WO2024021748A1 - 液滴制备装置及方法 - Google Patents

液滴制备装置及方法 Download PDF

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Publication number
WO2024021748A1
WO2024021748A1 PCT/CN2023/092550 CN2023092550W WO2024021748A1 WO 2024021748 A1 WO2024021748 A1 WO 2024021748A1 CN 2023092550 W CN2023092550 W CN 2023092550W WO 2024021748 A1 WO2024021748 A1 WO 2024021748A1
Authority
WO
WIPO (PCT)
Prior art keywords
pressure
chip
cap
oil storage
temperature control
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2023/092550
Other languages
English (en)
French (fr)
Inventor
夏江
王铸海
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pilot Gene Technology (hangzhou) Co Ltd
Original Assignee
Pilot Gene Technology (hangzhou) Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pilot Gene Technology (hangzhou) Co Ltd filed Critical Pilot Gene Technology (hangzhou) Co Ltd
Priority to EP23844963.1A priority Critical patent/EP4545178A4/en
Priority to US18/197,144 priority patent/US11964271B2/en
Publication of WO2024021748A1 publication Critical patent/WO2024021748A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6844—Nucleic acid amplification reactions
    • C12Q1/686—Polymerase chain reaction [PCR]
    • 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
    • B01L2400/0487—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics

Definitions

  • the present application relates to the field of biochip technology, and in particular to a droplet preparation device and method.
  • a droplet generating device is used to generate droplets.
  • the droplet generating device includes a chip.
  • the chip is set in a cavity and feeds the chip through the cavity.
  • the pressure applied within the chip changes so that droplets form within the chip.
  • problems such as pressure fluctuations, unsatisfactory droplet generation quality, and uneven droplet size may occur.
  • the purpose of this application is to provide a droplet preparation device and method that can improve the quality of droplet generation.
  • a droplet preparation device including a cavity, a chip, a pressure detection unit, a temperature control module, a lower pressure component and a small hole cap; the chip, the temperature control module and the pressure detection unit are all located in the cavity In the body, the temperature control module is used to adjust the temperature value in the chip, and the pressure detection unit is used to detect the pressure data in the cavity; the top of the chip has two chips: a sampling port and an oil storage port. Port; the small hole cap has a ventilation hole penetrating in the up and down direction, and the small hole cap can elastically deform up and down under the action of downward pressure to change the volume of the ventilation hole;
  • the ventilation hole is connected to the oil storage port, and the pressing assembly moves up and down to open or cover the top of the ventilation hole, Thereby correspondingly opening or sealing the oil storage port, and in the state where the pressing assembly covers the oil storage port, the cavity can apply positive pressure to the chip through the inlet, To create a pressure difference within the chip.
  • it further includes a vent cap.
  • a vent cap When the vent cap is directly connected to the inlet, a gap is formed between the inner side of the vent cap and the outer side of the part of the chip close to the inlet.
  • An air inlet channel, the bottom end of the air inlet channel is the inlet end and the top end is connected with the sample inlet.
  • the vent cap and the orifice cap can be switched and connected between the two chip ports; in a state where the vent cap and the orifice cap are respectively connected to the two chip ports,
  • the top surface of the small hole cap is higher than the top surface of the ventilation cap, and the pressing assembly seals the top surface of the ventilation hole by pressing down to cover the directly connected part of the small hole cap.
  • a chip port, and the other chip port is connected to the cavity;
  • vent cap when the vent cap is directly connected to the vent cap, the inner surface of the vent cap is close to the chip.
  • An air outlet channel is formed between the outer surfaces of the parts near the oil storage port. The bottom end of the air outlet channel is the outlet end and the top end is connected to the oil storage port.
  • part of the area is covered by the small hole cap, and the remaining area is aligned and connected with the vent hole.
  • the chip includes an inlet arm, an outlet arm and a bottom arm disposed between the bottom end of the inlet arm and the bottom end of the outlet arm, so that the inlet arm, the outlet arm and the bottom arm form a U
  • the top end of the inlet arm is the sample inlet
  • the top end of the outlet arm is the oil storage port.
  • the chip is pressed against the top surface of the temperature control module.
  • a droplet preparation method using the above droplet preparation device includes:
  • At least one of the adjustment steps is a first adjustment step, and the first adjustment step is: controlling only the temperature control module to adjust the temperature value.
  • At least one of the adjustment steps is a second adjustment step, and the second adjustment step The step is: only adjust the pressing force of the pressing component on the small hole cap.
  • At least one of the adjustment steps is a third adjustment step, and the third adjustment step is The steps are: controlling the temperature control module to adjust the temperature value, and at the same time adjusting the pressing force of the pressing component on the small hole cap.
  • the method further includes:
  • the lower pressure component is controlled to cover the vent hole to cover the sample inlet, and provide negative pressure to the oil storage port through the cavity to form a pressure difference within the chip.
  • the droplet preparation device includes a cavity, a chip, a pressure detection unit, a temperature control module, a lower pressure component and a small hole cap; the chip, temperature control module and pressure detection unit are all located in the cavity, and the temperature control module is In order to adjust the temperature value in the chip, the pressure detection unit is used to detect the pressure data in the cavity; the top of the chip has two chip ports, the sampling port and the oil storage port; the small hole cap has a vent hole that runs through the up and down direction, and is small The hole cap can elastically deform up and down under the action of downward pressure to change the volume of the vent hole.
  • the vent hole When the small hole cap is directly connected to the oil storage port, the vent hole is connected to the oil storage port, and the lower pressure assembly moves up and down to Open or cover the top of the vent hole, thereby correspondingly opening or covering the oil storage port, and in the state of pressing down the assembly to cover the oil storage port, the cavity can apply positive pressure to the chip through the injection port, so that the inside of the chip Create a pressure difference.
  • the pressure detection unit can detect pressure data in real time, and can control the temperature control module to adjust the temperature value and/or adjust the lower pressure of the lower pressure component to adjust the speed and size of droplets generated during the droplet preparation process. , to offset the impact of the current pressure data being different from the preset pressure data on the droplets, which can improve the quality of droplet generation.
  • the pressure component slowly rises until it leaves the small hole cap, so that the pressure difference between the inlet and the oil storage port is in a balanced state.
  • the droplets stop preparing and moving, and then are discharged through the exhaust hole in the chamber. After the air is released, the pressure difference inside the cavity is balanced with the outside world. At this time, a large number of droplets will be prepared uniformly and quickly.
  • a droplet preparation device in a first aspect, includes a shell, a chip arranged in the shell, a pressing assembly and a temperature control module; the temperature control module is arranged at the bottom of the shell, and the chip is arranged in the temperature control module. On the module, the pressing component is arranged on the top of the housing, and the temperature control module cooperates with the pressing component to adjust the size of the droplets formed.
  • a pressure source is externally connected to the housing, and a pressure detection unit is installed between the housing and the pressure source.
  • the chip is provided with a sample inlet and an oil storage port.
  • a small hole cap is installed at the oil storage port of the chip.
  • the small hole cap is provided with a through-ventilation hole in the vertical direction. The small hole The cap cooperates with the pressing component to adjust the pressure within the chip.
  • the small hole cap is set on the chip, and the small hole cap is an elastic member.
  • the projection of the ventilation hole falls within the projection range of the oil storage port.
  • the pressing assembly includes a pressing motor and a pressing plate, the pressing motor is fixedly connected to the housing, the pressing motor is slidingly connected to the pressing plate, and in the plane where the chip is located, The projection of the small hole cap falls within the projection range of the pressure plate.
  • a vent cap is installed at the sampling inlet of the chip, the vent cap is set on the chip, the vent cap has an air inlet channel opening toward the chip, and the air inlet channel is connected with the chip.
  • the chip includes an inlet arm and an outlet arm.
  • the inlet arm is fixedly connected to the chip and extends toward the pressure plate.
  • the outlet arm is fixedly connected to the chip and extends toward the pressure plate.
  • the inlet is provided on the The lower end of the inlet arm, and the oil storage port is provided at the lower end of the outlet arm.
  • a droplet preparation method includes the following steps:
  • Detect the pressure inside the chip through the pressure detection unit to determine whether the pressure inside the chip falls within the preset pressure range; if so, stop the temperature control adjustment and pressure adjustment; if not, perform the pressure adjustment and/or temperature control adjustment steps until the pressure inside the chip falls within the preset pressure range.
  • Figure 1 is a schematic structural diagram of a specific embodiment of the droplet preparation device provided by the present application.
  • Figure 2 is a top view of the droplet storage chamber in a specific embodiment of the chip in the droplet preparation device provided by the present application;
  • Figure 3 shows the cavity pressure control curve under ideal conditions
  • Figure 4 shows the actual cavity pressure control curve.
  • Figure 5 is a schematic structural diagram of a specific implementation of a droplet preparation device according to an embodiment of the present application.
  • Figure 6 is a schematic diagram of the internal structure of a droplet preparation device according to an embodiment of the present application.
  • Figure 7 is a schematic diagram of the exploded structure of the chip and temperature control module, mainly used to show the connection method of the chip.
  • Figure 8 is a schematic cross-sectional view of a droplet preparation device according to an embodiment of the present application.
  • Figure 9 is a schematic cross-sectional view of a droplet preparation device according to an embodiment of the present application.
  • Vent cap 1 air inlet channel 11, small hole cap 2, vent 21, chip 3, injection port 31, oil storage port 32, outlet arm 33.
  • the core of this application is to provide a droplet preparation device and method that can improve the quality of droplet generation.
  • a droplet preparation device provided according to an embodiment of the present application includes a cavity 5, a chip 3, a pressure detection unit 9, a temperature control module 6, a lower pressure component 4 and a small orifice cap 2.
  • the cavity 5 is connected to a pressure source 10, and the pressure in the closed cavity 5 can be changed.
  • the pressure source 10 can be a positive pressure or negative pressure device, used to pressurize or relieve the pressure in the closed cavity 5, and can also be used in the closed cavity 5.
  • An electromagnetic pressure relief valve is provided on the cavity 5 and combined with the pressure source 10 to accurately control the pressure in the sealed cavity 5 .
  • the chip 3 , the temperature control module 6 and the pressure detection unit 9 are all located in the cavity 5 . Specifically, the temperature control module 6 and the pressure detection unit 9 are located outside the chip 3 .
  • the chip 3 is specifically a microfluidic chip.
  • the top of the chip 3 has two chip ports: a sampling port 31 and an oil storage port 32 .
  • a pressure working chamber is formed inside the cavity 5, and the pressure working chamber can provide pressure to the inside of the chip 3 through its connected chip port.
  • the inside of chip 3 is first filled with the oil phase.
  • the sample is added from the injection port 31. Under the action of pressure, the sample generates droplets through the micro-channel inside the chip 3 and is dispersed in the oil phase. At the same time, part of the oil phase enters the oil storage port 32.
  • the pressure detection unit 9 is used to detect pressure data in the cavity 5 .
  • the pressure control curve of chamber 5 under ideal conditions is shown in Figure 3.
  • the pressure is stable and rises smoothly during the rising process.
  • the pressure control curve of chamber 5 will be as shown in Figure 4.
  • the data fluctuates up and down and is uncertain. Based on the detection results, the pressure in the corresponding cavity 5 or other parameters that affect droplet generation can be adjusted correspondingly to improve the droplet quality, control the rapid and stable generation of droplets, and solve the uneven droplet size caused by pressure fluctuations. The problem.
  • the temperature control module 6 is used to adjust the temperature value in the chip 3, and is mainly used to balance the changes in droplet size caused by pressure fluctuations in the cavity, and to achieve the purpose of controlling the uniform size of the droplets through combined pressure control. Specifically, the temperature control module 6 can only cool, only heat, or can both cool and heat. Optionally, the temperature control module 6 can perform a temperature control process of 20°C to 55°C when the droplets are generated. On the one hand, it can increase the fluidity of the oil and promote the spread of the droplets forward.
  • the small hole cap 2 has a through-hole in the up and down direction. The vent hole 21 is formed, and the small hole cap 2 can elastically deform up and down under the action of downward pressure to change the volume of the vent hole 21.
  • the small hole cap 2 is made of rubber, such as silicone rubber, polyurethane and other elastic materials. In some embodiments, orifice cap 2 is directly connected to oil reservoir 32 .
  • the pressing down component 4 includes a driving source and a pressure plate 7 connected to the bottom end of the driving source.
  • the driving source is specifically a pressing down motor 8 .
  • the driving source drives the pressure plate 7 to move up and down to separate or seal the small hole cap 2 .
  • the pressure plate 7 moves downward to compress the vent hole 21 on the small hole cap 2 to achieve a sealing effect, causing a pressure difference between the sample inlet 31 and the oil storage port 32; the pressure plate 7 moves upward to leave the vent hole. 21. Release the seal to eliminate the pressure difference between the injection port 31 and the oil storage port 32.
  • the pressing assembly 4 leaves the small hole cap 2
  • the sample inlet 31 and the oil storage port 32 can maintain balance instantly.
  • the small hole cap 2 When in use, the small hole cap 2 is directly connected to the oil storage port 32, and the ventilation hole 21 is connected with the oil storage port 32.
  • the pressing assembly 4 moves downward to seal the top of the ventilation hole 21, thereby sealing the oil storage port 32 and sealing the oil storage port 32.
  • the pressure source 10 is used to push the pressure into the cavity 5
  • the cavity 5 By applying positive pressure, the cavity 5 can then apply positive pressure into the chip 3 through the inlet 31 , so that a pressure difference is formed in the chip 3 , so that a large number of droplets are quickly formed in the chip 3 .
  • the pressure data in the cavity 5 is detected in real time through the pressure detection unit 9.
  • the temperature value in the chip 3 can be changed through the temperature control module 6.
  • the temperature and pressure joint control mode ensures uniform droplet size.
  • the small hole cap 2 is deformable under the pressure of the pressure plate 7, the volume of the vent hole 21 changes, causing the pressure at one end of the oil storage port 32 to change.
  • the pressure at one end of the oil storage port 32 can be accurately controlled by further controlling the pressing distance of the pressure plate 7. The greater the pressing distance of the pressure plate 7, the greater the pressure in the oil storage port 32, and conversely, the smaller the pressure in the oil storage port 32. Based on the above characteristics of the small orifice cap 2, the uniformity of the droplet size can be ensured through the joint control mode of the lifting and lowering of the pressure assembly 4 and the pressure.
  • the uniformity of droplet size can also be ensured through the joint control mode of temperature, pressure, and the lifting and lowering of the lower pressure component 4 (that is, adjusting the temperature control module 6 and the lower pressure component 4 at the same time).
  • the pressure detection unit 9 can detect pressure data in real time, and can control the temperature control module 6 to adjust the temperature value and/or adjust the downward pressure of the downward pressure component 4 to adjust the speed of droplet generation during the droplet preparation process. size to offset the impact of the current pressure data being different from the preset pressure data on the droplets, which can improve the quality of droplet generation.
  • the pressure assembly 4 slowly rises until it leaves the small hole cap 2, so that the pressure difference between the injection port 31 and the oil storage port 32 is in a balanced state.
  • the droplets stop preparing and moving, and then pass through the cavity 5 After the exhaust hole in the cavity is deflated, the pressure difference in the cavity 5 is balanced with the outside world. At this time, a large number of droplets will be prepared uniformly and quickly.
  • the droplet preparation device also includes a ventilation cap 1 .
  • a ventilation cap 1 As shown in Figure 1, an air inlet channel 11 is formed between the inner side of the vent cap 1 and the outer side of the chip 3 close to the injection port 31. The bottom end of the air inlet channel 11 is the inlet end and the top end is connected to the injection port 31.
  • the vent cap 1 can be an elastomer or a hard object, a plastic part, or a metal part.
  • the air in the cavity 5 can enter through the bottom end of the air inlet channel 11 and then enter the sample inlet 31 from the top of the air inlet channel 11 to drive the sample into the inside of the chip 3 .
  • the vent cap 1 ensures that the pressure in the cavity 5 can enter the injection port 31 through its air inlet channel 11. At the same time, the vent cap 1 limits the gas in the cavity 5 to enter through the inlet end located below the air inlet channel 11, which can avoid A large amount of undesired substances fall into the inlet 31 from above, affecting droplet preparation and contaminating the chip 3, thereby achieving the purpose of dust prevention and pollution prevention.
  • the top surface of the orifice cap 2 is higher than the top surface of the vent cap 1, and the pressing assembly 4 seals the vent hole by pressing down.
  • the top surface of 21 is used to cover the chip port directly connected to the small hole cap 2, and the other chip port is connected to the cavity 5. Since the ventilation cap 1 is lower than the small hole cap 2, it is easy to After the pressing assembly 4 is pressed down, only the vent hole 21 and the chip port directly connected to it are sealed, while the other chip port and the cavity 5 are in a ventilating state.
  • the vent hole 21 is a cylindrical hole with a diameter preferably between 0.5 and 3 mm. If the diameter is too small, it is difficult to process and is easily blocked. If the diameter is too large, it will easily cause droplets to flow back when the chip 3 releases pressure from the two chip ports.
  • the area of the vent hole 21 is smaller than the oil storage port 32, which can prevent large particulate matter from falling into the chip 3 and affecting droplet preparation.
  • the vent hole 21 can also prevent the liquid droplets from merging due to excessive changes in the cavity volume of the oil storage port 32 during the rising process of the lower pressure assembly 4 .
  • the chip 3 includes an inlet arm 33, an outlet arm 34 and a bottom arm located between the bottom end of the inlet arm 33 and the bottom end of the outlet arm 34, so that the inlet arm 33, the outlet arm 34 and the bottom arm form a U shape.
  • the top of the inlet arm 33 is the sample inlet 31
  • the top of the outlet arm 34 is the oil storage port 32
  • the structure is simple. Specifically, the heights of the top ends of the inlet arm 33 and the outlet arm 34 are the same.
  • the chip 3 is pressed against the top surface of the temperature control module 6 to avoid interfering with the movement of the pressing component 4 and to ensure the temperature control effect of the temperature control module 6 on the chip 3 .
  • the vent hole 21 of the small hole cap 2 is sealed by the pressing assembly 4.
  • the pressure formed inside the cavity 5 can
  • the inlet 31 provides pressure to the chip 3, and a pressure difference is formed between the two ends of the chip 3. Under the action of the pressure, a large number of droplets can be quickly formed in the chip 3.
  • the temperature value of the control module 6 and the pressing distance of the pressing component 4 can be adjusted to adjust the droplet generation speed, and a large number of uniform and stable droplets can be formed in a short time.
  • the droplet preparation device can effectively increase the speed of droplet generation, generate a large number of droplets in a short time, meet the needs of high-throughput testing, effectively reduce the occurrence of backflow phenomena, and enable the device itself to influence the structure of the microfluidic chip. Reduced requirements make it easier to achieve low-cost and easy processability of microfluidic chips.
  • the droplets can be controlled by dynamic balance to ensure the smooth rise and fall of pressure. The generated droplets are more uniform in size and the detection results are more reliable.
  • the vent cap 1 and the orifice cap 2 can be switched and connected between two chip ports.
  • the vent cap 1 is directly connected to the oil storage port 32
  • the small hole cap 2 is directly connected to the sample inlet 31 .
  • an air outlet channel is formed between the inner side of the vent cap 1 and the outer side of the chip 3 close to the oil storage port 32.
  • the bottom end of the air outlet channel is the outlet end and the top end is connected to the oil storage port 32.
  • the small hole cap 2 Connect to injection port 31.
  • the top surface of the small hole cap 2 is higher than the top surface of the vent cap 1 , and the pressing assembly 4 presses down to cover the top surface of the vent hole 21 to cover the sample inlet 31 .
  • the lower pressure component 4 passes through the lower pressure sealing vent 21, and the pressure in the cavity 5 first becomes negative pressure, and the oil is stored.
  • the pressure at port 32 decreases to form a pressure difference between the injection port 31 and the oil storage port 32.
  • the sample enters the microfluidic channel from the injection port 31 to form droplets, and the oil phase enters the oil storage port 32, and then the injection port 31 ends Perform pressure relief to complete the droplet generation process.
  • a droplet preparation device is provided in a housing, which includes a base, a chip 3 , a pressing assembly 4 , a pressure detection unit 9 , and a temperature control module 6 .
  • a closed cavity 5 is formed in the shell, and the shell has an airtight opening.
  • the shell is fixedly connected to a pressure pipe at the airtight opening.
  • the pressure pipe is fixedly connected to the pressure source 10.
  • the pressure in the closed cavity 5 The change can be controlled through the pressure source 10, which is used to pressurize or relieve the pressure in the closed cavity 5.
  • An electromagnetic pressure relief valve can also be installed on the closed cavity 5, combined with the pressure source 10, to accurately control the closed cavity. 5.
  • the pressure source 10 provides positive pressure into the cavity 5.
  • the lower pressure component 4, the chip 3, the temperature control module 6 and the base are installed in the housing in the vertical direction from top to bottom, and the pressure detection unit 9 is installed in the pressure pipe.
  • the pressure detection unit 9 is electrically connected to the operating system, and the temperature control module 6 is electrically connected to the operating system.
  • the pressure detection unit 9 can be a pressure sensor or other component for detecting pressure changes; in some embodiments, the temperature control module 6 can be a component such as a heating film or a semiconductor.
  • the chip 3 includes a chip body and a chip cover.
  • the chip body and the chip cover are stacked vertically, the connection between the chip cover and the chip body is sealed, and the chip body and the chip cover form a microfluidic channel.
  • the chip body has an inlet arm 34 and an outlet arm 33 extending in a direction away from the base. In this embodiment, the height of the inlet arm 34 and the end of the outlet arm 33 close to the pressing assembly 4 are flush.
  • the inlet arm 34 is provided with an inlet chamber that runs through in the vertical direction.
  • the inlet arm 34 has an inlet 31 at one end close to the base.
  • the inlet 31 is located at the bottom of the inlet chamber.
  • the inlet arm 34 is at one end away from the chip 3 body.
  • a first communication port is opened.
  • the first communication port is located at the top of the inlet chamber.
  • the area of the first communication port is larger than the sample inlet 31.
  • the inlet arm 34 is connected with the chip body.
  • the end of the inlet arm 34 away from the base is covered with a vent cap 1.
  • the vent cap 1 is detachably connected to the inlet arm 34.
  • the detachable connection method can be threads, slots, etc., with the vent cap 1 opening facing downwards.
  • An air inlet channel 11 is opened vertically downward on the inner wall of the vent cap 1, and the air inlet channel 11 is connected with the inlet cavity.
  • the outlet arm 33 is provided with an oil storage chamber extending in the vertical direction.
  • An oil storage port 32 is provided at one end of the outlet arm 33 away from the ground.
  • the oil storage port 32 is located at the bottom end of the oil storage chamber.
  • the outlet arm 33 has a second communication port at one end close to the chip body.
  • the second communication port is located at the top of the oil storage chamber.
  • the area of the second communication port is larger than the oil storage port 32.
  • the outlet arm 33 is connected with the chip body.
  • the end of the outlet arm 33 away from the base is detachably connected to a small hole cap 2, and the detachable connection method can be a thread, a slot, etc.
  • the orifice cap 2 is an elastic member.
  • the small hole cap 2 is provided with a through ventilation hole 21 along the vertical direction.
  • the small hole cap 2 is connected with the outlet arm 33, and the vertical projection of the small hole cap 2 falls into the projection of the oil storage cavity. Reinforcing ribs can also be fixedly connected between multiple small hole caps 2 to reduce the deformation variation of different small hole caps 2 .
  • the lower pressing assembly 4 includes a driving source, a fixing plate and a pressing plate 7 .
  • the fixing plate is fixedly connected to the shell.
  • the driving source is a push-down motor 8
  • the push-down motor 8 is electrically connected to the control device.
  • the control device can be a control system such as a PLC system.
  • the push-down motor 8 is fixedly installed on the top of the housing, and the push-down motor 8 and the pressure plate 7 are slidingly connected through a screw rod.
  • the pressing plate 7 is integrally formed with a lower pressing block, and the lower pressing block is arranged toward the base.
  • the pressing block When the pressing motor 8 drives the pressing plate 7 to slide towards the chip 3, the pressing block contacts the small hole cap 2 and blocks the ventilation hole 21 of the small hole cap 2. In this way, during the ventilation process of the injection port 31, A pressure difference is formed within the chip 3, causing the liquid in the microfluidic channel to form droplets. After the lower pressure block contacts the orifice cap 2, the pressure plate 7 continues to slide toward the chip 3, and the orifice cap 2 deforms under the action of pressure, thereby changing the volume of the vent hole 21, causing the pressure at the oil storage port 32 to change. , thereby adjusting the pressure difference in the microfluid channel and adjusting the size of the droplets formed.
  • the principle of this embodiment is as follows.
  • the lowering motor 8 is driven to drive the pressing plate 7 downward until the lowering block and the small hole cap 2 are tightly pressed, and the ventilation hole 21 is closed.
  • the pressure source 10 is adjusted to form a positive pressure in the cavity 5, so that the liquid in the microfluidic channel quickly forms a large number of uniform droplets, and the oil phase flows out from the oil storage port 32.
  • the pressure plate 7 can be continued to be driven down or up, so that the small hole cap 2 is deformed under pressure, and the volume of the vent hole 21 is changed, thereby changing the oil storage port. 32 pressure at one end.
  • the pressure data in the cavity 5 is detected through the pressure detection unit 9.
  • the temperature value in the chip 3 can be changed through the temperature control module 6 and the lower pressure component 4 can be controlled to change.
  • the pressure inside chip 3 is used to ensure the uniformity of droplet size.
  • the pressure plate 7 can be driven to rise slowly until the pressure plate 7 leaves the small hole cap 2 and the vent 21 is reconnected with the cavity 5 so that the pressure difference between the injection port 31 and the oil storage port 32 is in a balanced state.
  • the droplets stop preparing and moving. After the cavity 5 is deflated, the pressure difference in the cavity 5 is balanced with the outside world. At this time, a large number of droplets will be prepared uniformly and quickly.
  • the pressure provided by the pressure source 10 in the cavity 5 is negative pressure.
  • the orifice cap 2 is set on the inlet arm 34
  • the vent cap 1 is set on the outlet arm 33 .
  • the experimental principle is as follows.
  • the lower pressure assembly 4 covers the vent hole 21 by driving the pressure plate 7, and at the same time controls the pressure source 10 to change the pressure in the cavity 5 to negative pressure, so that the pressure in the oil storage port 32 is reduced, so that the injection port 31 A pressure difference is formed between the oil storage port 32 and the oil storage port 32 .
  • the sample enters the microfluidic channel from the injection port 31 and forms droplets under the action of pressure difference and temperature.
  • the oil phase enters the oil storage port 32 .
  • the pressure in the control chamber 5 is restored, and the pressure at the injection port 31 is released to complete the droplet generation process.
  • the present application also provides a droplet preparation method.
  • the droplet preparation method uses a droplet preparation device.
  • the droplet preparation device can specifically be the droplet preparation device provided in any of the above embodiments, The beneficial effects can be referred to each of the above embodiments accordingly.
  • the droplet preparation method includes:
  • At least one adjustment step is a first adjustment step, and the first adjustment step is: controlling only the temperature control module 6 to adjust the temperature value.
  • executing the first adjustment step specifically includes:
  • the temperature of the temperature control module 6 is lowered to slow down the droplet flow until the droplet size is consistent with the preset pressure data. size purpose;
  • the temperature of the temperature control module 6 will be increased to make the droplet flow faster, so that the droplet size is consistent with the preset pressure data. size purpose.
  • the preset pressure data is a value within the preset pressure range
  • the maximum pressure deviation setting value is the maximum value of the preset pressure range
  • the minimum pressure deviation setting value is the minimum value of the preset pressure range
  • the minimum pressure deviation setting value ⁇ Preset pressure data ⁇ maximum pressure deviation setting value.
  • the preset pressure data and preset pressure range at each moment can be set as needed, and can be the same or different.
  • At least one adjustment step is the second adjustment step.
  • the second adjustment step is to only adjust the pressing force of the pressing assembly 4 on the small hole cap 2 .
  • the droplet generation quality is improved by adjusting the pressing distance of the pressure plate 7 .
  • Executing the second adjustment step specifically includes:
  • the pressure plate 7 When the actual pressure data measured in real time is higher than the pressure deviation from the maximum set value, the pressure plate 7 is lowered and the small hole cap 2 is compressed, causing the air volume in the vent hole 21 to decrease and the pressure to increase, thereby increasing the pressure at both ends of the inlet and outlet of the chip 3 The difference becomes smaller, thereby slowing down the droplet flow, achieving the purpose of making the droplet size consistent with the preset pressure data;
  • the pressure plate 7 When the actual pressure data measured in real time is lower than the pressure deviation from the minimum setting value, the pressure plate 7 is raised to increase the air volume in the vent hole 21 and reduce the pressure, so that the pressure difference between the inlet and outlet of the chip 3 becomes larger, thereby causing the liquid to The droplet flow becomes faster to achieve the purpose of making the droplet size consistent with the preset pressure data.
  • the third adjustment step is: controlling the temperature control module 6 to adjust the temperature value, and at the same time adjusting the pressing force of the pressing assembly 4 on the small hole cap 2 .
  • the quality of droplet generation is improved by simultaneously controlling the temperature value of the temperature control module 6 and adjusting the pressing distance of the pressure plate 7 .
  • Executing the third adjustment step specifically includes:
  • the pressure plate 7 When the actual pressure data measured in real time is lower than the pressure deviation from the minimum set value, the pressure plate 7 is raised to increase the air volume in the vent hole 21, and at the same time, the temperature of the temperature control module 6 is raised to make the droplet flow faster to achieve the desired result.
  • the purpose of the size when the droplet size is consistent with the preset pressure data.
  • the control method of the temperature control module 6 and the pressure plate 7 can be tested and obtained according to the actual droplet generation conditions.
  • the temperature adjustment method of the temperature control module 6 can be obtained through actual testing based on different chip 3 structures, oil phase composition and other factors.
  • the compression amount of the descending distance of the lowering pressure plate 7 relative to the orifice cap 2 can be determined according to different orifice cap 2 structures. and other factors obtained through actual testing.
  • the method also includes: controlling the lower pressure assembly 4 to cover the vent hole 21 to seal the vent hole 21. Cover the sample inlet 31 and provide negative pressure to the oil storage port 32 through the cavity 5 to form a pressure difference in the chip 3 .
  • the droplet size can be accurately controlled by referring to the following empirical formula of a model that can control droplet generation with multiple parameters.
  • the pressure-boosting stage of droplet generation try to ensure that the actual droplet size is equal to the theoretical value of the droplet, and make the actual droplet size uniform; in the pressure-relief stage of droplet generation, effectively control the flow of the generated droplets on the chip 3 Medium and even distribution, minimizing droplet backflow and air overfilling, which results in large variability in the total number of droplets and affects the accuracy of the results.
  • r is the actual radius of the droplet
  • etat is the viscosity of the oil in chip 3 when the temperature control module 6 rises and falls;
  • etat0 is the viscosity of the oil in chip 3 at the melting point temperature
  • p is the actual measured value of the pressure of the pressure detection unit 9 in the cavity 5 (atm);
  • p0 is 1 standard atmospheric pressure
  • ⁇ d is the pressing origin point 0 when the pressure plate 7 is in sealing contact with the small hole cap 2, and the further downward pressing distance is a positive value;
  • A, B and C are constants.
  • This formula is applied in the pressure boosting stage of droplet generation: after the pressure plate 7 is in sealing contact with the orifice cap 2, when ⁇ d ⁇ 0, the cavity 5 The pressure begins to rise, and through the pressure detection unit 9, it is measured that p ⁇ 1), and the droplets begin to be generated.
  • the downward pressure or upward pressure of ⁇ d is controlled at the same time, and the temperature control module The temperature drop and rise of 6 are used to obtain the actual radius r of the droplet, which can be consistent and average with the theoretical radius R of the droplet.
  • This formula is applied in the pressure relief stage of droplet generation: the pressure in the cavity 5 begins to decrease, and the decrease in p value is measured through the pressure detection unit 9.
  • the Dynamic monitoring of the p value controls the rise or fall of ⁇ d and the temperature drop and rise of the temperature control module 6 to maintain the even distribution of the generated droplets in the chip 3 and reduce droplet backflow or air overfilling. situation, resulting in large variability in the total number of droplets, affecting the accuracy of the results.

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Abstract

一种液滴制备装置及方法，芯片（3）、温控模块（6）均设于腔体（5）内，温控模块（6）用于调节芯片（3）内的温度值，压力检测单元（9）用于检测腔体（5）内的压力数据；芯片（3）的顶部具有进样口（31）和储油口（32）两个端口；小孔帽（2）具有沿上下方向贯穿的通气孔（21），小孔帽（2）在下压力的作用下可上下弹性形变，以改变通气孔（21）的体积。在小孔帽（2）直接连接于储油口（32）的状态下，通气孔（21）与储油口（32）连通，下压组件（4）通过升降运动以打开或封盖通气孔（21）的顶端，在下压组件（4）封盖储油口（32）的状态下，腔体（5）可经进样口（31）向芯片（3）内施加正压力，以使芯片（3）内形成压力差。通过控制温控模块（6）和/或下压组件（4），可调节液滴生成的速度、大小，并可改善液滴生成质量。

Description

液滴制备装置及方法 技术领域
本申请涉及生物芯片技术领域，特别涉及一种液滴制备装置及方法。
背景技术
现有的一种数字PCR(聚合酶链式反应)液滴制备技术中，采用液滴生成装置生成液滴，该液滴生成装置中，包括芯片，芯片设置在腔体内，通过腔体向芯片内施加的压力变化，以使得芯片内形成液滴。但是，由于仅通过压力调节控制液滴的生成，会产生压力波动问题，液滴生成质量不理想，存在液滴大小不均一等问题。
因此，如何改善液滴生成质量，是本领域技术人员目前需要解决的技术问题。
发明内容
有鉴于此，本申请的目的是提供一种液滴制备装置及方法，能够改善液滴生成质量。
为实现上述目的，本申请提供如下技术方案：
一种液滴制备装置，包括腔体、芯片、压力检测单元、温控模块、下压组件和小孔帽；所述芯片、所述温控模块和所述压力检测单元均设于所述腔体内，所述温控模块用于调节所述芯片内的温度值，所述压力检测单元用于检测所述腔体内的压力数据；所述芯片的顶部具有进样口和储油口两个芯片端口；所述小孔帽具有沿上下方向贯穿的通气孔，且所述小孔帽在下压力的作用下可上下弹性形变，以改变所述通气孔的体积；
在所述小孔帽直接连接于所述储油口的状态下，所述通气孔与所述储油口连通，所述下压组件通过升降运动以打开或封盖所述通气孔的顶端，从而对应打开或封盖所述储油口，且在所述下压组件封盖所述储油口的状态下，所述腔体可经所述进样口向所述芯片内施加正压力，以使所述芯片内形成压力差。
优选地，还包括通气帽，所述通气帽在直接连接于所述进样口的状态下，所述通气帽的内侧面与所述芯片上靠近所述进样口部分的外侧面之间形成进气通道，所述进气通道的底端为进口端且顶端与所述进样口连通。
优选地，所述通气帽与所述小孔帽可在两个所述芯片端口之间切换连接；在所述通气帽与所述小孔帽分别连接于两个所述芯片端口的状态下，所述小孔帽的顶面高于所述通气帽的顶面，所述下压组件通过下压封盖所述通气孔的顶面，以封盖所述小孔帽所直接连接的所述芯片端口，而另一个所述芯片端口与所述腔体连通；
其中，在所述通气帽直接连接于所述通气帽的状态下，所述通气帽的内侧面与所述芯片上靠 近所述储油口部分的外侧面之间形成出气通道，所述出气通道的底端为出口端且顶端与所述储油口连通。
优选地，在所述小孔帽所直接连接的所述芯片端口的顶面上，部分面积被所述小孔帽覆盖，其余面积与所述通气孔对齐连通。
优选地，所述芯片包括进口臂、出口臂和设于所述进口臂的底端、所述出口臂的底端之间的底臂，以使进口臂、出口臂和所述底臂形成U形结构，所述进口臂的顶端为所述进样口，所述出口臂的顶端为所述储油口。
优选地，所述芯片贴合压在所述温控模块的顶面上。
一种液滴制备方法，应用如上液滴制备装置，所述方法包括：
实时接收所述压力检测单元检测的压力数据；
判断所述压力数据是否超过预设压力范围，若是，执行选定的调节步骤，以使所述芯片中的实际液滴大小等于所述预设压力值下的液滴大小；
其中，至少一个所述调节步骤为第一调节步骤，所述第一调节步骤为：仅控制所述温控模块调节温度值。
优选地，在所述小孔帽直接连接于所述储油口且所述下压组件封盖所述通气孔的状态下，至少一个所述调节步骤为第二调节步骤，所述第二调节步骤为：仅调节所述下压组件对所述小孔帽的下压力。
优选地，在所述小孔帽直接连接于所述储油口且所述下压组件封盖所述通气孔的状态下，至少一个所述调节步骤为第三调节步骤，所述第三调节步骤为：控制所述温控模块调节温度值，同时调节所述下压组件对所述小孔帽的下压力。
优选地，在所述小孔帽直接连接于所述进样口的状态下，在进行所述实时接收所述压力检测单元检测的压力数据之前，还包括：
控制所述下压组件封盖所述通气孔以封盖所述进样口，通过所述腔体向所述储油口提供负压，以使所述芯片内形成压力差。
本申请提供的液滴制备装置，包括腔体、芯片、压力检测单元、温控模块、下压组件和小孔帽；芯片、温控模块和压力检测单元均设于腔体内，温控模块用于调节芯片内的温度值，压力检测单元用于检测腔体内的压力数据；芯片的顶部具有进样口和储油口两个芯片端口；小孔帽具有沿上下方向贯穿的通气孔，且小孔帽在下压力的作用下可上下弹性形变，以改变通气孔的体积。
在小孔帽直接连接于储油口的状态下，通气孔与储油口连通，下压组件通过升降运动以 打开或封盖通气孔的顶端，从而对应打开或封盖储油口，且在下压组件封盖储油口的状态下，腔体可经进样口向芯片内施加正压力，以使芯片内形成压力差。
该液滴制备装置中，压力检测单元可实时检测压力数据，可以控制温控模块调节温度值和/或调节下压组件的下压情况，以调节液滴制备过程中液滴生成的速度、大小，以抵消当前压力数据不同于预设压力数据对液滴进行的影响，可改善液滴生成质量。之后，通过下压组件的缓慢上升，直至离开小孔帽，使得进样口和储油口的压差处于平衡状态，此时，液滴停止制备及移动，再通过腔体内的排气孔放气后，使腔体内压差与外界平衡。此时大量液滴会均一快速制备完成。
为了实现上述目的，本申请还提供了一个技术方案：
第一方面，一种液滴制备装置，包括壳体和设置在壳体内的芯片、下压组件和温控模块；所述温控模块设置在壳体底部，所述芯片设置在所述温控模块上，所述下压组件设置在壳体顶部，所述温控模块与下压组件配合用于调节液滴形成的大小。
优选地，所述壳体还外接有压力源，所述壳体和压力源之间安装有压力检测单元。
优选地，所述芯片开有进样口和储油口，所述芯片的储油口处安装有小孔帽，所述小孔帽沿竖直方向开设有贯穿的通气孔，所述小孔帽与下压组件配合用于调节芯片内的压力大小。
优选地，所述小孔帽套设在芯片上，所述小孔帽为弹性件。
优选地，在芯片所在的平面内，所述通气孔的投影落入储油口的投影范围内。
优选地，所述下压组件包括下压电机和压板，所述下压电机与壳体固定连接，所述下压电机与所述压板滑动连接，在芯片所在的平面内，所述小孔帽的投影落在所述压板的投影范围内。
优选地，所述芯片的进样口处安装通气帽，所述通气帽套设在芯片上，所述通气帽开有开口朝向芯片的进气通道，所述进气通道与芯片连通。
优选地，所述芯片包括进口臂和出口臂，所述进口臂与芯片固定连接并朝压板方向延伸，所述出口臂与芯片固定连接并朝压板方向延伸，所述进样口设置在所述进口臂下端，所述储油口设置在所述出口臂下端。
第二方面，一种液滴制备方法，包括如下步骤：
通过压力检测单元预设压力值；
通过所述温控模块调节芯片的温度；
通过所述下压组件调节芯片内压力；
通过压力检测单元检测芯片内压力，判断芯片内压力是否落在预设压力范围内；若是，停止温控调节和压力调节；若否，进行压力调节和/或温控调节步骤，直至芯片内压力落在预设压力范围内。
综上所述，本申请包括以下至少一种有益技术效果：
1.采用温控模块和压力检测单元分别对芯片内的温度和压力进行检测，并通过预设压力值，通过温控模块和下压组件调控芯片内的环境参数，令生成的液滴质量合适，大小更均一。
附图说明
为了更清楚地说明本申请实施方案或现有技术中的技术方案，下面将对实施方案或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本申请的实施方案，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据提供的附图获得其他的附图。
图1为本申请所提供的液滴制备装置的一种具体实施方式的结构示意图；
图2为本申请所提供的液滴制备装置中芯片的一种具体实施方式中液滴存储腔的俯视图；
图3为理想状态下的腔体压力控制曲线；
图4为实际腔体压力控制曲线。
图5为根据本申请一个实施方案的液滴制备装置的一种具体实施方式的结构示意图。
图6是根据本申请一个实施方案的液滴制备装置内部结构示意图。
图7是芯片和温控模块的爆炸结构示意图，主要用于展示芯片的连接方式。
图8是根据本申请一个实施方案的液滴制备装置的剖面示意图。
图9是根据本申请一个实施方案的液滴制备装置的剖面示意图。
附图标记：
通气帽1，进气通道11，小孔帽2，通气孔21，芯片3，进样口31，储油口32，出口臂
33，进口臂34，下压组件4，腔体5，温控模块6，压板7，下压电机8，压力检测单元9，压力源10。
具体实施方式
下面将结合本申请实施方案中的附图，对本申请实施方案中的技术方案进行清楚、完整地描述，显然，所描述的实施方案仅仅是本申请一部分实施方案，而不是全部的实施方案。基于本申请中的实施方案，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方案，都属于本申请保护的范围。
本申请的核心是提供一种液滴制备装置及方法，能够改善液滴生成质量。
参考图1和图2，根据本申请一个实施方案提供的一种液滴制备装置包括腔体5、芯片3、压力检测单元9、温控模块6、下压组件4和小孔帽2。
腔体5连接有压力源10，密闭的腔体5内的压力可以变化，压力源10可以是正压或负压装置，用于给密闭腔体5内加压或泄压，也可以在密闭腔体5上设置电磁泄压阀，结合压力源10，从而精确控制密闭腔体5内的压力。芯片3、温控模块6和压力检测单元9均设于腔体5内，具体地，温控模块6、压力检测单元9位于芯片3外侧。
芯片3具体为微流体芯片。芯片3的顶部具有进样口31和储油口32两个芯片端口。腔体5内部形成压力工作腔，压力工作腔可通过其连通的芯片端口向芯片3内部提供压力。生成液滴时，芯片3的内部先充满油相。样品从进样口31加入，在压力的作用下，样品通过芯片3内部的微流道生成液滴，分散在油相中，同时部分油相进入储油口32。
压力检测单元9用于检测腔体5内的压力数据。通常理想状态下的腔体5压力控制曲线如图3所示，压力是平稳的，上升过程中也圆滑上升，实际上，腔体5压力控制曲线会如图4所示，在某一具体压力数据上是上下波动的，具有不确定性。基于检测结果，可以对应调节相应腔体5内的压力，或者其他影响液滴生成的参数，以改善液滴质量，控制液滴快速、稳定地生成，解决压力波动带来的液滴大小不均一的问题。
温控模块6用于调节芯片3内的温度值，主要用来平衡腔内压力波动时带来的液滴大小变化，通过联合压力控制来达到控制液滴大小均一的目的。具体地，温控模块6可以只制冷，也可以是只制热，也可以是又能制冷又能制热。可选地，温控模块6可以在液滴生成时进行20℃～55℃的温度控制处理，一方面可增加油性流动性，促进液滴向前平铺，小孔帽2具有沿上下方向贯穿的通气孔21，且小孔帽2在下压力的作用下可上下弹性形变，以改变通气孔21的体积。可选地，小孔帽2采用橡胶、例如硅橡胶，聚氨酯等弹性材料制成。在一些实施方案中，小孔帽2直接连接于储油口32。
下压组件4包括驱动源和连接于驱动源底端的压板7，驱动源具体为下压电机8。驱动源通过驱动压板7上下移动，来对小孔帽2进行离开或密封小孔帽2。具体地，压板7向下移动可压紧小孔帽2上的通气孔21，达到密封效果，使得进样口31和储油口32之间产生压力差；压板7向上移动，可离开通气孔21，解除密封，使得进样口31和储油口32之间消除压力差。其中，在下压组件4离开小孔帽2时，进样口31和储油口32可瞬间保持平衡。
在使用时，小孔帽2直接连接于储油口32，通气孔21与储油口32连通，下压组件4通过下移封盖通气孔21的顶端，从而封盖储油口32，封盖后，通过压力源10向腔体5内 施加正压力，进而腔体5可经进样口31向芯片3内施加正压力，以使芯片3内形成压力差，从而使芯片3内快速形成大量液滴。
在液滴生成过程中，通过压力检测单元9实时检测腔体5内的压力数据，当检测到的压力数据与预设压力数据不符时，可以通过温控模块6改变芯片3内的温度值，通过温度和压力联控的模式来保证液滴大小均一化。
另外，由于小孔帽2在压板7的压力下是可变形的，从而导致通气孔21的体积发生变化，使储油口32一端的压力发生变化。压板7与通气孔21密封接触后，进一步通过控制压板7下压的距离，可以精确控制储油口32一端的压力。压板7下压距离越大，则储油口32内的压力越大，反之，则储油口32内的压力越小。基于小孔帽2的以上特征，可以通过下压组件4的升降和压力联控的模式来保证液滴大小均一化。
当然，还可以通过温度、压力、下压组件4的升降三者联控来的模式(即同时调节温控模块6、下压组件4)来保证液滴大小均一化。
在一些实施方案，压力检测单元9可实时检测压力数据，可以控制温控模块6调节温度值和/或调节下压组件4的下压情况，以调节液滴制备过程中液滴生成的速度、大小，以抵消当前压力数据不同于预设压力数据对液滴进行的影响，可改善液滴生成质量。之后，通过下压组件4的缓慢上升，直至离开小孔帽2，使得进样口31和储油口32的压差处于平衡状态，此时，液滴停止制备及移动，再通过腔体5内的排气孔放气后，使腔体5内压差与外界平衡。此时大量液滴会均一快速制备完成。
进一步地，该液滴制备装置还包括通气帽1。如图1所示，通气帽1的内侧面与芯片3上靠近进样口31部分的外侧面之间形成进气通道11，进气通道11的底端为进口端且顶端与进样口31连通。可选地，通气帽1可以为弹性体，也可以为硬质物体，可以为塑料件，也可以为金属件。
在一些实施方案中，腔体5内的空气可以通过进气通道11底端进入，再从进气通道11顶端进入进样口31，驱动样品进入芯片3内部。通气帽1确保了腔体5内压力可以通过其进气通道11进入进样口31，同时，通气帽1限定了腔体5的气体经位于进气通道11位于下方的进口端进入，能够避免大量非期望的物质从上方掉入进样口31、影响液滴制备及污染芯片3，可达到防尘防污染的目的。
进一步地，在通气帽1与小孔帽2分别连接于两个芯片端口的状态下，小孔帽2的顶面高于通气帽1的顶面，下压组件4通过下压封盖通气孔21的顶面，以封盖小孔帽2所直接连接的芯片端口，而另一个芯片端口与腔体5连通。由于通气帽1比小孔帽2高度要低，方 便下压组件4下压后，只密封通气孔21以及其直接连接的芯片端口，而另一芯片端口和腔体5之间处于通气状态。
进一步地，在小孔帽2所直接连接的芯片端口的顶面上，部分面积被小孔帽2覆盖，其余面积与通气孔21对齐连通。
其中，通气孔21为圆柱孔且直径优选在0.5～3mm之间，直径太小加工不易，容易堵塞，太大在芯片3从两个芯片端口泄压时容易造成液滴回流。
在一些实施方案中，通气孔21的面积小于储油口32，可以防止大颗粒物质掉入芯片3，对液滴制备产生影响。同时，通气孔21还可以防止在下压组件4上升过程中，储油口32空腔体5积变化过大带来的液滴融合。
进一步地，芯片3包括进口臂33、出口臂34和设于进口臂33的底端、出口臂34的底端之间的底臂，以使进口臂33、出口臂34和底臂形成U形结构，进口臂33的顶端为进样口31，出口臂34的顶端为储油口32，结构简单。具体地，进口臂33、出口臂34的顶端高度相同。
进一步地，芯片3贴合压在温控模块6的顶面上，以避免干涉下压组件4的运动，且可以保证温控模块6对芯片3的温控效果。
在一些实施方案中，在腔体5给芯片3增压之前，通过下压组件4对小孔帽2的通气孔21进行密封，腔体5内增压后，腔体5内部形成的压力可为进样口31向芯片3内提供压力，通过芯片3两端形成压力差的方式，在压力的作用下，芯片3内可快速形成大量液滴，通过调节腔体5内的压力数据，温控模块6的温度值，及下压组件4的下压距离等，可调节液滴生成速度，可在短时间内形成大量均一、稳定的液滴。
根据本申请的液滴制备装置，能够有效提高液滴生成速度，在短时间内生成大量的液滴，满足高通量试验需求，有效降低回流现象发生，能够使装置本身对微流体芯片的结构要求降低，更易实现微流体芯片的低成本化和易加工性，同时，能够使液滴通过动态平衡控制，保证压力的平稳上升和下降，生成的液滴大小更加均一，检测结果更加可靠。
在本申请的另一实施方案中，通气帽1与小孔帽2可在两个芯片端口之间切换连接。具体地，通气帽1直接连接于储油口32、小孔帽2直接连接于进样口31。在此情况下，通气帽1的内侧面与芯片3上靠近储油口32部分的外侧面之间形成出气通道，出气通道的底端为出口端且顶端与储油口32连通，小孔帽2连通进样口31。另外，小孔帽2的顶面高于通气帽1的顶面，下压组件4通过下压封盖通气孔21的顶面，以封盖进样口31。
液滴生成时，下压组件4通过下压封盖通气孔21，腔体5内的压力先变为负压，储油 口32压力降低，以使进样口31和储油口32之间形成压差，样品从进样口31进入微流道形成液滴，油相进入储油口32，然后进样口31端进行泄压，完成液滴生成过程。
在本申请的另一实施方案中，参照图5和图6，液滴制备装置设置在壳体内，其包括基座、芯片3、下压组件4、压力检测单元9、温控模块6。其中，壳体内形成一个密闭的腔体5，壳体开有气密开口，壳体在气密开口处固定连接有压力管道，压力管道与压力源10固定连接，密闭的腔体5内的压力可以通过压力源10控制变化，压力源10用于给密闭腔体5内加压或泄压，也可以在密闭腔体5上设置电磁泄压阀，结合压力源10，从而精确控制密闭腔体5内的压力，本实施方案中，压力源10向腔体5内提供正压。下压组件4、芯片3、温控模块6和基座沿竖直方向，从上到下依次安装在壳体内，压力检测单元9安装在压力管道内。压力检测单元9与操作系统电连接，温控模块6与操作系统电连接。在一些实施方案中，压力检测单元9可以为压力传感器或其他用于检测压力改变的组件；在一些实施方案中，温控模块6可以为加热膜或半导体等组件。
参照图7和8，芯片3包括芯片本体和芯片盖板。芯片本体和芯片盖板按竖直方向叠加，芯片盖板和芯片本体的连接处密封，芯片本体和芯片盖板形成一个微流通道。芯片本体沿远离基座的方向延伸有进口臂34和出口臂33。本实施方案中，进口臂34与出口臂33靠近下压组件4一端的高度齐平。进口臂34内开设有沿竖直方向贯通的进口腔，进口臂34靠近基座的一端开有进样口31，进样口31位于进口腔的底端，进口臂34远离芯片3本体的一端开有第一连通口，第一连通口位于进口腔的顶端，第一连通口的面积大于进样口31，进口臂34与芯片本体连通。进口臂34远离基座的一端套设有通气帽1，通气帽1与进口臂34可拆卸连接，可拆卸连接的方式可以为螺纹、卡槽等方式，通气帽1开口朝下。通气帽1内侧壁沿竖直方向向下开有进气通道11，进气通道11与进口腔连通。出口臂33内开设有沿竖直方向贯通的储油腔，出口臂33远离地面的一端开有储油口32，储油口32位于储油腔的底端。出口臂33靠近芯片本体的一端开有第二连通口，第二连通口位于储油腔的顶端，第二连通口的面积大于储油口32，出口臂33与芯片本体连通。出口臂33远离基座的一端可拆卸连接有小孔帽2，可拆卸连接的方式可以为螺纹、卡槽等方式。在一些实施方案中，小孔帽2为弹性件。小孔帽2沿竖直方向开设有贯穿的通气孔21，小孔帽2与出口臂33连通，小孔帽2竖直方向上的投影落入储油腔的投影内。多个小孔帽2之间还可以固定连接加强筋，以减少不同小孔帽2的形变量差。
参照图6和图8，下压组件4包括驱动源、固定板和压板7。固定板与壳体固定连接。在一些实施方式中，驱动源为下压电机8，下压电机8与控制装置电连接。本实施方案中， 控制装置可以是PLC系统等操控系统。下压电机8固定安装在壳体顶部，下压电机8与压板7通过丝杆滑动连接。压板7一体成型有下压块，下压块朝向基座设置。下压电机8驱动压板7朝向芯片3滑移的过程中，下压块与小孔帽2抵接并堵住小孔帽2的通气孔21，这样在进样口31通气的过程中，芯片3内形成压力差，从而令微流通道内的液体形成液滴。下压块与小孔帽2抵接后，压板7朝向芯片3继续滑移，小孔帽2在压力的作用下变形，从而改变通气孔21的体积，使得储油口32处的压力发生变化，进而调节微液通道内的压力差大小，调节液滴形成的大小。
本实施方案的原理如下。驱动下压电机8带动压板7下降，直至下压块与小孔帽2抵紧，封闭通气孔21。然后调控压力源10，使腔体5内形成正压力，进而使微流通道内的液体快速形成大量均一的液滴，并且油相从储油口32流出。另外，在液体生成的过程中，可以在通气孔21被关闭后，继续驱动压板7下降或上升，使小孔帽2在压力下产生形变，通气孔21的体积发生变化，进而改变储油口32一端的压力。此外，通过压力检测单元9检测腔体5内的压力数据，当检测到的压力数据与预设压力数据不符时，可以通过温控模块6改变芯片3内的温度值同时控制下压组件4改变芯片3内的压力大小，来保证液滴大小的均一化。液滴生成后，可以通过驱动压板7缓慢上升，直至压板7离开小孔帽2，通气孔21重新与腔体5连通，使得进样口31和储油口32的压差处于平衡状态，此时，液滴停止制备及移动。再将腔体5进行放气后，使腔体5内压差与外界平衡。此时大量液滴会均一快速制备完成。
在另一些实施方案中，腔体5内的压力源10提供的压力为负压，参考图9，小孔帽2套设在进口臂34上，通气帽1套设在出口臂33上。其实验原理如下。液滴生成时，下压组件4通过驱动压板7封盖通气孔21，同时控制压力源10使腔体5内的压力变为负压，使得储油口32压力降低，以使进样口31和储油口32之间形成压差。样品从进样口31进入微流通道，并在压力差和温度的作用下形成液滴，同时油相进入储油口32。然后控制腔体5压力恢复，进样口31端进行泄压，完成液滴生成过程。
除了上述液滴制备装置，本申请还提供了一种液滴制备方法，该液滴制备方法应用液滴制备装置，液滴制备装置具体可以为以上任一实施方案中提供的液滴制备装置，有益效果可以相应参考以上各个实施方案。
该液滴制备方法包括：
实时接收压力检测单元9检测的压力数据；
判断压力数据是否超过预设压力范围，若是，执行选定的调节步骤，以使芯片3中的实际液 滴大小等于预设压力值下的液滴大小；
其中，至少一个调节步骤为第一调节步骤，第一调节步骤为：仅控制温控模块6调节温度值。
具体地，在选定第一调节步骤时，执行第一调节步骤具体包括：
当实时测得的腔体5内的实际压力数据比压力偏离最大设置值高的时候，降低温控模块6的温度，使液滴流动变慢，达到使液滴大小与预设压力数据一致时的大小的目的；
当实时测得实际腔体5内压力数据比压力偏离最小设置值低的时候，会通过升高温控模块6的温度，使液滴流动变快，达到使液滴大小与预设压力数据一致时的大小的目的。
其中，预设压力数据为预设压力范围内的一个值，压力偏离最大设置值为预设压力范围的最大值，压力偏离最小设置值为预设压力范围的最小值，压力偏离最小设置值＜预设压力数据＜压力偏离最大设置值。另外，每个时刻预设压力数据、预设压力范围可以根据需要进行设置，可以是相同的，也可以是不同的。
进一步地，在小孔帽2直接连接于储油口32且下压组件4封盖通气孔21的状态下，至少一个调节步骤为第二调节步骤。第二调节步骤为：仅调节下压组件4对小孔帽2的下压力。
具体地，在选定第二调节步骤时，通过调节压板7的下压距离来改善液滴生成质量。
执行第二调节步骤具体包括：
在实时测得实际压力数据比压力偏离最大设置值高的时候，下降压板7，小孔帽2被压缩，使通气孔21的空气体积变小压强增大，进而芯片3的进出口两端的压力差变小，从而使液滴流动变慢，达到使液滴大小与预设压力数据一致时的大小的目的；
在实时测得实际压力数据比压力偏离最小设置值低的时候，上升压板7，使通气孔21的空气体积变大压强减小，使得芯片3的进出口两端的压力差变大，从而使液滴流动变快，达到使液滴大小与预设压力数据一致时的大小的目的。
进一步地，在小孔帽2直接连接于储油口32且下压组件4封盖通气孔21的状态下，至少一个调节步骤为第三调节步骤。第三调节步骤为：控制温控模块6调节温度值，同时调节下压组件4对小孔帽2的下压力。
具体地，在选定第三调节步骤时，通过同时控制温控模块6的温度值和调节压板7的下压距离来改善液滴生成质量。
执行第三调节步骤具体包括：
在实时测得实际压力数据比压力偏离最大设置值高的时候，下降压板7，使通气孔21的空 气体积变小，同时降低温控模块6的温度，使液滴流动变慢，达到使液滴大小与预设压力数据一致时的大小的目的；
在实时测得实际压力数据比压力偏离最小设置值低的时候，上升压板7，使通气孔21的空气体积变大，同时升高温控模块6的温度，使液滴流动变快，达到使液滴大小与预设压力数据一致时的大小的目的。
其中，温控模块6和压板7控制方法可以根据实际的液滴生成条件进行测试获得。具体地，温控模块6的温度调节方法可以根据不同的芯片3结构、油相组成等因素实际测试得到，下降压板7相对小孔帽2的下降距离压缩量，可以根据不同小孔帽2结构等因素实际测试得到。
进一步地，在小孔帽2直接连接于进样口31的状态下，在进行实时接收压力检测单元9检测的压力数据之前，该方法还包括：控制下压组件4封盖通气孔21以封盖进样口31，通过腔体5向储油口32提供负压，以使芯片3内形成压力差。
在以上各个实施方案的基础上，针对液滴大小，可以参照以下可多参数控制液滴生成的模型的经验公式进行精确控制。在液滴生成的升压阶段，尽可能保证实际液滴尺寸等于液滴理论值，并让实际液滴大小均一性；在液滴生成的泄压阶段，有效控制已生成的液滴在芯片3中平均分布，最大程度降低液滴回流、空气过充入，导致液滴总数量变异性大，影响结果的精准。
公式为：
r＝R-A×(ηt-ηt0)×ln(1+(p-p0))-B×(ηt-ηt0)2-C×Δd
式中，
r为液滴实际半径；
R为液滴理论半径＝(芯片3的微流道出口结构设计尺寸在整个液滴生成装置反应过程中的理论预期值)；
ηt为芯片3中的油在温控模块6升降温度时的黏度；
ηt0为芯片3中的油在熔点温度时的黏度；
p为压力检测单元9在腔体5中的压力实测值(atm)；
p0为1标准大气压；
△d以压板7与小孔帽2密封接触时为下压原点0值，再继续向下压距离为正值；
A、B和C为常数。
该公式应用在液滴生成的升压阶段：压板7与小孔帽2密封接触后，△d≥0时，腔体5 压力开始上升，并透过压力检测单元9，测得p≥1)，液滴方开始生成，并透过不断监控p的数值，同时控制△d的向下压或向上升，与温控模块6的温度下降与上升来取得液滴实际半径r能与液滴理论半径R一致且平均。
该公式应用在液滴生成的泄压阶段：腔体5压力开始下降，并透过压力检测单元9，测得p值的下降状况，为确保腔体5内的液滴质量与分布平均，经过p值的动态监控，控制△d的上升或下降，与与温控模块6的温度下降与上升，来维持已生成的液滴能在芯片3中平均分布，减少液滴回流或空气过充入的情况，导致液滴总数量变异性大，影响结果的精准。
以上对本申请所提供的液滴制备装置及方法进行了详细介绍。本文中应用了具体个例对本申请的原理及实施方式进行了阐述，以上实施方案的说明只是用于帮助理解本申请的方法及其核心思想。应当指出，对于本技术领域的普通技术人员来说，在不脱离本申请原理的前提下，还可以对本申请进行若干改进和修饰，这些改进和修饰也落入本申请权利要求的保护范围内。

Claims (10)

  1. 一种液滴制备装置，其特征在于，包括腔体(5)、芯片(3)、压力检测单元(9)、温控模块(6)、下压装置(4)和小孔帽(2)；所述芯片(3)、所述温控模块(6)和所述压力检测单元(9)均设于所述腔体(5)内，所述温控模块(6)用于调节所述芯片(3)内的温度值，所述压力检测单元(9)用于检测所述腔体(5)内的压力数据；所述芯片(3)的顶部具有进样口(31)和储油口(32)两个芯片端口；所述小孔帽(2)具有沿上下方向贯穿的通气孔(21)，且所述小孔帽(2)在下压力的作用下可上下弹性形变，以改变所述通气孔(21)的体积；
    在所述小孔帽(2)直接连接于所述储油口(32)的状态下，所述通气孔(21)与所述储油口(32)连通，所述下压装置(4)通过升降运动以打开或封盖所述通气孔(21)的顶端，从而对应打开或封盖所述储油口(32)，且在所述下压装置(4)封盖所述储油口(32)的状态下，经所述进样口(31)向所述芯片(3)内施加正压力，以使所述芯片(3)内形成压力差。
  2. 一种液滴制备装置，其特征在于，包括壳体和设置在壳体内的芯片(3)、下压组件(4)和温控模块(6)；所述温控模块(6)设置在壳体底部，所述芯片(3)设置在所述温控模块(6)上，所述下压组件(4)设置在壳体顶部，所述温控模块(6)与下压组件(4)配合用于调节液滴形成的大小。
  3. 根据权利要求2所述的液滴制备装置，其特征在于，所述壳体还外接有压力源(10)，所述壳体和压力源(10)之间安装有压力检测单元(9)。
  4. 根据权利要求2所述的液滴制备装置，其特征在于，所述芯片(3)开有进样口(31)和储油口(32)，所述芯片(3)的储油口(32)处安装有小孔帽(2)，所述小孔帽(2)沿竖直方向开设有贯穿的通气孔(21)，所述小孔帽(2)与下压组件(4)配合用于调节芯片(3)内的压力大小。
  5. 根据权利要求4所述的液滴制备装置，其特征在于，所述小孔帽(2)套设在芯片(3)上，所述小孔帽(2)为弹性件。
  6. 根据权利要求5所述的液滴制备装置，其特征在于，在芯片(3)所在的平面内，所述通气孔(21)的投影落入储油口(32)的投影范围内。
  7. 根据权利要求4所述的液滴制备装置，其特征在于，所述下压组件(4)包括下压电机(8)和压板(7)，所述下压电机(8)与壳体固定连接，所述下压电机(8)与所述压板(7)滑动连接，在芯片(3)所在的平面内，所述小孔帽(2)的投影落在所述压板(7)的投影范围内。
  8. 根据权利要求7所述的液滴制备装置，其特征在于，所述芯片(3)的进样口(31)处安装通气帽(1)，所述通气帽(1)套设在芯片(3)上，所述通气帽(1)开有开口朝向芯片(3)的进气通道(11)，所述进气通道(11)与芯片(3)连通。
  9. 根据权利要求8所述的液滴制备装置，其特征在于，所述芯片(3)包括进口臂(34)和出口臂(33)，所述进口臂(34)与芯片(3)固定连接并朝压板(7)方向延伸，所述出口臂(33)与芯片(3)固定连接并朝压板(7)方向延伸，所述进样口(31)设置在所述进口臂(34)下端，所述储油口(32)设置在所述出口臂(33)下端。
  10. 利用权利要求1-9任一项所述的液滴制备装置进行的液滴制备方法，其特征在于，
    通过压力检测单元(9)预设压力值；
    通过所述温控模块(6)调节芯片(3)的温度；
    通过所述下压组件(4)调节芯片(3)内压力；
    通过压力检测单元(9)检测芯片(3)内压力，判断芯片(3)内压力是否落在预设压力范围内；若是，停止温控调节和压力调节；若否，进行压力调节和/或温控调节步骤，直至芯片(3)内压力落在预设压力范围内。
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