WO2019080519A1 - 一种多组份液滴的电融合制备装置及控制方法 - Google Patents

一种多组份液滴的电融合制备装置及控制方法

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Publication number
WO2019080519A1
WO2019080519A1 PCT/CN2018/091966 CN2018091966W WO2019080519A1 WO 2019080519 A1 WO2019080519 A1 WO 2019080519A1 CN 2018091966 W CN2018091966 W CN 2018091966W WO 2019080519 A1 WO2019080519 A1 WO 2019080519A1
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Prior art keywords
discrete phase
stepped
electrofusion
joint
signal
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PCT/CN2018/091966
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English (en)
French (fr)
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许忠斌
黄兴
罗晓晔
谭小红
何斌斌
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浙江大学
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Publication of WO2019080519A1 publication Critical patent/WO2019080519A1/zh

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
    • B01F23/40—Mixing liquids with liquids; Emulsifying
    • B01F23/41—Emulsifying
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F33/00—Other mixers; Mixing plants; Combinations of mixers
    • B01F33/30—Micromixers
    • B01F33/302—Micromixers the materials to be mixed flowing in the form of droplets
    • B01F33/3021—Micromixers the materials to be mixed flowing in the form of droplets the components to be mixed being combined in a single independent droplet, e.g. these droplets being divided by a non-miscible fluid or consisting of independent droplets
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/20—Measuring; Control or regulation
    • B01F35/21—Measuring
    • B01F35/211—Measuring of the operational parameters
    • B01F35/2111—Flow rate
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/20—Measuring; Control or regulation
    • B01F35/22—Control or regulation
    • B01F35/2201—Control or regulation characterised by the type of control technique used
    • B01F35/2209—Controlling the mixing process as a whole, i.e. involving a complete monitoring and controlling of the mixing process during the whole mixing cycle
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/71—Feed mechanisms
    • B01F35/712—Feed mechanisms for feeding fluids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/71—Feed mechanisms
    • B01F35/716—Feed mechanisms characterised by the relative arrangement of the containers for feeding or mixing the components
    • B01F35/7163—Feed mechanisms characterised by the relative arrangement of the containers for feeding or mixing the components the containers being connected in a mouth-to-mouth, end-to-end disposition, i.e. the openings are juxtaposed before contacting the contents
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/71—Feed mechanisms
    • B01F35/717—Feed mechanisms characterised by the means for feeding the components to the mixer
    • B01F35/7176—Feed mechanisms characterised by the means for feeding the components to the mixer using pumps
    • 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
    • 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
    • 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
    • B01L2200/10—Integrating sample preparation and analysis in single entity, e.g. lab-on-a-chip concept
    • 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
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • 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
    • B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
    • 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
    • B01L2400/08—Regulating or influencing the flow resistance
    • B01L2400/082—Active control of flow resistance, e.g. flow controllers

Definitions

  • the invention relates to the field of microfluidics and the fields of chemical engineering, medicine and new materials, in particular to an electrofusion preparation device and a control method for multi-component droplets.
  • Microfluidic fusion operation to prepare multi-component droplet technology can be used as a droplet template for multi-component microparticles, mixing different chemical reagents, mixed viruses and candidate liposomes for antiviral drug screening, etc. It has a wide range of applications in materials preparation, micro-chemical reactions and biomedicine.
  • the step emulsification method is a method for preparing droplets by using a Laplacian pressure difference of a discrete phase fluid at a step structure, which has the advantages of good monodispersity, low energy consumption, and small shear, and can be used for shearing sensitive materials. Droplet preparation and suitable for flux amplification.
  • multi-component droplet preparation based on the step emulsification method relies on mutual contact collision between droplets to induce fusion.
  • This passive method has insufficient controllability, can not control the position of droplet fusion, and the stability will decrease when the composition is increased, and it is easy to occur that individual components do not participate in the fusion. Passive collision fusion can also become difficult when the surfactant concentration is high.
  • the size of the droplets in the step emulsification mainly depends on the size of the structure, and the increase in the flow rate causes the droplet size to become larger, but the variation range is small. Therefore, the control of droplet size in step emulsification is still a difficult problem to be solved.
  • the present invention provides an electrofusion preparation apparatus and a control method for multi-component droplets, which can ensure stable preparation of multi-component droplets, and can control the position of droplet fusion, and realize droplet size.
  • the specific scheme is as follows:
  • An electrofusion preparation device for multi-component droplets comprising a discrete phase flow channel, a microchannel structure, a stepped emulsion joint, a continuous phase vessel and a controllable power source, wherein the discrete phase flow channel is connected to the microchannel structure
  • the stepped emulsification joint is a square tube with a cavity, the microchannel structure is inserted into a cavity of the stepped emulsification joint, and the stepped emulsification joint is immersed in the continuous phase In the continuous phase fluid contained in the container;
  • the discrete phase flow channels are two or more, and each of the two comprises a syringe pump and a metal electrode interface tube connected in series through a pipeline;
  • the microchannel structure includes a plurality of parallel microchannels, and the metal electrode interface The tube and the microchannel are connected by a pipeline, and the controllable power source is connected to the metal electrode interface tube;
  • the material of the stepped emulsification joint is sparse with the discrete phase fluid in the syringe pump
  • the syringe pump contains discrete phase fluids, and the discrete phases in different syringe pumps are different and mutually soluble, but the discrete phases and the continuous phase contained in the continuous phase vessel are not mutually soluble;
  • the distance L between the end of the microchannel structure and the end of the stepped emulsification joint satisfies L>1.5S and L ⁇ 3W, wherein S is the distance between adjacent microchannels of the microchannel structure, and W is The cavity of the stepped emulsification joint is perpendicular to the length of the discrete phase flow plane.
  • the device further includes a flow sensor and a single chip, wherein the flow sensor is connected between the injection pump and the metal electrode interface tube through a pipeline, and the signal output end of the flow sensor is connected to the signal input end of the single chip, and the signal of the single chip microcomputer The output is connected to the signal input of the controllable power supply.
  • the device further comprises a single chip microcomputer and a marker detecting system, wherein the marker detecting system is located directly in front of the horizontal direction of the outer phase of the continuous phase container, and the signal output end is connected to the signal input end of the single chip microcomputer, and the signal of the single chip microcomputer The output is connected to the signal input of the controllable power supply.
  • the stepped emulsification joint may also be two flat plates, and the distance between the flat plates is equal to the length of the cavity of the stepped emulsification joint in a plane perpendicular to the discrete phase flow plane, and The material of the flat plate is sparse with the discrete phase.
  • the continuous phase or the discrete phase contains a surfactant.
  • An electrofusion preparation device for running multi-component droplets, and setting the flow rate of each discrete phase flow channel to be equal, and the polarity of the electrical signal of the metal electrode interface tube of the adjacent discrete phase flow channel is opposite, and The flow sensor detects the flow of the discrete phase flow channel;
  • the device of the present invention has good stability, rich functions, and can be applied to a case where the concentration of the surfactant is high. Precise control of the fusion of a particular droplet can be achieved by detecting a marker signal or applying a specific electrical signal.
  • the device of the invention has simple structure, convenient manufacture, low cost, low energy consumption, and is suitable for shear-sensitive Droplet preparation of matter.
  • most electrofusion devices require the electrode to be embedded in the microfluidic chip, which is cumbersome and costly, and the method only needs to connect the electrode to the fluid pipeline, which simplifies the fabrication process of the device. .
  • the invention can control the fusion position of the discrete phase fluid, in particular, the discrete phase fluid can be fused outside the step, that is, the contact of different component fluids in the microstructure is completely avoided, which is special for the microreaction which will cause precipitation.
  • the occasion has important potential application value.
  • the device according to the present invention can accurately control the droplet size, and can customize the response of the droplet diameter to the flow rate, and thus can be used in chemical and biological engineering fields such as ultra-uniform droplet preparation and high-precision sample addition. Has significant practical value.
  • FIG. 1 is a schematic structural view of one embodiment of an electrofusion preparation apparatus for multi-component droplets of the present invention
  • FIG. 2 is a schematic structural view of another embodiment of an electrofusion preparation apparatus for another multi-component droplet according to the present invention.
  • 3 is an assembled dimension view of the microchannel structure 4 and the stepped emulsification joint 5;
  • Figure 4 is a photograph of the preparation of the three component droplets in Example 1;
  • Figure 5 is a photograph of the preparation of the four component droplets in Example 2.
  • Figure 6 is a photograph of alternately performing droplet fusion and non-fusion in Example 3.
  • Figure 7 is a photograph showing the process of the out-of-channel fusion of the discrete phase fluid in Example 4.
  • Figure 8 is a graph showing the relationship between droplet diameter and flow rate and voltage obtained by experiment in Example 5;
  • a syringe pump 1 1, a flow sensor 2, a metal electrode interface tube 3, a microchannel structure 4, a stepped emulsification joint 5, a continuous phase container 6, a single chip microcomputer 7, a controllable power source 8, and a marker detecting system 9.
  • a multi-component droplet electrofusion preparation apparatus includes a discrete phase flow channel, a microchannel structure 4, a stepped emulsion joint 5, a continuous phase vessel 6 and a controllable power source 8, and a discrete phase flow.
  • the channel is connected to the microchannel structure 4, the stepped emulsification joint 5 is a square tube with a cavity, the microchannel structure 4 is inserted into the cavity of the stepped emulsification joint 5, and the stepped emulsification joint 5 is immersed in the In the continuous phase fluid contained in the continuous phase vessel 6;
  • each of them includes a syringe pump 1 and a metal electrode interface tube 3 which are sequentially connected by a pipe; the microchannel structure 4 contains 4 parallel microchannels, and the metal electrode interface tube 3 and the microchannel pass through the pipeline.
  • the controllable power source 8 is connected to the metal electrode interface tube 3; the number of discrete phase flow channels can be set according to actual needs, and the number of parallel microchannels in the microchannel structure is equal to the number of discrete phase flow channels.
  • the material of the stepped emulsification joint 5 is indistinguishable from the discrete phase fluid in the syringe pump 1.
  • the syringe pump 1 contains discrete phase fluids, and the discrete phases in the different syringe pumps 1 are different and mutually soluble, but the discrete phases and the continuous phase contained in the continuous phase vessel 6 are immiscible.
  • the distance L between the end of the microchannel structure 4 and the end of the stepped emulsification joint 5 satisfies L>1.5S and L ⁇ 3W, as shown in FIG. 3, where S is the adjacent microchannel between the microchannel structures 4.
  • the distance W is the length of the cavity of the stepped emulsification joint 5 perpendicular to the plane of flow of the discrete phase.
  • the device When the flow sensor is used for detecting, as shown in FIG. 1, the device further includes a flow sensor 2 and a single-chip microcomputer 7, and the flow sensor 2 is connected between the syringe pump 1 and the metal electrode interface tube 3 through a pipe, and the signal output of the flow sensor 2
  • the terminal is connected to the signal input end of the single chip microcomputer 7, and the signal output end of the single chip microcomputer 7 is connected to the signal input end of the controllable power source 8,
  • the device further includes a single chip microcomputer 7 and a marker detecting system 9, and the marker detecting system 9 is located directly in front of the horizontal phase of the outer phase of the outer phase of the emulsion joint 5, and the signal output thereof
  • the terminal is connected to the signal input end of the single chip microcomputer 7, and the signal output end of the single chip microcomputer 7 is connected to the signal input end of the controllable power source 8.
  • the step type emulsification joint 5 can also be two flat plates. At this time, the distance between the flat plates and the cavity of the step type emulsification joint 5 are equal to the length perpendicular to the flow plane of the discrete phase, and the material of the flat plate and the discrete phase are sparse.
  • a surfactant may also be included in the continuous or discrete phase.
  • the control method of the electrofusion preparation device using the multi-component droplets as shown in FIG. 1 is as follows:
  • the continuous phase was selected as dimethyl silicone oil, and 10 wt% of surfactant DC749 was added.
  • the three discrete phase fluids were 80% aqueous glycerol + 1% sodium chloride, but red, green and blue dyes were added, respectively.
  • the pitch of adjacent microchannels in the microchannel structure 4 is 250 ⁇ m
  • the length of the stepped emulsification joint 5 is 200 ⁇ m perpendicular to the plane of the discrete phase flow
  • the distance between the end of the microchannel structure 4 and the end of the stepped emulsification joint 5 is 1000 ⁇ m.
  • Material and structural parameters of the four discrete phases are the same as in Example 1, except that the fourth discrete phase is added with a purple dye, and the distance between the end of the microchannel structure 4 and the end of the stepped emulsion joint 5 It is 1200 ⁇ m.
  • Example 3 Controlling droplet fusion or not
  • Material and structural parameters The materials of the two discrete phases are deionized water + 1% sodium chloride, but red and green dyes are added respectively.
  • the structural parameters are the same as in the first embodiment.
  • Example 4 By controlling the voltage, the discrete phase fluid is fused outside the channel and forms a two-component droplet
  • the continuous phase was selected as dimethyl silicone oil, and 10 wt% of surfactant DC749 was added. Both discrete phase fluids were 80% aqueous glycerol + 1% sodium chloride, but red and green dyes were added, respectively.
  • the spacing of adjacent microchannels in the microchannel structure 4 is 250 ⁇ m
  • the length of the discrete phase junction 5 is perpendicular to the plane of the discrete phase flow of 120 ⁇ m
  • the distance between the end of the microchannel structure 4 and the end of the stepped emulsion joint 5 is 400 ⁇ m.
  • Two discrete phase fluids are injected into the two channels of the microchannel structure 4, respectively, and the distance between the two channels is 750 ⁇ m.
  • the flow rates of the two discrete phase fluids are both 0.1 mL/h.
  • the positive and negative electrodes are respectively connected to the electrode interface tubes of the two channels.
  • the program in the MCU is set to ignore the flow signal, and the controllable power supply outputs a DC voltage of 2V through the communication interface.
  • Example 5 Controlling droplet size by electrofusion so that it does not change with flow rate
  • the continuous phase was selected as dimethyl silicone oil, and 10 wt% of surfactant DC749 was added.
  • the discrete phase fluids of both channels are 80% aqueous glycerol solution + 1% sodium chloride, the spacing of adjacent microchannels in microchannel structure 4 is 250 ⁇ m, and the length of discrete phase junction 5 is 300 ⁇ m perpendicular to the plane of the discrete phase flow.
  • the distance between the end of the microchannel structure 4 and the end of the stepped emulsification joint 5 was 1000 ⁇ m.
  • Two discrete phase fluids are injected into the two channels of the microchannel structure 4, respectively, and the distance between the two channels is 500 ⁇ m.
  • the positive and negative electrodes are respectively connected to the electrode interface tubes of the two channels.
  • the MCU uses the STM32 type.
  • the droplet size of the controlled droplets at different flow rates and the droplet size when not controlled are shown in Fig. 9. It can be seen that, if not controlled, when the flow rate is increased from 0.1 to 0.3 mL/hr, the droplet diameter is increased from 990 to about 1050 ⁇ m, and after electrofusion control by the above method, the droplet size is uniform and does not vary with the flow rate. The droplet diameter is always around 1050 microns. The results show that the stability of the droplets prepared by the step emulsification can be improved by the electrofusion control, and the droplet diameter is not easily affected by the flow fluctuation.

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Abstract

一种多组份液滴的电融合制备装置及其控制方法。装置包括注射泵（1）、流量传感器（2）、金属电极接口管（3）、微通道结构（4）、台阶式乳化接头（5）、连续相容器（6）、单片机（7）、可控电源（8）和标志物检测系统（9）。前四者依次连接，微通道结构（4）插入台阶式乳化接头（5）的空腔中，台阶式乳化接头（5）浸没在连续相容器（6）中盛装的连续相流体中。根据流量传感器（2）或标志物检测系统（9）的检测信号，利用单片机（7）进行处理，并由可控电源（8）输出的电信号控制不同通道离散相的融合与否以及融合位置，从而制备所需直径的多组分液滴。

Description

一种多组份液滴的电融合制备装置及控制方法 技术领域
本发明涉及微流控领域以及化工、医药、新材料领域，尤其涉及一种多组份液滴的电融合制备装置及控制方法。
背景技术
微流控中融合操作制备多组分液滴技术可用于作为多组分微粒的液滴模板、混合不同的化学反应试剂、混合病毒和待选脂质体以进行抗病毒药物筛选等，从而在材料制备、微化学反应和生物医药等领域具有广泛的应用。台阶式乳化法是一种利用离散相流体在台阶结构处的拉普拉斯压力差制备液滴的方法，具有单分散性好、能耗低以及剪切小等优点，可用于剪切敏感材料液滴制备，且适合于通量放大。
目前基于台阶式乳化法的多组分液滴制备都是依靠液滴间的相互接触碰撞诱发融合。这种被动式方法可控性不足，不能控制液滴融合的位置，且当组分增多时稳定性会降低，容易发生个别组分不参与融合的情况。而当表面活性剂浓度较高时，被动式碰撞融合也会变得困难。此外，台阶式乳化中液滴的尺寸主要依赖于结构尺寸，流量增大会引起液滴尺寸变大，但变化幅度较小。因此，在台阶式乳化中液滴尺寸的控制也仍然是待解决的难题。
发明内容
鉴于以上技术问题，本发明提供一种多组份液滴的电融合制备装置及控制方法，该方法能保证稳定制备多组分液滴，并能控制液滴融合的位置，实现液滴尺寸的精确调节，具体方案如下：
一种多组份液滴的电融合制备装置，该装置包括离散相流动通道、微通道结构、台阶式乳化接头、连续相容器和可控电源，所述的离散相流动通道与微通道结构连接，所述的台阶式乳化接头为带有空腔的方形管，所述的微通道结构插入所述的台阶式乳化接头的空腔中，所述的台阶式乳化接头浸没在所述的连续相容器中盛装的连续相流体中；
所述的离散相流动通道为两条以上，且每条均包括通过管道依次连接的注射泵、金属电极接口管；所述的微通道结构内含多条平行微通道，所述的金属电极接口管与所述的微通道通过管道连接，所述的可控电源与所述的金属电极接口管连接；
所述的台阶式乳化接头的材料与所述的注射泵中的离散相流体相疏；
所述的注射泵中盛装离散相流体，且不同的注射泵中的离散相各不相同，相互之间互溶，但所述的离散相和连续相容器中盛装的连续相均不互溶；
所述的微通道结构的末端与台阶式乳化接头的末端的距离L满足L>1.5S且L≥3W，其中，S为所述的微通道结构的相邻微通道间的距离，W为所述的台阶式乳化接头的空腔在垂直于离散相流动平面的长度。
进一步地，该装置还包括流量传感器和单片机，所述的流量传感器通过管道连接在注射泵和金属电极接口管之间，所述的流量传感器的信号输出端连接单片机的信号输入端，单片机的信号输出端连接可控电源的信号输入端。
进一步地，该装置还包括单片机和标志物检测系统，所述的标志物检测系统位于所述的连续相容器外乳化接头的水平正前方，其信号输出端连接单片机的信号输入端，单片机的信号输出端连接可控电源的信号输入端。
进一步地，所述的台阶式乳化接头也可以为两块平板，所述的平板之间的距离与所述的台阶式乳化接头的空腔在垂直于离散相流动平面的长度相等，且所述的平板的材质和所述的离散相相疏。
进一步地，所述的连续相或离散相中包含表面活性剂。
一种如上所述的多组份液滴的电融合制备装置的控制方法，其特征在于，该方法包括如下步骤：
(1)运行多组份液滴的电融合制备装置，且设定每条离散相流动通道的流量相等，相邻离散相流动通道的金属电极接口管所接电信号的极性相反，并由流量传感器检测离散相流动通道的流量；
(2)将所需要的液滴直径对流量的响应规律D＝g(Q)代入多组分液滴直径D与离散相流动通道的流量Q、可控电源的电压V三者之间的关系式D＝f(Q,V)中，得到电压的控制规律V＝k(Q)；
(3)读取流量传感器的信号，并根据控制规律V＝k(Q)输出控制信号；
(4)可控电源将控制信号转换为特定电压的电信号，并施加到金属电极接口管上，从而获得符合响应规律D＝g(Q)的多组分液滴。
进一步地，将电压的控制规律V＝k(Q)编入单片机的程序中，通过单片机读取流量传感器的信号，并根据控制规律V＝k(Q)输出控制信号。
与现有技术相比，本发明的有益效果在于：
(1)相比于台阶式乳化中基于被动式融合的多组分液滴制备方法，本发明的装置制备液滴的稳定性好，功能丰富，且可适用于表面活性剂浓度较高的场合。通过检测标志物信号或施加特定的电信号可以实现对特定液滴融合与否的精确控制。
(2)相较于其他在微流控芯片中利用电融合制备多组分液滴的方法，本发明的装置结构简单，制作方便，成本低，能耗小，且适用于对剪切敏感的物质的液滴制备。尤其是，大部 分电融合装置都需要将电极嵌入到微流控芯片中，加工过程繁琐，成本较高，而本方法只需将电极连接到流体管路上即可，显著简化了装置的制作工艺。
(3)本发明可控制离散相流体的融合位置，尤其是可以使得离散相流体在台阶外融合，即完全避免不同组分流体在微结构内的接触，这对于会产生沉淀的微反应等特殊场合具有重要的潜在应用价值。
(4)本发明所述的装置可以准确控制液滴尺寸，且可以自定义液滴直径对流量的响应规律，因此可用于超均匀液滴制备、高精度试样添加等化学和生物工程领域，具有显著的实用价值。
附图说明
图1为本发明的多组份液滴的电融合制备装置其中一个实施例的结构示意图；
图2为本发明另一种多组份液滴的电融合制备装置另一个实施例的结构示意图；
图3为微通道结构4与台阶式乳化接头5的装配尺寸图；
图4为实施例1中三组份液滴制备照片；
图5为实施例2中四组份液滴制备照片；
图6为实施例3中液滴融合与不融合交替进行的照片；
图7为实施例4中离散相流体在通道外融合过程照片；
图8为实施例5中通过实验得到的液滴直径与流量和电压的关系；
图9为实施例5中通过电融合控制后得到的液滴直径与流量的关系；
图中，注射泵1、流量传感器2、金属电极接口管3、微通道结构4、台阶式乳化接头5、连续相容器6、单片机7、可控电源8和标志物检测系统9。
具体实施方式
以下结合附图和具体实施例对本发明作进一步详细描述。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。
如图1所示，一种多组份液滴的电融合制备装置，其包括离散相流动通道、微通道结构4、台阶式乳化接头5、连续相容器6和可控电源8，离散相流动通道与微通道结构4连接，台阶式乳化接头5为带有空腔的方形管，微通道结构4插入所述的台阶式乳化接头5的空腔中，台阶式乳化接头5浸没在所述的连续相容器6中盛装的连续相流体中；
离散相流动通道为4条，且每条均包括通过管道依次连接的注射泵1、金属电极接口管3；微通道结构4内含4条平行微通道，金属电极接口管3与微通道通过管道连接，可控电源8与金属电极接口管3连接；离散相流动通道的数目可根据实际需要设定，同时，微通道结构中平行微通道的数目和离散相流动通道的数目相等。
台阶式乳化接头5的材料与注射泵1中的离散相流体相疏。
注射泵1中盛装离散相流体，且不同的注射泵1中的离散相各不相同，相互之间互溶，但所述的离散相和连续相容器6中盛装的连续相均不互溶。
微通道结构4的末端与台阶式乳化接头5的末端的距离L满足L>1.5S且L≥3W，如图3所示，其中，S为所述的微通道结构4的相邻微通道间的距离，W为台阶式乳化接头5的空腔在垂直于离散相流动平面的长度。
当采用流量传感器进行检测时，如图1所示，该装置还包括流量传感器2和单片机7，流量传感器2通过管道连接在注射泵1和金属电极接口管3之间，流量传感器2的信号输出端连接单片机7的信号输入端，单片机7的信号输出端连接可控电源8的信号输入端，
当采用标志物检测系统进行检测时，如图2所示，该装置还包括单片机7和标志物检测系统9，标志物检测系统9位于连续相容器外乳化接头5的水平正前方，其信号输出端连接单片机7的信号输入端，单片机7的信号输出端连接可控电源8的信号输入端。
台阶式乳化接头5也可以为两块平板，此时，平板之间的距离与台阶式乳化接头5的空腔在垂直于离散相流动平面的长度相等，且平板的材质和离散相相疏。
为了使得产生的多组分液滴能稳定储存，连续相或离散相中还可以包含表面活性剂。
采用如图1所示的多组份液滴的电融合制备装置的控制方法，具体步骤如下：
(1)运行多组份液滴的电融合制备装置，且设定每条离散相流动通道的流量相等，相邻离散相流动通道的金属电极接口管3所接电信号的极性相反，并由流量传感器2检测离散相流动通道的流量；通过实验得到多组分液滴直径与离散相流动通道的流量、可控电源8的电压的关系，即D＝f(Q,V)，其中D为液滴直径，Q为流量，V为电压；
(2)将所需要的液滴直径对流量的响应规律D＝g(Q)代入多组分液滴直径D与离散相流动通道的流量Q、可控电源8的电压V三者之间的关系式D＝f(Q,V)中，得到电压的控制规律V＝k(Q)；
(3)将电压的控制规律V＝k(Q)编入单片机7的程序中，通过单片机7读取流量传感器2的信号，并根据控制规律V＝k(Q)输出控制信号；
(4)可控电源8将控制信号转换为特定电压的电信号，并施加到金属电极接口管3上，从而获得符合响应规律D＝g(Q)的多组分液滴。
下面的实施例1-2、4-5的测试均基于图1中的多组分液滴制备及尺寸控制的装置，实施例3的测试基于图2中的多组分液滴制备及尺寸控制的装置。
实施例1：三组份液滴的制备
(1)材料及结构参数：选择连续相为二甲基硅油，并添加10wt％表面活性剂DC749。三种离散相流体都为80％甘油水溶液+1％氯化钠，但分别添加红色、绿色和蓝色的染色剂。 微通道结构4内相邻微通道的间距为250μm，台阶式乳化接头5在垂直于离散相流动平面的长度为200μm，微通道结构4末端与台阶式乳化接头5末端的距离为1000μm。
(2)操作参数：三种离散相流体分别注入微通道结构的三个通道中，流量均为0.1mL/h。三个通道中，中间的通道接正极，另外两个通道接负极。单片机中的程序设定为忽视流量信号，通过通讯接口使得可控电源输出5V的直流电压。
(3)结果获取：使用显微镜拍摄液滴产生区域，如图4所示，可见制备得到了均匀的三组份液滴，三种组分之间界面分明，其中中间一种组分流体的形状为圆盘状，而两边的两组组分流体的形状为球盖状，因此可以利用这种方法为模板制备非球状的固体颗粒。
实施例2：四组份液滴的制备
(1)材料及结构参数：四种离散相的材料和结构参数均与实施例1相同，仅第四种离散相添加紫色染色剂，且微通道结构4末端与台阶式乳化接头5末端的距离为1200μm。
(2)操作参数：四种离散相流体分别注入微通道结构的四个通道中，流量均为0.1mL/h。四个通道中，从左到右第一、三个通道接正极，另外两个通道接负极。单片机中的程序设定为忽视流量信号，通过通讯接口使得可控电源输出5V的直流电压。
(3)结果获取：使用显微镜拍摄液滴产生区域，如图5所示，可见制备得到了均匀的三组份液滴，三种组分之间界面分明，其中中间两种组分流体的形状为圆盘状，而两边的两组组分流体的形状为球盖状，因此可以利用这种方法为模板制备非球状的固体颗粒。当单个通道的流量相同时，所制备得到的液滴的组分越多，液滴直径也就越大。
实施例3：控制液滴融合与否
(1)材料及结构参数：两种离散相的材料都为去离子水+1％氯化钠，但分别添加了红色和绿色的染色剂。结构参数与实施例1相同。
(2)操作参数：两种离散相流体分别注入微通道结构的两个通道中，流量均为1.0mL/h。两个通道中，左边接正极，右边接负极。测量得到融合液滴制备的周期为1.002s，未融合液滴制备的周期为0.663s。单片机中的程序设定为忽视标志物检测系统的输入信号，通过通讯接口使得可控电源输出一个0～5V，周期为1.665s，占空比为50％的电压信号。
(3)结果获取：使用显微镜拍摄液滴产生区域，如图6所示，可见在得到的液滴中，融合与不融合的行为交替发生。当电压值为0V时，液滴不融合，两种组分的流体各自生成单独的液滴。当电压值为5V直流电时，液滴在台阶式乳化接头5内发生融合，形成双组分液滴。由于电信号的频率已经与液滴制备的频率协调好，所以该交替形成的过程是稳定持续的。
实施例4：通过控制电压使得离散相流体在通道外融合并形成双组份液滴
(1)材料及结构参数：选择连续相为二甲基硅油，并添加10wt％表面活性剂DC749。两种离散相流体都为80％甘油水溶液+1％氯化钠，但分别添加红色和绿色的染色剂。微通道结构4内相邻微通道的间距为250μm，离散相接头5在垂直于离散相流动平面的长度为120μm，微通道结构4末端与台阶式乳化接头5末端的距离为400μm。两个离散相流体分别注入微通道结构4的两个通道中，这两个通道之间的距离为750μm。
(2)操作参数：两个离散相流体的流量均为0.1mL/h。两个通道的电极接口管上分别接正极和负极。单片机中的程序设定为忽视流量信号，通过通讯接口使得可控电源输出2V的直流电压。
(3)结果获取：使用显微镜拍摄液滴产生区域，离散相流体的融合过程如图7所示，从图中可以看出，两种离散相流体在台阶上不会接触，而在台阶式乳化形成液滴的过程中逐渐靠近。在电压的作用下，两者融合，并迅速断裂，形成双组份液滴。这个融合过程都在连续相容器中进行，而对微结构没有影响。
实施例5：通过电融合控制液滴尺寸，使其不随流量变化
(1)材料、结构及操作参数：选择连续相为二甲基硅油，并添加10wt％表面活性剂DC749。两个通道的离散相流体都为80％甘油水溶液+1％氯化钠，微通道结构4内相邻微通道的间距为250μm，离散相接头5在垂直于离散相流动平面的长度为300μm，微通道结构4末端与台阶式乳化接头5末端的距离为1000μm。两种离散相流体分别注入微通道结构4的两个通道中，这两个通道之间的距离为500μm。两个通道的电极接口管上分别接正极和负极。单片机采用STM32型。
(2)电压控制规律获取：通过多次实验，得到在该结构尺寸下，液滴直径与流量和电压的关系如图8所示，经过拟合可得液滴尺寸的函数为D＝f(Q,V)＝318.64/V 3.1458/Q-7.34+1005.95，本实施例中要求控制产生液滴的尺寸为1050μm，且不随流量变化，故液滴的尺寸对流量的响应关系为D＝g(Q)＝1050μm，将其代入D＝f(Q,V)，得到电压的控制规律为V＝k(Q)＝7.2336 Q/(3.1458-7.34Q)。将该公式编写成程序，输入STM32单片机中。单片机根据程序和流量传感器的信号，处理后输出通讯信号，经可控电源放大到1.10～1.81V之后施加到两种离散相流体上。
(3)经过单片机的控制，得到的不同流量下经过控制的液滴尺寸与不控制时(电压恒为20V)的液滴尺寸对比如图9所示。可见，如果不控制，当流量从0.1增大到0.3mL/hr时，液滴直径从990增大到约1050微米，而通过上述方法进行电融合控制之后，液滴尺寸均匀且不随流量变化，液滴直径始终为1050微米左右。该结果显示，通过电融合控制，可以使得台阶式乳化制备液滴的稳定性提高，液滴直径不容易受到流量波动的影响。

Claims (7)

  1. 一种多组份液滴的电融合制备装置，其特征在于，该装置包括离散相流动通道、微通道结构(4)、台阶式乳化接头(5)、连续相容器(6)和可控电源(8)，所述的离散相流动通道与微通道结构(4)连接，所述的台阶式乳化接头(5)为带有空腔的方形管，所述的微通道结构(4)插入所述的台阶式乳化接头(5)的空腔中，所述的台阶式乳化接头(5)浸没在所述的连续相容器(6)中盛装的连续相流体中；
    所述的离散相流动通道为两条以上，且每条均包括通过管道依次连接的注射泵(1)、金属电极接口管(3)；所述的微通道结构(4)内含多条平行微通道，所述的金属电极接口管(3)与所述的微通道通过管道连接，所述的可控电源(8)与所述的金属电极接口管(3)连接；
    所述的台阶式乳化接头(5)的材料与所述的注射泵(1)中的离散相流体相疏；
    所述的注射泵(1)中盛装离散相流体，且不同的注射泵(1)中的离散相各不相同，相互之间互溶，但所述的离散相和连续相容器(6)中盛装的连续相均不互溶；
    所述的微通道结构(4)的末端与台阶式乳化接头(5)的末端的距离L满足L>1.5S且L≥3W，其中，S为所述的微通道结构(4)的相邻微通道间的距离，W为所述的台阶式乳化接头(5)的空腔在垂直于离散相流动平面的长度。
  2. 根据权利要求1所述的电融合制备装置，其特征在于，该装置还包括流量传感器(2)和单片机(7)，所述的流量传感器(2)通过管道连接在注射泵(1)和金属电极接口管(3)之间，所述的流量传感器(2)的信号输出端连接单片机(7)的信号输入端，单片机(7)的信号输出端连接可控电源(8)的信号输入端。
  3. 根据权利要求1所述的电融合制备装置，其特征在于，该装置还包括单片机(7)和标志物检测系统(9)，所述的标志物检测系统(9)位于所述的连续相容器外乳化接头(5)的水平正前方，其信号输出端连接单片机(7)的信号输入端，单片机(7)的信号输出端连接可控电源(8)的信号输入端。
  4. 根据权利要求1或2或3所述的电融合制备装置，所述的台阶式乳化接头(5)也可以为两块平板，所述的平板之间的距离与所述的台阶式乳化接头(5)的空腔在垂直于离散相流动平面的长度相等，且所述的平板的材质和所述的离散相相疏。
  5. 根据权利要求1-4中任意一项所述的电融合制备装置，所述的连续相或离散相中包含表面活性剂。
  6. 一种如权利要求2所述的多组份液滴的电融合制备装置的控制方法，其特征在于，该方法包括如下步骤：
    (1)运行多组份液滴的电融合制备装置，且设定每条离散相流动通道的流量相等，相邻 离散相流动通道的金属电极接口管(3)所接电信号的极性相反，并由流量传感器(2)检测离散相流动通道的流量；
    (2)将所需要的液滴直径对流量的响应规律D＝g(Q)代入多组分液滴直径D与离散相流动通道的流量Q、可控电源(8)的电压V三者之间的关系式D＝f(Q,V)中，得到电压的控制规律V＝k(Q)；
    (3)读取流量传感器(2)的信号，并根据控制规律V＝k(Q)输出控制信号；
    (4)可控电源(8)将控制信号转换为特定电压的电信号，并施加到金属电极接口管(3)上，从而获得符合响应规律D＝g(Q)的多组分液滴。
  7. 根据权利要求6所述的控制方法，将电压的控制规律V＝k(Q)编入单片机(7)的程序中，通过单片机(7)读取流量传感器(2)的信号，并根据控制规律V＝k(Q)输出控制信号。
PCT/CN2018/091966 2017-10-26 2018-06-20 一种多组份液滴的电融合制备装置及控制方法 WO2019080519A1 (zh)

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