micro-spotting device based on electrohydrodynamics (EHD).
  • EHD electrohydrodynamics
  • one aspect of the present invention provides a microfluidic chip based on electrohydrodynamics, the chip comprising:
  • At least one capillary tube having an inlet end and an outlet end;
  • a chip body comprising at least one injection port, a micro flow channel connected to the injection port, a capillary embedding channel connected to the micro flow channel, the capillary embedding channel having an outlet end, and the capillary is placed in the capillary embedding channel
  • the inside is connected to the micro-channel, and the length of the capillary is greater than the length of the capillary embedded channel;
  • the upper electrode, the upper electrode is located on the chip body, close to the capillary;
  • the lower electrode, the lower electrode has an insulating support, and the lower electrode is located below the capillary outlet.
  • outlet end of the capillary insertion channel is glued to the outer wall of the capillary.
  • the material of the chip body is glass or high molecular polymer.
  • the material of the chip body is silicate glass, quartz glass, calcium fluoride glass, PDMS (polydimethylsiloxane) or PMMA (polymethylmethacrylate), preferably , Is PDMS.
  • the material of the insulating support is glass or high molecular polymer.
  • the material of the insulating support is silicate glass, quartz glass, calcium fluoride glass, PDMS (polydimethylsiloxane) or PMMA (polymethylmethacrylate), preferably ⁇ , ⁇ PDMS.
  • the chip body and the insulating support of the lower electrode are made of the same material.
  • the chip body and the insulating support of the lower electrode are integrally formed.
  • the chip body and the insulating support of the lower electrode are made of different materials.
  • the chip body and the insulating substrate are separable.
  • the diameter of the capillary embedded channel is larger than the diameter of the microfluidic channel.
  • the inner diameter of the capillary tube is greater than or equal to the diameter of the micro flow channel.
  • the inner diameter of the capillary tube is 50-700um, preferably 100um.
  • the length of the capillary tube is 5-10 mm, preferably 6 mm.
  • the length of the capillary tube is 1-5 mm longer than the capillary insertion channel, preferably 2 mm.
  • the height of the microfluidic chip channel is 10-5000um, preferably 120um.
  • the material used as the upper and lower electrodes is liquid metal or salt water or solder, preferably liquid metal.
  • the electrode has an axisymmetric shape, and the axis of symmetry is a straight line where the capillary is located.
  • the distance between the upper and lower electrodes is 4-10 mm, preferably 5 mm.
  • the distance between the two parts of the lower electrode is 3-10 mm, preferably 6 mm.
  • the chip includes at least one water phase injection port and at least one oil phase injection port.
  • the chip also includes an optical fiber channel, which is used for embedding the optical fiber, and preferably, the optical fiber channel is located under the upper electrode.
  • the electrode is connected to an external high-voltage power supply.
  • the chip can be used for spotting biological materials and material samples.
  • Biological samples include: plant flowers, leaves, stems, roots, seeds, etc., animal (including human) body fluids (such as urine, blood, saliva, bile, gastric juice, lymph fluid and other secretions of organisms, etc.), hair, Muscles and some tissues and organs (such as thymus, pancreas, liver, lung, brain, stomach, kidney, etc.) and various microorganisms.
  • animal body fluids such as urine, blood, saliva, bile, gastric juice, lymph fluid and other secretions of organisms, etc.
  • hair such as thymus, pancreas, liver, lung, brain, stomach, kidney, etc.
  • tissues and organs such as thymus, pancreas, liver, lung, brain, stomach, kidney, etc.
  • Material samples include: metallic materials, inorganic non-metallic materials, polymer materials and composite materials.
  • micro-spotting device based on electrohydrodynamics, including:
  • a microfluidic chip the microfluidic chip has at least two sample inlets and is provided with two opposing optical fiber channels;
  • Laser transmitter emitting visible light wave band laser
  • Laser detectors are used to detect light signals and convert the light signals into electrical signals
  • optical fibers Two optical fibers, the optical fibers are embedded in the optical fiber channel, one of the optical fibers is connected to the laser transmitter, and the other optical fiber is connected to the laser detector;
  • Relay used to control the switch of the circuit
  • a high-voltage direct current power supply, the two poles of the high-voltage direct current power supply are respectively connected with the upper electrode and the lower electrode of the microfluidic chip;
  • Data acquisition card used to collect and transmit the signal detected by the laser detector and transmit it to the computer, and to control the output voltage or current of the high-voltage DC power supply;
  • the computer is connected with the data acquisition card and the mobile platform, and realizes the reading of the laser signal, the control of the movement of the mobile platform and the switching of the high-voltage DC power supply circuit through the program.
  • the laser detector is a photodiode or a photomultiplier tube.
  • Another aspect of the present invention provides a micro-spotting method based on electrohydrodynamics, including:
  • the microfluidic chip has two injection ports, one of the injection ports is fed with a mixed liquid of oil and microbial droplets, and the other is fed with a pure oil phase.
  • the mixed liquid is under the action of the oil phase,
  • the interval between the microbial droplets and the microbial droplets is increased, so that the microbial droplets enter the capillary from the micro-channel;
  • the laser emitter emits laser light through the capillary through the optical fiber, and is transmitted to the laser detector through the optical fiber, and then passes through the data acquisition card Transmit this signal to the computer; when the droplet passes through the capillary tube, it will cause a change in the light signal, so that the signal data displayed by the computer program can determine that a droplet passes.
  • the program controls the data acquisition card to output the set voltage.
  • a relay is used to turn on the circuit of the high-voltage direct current power supply, so that the high-voltage direct current power supply applies a voltage on the upper electrode and the lower electrode of the microfluidic chip to make the microbial droplets drip out.
  • the microbial droplets are a microbial sample solution collected in the environment, a cultured microbial solution, or a mixed solution of multiple microorganisms.
  • the separation distance between the microbial droplets and the microbial droplets is adjusted by adjusting the flow rates of the two injection ports.
  • the flow rate is controlled by a constant flow injection pump or a constant pressure injection device.
  • the oil phase is one or more of fluorocarbon oil, mineral oil, silicone oil, vegetable oil, and petroleum ether.
  • microfluidic chip based on electrohydrodynamics (EHD).
  • EHD electrohydrodynamics
  • the capillary is embedded in the microfluidic chip, which has an accurate fixing effect and simplifies the structure; it uses electrohydrodynamics to drive the capillary to apply high pressure to the emulsion Droplets exert a controllable force to form a double emulsion (water/oil/air droplets); the microfluidic chip can be reused, and can realize large-scale production and reduce operating costs; it is easy and safe to use and operate, and non-professionals can also be skilled operate.
  • microfluidic chip and the micro-spotting device formed by coupling simple external devices can realize the automatic spotting of microbial droplets.
  • the device is simple, safe and easy to operate, which greatly reduces the technical threshold of microbial spotting.
  • Figure 1 is a schematic diagram of the structure of a microfluidic chip with two injection ports
  • Figure 2 is a schematic diagram of the structure of a microfluidic chip with a sample inlet
  • Figure 3 is a schematic diagram of other alternatives of the microfluidic chip structure
  • Figure 4 is a schematic diagram of the structure of the microbial spotting device.
  • 1 Microfluidic chip; 1-1: Upper electrode; 1-2: Injection port; 1-2-1: Oil phase injection port; 1-2-2: Water phase injection port; 1-3: Fiber Channel 1-4: Capillary; 1-5: Lower Electrode; 1-6: Chip Body; 1-7: Micro Channel; 2: Laser Transmitter; 3: Laser Detector; 4: Data Acquisition Card; 5: Relay; 6: High-voltage DC power supply; 7: Computer; 8: Mobile platform.
  • the structure of the prepared microfluidic chip is shown in FIG. 1, and the chip is an integrated structure.
  • FIG. 1 Use CAD to design the channel structure of the microfluidic chip as shown in Figure 1, including microchannels 1-7, capillary embedded channels at the exit of the microchannels, fiber channels 1-3, and electrode channels, and perform film masking. Film printing. The cleaned silicon wafer is dripped with SU-8 photoresist and the thickness is about 120um. Afterwards, it is covered with a mask, exposed in an exposure machine, and the uncured part is cleaned with a developer to obtain a silicon wafer template.
  • 2Mix PDMS monomer and curing agent in a certain proportion to obtain PDMS polymer.
  • the lower-layer bonded chip is a PDMS smooth substrate with a thickness of 1-10 mm and no etching pattern.
  • Plasma bonding is performed on the upper and lower layers of the chips, and they are placed at 70°C overnight to restore the hydrophobicity of the chips. Cut according to the contour lines of the designed chip body 1-6, and the final structure is shown in Figure 1.
  • the length of the capillary is 6mm
  • the outer diameter is about 360um
  • the inner diameter is 100um.
  • the body of the microfluidic chip and the insulating support of the lower electrode are integrated.
  • the chip body and the insulating support of the lower electrode can also be made into a separate structure.
  • the number of injection ports in the chip, the arrangement structure, and the electrode structure can be adjusted according to requirements.
  • Figures 2 and 3 show other variable structures of the chip. The scope of protection of the present invention is not limited to the above structures.
  • a microbial spotting device based on electrohydrodynamics includes: a microfluidic chip 1, the microfluidic chip has at least two injection ports, and is provided with two opposing optical fibers aisle;
  • Laser transmitter 2 emitting visible light waveband laser
  • the laser detector 3 is used to detect light signals and convert the light signals into electrical signals; the laser detector includes but is not limited to a photodiode or a photomultiplier tube;
  • optical fibers Two optical fibers, the optical fibers are embedded in the optical fiber channel, one of the optical fibers is connected to the laser transmitter, and the other optical fiber is connected to the laser detector;
  • Relay 5 used to control the switch of the circuit
  • a high-voltage direct current power supply 6 the two poles of the high-voltage direct current power supply are respectively connected to the upper electrode and the lower electrode of the microfluidic chip;
  • the data acquisition card 4 is used to collect and transmit the signal detected by the laser detector and transmit it to the computer, and to control the output voltage or current of the high-voltage DC power supply;
  • the mobile platform 8 is used to place the receiving container
  • the computer 7 which is connected with the data acquisition card and the mobile platform, realizes the reading of the laser signal, the control of the movement of the mobile platform, and the switching of the high-voltage DC power supply circuit through the program.
  • the chip structure is the chip structure prepared in Example 1 ( Figure 1) as an example:
  • the size of the droplets is 10um-100um, preferably 80um. Collect them into EP tubes and place them in an incubator for a period of time to make the target Microorganisms multiply in large numbers and are full of droplets.
  • the use of a label-free growth phenotype droplet sorting system based on scattered light can sort the cultured droplets, and the droplets full of target microorganisms can be sorted out and collected in a one-ml centrifuge tube.
  • a microfluidic chip based on electro-hydraulic droplet jet printing is used to separate the collected droplets.
  • the specific operations are as follows:
  • the main principle for adjusting the size of the spotted droplets is: only the spotted droplets A cultured droplet;
  • the laser transmitter 2 emits laser light through the capillary through the optical fiber, and transmits it to the laser detector 3 through the optical fiber, and then transmits this signal to the computer 7 through the data acquisition card 4.
  • the program controls the data acquisition card 4 to output the set voltage, and the relay 5 is used to turn the high voltage
  • the circuit of the DC power supply 6 is turned on, so that the high-voltage DC power supply 6 applies a voltage on the upper electrode 1-1 and the lower electrode 1-5 of the microfluidic chip to cause the droplets to drip out.
  • the program controls the movement of the mobile platform 8 so that the droplet accurately drops into the set position on the MALDI board.
  • the chip will not be used again for a short time, after removing the chip, rinse the liquid channel with absolute ethanol, put it in an oven to dry it, and then recycle it.
  • the structure of the microfluidic chip used in this embodiment is shown in FIG. 2:
  • the chip is an integrated structure, and the chip has only one injection port 1-2, and no fiber channel is required.
  • 3Fix the above-mentioned chip with a simple fixing device Place a two-dimensional mobile platform 8 below the chip. On the two-dimensional mobile platform 8, place a solid medium or a 96-well culture plate with liquid medium, and place next to the two-dimensional mobile platform. An ignited alcohol lamp to create a sterile environment;
  • the culture medium is placed in an incubator, the chip is washed with absolute ethanol in the liquid channel, and then dried for recycling.
  • the size of the droplets is 10um-100um, preferably 80um. Collect them into EP tubes and place them in an incubator for a period of time to make the target Microorganisms multiply in large numbers and are full of droplets.
  • the use of a label-free growth phenotype droplet sorting system based on scattered light can sort the cultured droplets, and the droplets full of target microorganisms can be sorted out and collected.
  • a microfluidic chip based on electro-hydraulic droplet jet printing is used to separate the collected droplets.
  • the specific operations are as follows:
  • the laser transmitter 2 emits laser light through the capillary through the optical fiber, and transmits it to the laser detector 3 through the optical fiber, and then transmits this signal to the computer 7 through the data acquisition card 4.
  • the program controls the data acquisition card to output the set voltage, and the relay 5 is used to turn the high voltage DC
  • the circuit of the power supply 6 is turned on, so that the high-voltage direct current power supply 6 applies voltage on the upper electrode 1-1 and the lower electrode 1-5 of the microfluidic chip to cause the droplets to drip out.
  • the program controls the movement of the mobile platform 8 to accurately drop the liquid drop into the hole at the set position of the 96-well plate.
  • the LABVIEW program is used to realize the coupling control of droplet signal recognition-high voltage power on-movement of the mobile platform, so that each droplet can be accurately dropped into the well of the 96-well plate.
  • the bacterial liquid in the EP tube is sequenced, and various information of the target microorganism can be obtained through the sequencing.
  • the Raman flow sorting system can perform Raman spectroscopy measurement on single cells, and perform droplet single wrapping of single cells, and judge whether it is a target cell by Raman spectroscopy, and if the target cell is sorted by dielectric, it contains the target cell Droplets.
  • a microfluidic chip based on electro-hydraulic droplet jet printing is used to separate the collected droplets.
  • the specific operations are as follows:
  • the laser transmitter 2 emits laser light through the capillary through the optical fiber, and transmits it to the laser detector 3 through the optical fiber, and then transmits this signal to the computer 7 through the data acquisition card 4.
  • the program controls the data acquisition card to output the set voltage, and the relay 5 is used to turn the high-voltage direct current
  • the circuit of the power supply 6 is turned on, so that the high-voltage direct current power supply 6 applies voltage on the upper electrode 1-1 and the lower electrode 1-5 of the microfluidic chip 1 to cause the droplets to drip out.
  • the program controls the movement of the mobile platform 8 so that the droplet accurately drops into the set position hole of the 96-well plate.
  • Single cell sequencing is performed on single cell droplets in 96-well plates, and the genetic information of the target single cell can be obtained through sequencing.

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Abstract

一种基于电流体动力学的微流控芯片（1），芯片（1）包括：至少一个毛细管（1-4），毛细管（1-4）具有入口端和出口端；芯片本体（1-6），芯片本体（1-6）包括至少一个进样口（1-2），以及与进样口（1-2）连接的微流道（1-7），与微流道（1-7）连接的毛细管（1-4）嵌入通道，毛细管（1-4）嵌入通道具有出口端，毛细管（1-4）的长度大于毛细管（1-4）嵌入通道的长度；上电极（1-1），上电极（1-1）位于芯片本体（1-6）上，靠近毛细管（1-4）的位置；下电极（1-5），下电极（1-5）具有绝缘支撑体，下电极（1-5）位于毛细管（1-4）出口下方。一种基于电流体动力学的微量点样装置及方法，装置包括：微流控芯片（1），微流控芯片（1）具有至少两个进样口（1-2-1、1-2-2），并设有相对的两个光纤通道（1-3）；激光发射器（2）；激光检测器（3）；两根光纤；继电器（5）；高压直流电源（6）；数据采集卡（4）；移动平台（8）；计算机（7）。

Description

基于电流体动力学的微流控芯片、微量点样装置及方法 技术领域
本发明属于微流控芯片领域，具体涉及一种基于电流体动力学的微流控芯片、微量点样装置及方法。
背景技术
液滴发生技术是微流控芯片技术的一个重要分支。基于液滴的微流控芯片技术能够与众多的化学和生物试剂和“电子控制”相互兼容，并且具有良好的可编程和构建性。微流控芯片液滴发生平台能够精确控制和快速混合液滴中的样品，从而减少了反应时间。鉴于微流控芯片液滴技术能够精确控制液滴的发生和操控，产生均一的单分散液滴，使其成为了生物医学及化学研究的高通量平台。所产生的液滴尺寸为nL和pL级的，可以用来作为反应器直接合成颗粒或者包载试剂应用于生物医学领域。
基于液滴的微流控技术在药物运输和生物传感等方面具有巨大潜能，近些年的应用越来越广泛，其优势表现为：试剂消耗低，每个微液滴可作为独立的微反应容器用于各种生化反应，可实现独立控制，并且液滴其巨大的比表面积对许多反应具有催化作用等。
电流体动力喷射打印是由J.U.Park 1等人提出和发展的基于电流体动力学(EHD)微液滴喷射成型沉积技术，基本原理是在导电喷嘴(第一电极)和导电衬底(第二电极)之间施加电压为几千至几万伏的高压电，两者之间形成强电场，在电场的作用下，喷嘴尖端液滴将被极化并在其表面形成正电荷聚集；由于库仑斥力的存在，带电液滴被逐渐拉长，形成泰勒锥；当喷嘴尖端液滴所受电场力超过液体表面张力时，带正电荷的微小液滴从泰勒锥顶部喷射出来，形成直径比喷嘴尺寸小1～2个数量级的极细锥射流；结合运动平台的控制，实现微滴在衬底上的精准沉积。
电流体动力喷射打印技术最初是应用于材料领域上的，经过发展，目前的电流体动力喷射打印技术也已应用于生物领域，且与微流控芯片有部分的耦合，但是目前该技术普遍存在需要精密复杂的支撑对准设备、尺寸精密的打印喷嘴、繁琐的导电电极，故需要复杂且精密的设备来支撑此技术，故大部分的 实验室不具备从事此研究的基础。
发明内容
为解决上述问题，本发明提供了一种基于电流体动力学(EHD)的微流控芯片和微量点样装置，将毛细管嵌入微流控芯片中，具有准确的固定效果，简化结构，可实现样品的全自动点样。
为实现上述目的，本发明一方面提供了一种基于电流体动力学的微流控芯片，所述芯片包括：
至少一个毛细管，所述毛细管具有入口端和出口端；
芯片本体，所述芯片本体包括至少一个进样口，以及与进样口连接的微流道，与微流道连接的毛细管嵌入通道，毛细管嵌入通道具有出口端，所述毛细管置于毛细管嵌入通道内部，与微流道连接，所述毛细管的长度大于毛细管嵌入通道的长度；
上电极，所述上电极位于芯片本体上，靠近毛细管的位置；
下电极，所述下电极具有绝缘支撑体，所述下电极位于毛细管出口下方。
在另一优选例中，所述毛细管嵌入通道的出口端与毛细管外壁胶接。
在另一优选例中，所述芯片本体的材质为玻璃或高分子聚合物。
在另一优选例中，所述芯片本体的材质为硅酸盐玻璃、石英玻璃、氟化钙玻璃、PDMS(聚二甲基硅氧烷)或PMMA(聚甲基丙烯酸甲酯)，优选地，为PDMS。
在另一优选例中，所述绝缘支撑体的材质为玻璃或高分子聚合物。
在另一优选例中，所述绝缘支撑体的材质为硅酸盐玻璃、石英玻璃、氟化钙玻璃、PDMS(聚二甲基硅氧烷)或PMMA(聚甲基丙烯酸甲酯)，优选地，为PDMS。
在另一优选例中，所述芯片本体与下电极的绝缘支撑体为同种材质。
在另一优选例中，芯片本体与下电极的绝缘支撑体为一体成型结构。
在另一优选例中，所述芯片本体与下电极的绝缘支撑体为不同种材质。
在另一优选例中，芯片本体与绝缘衬底可分离。
在另一优选例中，所述毛细管嵌入通道的直径大于微流道的直径。
在另一优选例中，所述毛细管的内径大于或等于微流道的直径。
在另一优选例中，所述毛细管的内径为50-700um，优选为100um。
在另一优选例中，所述毛细管的长度为5-10mm，优选为6mm。
在另一优选例中，所述毛细管长度比毛细管嵌入通道长1-5mm，优选为2mm。
在另一优选例中，所述微流控芯片通道的高度为10-5000um，优选为120um。
在另一优选例中，所述作为上下电极的材质为液态金属或盐水或焊锡，优选为液态金属。
在另一优选例中，所述电极为轴对称形状，对称轴为毛细管所在直线。
在另一优选例中，所述上下电极间隔距离为4-10mm，优选为5mm。
在另一优选例中，所述下电极两部分间隔距离为3-10mm，优选为6mm。
在另一优选例中，所述芯片包括至少一个水相进样口和至少一个油相进样口。
所述芯片还包括光纤通道，所述光纤通道用于光纤的嵌入，优选地，所述光纤通道位于上电极的下方。
在另一优选例中，所述电极外接高压电源。
在另一优选例中，所述芯片可以用于生物材料、材料样品点样。
生物样品包括：植物的花、叶、茎、根、种子等，动物(包括人)的体液(如尿、血、唾液、胆汁、胃液、淋巴液及生物体的其他分泌液等)、毛发、肌肉和一些组织器官(如胸腺、胰腺、肝、肺、脑、胃、肾等)以及各种微生物。
材料样品包括：金属材料、无机非金属材料、高分子材料和复合材料。
本发明又一方面提供了一种基于电流体动力学的微量点样装置，包括：
微流控芯片，所述微流控芯片具有至少两个进样口，并设有相对的两个光纤通道；
激光发射器，发射可见光波段激光；
激光检测器，用于检测光信号，并将光信号转化成电信号；
两根光纤，所述光纤嵌入光纤通道内，其中一根光纤与激光发射器相连，另一根光纤与激光检测器相连；
继电器，用于控制电路的开关；
高压直流电源，所述高压直流电源两极分别与微流控芯片上电极及下电极连接；
数据采集卡，用于采集和传输激光检测器检测的信号采集并传输到计算 机，以及控制高压直流电源输出电压或者电流；
移动平台，用于放置接收容器；
计算机，所述计算机与数据采集卡和移动平台相连，通过程序实现激光信号的读取、控制移动平台的移动和高压直流电源电路的开关。
在另一优选例中，所述激光检测器为光电二极管或光电倍增管。
本发明又一方面提供了一种基于电流体动力学的微量点样方法，包括：
所述微流控芯片具有两个进样口，其中一个进样口通入油与微生物液滴的混合液体，另一个进样口通入纯油相，所述混合液体在油相作用下，微生物液滴与微生物液滴之间的间隔加大，使微生物液滴由微流道进入毛细管；激光发射器发出激光通过光纤照射穿过毛细管，并通过光纤传递至激光检测器，通过数据采集卡将此信号传输至计算机；当液滴通过毛细管时，会引起光信号的改变，从而通过计算机程序显示的信号数据可以判断有一个液滴通过，此时程序控制数据采集卡输出设定的电压，利用继电器将高压直流电源的电路导通，使高压直流电源在微流控芯片上电极与下电极上施加电压，使微生物液滴滴出。通过调整施加电压的大小，可以控制滴出的液滴大小和滴出液滴的响应时间，实现单个液滴单个滴出；控制移动平台，使液滴准确滴入接收容器中。
在另一优选例中，所述微生物液滴为环境中采集的微生物样品溶液、培养过的微生物溶液或多种微生物的混合溶液。
在另一优选例中，所述微生物液滴与微生物液滴之间的间隔距离通过调整两个进样口的流速来调整。
在另一优选例中，所述流速通过恒流注射泵或恒压注射设备控制。
在另一优选例中，所述油相为氟碳油、矿物油、硅油、植物油、石油醚中的一种或多种。
本发明有益效果：
发明了基于电流体动力学(EHD)的微流控芯片，将毛细管嵌入微流控芯片中，具有准确的固定效果，简化结构；采用电流体动力学驱动，对毛细管施加高压，对乳化液液滴施加可控力，形成双乳化液(水/油/空气液滴)；微流控芯片可重复利用，并可实现规模化生产，降低操作成本；使用操作简便安全，非专业人员也可熟练操作。
微流控芯片以及耦合外部简单的器件所形成的微量点样装置可以实现微生物液滴的全自动点样，装置简便安全易操作，大大降低了微生物点样的技术门槛。
附图说明
在所属附图中，相同部分和特征具有相同的附图标记。许多附图为示意图，其比例可能不准确。
图1为具有两个进样口的微流控芯片结构示意图；
图2为具有一个进样口的微流控芯片结构示意图；
图3为微流控芯片结构其他替代方案的示意图；
图4为微生物点样装置的结构示意图。
具体附图标记如下：
1：微流控芯片；1-1：上电极；1-2：进样口；1-2-1：油相进样口；1-2-2：水相进样口；1-3：光纤通道1-4：毛细管；1-5：下电极；1-6：芯片本体；1-7：微流道；2：激光发射器；3：激光检测器；4：数据采集卡；5：继电器；6：高压直流电源；7：计算机；8：移动平台。
具体实施方式
为便于对本发明实施例的理解，下面将结合附图以几个具体实施例做进一步的解释说明，且各个实施例并不构成对本发明实施例的限定。此外，附图为示意图，因此本发明装置和设备并不受所述示意图的尺寸或比例限制。
需要说明的是，在本专利的权利要求和说明书中，术语“包括”、“包含”或者其任何其他变体意在涵盖非排他性的包含，从而使得包括一系列要素的过程、方法、物品或者设备不仅包括那些要素，而且还包括没有明确列出的其他要素，或者是还包括为这种过程、方法、物品或者设备所固有的要素。在没有更多限制的情况下，由语句“包括一个”限定的要素，并不排除在包括所述要素的过程、方法、物品或者设备中还存在另外的相同要素。
实施例1
微流控芯片的制备：
制备的微流控芯片结构如图1所示，所述芯片为一体化结构。
①用CAD设计如图1所示的微流控芯片的通道结构，包括微流道1-7、微流道出口处的毛细管嵌入通道、光纤通道1-3以及电极通道的结构，进行菲林掩膜打印。将清洗过的硅片滴上SU-8光刻胶进行甩胶，厚度约为120um。后将其覆盖掩膜，在曝光机下进行曝光，并用显影液将未固化部分清洗干净，得到硅片模板。
②将PDMS单体与固化剂按一定比例混匀，得到PDMS高聚物。将PDMS高聚物倒在硅片模板上，厚约1-10mm，烘干后得到带有通道结构的PDMS芯片。
③将带有通道结构的PDMS芯片上用打孔器打出油相进样口1-2-1、水相进样口1-2-2、液态电极进样口。下层键合的芯片为PDMS光滑基片，厚度为1-10mm，无刻蚀图案。
④上下两层芯片打等离子体键合，置于70℃过夜使芯片恢复疏水性。根据所设计的芯片本体1-6的轮廓线进行切割，最终的结构如图1所示。
⑤将毛细管嵌入通道处插入毛细管1-4，毛细管长度为6mm，外径约为360um，内径为100um。将芯片放置于90摄氏度的烘胶板上加热，用PDMS封住毛细管与微流控通道末端的出口，使所有液体只会从毛细管末端流出。
⑥从上电极通道和下电极通道的进样口灌入液态金属，形成上、下电极1-1、1-5。
本实施例中，微流控芯片的本体与下电极的绝缘支撑为一体结构，在其他实施例中，也可以将芯片本体和下电极绝缘支撑做成分离结构。此外芯片中进样口的个数，排布结构以及电极结构均可以根据需求调整，图2，图3中示出了芯片的其他可变结构，本发明的保护范围并不限于以上结构。
实施例2
一种基于电流体动力学的微生物点样装置，如图4所示，包括了：微流控芯片1，所述微流控芯片具有至少两个进样口，并设有相对的两个光纤通道；
激光发射器2，发射可见光波段激光；
激光检测器3，用于检测光信号，并将光信号转化成电信号；所述激光检测器包括但不限于光电二极管或光电倍增管；
两根光纤，所述光纤嵌入光纤通道内，其中一根光纤与激光发射器相连， 另一根光纤与激光检测器相连；
继电器5，用于控制电路的开关；
高压直流电源6，所述高压直流电源两极分别与微流控芯片上电极及下电极连接；
数据采集卡4，用于采集和传输激光检测器检测的信号采集并传输到计算机，以及控制高压直流电源输出电压或者电流；
移动平台8，用于放置接收容器；
计算机7，所述计算机与数据采集卡和移动平台相连，通过程序实现激光信号的读取、控制移动平台的移动、和高压直流电源电路的开关。
实施例3
以微流控芯片应用于微生物组液滴培养后的流式分选与质谱分析的耦合接口为示范，芯片结构以实施例1所制备的芯片结构(图1)为例：
1、液滴中微生物液体培养和扩增
将含有微生物的选择培养基使用常见的微流控十字型液滴发生芯片生成液滴，液滴尺寸在10um-100um，优选80um，收集到EP管中放在培养箱中培养一段时间，使目标微生物大量繁殖，充满液滴。
2、基于散射光的无标记的生长表型液滴分选
使用基于散射光的无标记的生长表型液滴分选系统可以将培养过的也液滴进行分选，长满目标微生物的液滴可以被分选出来并收集到一毫升离心管中。
3、单个液滴的分离
基于电液动力学的液滴喷射印刷的微流控芯片来进行收集的液滴的分离，具体操作如下：
前期准备：
①首先，准备高压直流电源、移动平台、进样泵、计算机(LABVIEW软件控制系统运行)、光电二极管(或者光电倍增管)、激光发射器、光纤两根、数据采集卡以及相关控制电路；
②将油相和含有培养过的细胞的液滴的油相的进样端分别接入1-2-1和1-2-2进样口中；
③将信号接受端和激光信号输出端的光纤分别插入1-3光纤通道的两侧；
④将高压直流电源6的两电极分别连接芯片的上下两电极1-1、1-5；
⑤将微流控芯片用简单的夹具等固定装置固定在移动平台上方。
实验过程：
①将油相和含有培养过的细胞的液滴的油相的注射泵调整到恰当的流速并使培养过的液滴可以有间隔得稳定的流出；
②打开激光发射器，运行计算机里LABVIEW软件里编好的程序。
③将高压直流电源输出端调到零伏特后打开，然后根据所需要点出的液滴大小调整好电压的大小，调整点出的液滴大小主要根据的原则是：点出的液滴里只有一个培养过的液滴；
④将MALDI(基质辅助激光解吸电离)板放在移动平台上收集液滴；
⑤激光发射器2发出激光通过光纤照射穿过毛细管，并通过光纤传递至激光检测器3，然后通过数据采集卡4将此信号传输至计算机7。而当液滴通过毛细管时，会引起光信号的改变，从而通过计算机程序显示的信号数据可以判断有一个液滴通过，此时程序控制数据采集卡4输出设定的电压，利用继电器5将高压直流电源6的电路导通，使高压直流电源6在微流控芯片上电极1-1与下电极1-5上施加电压，使上述液滴滴出。通过调整施加电压的大小，可以控制滴出的液滴大小和滴出液滴的响应时间，通过调整实现单个液滴单个滴出。
⑥同时，当计算机程序显示的信号数据可以判断有一个液滴通过时，通过程序控制移动平台8移动，使液滴准确滴入MALDI板上设定位置。
⑦通过LABVIEW程序实现液滴信号识别-高压直流电源电路接通-移动平台移动的耦合控制。
⑧对点有液滴的MALDI板样品做预处理，做MALDI-TOF质谱分析。
实验结束：
若短时间不会再用芯片时，将芯片取下后，用无水乙醇将液体通道冲洗干净后，放入烘箱烘干后可以循环再用。
实施例4
液滴的平板划线培养：
本实施例中采用的微流控芯片结构如图2所示：所述芯片为一体化的结构， 芯片只有一个进样口1-2，并且不需要光纤通道。
①将液体的进样口1-2连接含有菌液的注射器，并用泵从进样口1-2泵入菌液充满通道，设置好进样速度；
②将上下电极1-1和1-5分别连接高压直流电源6的两极；
③将上述芯片用简单的固定装置固定好，在芯片下方放置是二维移动平台8，二维移动平台8上放置固体培养基或者有液体培养基的96孔培养板，二维移动平台旁边放置一个点燃的酒精灯，制造无菌环境；
④打开泵，使液体进入毛细管通道1-3，打开高压电源6，调整电压的大小，在一定的电压范围内，电压越高，菌液从毛细管滴出所生成的液滴越小。电压控制形成的液滴的产生速度和尺寸大小；
⑤调整移动平台8的移动速度和液滴的产生速度相匹配，使每个液滴均匀滴落在固体培养基上或者含有液体培养基的96孔板里；
⑥实验结束后，将培养基放在培养箱中培养，芯片用无水乙醇冲洗液体通道，后烘干做循环利用。
实施例5
作为微生物组液滴培养后的流式分选与细胞测序的耦合接口，采用的芯片结构如图1所示：
1、液滴中微生物液体培养和扩增
将含有微生物的选择培养基使用常见的微流控十字型液滴发生芯片生成液滴，液滴尺寸在10um-100um，优选80um，收集到EP管中放在培养箱中培养一段时间，使目标微生物大量繁殖，充满液滴。
2、基于散射光的无标记的生长表型液滴分选
使用基于散射光的无标记的生长表型液滴分选系统可以将培养过的也液滴进行分选，长满目标微生物的液滴可以被分选出来并收集到。
3、单个液滴的分离
基于电液动力学的液滴喷射印刷的微流控芯片来进行收集的液滴的分离，具体操作如下：
前期准备：
①首先，准备高压直流电源、移动平台、进样泵、计算机(LABVIEW软件控制 系统运行)、光电二极管(或者光电倍增管)、激光发射器、光纤两根、数据采集卡以及相关控制电路；
②将油相和含有培养过的细胞的液滴的油相的进样端分别接入1-2-1和1-2-2进样口中；
③将信号接受端和激光信号输出端的光纤分别插入1-3光纤通道的两侧；
④将高压直流电源的两电极分别连接芯片的上下两电极1-1和1-5；
⑤将微流控芯片用简单的夹具等固定装置固定在二维移动平台上方，二维移动平台旁放置点燃的酒精灯，制造无菌环境。
实验中：
⑥将油相和分选出的含有目标微生物的液滴的油相的注射泵调整到恰当的流速，使培养过的液滴之间可以有较大间隔且可以稳定的流出；
⑦打开激光发射器2，运行计算机里LABVIEW软件里编好的程序。
⑧将高压直流电源6输出端调到零伏特后打开，然后根据所需要点出的液滴大小调整好电压的大小，调整点出的液滴大小主要根据的原则是：点出的液滴里只有一个培养过的液滴；
⑨将96孔板放在移动平台8上收集液滴；
⑩激光发射器2发出激光通过光纤照射穿过毛细管，并通过光纤传递至激光检测器3，然后通过数据采集卡4将此信号传输至计算机7。而当液滴通过毛细管时，会引起光信号的改变，从而通过计算机程序显示的信号数据可以判断有一个液滴通过，此时程序控制数据采集卡输出设定的电压，利用继电器5将高压直流电源6的电路导通，使高压直流电源6在微流控芯片上电极1-1与下电极1-5上施加电压，使上述液滴滴出。通过调整施加电压的大小，可以控制滴出的液滴大小和滴出液滴的响应时间，通过调整实现单个液滴单个滴出。
Figure PCTCN2021086739-appb-000001
同时，当计算机程序显示的信号数据可以判断有一个液滴通过时，通过程序控制移动平台8移动，使液滴准确滴入96孔板上设定位置孔。
Figure PCTCN2021086739-appb-000002
通过LABVIEW程序实现液滴信号识别-高压电源接通-移动平台移动的耦合控制，实现每个滴出的液滴精准滴入96孔板的孔里。
Figure PCTCN2021086739-appb-000003
点样结束后，用移液枪从96孔分别取出部分菌液分别放入单独的EP管中，并做好标记。
4、细胞测序
将EP管中的菌液进行测序，通过测序可以得到目标微生物的各种信息。
实施例6
作为拉曼流式分选与单细胞测序的耦合接口，采用的微流控芯片结构如图1所示。
1、拉曼流式分选
拉曼流式分选系统可以对单细胞进行拉曼光谱测量，并对单细胞进行液滴单包裹，通过拉曼光谱判断是否是目标细胞，若是目标细胞通过介电来分选出含有目标细胞的液滴。
2、液滴的分离
基于电液动力学的液滴喷射印刷的微流控芯片来进行收集的液滴的分离，具体操作如下：
前期准备：
①首先，准备高压直流电源、移动平台、进样泵、计算机(LABVIEW软件控制系统运行)、光电二极管(或者光电倍增管)、激光发射器、光纤两根、数据采集卡以及相关控制电路；
②将油相和含有培养过的细胞的液滴的油相的进样端分别接入1-2-1和1-2-2进样口中；
③将信号接受端和激光信号输出端的光纤分别插入1-3光纤通道的两侧；
④将高压直流电源的两电极分别连接芯片的上下两电极1-1和1-5；
⑤将微流控芯片用简单的夹具等固定装置固定在二维移动平台上方，二维移动平台旁放置点燃的酒精灯，制造无菌环境。
实验中：
⑥将油相和分选出的含有目标单细胞的液滴的油相的注射泵调整到恰当的流速，使每个液滴之间可以有较大间隔且可以稳定的流出；
⑦将含有纯水的96孔板放在移动平台上收集滴出的液滴；
⑧激光发射器2发出激光通过光纤照射穿过毛细管，并通过光纤传递至激光检测器3，然后通过数据采集卡4将此信号传输至计算机7。而当液滴通过毛细管时，会引起光信号的改变，从而通过计算机程序显示的信号数据可以判断有一个液滴通过，此时程序控制数据采集卡输出设定的电压，利用继电器5 将高压直流电源6的电路导通，使高压直流电源6在微流控芯片1上电极1-1与下电极1-5上施加电压，使上述液滴滴出。通过调整施加电压的大小，可以控制滴出的液滴大小和滴出液滴的响应时间，通过调整实现单个液滴单个滴出。
⑨同时，当计算机程序显示的信号数据可以判断有一个液滴通过时，通过程序控制移动平台8移动，使液滴准确滴入96孔板上设定位置孔。
⑩通过LABVIEW程序实现液滴信号识别-高压直流电源接通-移动平台移动的耦合控制，实现每个滴出的液滴精准滴入96孔板的孔里。
3、细胞测序
对96孔板里的单细胞液滴进行单细胞测序操作，通过测序可以得到目标单细胞的基因信息。

Claims (10)

  1. 一种基于电流体动力学的微流控芯片，其特征在于，所述芯片包括：
    至少一个毛细管，所述毛细管具有入口端和出口端；
    芯片本体，所述芯片本体包括至少一个进样口，以及与进样口连接的微流道，与微流道连接的毛细管嵌入通道，毛细管嵌入通道具有出口端，所述毛细管置于毛细管嵌入通道内部，与微流道连接，所述毛细管的长度大于毛细管嵌入通道的长度；
    上电极，所述上电极位于芯片本体上，靠近毛细管的位置；
    下电极，所述下电极具有绝缘支撑体，所述下电极位于毛细管出口下方。
  2. 根据权利要求1所述的一种基于电流体动力学的微流控芯片，其特征在于，所述芯片本体的材质为玻璃或高分子聚合物；所述绝缘支撑体的材质为玻璃或高分子聚合物。
  3. 根据权利要求2所述的一种基于电流体动力学的微流控芯片，其特征在于，所述芯片本体与下电极的绝缘支撑体为同种材质，芯片本体与下电极的绝缘支撑体为一体成型结构。
  4. 根据权利要求1所述的一种基于电流体动力学的微流控芯片，其特征在于所述毛细管嵌入通道的直径大于微流道的直径。
  5. 根据权利要求1所述的一种基于电流体动力学的微流控芯片，所述毛细管的内径大于或等于微流道的直径。
  6. 根据权利要求1所述的一种基于电流体动力学的微流控芯片，所述作为上下电极的材质为液态金属或盐水或者焊锡。
  7. 一种基于电流体动力学的微量点样装置，其特征在于，包括：
    前述任一所述的微流控芯片，所述微流控芯片具有至少两个进样口，并设有相对的两个光纤通道；
    激光发射器，发射可见光波段激光；
    激光检测器，用于检测光信号，并将光信号转化成电信号；
    两根光纤，所述光纤嵌入光纤通道内，其中一根光纤与激光发射器相连，另一根光纤与激光检测器相连；
    继电器，用于控制电路的开关；
    高压直流电源，所述高压直流电源两极分别与微流控芯片上电极及下电极连接；
    数据采集卡，用于采集和传输激光检测器检测的信号采集并传输到计算机，以及控制高压直流电源输出电压或者电流；
    移动平台，用于放置接收容器；
    计算机，所述计算机与数据采集卡和移动平台相连，通过程序实现激光信号的读取、控制移动平台的移动和高压直流电源电路的开关。
  8. 根据权利要求7所述的一种基于电流体动力学的微量点样装置，其特征在于，所述激光检测器为光电二极管或光电倍增管。
  9. 一种基于电流体动力学的微量点样方法，其特征在于，包括：
    所述在微流控芯片两个进样口中分别通入油与液滴的混合液体与纯油相，使液滴之间产生间隔并由微流道进入毛细管；
    激光发射器发出激光通过光纤照射穿过毛细管，并通过光纤传递至激光检测器，通过光信号判断液滴信息；
    当判断为一个液滴时，计算机控制采集卡输出设定的电压，利用继电器将高压直流电源的电路导通，使高压直流电源在微流控芯片上电极与下电极上施加电压，通过调整施加电压的大小，可以控制滴出的液滴大小和滴出液滴的响应时间，并使液滴滴出；
    控制移动平台，使液滴准确滴入接收容器中。
  10. 根据权利要求9所述的一种基于电流体动力学的微量点样方法，其特征在于，所述液滴内的液体可以为环境中采集的微生物样品溶液、培养过的单一微生物溶液或多种微生物的混合溶液生物样品。
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