WO2018054134A1 - 电动微流控液滴分配器 - Google Patents

电动微流控液滴分配器 Download PDF

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Publication number
WO2018054134A1
WO2018054134A1 PCT/CN2017/092391 CN2017092391W WO2018054134A1 WO 2018054134 A1 WO2018054134 A1 WO 2018054134A1 CN 2017092391 W CN2017092391 W CN 2017092391W WO 2018054134 A1 WO2018054134 A1 WO 2018054134A1
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Prior art keywords
microfluidic
droplet dispenser
electro
liquid
microfluidic chip
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PCT/CN2017/092391
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English (en)
French (fr)
Inventor
李保庆
禇家如
毛宇盺
李璇
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中国科学技术大学
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Publication of WO2018054134A1 publication Critical patent/WO2018054134A1/zh

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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
    • 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
    • B01L3/502707—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 manufacture of the container or its components
    • 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
    • B01L2200/061—Counting droplets
    • 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
    • B01L2300/0887—Laminated structure
    • 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
    • B01L2300/12—Specific details about materials
    • 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
    • B01L2400/02—Drop detachment mechanisms of single droplets from nozzles or pins

Definitions

  • the present disclosure belongs to the technical field of experimental instruments, and in particular relates to an electric microfluidic droplet dispenser for quantitative metering, dispensing and extraction of liquid.
  • Dispensers and pipettes are hand-operated instruments for small amounts of liquids that are commonly used in biological and chemical laboratories. Their main working principle is to transfer liquid by suction and extrusion of the piston: suction and discharge.
  • This type of pipette also known as the "air displacement pipette”
  • the initial principle was proposed by Heinrich Schnitger as early as 1957. And applied for a patent.
  • a series of patented technologies have resulted in the basic structure and form of modern pipettes, such as the US patent "Pipetting system” (patent number: US3494201A, date: February 10, 1970).
  • This printing mode drives and spouts (also called orifices)
  • the nozzle is easy to be blocked and the nozzle can not be easily replaced.
  • the US patent "method for rapid dispensing of minute quantities of viscous material" (patent number: 5320250, date: June 14, 1994)
  • a method of using an electromagnetic actuator to impact an elastic cavity to print a viscous material is proposed.
  • the cavity with the spout can be replaced, but it cannot be inserted as a disposable pipette tip.
  • the microfluidic droplet dispenser has the function of pumping liquid, and the present disclosure proposes a microfluidic printing based on microfluidic printing.
  • the electric microfluidic droplet dispenser realizes the suction of liquid and the distribution of liquid, and can achieve the resolution of Yana upgrade.
  • the present disclosure provides an electrodynamic microfluidic droplet dispenser for continuously generating a micro volume of droplets, quantifying to obtain a desired volume of liquid, including: a displacement actuator for providing displacement to the microfluidic chip or a force impact comprising a rigid extension member; a microfluidic chip separated from and replaceable with the displacement actuator, comprising a cavity and a spout, the cavity being knocked by a rigid extension of the displacement actuator The liquid is ejected from the nozzle by droplets.
  • the microfluidic chip is a plug-and-play chip.
  • the microfluidic chip includes a support layer, an elastic layer, and a pipe layer that are sequentially stacked; the cavity is formed in the pipe layer; the spout is formed on the pipe layer or support Floor.
  • the microfluidic chip further includes: forming the elasticity a liquid injection port of the layer; and a pipe formed in the pipe layer, communicating the cavity and the liquid inlet.
  • the microfluidic chip further includes: a reservoir formed in the pipe layer and a pipe, the pipe communicating with the cavity and the reservoir, the reservoir opening There is a connecting hole.
  • the elastic layer and the pipe layer are polymer materials
  • the support layer is a polymer material or glass.
  • the method further includes: a liquid taking device for extracting the liquid.
  • the liquid take-off device is a set of piston systems.
  • the piston system includes a sleeve and a piston; the bottom end of the piston is provided with a spring, and a piston inner bore is formed, and the inner bore of the piston is connected to the air valve through the through hole;
  • the microfluidic chip is mounted on the bottom end of the sleeve, and the connecting hole communicates with the inner hole of the piston, and the cavity is opposite to the rigid extension of the displacement actuator.
  • the end of the microfluidic chip nozzle is at the tip end.
  • the sleeve is provided with a detaching mechanism for removing the microfluidic chip.
  • the nozzle end face of the microfluidic chip has a micro-nano-trench structure that causes the nozzle end face to change from a hydrophobic surface to a permanent super-hydrophobic surface.
  • the method further includes: a housing for loading and fixing the displacement actuator, the microfluidic chip, and the control system.
  • the bottom end of the housing is provided with a space for mounting a microfluidic chip and a mounting structure, and the microfluidic chip is mounted to the bottom end of the housing by a mounting structure.
  • the mounting structure is a receiving slot.
  • the method further includes: a control system, the control system comprising: a control module for accepting input of a parameter, outputting a control signal required by the displacement actuator; and a display module for inputting the parameter And outputting an operating parameter of the electric microfluidic droplet dispenser; and a power module for supplying power to the entire motorized microfluidic droplet distributor.
  • a control system comprising: a control module for accepting input of a parameter, outputting a control signal required by the displacement actuator; and a display module for inputting the parameter And outputting an operating parameter of the electric microfluidic droplet dispenser; and a power module for supplying power to the entire motorized microfluidic droplet distributor.
  • control module includes: a microprocessor for generating a pulse control signal; and a DC voltage stabilizing circuit for providing a drive to the displacement actuator through the switch selection circuit a signal selection switch circuit that controls the on and off of the drive signal in response to a pulse control signal of the microprocessor.
  • the motorized microfluidic droplet dispenser is a handheld or desktop desktop
  • the power module is a built-in battery or an external power source.
  • the displacement actuator vibrates for one cycle, the orifice of the microfluidic chip ejects a droplet; and/or the droplet size is affected by the displacement actuator velocity, Stroke regulation.
  • the displacement actuator is electromagnetically driven, piezoelectrically driven, or electrostatically driven; and/or the displacement actuator is reusable; and/or the rigid extension is movable along it
  • the direction is not scalable; and/or the microfluidic chip is used as a disposable ink cartridge for liquid storage and transportation.
  • microfluidic chip can be plugged and replaced, which is convenient and quick to use.
  • the microfluidic chip is separated from the displacement actuator without cleaning and no cross contamination;
  • the volume of a single droplet produced is smaller, the typical volume is from 0.1 nanoliter to 10 nanoliters, the single droplet volume CV value is less than 3.4%, the printing direction can be any direction, and the submicroliter volume is added by multiple printing. In the case of the sample, the average effect will further reduce the random error;
  • the droplet printing frequency is high, the frequency of droplet generation can reach 50Hz and 500-1000Hz; the liquid residual volume of the microfluidic chip is less than 1 microliter, and the waste is less;
  • the microfluidic chip is made of polymer material, has low cost, simple device, small size, and is easy to design as a handheld or portable desktop instrument.
  • FIG. 1 is a schematic diagram of functional modules of an electric microfluidic droplet dispenser according to an embodiment of the present disclosure.
  • FIG. 2 is a schematic structural view of an electric microfluidic droplet dispenser according to an embodiment of the present disclosure.
  • FIG 3 is a schematic view showing a printing process of an electric microfluidic droplet dispenser according to an embodiment of the present disclosure.
  • FIG. 4 is a schematic structural view of a microfluidic chip of an electro-microfluidic droplet dispenser according to an embodiment of the present disclosure.
  • FIG. 5 is a schematic view showing the structure of a pipe of an electric microfluidic droplet dispenser according to an embodiment of the present disclosure.
  • FIG. 6 is a schematic diagram of a control module of an electric microfluidic droplet dispenser according to an embodiment of the present disclosure.
  • FIG. 7 is a circuit schematic diagram of a control module of an electric microfluidic droplet dispenser according to an embodiment of the present disclosure.
  • Figure 8 is a schematic view showing the distribution of the photographed droplets and the droplet size, wherein (a) is a photograph of the printed droplet, (b) is a distribution diagram of the droplet size, and (b) the abscissa is the droplet volume. The unit is nanoliter, and the ordinate is the number of droplets.
  • FIG. 9 is a schematic structural view of a microfluidic chip of an electric microfluidic droplet dispenser according to another embodiment of the present disclosure.
  • FIG. 10 is a schematic diagram of liquid production of an electro-microfluidic droplet dispenser of another embodiment of the present disclosure.
  • FIG. 11 is a schematic diagram of functional modules of an electric microfluidic droplet dispenser according to another embodiment of the present disclosure.
  • FIG. 12 is a schematic structural view of an electric microfluidic droplet dispenser according to another embodiment of the present disclosure.
  • Figure 13 is a photograph of the droplets detached from the cross section before and after the nozzle end face treatment; (a) shows the untreated hydrophobic surface droplets falling off; (b) shows the droplets falling off after the superhydrophobic treatment; (c) shows the untreated The contact angle of the surface water droplets; (d) shows the contact angle of the surface water droplets after the superhydrophobic treatment.
  • Figure 14 is a diagram showing the size distribution of printed liquid droplets in another embodiment of the present disclosure.
  • 2-microfluidic chip 21-connection hole; 22-reservoir; 23-cavity; 25-elastic layer; 26-pipe layer; 27-support layer; 28-injection port;
  • the inner functional area of the droplet dispenser comprises three parts: a microfluidic chip as a liquid cartridge, a displacement actuator, A control system consisting of a power module, a control module and a display module.
  • the main functions of the control system are parameter input, result display and signal output.
  • the droplet dispenser of this embodiment may be hand-held or desktop, and the power module may be either a built-in battery or an external power source.
  • the various components of the droplet dispenser are located in the casing 4, and the battery 5 as a power module is connected to the circuit board 8 by wires.
  • the control module includes a circuit board 8, a button 7 for parameter input, a switch selection circuit and a single-chip microcomputer, and a display screen 6 as a display module is disposed on the circuit board.
  • the circuit board 8 is connected to the displacement actuator 1, which is, for example, an electromagnetic displacement actuator, and may also be a piezoelectric displacement actuator or an electrostatic displacement actuator.
  • the bottom end of the outer casing 4 is provided with a space for mounting a microfluidic chip and a mounting structure.
  • the microfluidic chip is mounted on the bottom end of the outer casing through a mounting structure, and the displacement actuator 1 strikes the microfluidic chip through a rigid extension connected thereto.
  • the cavity on the second body causes the liquid in the cavity to be ejected by droplets, and the rigid extension member is an elongated structure.
  • the mounting structure can be, for example, a receiving slot, and the microfluidic chip can be inserted and removed in the receiving slot. As shown in FIG.
  • the microfluidic chip 2 is designed based on the microfluidic principle, and includes a three-layer structure: an upper elastic layer, an intermediate pipe layer and a lower support layer, and the elastic layer and the pipe layer can be supported by a polymer material.
  • the layer may be a polymer material or glass, and the polymer material is, for example, PDMS (polydimethylsiloxane).
  • the elastic layer is formed with a liquid filling port 28, which is also a liquid storage tank of the microfluidic chip.
  • the pipe layer is formed with a cavity and a pipe connecting the liquid injection port 28 and the cavity, and the cavity position is positively displaced.
  • the rigid extension of the device 1 has a nozzle 3 having a smaller diameter.
  • the nozzle size is from 25 micrometers to 100 micrometers in diameter, and the height and width of the conduit are generally selected from the range of 50 micrometers to 200 micrometers and the length is about 10 to 30 millimeters.
  • the chamber for receiving the impact has a diameter ranging from 200 microns to 2 mm.
  • the liquid can be dripped into the liquid injection port of the microfluidic chip through a tool such as a syringe, and the liquid flows into the cavity through the pipeline until the cavity, the pipe and the liquid injection port are charged. Full of liquid, the injection port is now used as a reservoir.
  • the microfluidic chip of this embodiment is a plug-and-play type chip. Specifically, the microfluidic chip is mounted in a receiving groove at the bottom end of the housing, and the cavity position is opposite to the rigid extension of the actuator.
  • the pipe structure of the embodiment is such that the cavity is impacted by the rigid extension member, the flow resistance from the cavity to the nozzle is larger than the flow resistance of the cavity to the liquid injection port, and a small amount (nanoliter and below) of the droplet in the cavity is discharged from the nozzle.
  • the liquid in the liquid injection port is automatically injected into the cavity through the pipe to prepare the droplet printing of the next impact.
  • the microfluidic chip is pulled out from the receiving groove at the bottom end of the casing, and other microfluidic chips can be replaced.
  • the displacement actuator of the droplet dispenser of the present disclosure is separate from the microfluidic chip, and the displacement actuator is not in contact with the reagent liquid.
  • the reagent is replaced, only the low-cost microfluidic chip needs to be replaced, and the microfluidic chip can be plugged and replaced, which is convenient and quick to use, which makes the present disclosure different from the conventional printing droplet generating method.
  • the processing of the microfluidic chip is described as follows: firstly apply SU-8 photoresist to a specified thickness (typically 75 microns), photolithography to obtain a pattern opposite to the desired structure; then spin-on PDMS to cover it to a specified thickness (Typical value 200 microns), demoulding after heating and baking, hand-punching to obtain liquid injection holes; spin-coating on glass to obtain 100 micron thick PDMS film, laser drilling to form nozzle (typical diameter 100 microns), convenient The PDMS film is peeled off, and a layer of 1-2 micron thick photoresist can be spin-coated on the glass. After the plasma treatment of the two obtained PDMS, the alignment is bound to form a desired microfluidic chip. If the support layer is chosen for glass (such as a common cover slip), the glass can be directly punched with a laser and then bonded to PDMS using the same treatment.
  • the spout 3 can be opened in the lower support layer; as shown in Fig. 4 (c), the pipe layer can also be opened in the middle, that is, the liquid droplets can be printed in parallel impact direction. It can also be printed in the direction of vertical impact.
  • the nozzle position can be directly below the impact point, i.e., directly opposite the position of the rigid extension of the displacement actuator 1.
  • the position of the displacement actuator 1 may not be displaced immediately below the impact point. If the spout is on the same floor as the pipe, as shown in Figure 4(c), the spout structure can be machined with the pipe without punching holes in the support layer.
  • the pipe may be a straight pipe or a curved one, and the length and structure thereof may be flexibly set.
  • the control module generally includes a single chip microprocessor, a DC voltage regulator circuit, and a switch selection circuit.
  • a single chip microprocessor When using, first manually input the number of droplets, that is, the number of electric pulses, liquid The parameters such as the drop size are given to the microcontroller of the single chip microcomputer, and the single chip microcomputer generates the pulse control signal with the specified parameters.
  • the switch selection circuit When the pulse control signal is high, the switch selection circuit is turned on, so that the current passing through the DC voltage regulator circuit passes through the switch selection circuit, and the electromagnetic displacement actuator is loaded with a voltage to generate a forward shock.
  • the switch selection circuit When the pulse control signal is low, the switch selection circuit is turned off, and the electromagnetic displacement actuator has no electromagnetic force and is retracted under the spring restoring force.
  • RL is a displacement actuator
  • U0, U1 are DC voltage regulator circuit chips, transistors Q1 and Q2, and impedance components R1, R2, RS1, and RS2 form a switch selection circuit.
  • the external 9V power supply is connected to the DC voltage regulator circuit chip U1 (SP1117-3.3) and the DC voltage regulator circuit chip U0 (LM7806KC), which are powered by three ports and one port.
  • the 2-port of the DC voltage regulator circuit chip U1 is connected to the VIO and VDD pins of the microprocessor (EFM8LB12F64E) to provide 3.3V for the microprocessor.
  • the P1.5 pin of the microprocessor is connected to the transistor Q1 via RS1 (2.2K ⁇ ).
  • the 3-port of the DC voltage regulator circuit chip U0 is connected to the collector of the transistor Q2, and is connected to the collector of Q1 via R1 (330 ⁇ ) and R2 (480 ⁇ ).
  • the collector of Q1 is connected to the base of the transistor Q2 via R2 (480 ⁇ ) and RS2.
  • the emitter of Q2 is connected to the displacement actuator RL, and the other end of the displacement actuator RL is grounded.
  • Such a pulse control signal causes the electromagnetic displacement actuator and its rigid extension to generate a pulse displacement shock vibration, and the vibration frequency and vibration width of the pulse displacement shock vibration are controlled by the microprocessor, and the vibration amplitude is regulated by DC Circuit control.
  • the vibration of the electromagnetic displacement actuator impinges on the surface of the elastic layer corresponding to the microfluidic chip cavity, so that the liquid in the chip tube is accelerated.
  • the minimum velocity of a single droplet is:
  • ⁇ is the surface tension coefficient
  • ⁇ is the liquid density
  • d n is the nozzle diameter
  • V i is a cavity deformation volume caused by the displacement actuator striking the microfluidic chip cavity, or a volume of the liquid discharged by the deformation, which is determined by the impact displacement s of the cavity and the cavity diameter d i ;
  • R n And R r represent the flow resistance from the cavity to the spout and the cavity to the injection port, respectively.
  • the flow resistance ratio is only affected by the microfluidic chip tube size and nozzle size.
  • the ratio of impact displacement, cavity diameter, and flow resistance can affect the droplet volume.
  • d n is the diameter of the nozzle
  • h, w, L, l represent the height and width of the microfluidic chip tube, the length of the liquid injection port to the cavity and the length of the nozzle, respectively. It can be seen that when the diameter of the nozzle is small, the volume of the droplet decreases by four times as the diameter decreases. Therefore, the most direct method is to control the droplet size by regulating the size of the orifice, and it is possible to obtain droplets having a single volume ranging from 0.1 nanoliter to several nanoliters.
  • the droplet print frequency of the droplet dispenser of the present disclosure is high, and the frequency of droplet generation depends on the displacement actuator frequency at low frequencies.
  • the general electromagnetic displacement actuator frequency is below 50 Hz, and the droplet generation frequency can also reach 50 Hz.
  • the droplet generation frequency depends on the liquid filling speed in the chamber, which can generally reach 500-1000 Hz.
  • Figure 8 is a photograph of a print drop (Figure 8 (a)) and droplet size distribution ( Figure 8 (b)).
  • the mean volume of the droplets was 1.3 nanoliters, and the statistical dispersion of the 73 droplet samples was CV ⁇ 3.6%.
  • the droplet dispenser is based on the principle of droplet printing, and can perform reagent loading with high precision. It can be used for basic operations such as liquid injection and dilution commonly used in biochemical laboratories.
  • the resolution of a single injection can be as high as 0.1 nanoliters, and the upper limit of a typical range is 10 microliters, which can solve the problem that the precision of the high precision micropipette in the microliter and submicroliter droplets is low.
  • the entire instrument is simple in structure and convenient to operate. It can not only replace the current highest precision micropipettes, but also further expand the ability to operate on smaller volumes of liquid. Has a promising application prospect.
  • the microfluidic chip 2 includes an elastic layer 25, a pipe layer 26 and a support layer 27.
  • the pipe layer is formed with a reservoir, a cavity and a spout which are connected by a pipe, and the cross-sectional area of the end of the spout 3 of the microfluidic chip is
  • the taper is formed to form a tip end at the opposite end of the spout, and the reservoir 22 is further provided with a connecting hole 21 for communicating with the outside.
  • the flow resistance from the cavity to the nozzle is larger than the flow resistance of the cavity to the reservoir, and a small amount (nanoliter and below) of droplets in the cavity is ejected from the nozzle, as shown in FIG. 10;
  • the liquid in the reservoir is automatically injected into the cavity from the inlet of the chamber, ready for the next impact of the droplet printing.
  • the electro-microfluidic droplet dispenser further includes a liquid take-off device.
  • the liquid take-up device is a set of piston systems including a sleeve 10 and a piston 9, a battery 5 and a displacement actuator. 1 Installed in the mounting cavity of the outer wall of the sleeve, the circuit board 8, the control module and the display screen 6 are fixed on the outer wall of the sleeve.
  • the bottom end of the piston 9 is provided with a spring returning structure, and a piston inner hole is formed.
  • the inner hole of the piston is a hollow cylinder, and the outer wall of the hollow cylinder is provided with a through hole.
  • the through hole is connected with an air valve 102, and the switch of the air valve can be Control the gas pressure in the bore of the piston.
  • the microfluidic chip 2 is mounted on the bottom end of the sleeve 10.
  • the connection hole 21 of the microfluidic chip is in communication with the inner bore of the piston, and the cavity of the microfluidic chip faces the rigid extension 11 of the displacement actuator.
  • the sleeve 10 is further provided with a detaching mechanism. When the printing is completed, the microfluidic chip 2 is removed from the motorized microfluidic droplet dispenser by pressing the detaching button 101 to replace the new microfluidic chip.
  • the air valve is opened, and the rest of the process is similar to that of the previous embodiment, and the liquid in the microfluidic chip is printed into a uniform volume liquid by microfluidic impact printing. drop.
  • the number of prints determines the number of drops, which in turn controls the volume of the sample.
  • the number of droplets can be pre-set using the control module and control the number of displacement actuator impacts during printing.
  • the printing process is as follows: using the impact generated by the electric displacement actuator, hitting the elastic layer corresponding to the cavity of the microfluidic chip, the deformation of the elastic layer accelerates the liquid in the chip tube, and the liquid enters the cavity inlet and the nozzle Flowing in direction, the liquid flowing out of the spout has sufficient velocity to overcome the surface tension at the outlet, and at the same time has a small volume, and finally ejects from the nozzle of the chip to form an ultra-small volume (ranging from 0.1 nanoliter to 100 nanoliter). .
  • the displacement actuator is retracted, the elastic layer retracts under the restoring force of its own structure, and a negative pressure is generated in the cavity.
  • the liquid at the spout and inlet has a tendency to flow toward the cavity.
  • the flow resistance in the direction of the nozzle is large, preventing air from flowing back into the cavity; the flow resistance in the inlet direction is small, so that the liquid completes the liquid replacement from the reservoir into the cavity. Wait for the next drop generation.
  • the microfluidic chip can be replaced without cleaning.
  • the air valve When the electric microfluidic droplet dispenser extracts the liquid, the air valve is closed, and the nozzle of the microfluidic chip is immersed in the liquid. Under the action of the spring restoring force, the piston retracts to generate a negative pressure in the inner hole of the piston, and the liquid flows through the microflow. The nozzle, cavity and pipeline of the control chip flow into the liquid storage tank to complete liquid extraction.
  • the piston system can be either electronically controlled or manual, and the piston button 91 has a volume adjustment function that adjusts the volume of the extracted liquid.
  • the nozzle end face of the microfluidic chip has a micro-nano groove structure with a width of 20 micrometers and a pitch of 30 micrometers, and forms a microfluidic chip with a superhydrophobic end face.
  • the groove structure can make the nozzle end face change from the original hydrophobic surface (contact angle is about 93 degrees) to a permanent superhydrophobic surface (contact angle is greater than 150 degrees, 154 degrees), and Figure 13 shows the nozzle before and after the nozzle end face treatment.
  • the effect map is produced, (a) shows the untreated hydrophobic surface droplets falling off, (b) shows the droplets falling off after the superhydrophobic treatment, (c) shows the contact angle of the untreated surface water droplets, and (d) shows the superhydrophobic treatment
  • the contact angle of the water droplets on the back surface Applicant's research has found that when the droplets are desorbed from the surface of the nozzle against surface tension, the droplet size is affected by the size of the nozzle, and there are ultra-small droplets on the common surface (including the general hydrophobic surface), which affects the droplets. The consistency of size. At the same time, after the chip nozzle is immersed in the liquid suction liquid, liquid is easily left at the end face of the nozzle.
  • Figure 14 is a statistical effect of photographing 75 liquid volumes using a high speed camera with a volume coefficient of variation (CV) of less than 3.4%.
  • the processing process of the microfluidic chip in this example is as follows: first, the mold is manufactured by 3D printing, and then the microfluidic chip is processed by demolding and bonding. There are two molds, one for processing the elastic layer, here the upper layer, and the other for integrally processing the pipe layer and the support layer, referred to herein as the lower layer.
  • the specific processing process is described as follows: Firstly, the mold model of the elastic layer (upper layer) and the pipe layer support layer (lower layer) is respectively established by using the three-dimensional modeling software Solidworks, and then the precision 3D printer (Projet 3500HDMax, 3D Systems) and the 3D printing material (VisiJet M3Crystal) are utilized. ) Print molding.
  • PDMS two-component reagent ( 184, Dow Corning) was mixed at a mass ratio of 10:1, and then the two molds were respectively poured, placed in a 90 ° C oven for 30 minutes, and taken out, and the solidified PDMS was released after cooling. Then, using a plasma cleaner (PDC-MG, Ming Heng), the PDMS structure obtained by the two demoldings was subjected to a plasma treatment in an environment of about 100 Pa for about 50 seconds, and then aligned to form a desired one. Microfluidic Chip.
  • a plasma cleaner PDC-MG, Ming Heng
  • a femtosecond laser (Chameleon Vision-S / Legend Elite F HE-1K, Coherent) was used to ablate the entire end face by 20 micrometers at a power of 60 milliwatts and a scan speed of 1 millimeter per second.
  • the present disclosure separates the displacement actuator from the microfluidic chip, which is not in contact with the reagent liquid.
  • the droplet dispenser is based on the principle of droplet printing, and can perform reagent loading with high precision, which is different from the traditional pipette working mode. It can be used in basic operations such as transfer liquids and diluted samples commonly used in biochemical laboratories.
  • the resolution of a single injection can be as high as 0.1 nanoliter, which can solve the problem that the current high precision micropipette has low precision in microliter and submicroliter droplet operation.
  • the entire instrument is simple in structure and convenient to operate. It can not only replace the current highest precision micropipettes, but also further expand the ability to operate on smaller volumes of liquid. Has a promising application prospect.

Abstract

一种电动微流控液滴分配器，包括：位移致动器(1)，用于给微流控芯片(2)提供位移或者力冲击，包括刚性延长件(11)；微流控芯片(2)，与位移致动器(1)分离并可更换，包括腔体(23)和喷口(3)，腔体(23)被位移致动器(1)的刚性延长件(11)敲击，使液体以液滴方式从喷口(3)喷出。

Description

电动微流控液滴分配器 技术领域
本公开属于实验器具技术领域，特别涉及一种电动微流控液滴分配器，用于液体的定量化加样、分配和抽取。
背景技术
分液器与移液器是生物、化学实验室常用的小量移取液体的可手持操作的仪器，其主要工作原理是通过活塞的抽吸与挤压完成对液体的转移：吸取与排出。这一种移液器又被称为“空气移位移液器(air displacement pipette)，利用活塞中密封的空气垫的移位来将液体吸入与排出。其初始原理早在1957被Heinrich Schnitger提出并申请了专利。其后一系列专利技术造就了现代移液器的基本结构与形式，如美国专利《Pipetting system》(专利号：US3494201A，日期：1970年2月10日)。不同于活塞式操作连续液体，另一种方法——打印将液体/试剂分割成一个个离散的液滴，而单个液滴体积可以小至皮升量级。目前，这一技术已广泛应用于图文制备，如目前商用的压电与热电喷墨打印。欧洲专利《Droplet deposition apparatus》(专利号：EP0277703A1，公开日：1988年8月10日)揭示了一种压电喷墨打印装置，包括压电致动器、喷口、与喷口相连的腔体，脉冲电信号驱动压电致动器进行按需打印(drop-on-demand)。这种打印方式驱动器与喷口(也称喷孔)一体化，喷口容易被堵塞，也不能轻易更换喷孔。在喷墨打印的基础上，美国专利《method for rapid dispensing of minute quantities of viscous material》(专利号：5320250，日期：1994年6月14)提出了利用电磁驱动器冲击弹性腔体，进行粘性材料打印的方法。为避免需要清洗堵塞的喷口，带有喷口的腔体可以更换，但并不能像一次性移液器吸头那样即插即换。打印时，需要通过一个外接气源从墨盒向腔体内注入粘性墨水，效率很低。采用即插即用可更换墨盒芯片进行液滴打印的原理研究近年来开始国际上出现报道：如2013年《Lab on a chip》(13卷，1902)，2015年《Biomicrofluidics》(9卷，054101)报道了Tingrui Pan的研究组在此方面的探索，2016年Anas Bsoul在《Lab on a chip》(16卷，3351)也提出类似方法，均指出这种采用冲击打印，可更换墨盒芯片方法在微量 液体操作方面精度高，成本低，具有巨大应用前景。
传统的滴定管、移液器等器具操作体积在微升及以上液体时，具有较高的精确度。但在实现1微升以下体积的加样时，误差较大。如Eppendorf公司的0.1μL-2.5μL量程的微移液器，加样0.25微升液体，随机误差(CV值，变异系数)达到6％，0.1微升时，随机误差达到12％。Rainin公司的0.1μL-2μL量程的微移液器在0.2μL时，随机误差为6％。对于超小体积液体的操作，一般通过气动式或打印方式实现。目前产品有：TTP Labtech公司的Mosquito系列，Tecan公司的D300e数字分液器等。但都是自动化操作平台，在手持器具或小型便携式台式设备领域尚未涉及。这是因为气动式一般需要后接气源与气路控制，移动受限。而打印方式目前流行的喷墨打印由于其打印头需要经常清洗或更换，使用成本太高，不利用手持型小型化。采用微流控冲击打印方式可以实现皮升到纳升分辨率液滴的打印；采用低成本可更换芯片可以实现即插即用，无交叉污染应用；其简单结构设计有望实现手持式高精度液体的分配。
发明内容
为了解决现有分液器/移液器在操作更小体积液体时误差过大的问题，实现微流控液滴分配器具有抽吸液体的功能，本公开提出一种基于微流控打印的电动微流控液滴分配器，实现了液体的抽吸与液体的分配，并可达到亚纳升级分辨率。
本公开提供了一种电动微流控液滴分配器，用于连续产生微量体积液滴，定量化获得所需体积液体，包括：位移致动器，用于给微流控芯片提供位移或者力冲击，其包括一刚性延长件；微流控芯片，与所述位移致动器分离并可更换，包括一腔体和喷口，所述腔体被所述位移致动器的刚性延长件敲击，使液体以液滴方式从喷口喷出。
在本公开的一些实施例中，所述微流控芯片为即插即换式芯片。
在本公开的一些实施例中，所述微流控芯片包括依次层叠的支撑层、弹性层和管道层；所述腔体形成于所述管道层；所述喷口形成于所述管道层或支撑层。
在本公开的一些实施例中，所述微流控芯片还包括：形成于所述弹性 层的注液口；以及形成于所述管道层、连通所述腔体和注液口的管道。
在本公开的一些实施例中，所述微流控芯片还包括：形成于所述管道层的储液池和管道，所述管道连通所述腔体和储液池，所述储液池开有一连接孔。
在本公开的一些实施例中，所述弹性层、管道层为高分子材料，所述支撑层为高分子材料或玻璃。
在本公开的一些实施例中，还包括：一取液装置，用于抽取液体。
在本公开的一些实施例中，所述取液装置为一套活塞系统。
在本公开的一些实施例中，所述活塞系统包括套筒和活塞；所述活塞底端带有弹簧，并形成有一活塞内孔，所述活塞内孔经通孔与空气阀连接；所述微流控芯片安装于套筒底端，其连接孔与活塞内孔连通，其腔体正对位移致动器的刚性延长件。
在本公开的一些实施例中，微流控芯片的喷口所在的一端为尖端。
在本公开的一些实施例中，所述套筒设置有脱附机构，用于卸除微流控芯片。
在本公开的一些实施例中，所述微流控芯片的喷口端面具有微纳米沟槽结构，所述微纳米沟槽结构使喷口端面由疏水表面变为永久性超疏水表面。
在本公开的一些实施例中，还包括：外壳，用于位移致动器、微流控芯片与控制系统的装卡与固定。
在本公开的一些实施例中，所述外壳底端设有用于安装微流控芯片的空间及安装结构，所述微流控芯片通过安装结构安装于外壳底端。
在本公开的一些实施例中，所述安装结构是容置槽。
在本公开的一些实施例中，还包括：控制系统，所述控制系统包括：控制模块，用于接受参数的输入，输出位移致动器所需控制信号；显示模块，用于在参数的输入、输出时显示电动微流控液滴分配器的工作参数；以及电源模块，用于给整个电动微流控液滴分配器供电。
在本公开的一些实施例中，所述控制模块包括：微处理器，用于产生脉冲控制信号；直流稳压电路，通过开关选择电路向位移致动器提供驱动 信号；开关选择电路，响应于微处理器的脉冲控制信号而控制驱动信号的通断。
在本公开的一些实施例中，其中：所述电动微流控液滴分配器为手持式或桌面台式；所述电源模块是内置电池或外接电源。
在本公开的一些实施例中，所述位移致动器振动一个周期，所述微流控芯片的喷孔喷射出一个液滴；和/或，所述液滴大小受位移致动器速度、冲程调控。
在本公开的一些实施例中，所述位移致动器由电磁驱动、压电驱动或静电驱动；和/或所述位移致动器可重复使用；和/或所述刚性延长件沿其运动方向不可伸缩；和/或所述微流控芯片作为可抛弃墨盒，用于液体的储存、输运。
从上述技术方案可以看出，本公开电动微流控液滴分配器至少具有以下有益效果其中之一：
(1)微流控芯片可以即插即换，使用方便快捷，微流控芯片与位移致动器分离，无需清洗，没有交叉污染；
(2)不仅可以分配液体还可以抽取液体，功能多样。
(3)产生的单个液滴体积更小，典型体积在0.1纳升至10纳升，单个液滴体积CV值小于3.4％，打印方向可以是任意方向，通过多次打印进行亚微升体积加样时，平均效应会进一步减小随机误差；
(4)液滴打印频率高，液滴产生的频率可以达到在50Hz和500-1000Hz；微流控芯片的液体剩余体积小于1微升，浪费少；
(5)采用单片机控制打印液滴数量，电动打印分液，自动化程度高；
(6)微流控芯片采用高分子材料制作，成本低，装置简单、体积小、易设计为手持式或便携桌面台式仪器。
附图说明
附图是用来提供对本公开的进一步理解，并且构成说明书的一部分，与下面的具体实施方式一起用于解释本公开，但并不构成对本公开的限制。在附图中：
图1是本公开一实施例电动微流控液滴分配器的功能模块示意图。
图2是本公开一实施例电动微流控液滴分配器的结构示意图。
图3是本公开一实施例电动微流控液滴分配器的打印过程示意图。
图4是本公开一实施例电动微流控液滴分配器的微流控芯片结构示意图。
图5是本公开一实施例电动微流控液滴分配器的管道结构示意图。
图6是本公开一实施例电动微流控液滴分配器的控制模块示意图。
图7是本公开一实施例电动微流控液滴分配器的控制模块电路原理图。
图8为所打印液滴照片与液滴尺寸的分布示意图，其中，(a)为所打印液滴照片，(b)为液滴尺寸的分布示意图，(b)中横坐标是液滴体积，单位是纳升，纵坐标是液滴个数。
图9是本公开另一实施例电动微流控液滴分配器的微流控芯片结构示意图。
图10是本公开另一实施例电动微流控液滴分配器的液体产生示意图。
图11是本公开另一实施例电动微流控液滴分配器的功能模块示意图。
图12是本公开另一实施例电动微流控液滴分配器的结构示意图。
图13为喷口端面处理前后，液滴从断面脱附的照片；(a)显示了未处理疏水表面液滴脱落；(b)显示了超疏水处理后液滴脱落；(c)显示了未处理表面水滴接触角；(d)显示了超疏水处理后表面水滴的接触角。
图14是本公开另一实施例打印液滴的尺寸分布图。
【符号说明】
1-位移致动器；11-刚性延长件；
2-微流控芯片；21-连接孔；22-储液池；23-腔体；25-弹性层；26-管道层；27-支撑层；28-注液口；
3-喷口；4-外壳；5-电池；6-显示屏；7-按键；8-电路板；9-活塞；10-套筒；91-活塞按钮；101-脱附按钮；102-空气阀。
具体实施方式
为使本公开的目的、技术方案和优点更加清楚明白，以下结合具体实施例，并参照附图，对本公开进一步详细说明。
下面将结合本公开实施例中的附图，对本公开实施例中的技术方案进 行清楚、完整地描述，显然，所描述的实施例仅仅是本公开一部分实施例，而不是全部的实施例。基于本公开中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本公开保护的范围。
如图1所示，本公开一实施例的电动微流控液滴分配器，该液滴分配器内部功能区包括三部分：一个微流控芯片作为盛液体的墨盒，一个位移致动器，一个由电源模块、控制模块与显示模块组成的控制系统，该控制系统主要功能是参数输入、结果显示与信号输出。
本实施例的液滴分配器可以是手持式的，也可以是桌面台式的，电源模块既可以是内置电池，也可以是外接电源。以内置电池供电的手持式液滴分配器为例，参见图2，液滴分配器的各个部件位于外壳4内，作为电源模块的电池5通过导线连接电路板8。控制模块包括电路板8、用于参数输入的按键7、开关选择电路和单片机微处理器，电路板上设置有作为显示模块的显示屏6。电路板8连接位移致动器1，位移致动器1例如为电磁位移致动器，也可以是压电位移致动器或静电位移致动器。外壳4底端设有用于安装微流控芯片的空间及安装结构，微流控芯片通过安装结构安装于外壳底端，位移致动器1通过其上连接的刚性延长件敲击微流控芯片2上的腔体，使腔体内的液体以液滴方式喷出，刚性延长件为一细长结构。其中，该安装结构例如可以是容置槽，微流控芯片可插拔的安装在该容置槽中。如图3所示，微流控芯片2基于微流控原理设计，包括三层结构：上层的弹性层，中间的管道层和下层的支撑层，弹性层和管道层可以采用高分子材料，支撑层可以采用高分子材料或玻璃，高分子材料例如是PDMS(聚二甲基硅氧烷)。弹性层形成有注液口28，注液口28同时也是微流控芯片的储液池，管道层形成有腔体以及连通注液口28和腔体的管道，腔体位置正对位移致动器1的刚性延长件，腔体开有一个直径较小的喷口3。喷口尺寸直径在25微米到100微米，管道高度与宽度一般选择50微米到200微米范围，长度约10到30毫米。用于接受冲击的腔体直径从200微米到2毫米。
电动微流控液滴分配器工作时，可以通过注射器等工具将液体滴入微流控芯片的注液口，液体经管道流进腔体，直到腔体、管道和注液口均充 满液体，注液口此时作为储液池使用。
本实施例的微流控芯片为即插即换式的芯片，具体来说，将微流控芯片安装于外壳底端的容置槽中，腔体位置正对移致动器的刚性延长件。本实施例的管道结构使得腔体被刚性延长件冲击时，从腔体到喷口的流阻大于腔体到注液口的流阻，腔体中的微量(纳升及以下)液滴从喷口喷出，且在冲击结束位移致动器回缩时，由于喷口的流阻Rn流阻较大，使得注液口中的液体自动经管道注入腔体，准备下一次冲击的液滴打印。打印完成或需要更换类型液体试剂时，将微流控芯片从外壳底端的容置槽中拔出，更换其他微流控芯片即可。
本公开液滴分配器的位移致动器与微流控芯片相分离，位移致动器不接触试剂液体。更换试剂时只需要更换低成本微流控芯片，微流控芯片可即插即换，使用方便快捷，这使本公开区别于传统打印液滴生成方式。
微流控芯片的加工过程描述如下：先旋涂SU-8光刻胶到指定厚度(典型值75微米)，光刻得到与所需结构相反的图形；再旋涂PDMS覆盖其上到指定厚度(典型值200微米)，加热烘烤后脱模，手工打孔得到注液孔；在玻璃上旋涂得到100微米厚PDMS薄膜，用激光打孔形成喷口(典型值直径100微米)，为方便PDMS薄膜剥离，可以在玻璃上先旋涂一层1-2微米厚光刻胶；对两次得到的PDMS进行等离子体处理后，对准绑定在一起形成所需微流控芯片。如果支撑层选择玻璃(如常用盖玻片)，可以直接用激光对玻璃打孔，然后用同样处理方法与PDMS绑定。
如图4(a)，4(b)所示，喷口3可以开设在下层的支撑层；如图4(c)所示，也可以开设在中间的管道层，即液滴可以平行冲击方向打印，也可以垂直冲击方向打印。如图4(a)所示，喷口位置可以在冲击点正下方，即与位移致动器1的刚性延长件位置正对。如图4(b)所示，也可以不在冲击点正下方，即与位移致动器1位置错开。如果喷口与管道在同一层，如图4(c)，则喷口结构可以与管道一起加工，无需在支撑层打孔。如图5所示，示出了管道层的各种结构，管道一端连接注液口，另一端连接腔体，管道可以是直管，也可以是弯曲的，其长度、结构可以灵活设置。
如图6所示，控制模块一般包括一个单片机微处理器、直流稳压电路和开关选择电路。使用时，首先手工输入液滴滴数，即产生电脉冲数，液 滴大小等参数给单片机微处理器，单片机产生指定参数的脉冲控制信号。当脉冲控制信号为高电平时，开关选择电路打开，让经过直流稳压电路的电流通过开关选择电路，电磁位移致动器被加载电压，产生向前的冲击。当脉冲控制信号为低电平时，开关选择电路关闭，电磁位移致动器没有电磁力，在弹簧回复力作用下回缩。
控制模块的电路图如图7所示，图中RL为位移致动器，U0，U1为直流稳压电路芯片，三极管Q1、Q2以及阻抗元件R1、R2、RS1、RS2等组成开关选择电路。外接9V电源分别接直流稳压电路芯片U1(SP1117-3.3)和直流稳压电路芯片U0(LM7806KC)的3端口和1端口，为二者供电。直流稳压电路芯片U1的2端口接微处理器(EFM8LB12F64E)的VIO和VDD管脚，为微处理器提供3.3V电压，微处理器的P1.5管脚经RS1(2.2KΩ)接三极管Q1的基极。直流稳压电路芯片U0的3端口接三极管Q2的集电极，并经R1(330Ω)和R2(480Ω)接Q1的集电极，Q1的集电极经R2(480Ω)和RS2接三极管Q2的基极，Q2的发射极接位移致动器RL，位移致动器RL另一端接地。
这样一个脉冲控制信号使得电磁位移致动器及其刚性延长件产生一个脉冲式位移冲击振动，且该脉冲式位移冲击振动的振动频率、振动宽度受微处理器控制，振动幅度大小受稳压直流电路控制。电磁位移致动器的振动冲击到微流控芯片腔体所对应的弹性层表面，使得芯片管道内液体加速。
当液体速度足够时，其将克服表面张力作用，从喷口喷射形成单个液滴。单个液滴最小速度为：
Figure PCTCN2017092391-appb-000001
其中，σ是表面张力系数，ρ是液体密度，dn是喷口直径。
设液滴体积大小表示为Vn，
Figure PCTCN2017092391-appb-000002
其中，Vi是位移致动器冲击微流控芯片腔体时引起的腔体变形体积，或者说变形排出的液体体积，它由腔体的冲击位移s和腔体直径di决定； Rn和Rr分别代表腔体到喷口和腔体到注液口的流阻。流阻之比仅仅受微流体芯片管道尺寸、喷口尺寸影响。冲击位移、腔体直径、流阻之比都可以影响液滴体积大小。当Rn＞10Rr时，液滴体积近似可表示为
Figure PCTCN2017092391-appb-000003
其中，dn是喷口直径，h，w，L，l分别代表微流控芯片管道的高度、宽度、注液口到腔体的长度和喷口长度。可见，当喷口直径较小时，液滴体积随直径减小四次方缩减。因此最直接方法的是通过调控喷孔尺寸来调控液滴大小，可以获得单个体积大小从0.1纳升到几个纳升的液滴。
本公开液滴分配器的液滴打印频率高，液滴产生的频率在低频时取决于位移致动器频率。例如：一般电磁位移致动器频率在50Hz以下，液滴产生频率也可以达到50Hz。采用工作频率可高达数千赫兹的压电位移致动器时，液滴产生频率取决于腔体内液体填充速度，一般可以达到500-1000Hz。
图8是打印液滴的照片(图8(a))与液滴尺寸的分布(图8(b))。液滴体积均值1.3纳升，73个液滴样本统计分散性CV＜3.6％。
该液滴分配器基于液滴打印的原理，可以高精度定量化进行试剂的加样。可用于生化实验室常用的注液、稀释等基本操作。单次注液的分辨率可高达0.1纳升，典型量程上限在10微升，可以解决目前高精度微移液器在微升、亚微升液滴操作精度低的问题。同时，整个仪器结构简单，操作方便。不仅可以替代目前最高精度的微移液器，还进一步扩展的对更小体积液体的操作能力。具有可期的应用前景。
本公开另一实施例的电动微流控液滴分配器，为了达到简要说明的目的，上述第一实施例中任何可作相同应用的技术特征叙述皆并于此，无需再重复相同叙述。
该电动微流控液滴分配器不仅可以分配液体，还可以吸取液体。参见 图9，微流控芯片2包括弹性层25、管道层26和支撑层27，管道层形成有管道连通的储液池、腔体和喷口，微流控芯片的喷口3所在的一端截面积渐缩，形成一尖端，在于喷口相对的一端，储液池22还开有一连接孔21与外界连通。腔体23被冲击时，从腔体到喷口的流阻大于腔体到储液池的流阻，腔体中的微量(纳升及以下)液滴从喷口喷出，如图10所示；在冲击结束位移致动器回缩时，由于喷口的流阻Rn流阻较大，使得储液池中的液体从腔体入口自动注入腔体，准备下一次冲击的液滴打印。
参见图11，该电动微流控液滴分配器还包括一取液装置，同时参见图12，该取液装置为一套活塞系统，包括套筒10和活塞9，电池5和位移致动器1安装于套筒外壁的安装腔体内，电路板8、控制模块和显示屏6固定在套筒外壁。活塞9底端带有弹簧回复结构，并形成有一活塞内孔，活塞内孔为中空的圆柱体，中空圆柱体外壁开有通孔，该通孔与一个空气阀102连接，空气阀的开关可以控制活塞内孔的气体压力。微流控芯片2安装于套筒10底端，微流控芯片的连接孔21与活塞内孔连通，且微流控芯片的腔体正对位移致动器的刚性延长件11。套筒10上还设置有脱附机构，当打印完成时，通过按压脱附按钮101将微流控芯片2从电动微流控液滴分配器卸除下来，以更换新的微流控芯片。
本实施例的电动微流控液滴分配器分配液体时，空气阀打开，其余过程与上一实施例类似，利用微流控冲击打印，将微流控芯片中的液体打印成体积均匀的液滴。打印的次数决定液滴数量，进而来控制加样的体积。液滴的数量可以利用控制模块进行预先的设置，并在打印时控制位移致动器冲击次数。打印具体过程如下：利用电动位移致动器产生的冲击，击打微流控芯片的与腔体对应的弹性层，弹性层的变形加速芯片管道中的液体，液体向腔体入口和喷口两个方向流动，从喷口流出的液体具有足够速度克服出口处的表面张力，同时具有较小的体积，最终从芯片的喷口喷射出形成体积超小的(范围从0.1纳升到100纳升)液滴。位移致动器回缩时，弹性层在自身结构回复力作用下回缩，在腔体产生负压。喷口与入口的液体有向腔体流动趋势。喷口方向的流阻较大，阻止空气回流到腔体内；入口方向流阻较小，使得液体完成从储液池进入腔体完成补液。等待下一次液滴的产生。当需要更换试剂种类时，可以更换微流控芯片，无需清洗。
当电动微流控液滴分配器抽取液体时，空气阀关闭，微流控芯片的喷口浸入液体，在弹簧回复力的作用下，活塞回缩运动使活塞内孔产生负压，液体经微流控芯片的喷口、腔体、管道流到储液池内，完成液体抽取。活塞系统可以是电控式也可以是手动式，活塞按钮91带有体积调节功能，可对抽取液体体积进行调节。
进一步地，本实施例的电动微流控液滴分配器，微流控芯片的喷口端面具有宽20微米、间距30微米的微纳米沟槽结构，形成带有超疏水端面的微流控芯片。该沟槽结构可以使喷口端面由原来的疏水表面(接触角约为93度)变为永久性超疏水表面(接触角大于150度，为154度)，图13为喷口端面处理前后，液滴产生效果图，(a)显示了未处理疏水表面液滴脱落，(b)显示了超疏水处理后液滴脱落，(c)显示了未处理表面水滴接触角，(d)显示了超疏水处理后表面水滴的接触角。申请人研究发现，液滴克服表面张力从喷口表面脱附时，液滴大小受喷口外形尺寸影响，而且在普通表面(包括一般疏水表面)会有超小的液滴残留，这会影响液滴大小的一致性。同时，在芯片喷口浸入液体抽吸液体后，在喷口端面也容易残留液体。而采用超疏水处理的喷口端面可以使得液滴大小不受喷口外结构影响，表面无残留，有利于提高转移液体的精确性。图14是采用高速相机拍摄75个液体体积的统计效果，其体积变异系数(CV)小于3.4％。
本实例中微流控芯片的加工过程为：首先通过3D打印制造模具，然后脱模再键合的方法加工微流控芯片。模具有两个，一个用于加工弹性层，这里成为上层，另一个用于一体加工管道层与支撑层，这里称为下层。具体加工过程描述如下：首先利用三维造型软件Solidworks分别建立弹性层(上层)与管道层支撑层(下层)的模具模型，然后利用精密3D打印机(Projet 3500HDMax，3D Systems)与3D打印材料(VisiJet M3Crystal)打印成型。将PDMS双组份试剂(
Figure PCTCN2017092391-appb-000004
184，Dow Corning)按10∶1的质量比进行混合，而后分别对两个模具进行浇筑，置入90℃烤箱中烘烤30分钟后取出，待冷却完全后对已固化的PDMS进行脱模。而后使用等离子体清洗机(PDC-MG，铭恒)对两次脱模所得到的PDMS结构在约100帕的环境下进行约50秒的等离子体处理，再对准键合，形成所需的微流控芯片。在芯片的喷口端面处，使用飞秒激光器(Chameleon Vision-S /Legend Elite F HE-1K，Coherent)以60毫瓦功率及1毫米每秒的扫描速度在其整个端面烧蚀出宽20微米，间距30微米的沟槽结构。
本公开将位移致动器与微流控芯片分离，位移致动器不接触试剂液体。更换试剂时只需要更换低成本微流控芯片，避免试剂的交叉污染。该液滴分配器基于液滴打印的原理，可以高精度定量化进行试剂的加样，不同于传统移液器工作方式。可用于生化实验室常用的转移液体、稀释配样等基本操作。单次注液的分辨率可高达0.1纳升，可以解决目前高精度微移液器在微升、亚微升液滴操作精度低的问题。同时，整个仪器结构简单，操作方便。不仅可以替代目前最高精度的微移液器，还进一步扩展的对更小体积液体的操作能力。具有可期的应用前景。
至此，已经结合附图对本实施例进行了详细描述。依据以上描述，本领域技术人员应当对本公开有了清楚的认识。
以上为本公开的最优实施例，需要说明的，该最优的实施例仅用于理解本公开，并不用于限制本公开的保护范围。并且，最优实施例中的特征，在无特别注明的情况下，均同时适用于方法实施例和装置实施例，在相同或不同实施例中出现的技术特征在不相互冲突的情况下可以组合使用。
需要说明的是，上述对各元件的定义并不仅限于实施方式中提到的各种具体结构或形状，本领域的普通技术人员可对其进行简单地熟知地替换，以上所述的具体实施例，对本公开的目的、技术方案和有益效果进行了进一步详细说明，所应理解的是，以上所述仅为本公开的具体实施例而已，并不用于限制本公开，凡在本公开的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本公开的保护范围之内。

Claims (20)

  1. 一种电动微流控液滴分配器，用于连续产生微量体积液滴，定量化获得所需体积液体，包括：
    位移致动器，用于给微流控芯片提供位移或者力冲击，其包括一刚性延长件；
    微流控芯片，与所述位移致动器分离并可更换，包括一腔体和喷口，所述腔体被所述位移致动器的刚性延长件敲击，使液体以液滴方式从喷口喷出。
  2. 根据权利要求1所述电动微流控液滴分配器，其中：所述微流控芯片为即插即换式芯片。
  3. 根据权利要求1或2所述电动微流控液滴分配器，所述微流控芯片包括依次层叠的支撑层、弹性层和管道层；
    所述腔体形成于所述管道层；
    所述喷口形成于所述管道层或支撑层。
  4. 根据权利要求3所述电动微流控液滴分配器，所述微流控芯片还包括：
    形成于所述弹性层的注液口；以及
    形成于所述管道层、连通所述腔体和注液口的管道。
  5. 根据权利要求3所述电动微流控液滴分配器，所述微流控芯片还包括：形成于所述管道层的储液池和管道，所述管道连通所述腔体和储液池，所述储液池开有一连接孔。
  6. 根据权利要求3所述电动微流控液滴分配器，所述弹性层、管道层为高分子材料，所述支撑层为高分子材料或玻璃。
  7. 根据权利要求5所述的电动微流控液滴分配器，还包括：
    一取液装置，用于抽取液体。
  8. 根据权利要求7所述的电动微流控液滴分配器，所述取液装置为一套活塞系统。
  9. 根据权利要求8所述的电动微流控液滴分配器，所述活塞系统包 括套筒和活塞；
    所述活塞底端带有弹簧，并形成有一活塞内孔，所述活塞内孔经通孔与空气阀连接；
    所述微流控芯片安装于套筒底端，其连接孔与活塞内孔连通，其腔体正对位移致动器的刚性延长件。
  10. 根据权利要求7至9任一项所述的电动微流控液滴分配器，微流控芯片的喷口所在的一端为尖端。
  11. 根据权利要求9所述的电动微流控液滴分配器，所述套筒设置有脱附机构，用于卸除微流控芯片。
  12. 根据权利要求10所述的电动微流控液滴分配器，所述微流控芯片的喷口端面具有微纳米沟槽结构，所述微纳米沟槽结构使喷口端面由疏水表面变为永久性超疏水表面。
  13. 根据权利要求1所述电动微流控液滴分配器，还包括：
    外壳，用于位移致动器、微流控芯片与控制系统的装卡与固定。
  14. 根据权利要求13所述电动微流控液滴分配器，所述外壳底端设有用于安装微流控芯片的空间及安装结构，所述微流控芯片通过安装结构安装于外壳底端。
  15. 根据权利要求14所述电动微流控液滴分配器，所述安装结构是容置槽。
  16. 根据权利要求1所述的电动微流控液滴分配器，还包括：控制系统，所述控制系统包括：
    控制模块，用于接受参数的输入，输出位移致动器所需控制信号；
    显示模块，用于在参数的输入、输出时显示电动微流控液滴分配器的工作参数；以及
    电源模块，用于给整个电动微流控液滴分配器供电。
  17. 根据权利要求16所述的电动微流控液滴分配器，所述控制模块包括：
    微处理器，用于产生脉冲控制信号；
    直流稳压电路，通过开关选择电路向位移致动器提供驱动信号；
    开关选择电路，响应于微处理器的脉冲控制信号而控制驱动信号的通断。
  18. 根据权利要求16或17所述的电动微流控液滴分配器，其中：
    所述电动微流控液滴分配器为手持式或桌面台式；
    所述电源模块是内置电池或外接电源。
  19. 根据权利要求1所述电动微流控液滴分配器，所述位移致动器振动一个周期，所述微流控芯片的喷孔喷射出一个液滴；和/或，所述液滴大小受位移致动器速度、冲程调控。
  20. 根据权利要求1所述的电动微流控液滴分配器，所述位移致动器由电磁驱动、压电驱动或静电驱动；和/或
    所述位移致动器可重复使用；和/或
    所述刚性延长件沿其运动方向不可伸缩；和/或
    所述微流控芯片作为可抛弃墨盒，用于液体的储存、输运。
PCT/CN2017/092391 2016-09-23 2017-07-10 电动微流控液滴分配器 WO2018054134A1 (zh)

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CN111665170A (zh) * 2020-06-16 2020-09-15 中国石油大学(华东) 一种通气定量控制柔性基底变形和张力的液滴冲击实验装置
CN112840012A (zh) * 2018-10-01 2021-05-25 Sm分子生物研究有限公司 用于形成微液滴的微量移液器吸头
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CN115722280A (zh) * 2021-08-26 2023-03-03 北京达微生物科技有限公司 一种用于微液滴制备的控制装置及制备微液滴的方法
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