WO2020082487A1 - 微流控芯片 - Google Patents

微流控芯片 Download PDF

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Publication number
WO2020082487A1
WO2020082487A1 PCT/CN2018/117220 CN2018117220W WO2020082487A1 WO 2020082487 A1 WO2020082487 A1 WO 2020082487A1 CN 2018117220 W CN2018117220 W CN 2018117220W WO 2020082487 A1 WO2020082487 A1 WO 2020082487A1
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WO
WIPO (PCT)
Prior art keywords
droplet
continuous phase
area
chip
channel
Prior art date
Application number
PCT/CN2018/117220
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English (en)
French (fr)
Inventor
於林芬
阳巍
Original Assignee
深圳市博瑞生物科技有限公司
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Publication date
Application filed by 深圳市博瑞生物科技有限公司 filed Critical 深圳市博瑞生物科技有限公司
Priority to US17/277,935 priority Critical patent/US20210362159A1/en
Priority to JP2021540347A priority patent/JP2022502680A/ja
Priority to EP18938038.9A priority patent/EP3871772A1/en
Publication of WO2020082487A1 publication Critical patent/WO2020082487A1/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
    • B01L3/502769—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by multiphase flow arrangements
    • B01L3/502784—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by multiphase flow arrangements specially adapted for droplet or plug flow, e.g. digital microfluidics
    • 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
    • B01L3/508—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above
    • B01L3/5085—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates
    • B01L3/50851—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates specially adapted for heating or cooling samples
    • 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
    • B01L2200/02—Adapting objects or devices to another
    • B01L2200/026—Fluid interfacing between devices or objects, e.g. connectors, inlet details
    • B01L2200/027—Fluid interfacing between devices or objects, e.g. connectors, inlet details for microfluidic devices
    • 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
    • B01L2200/0689—Sealing
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/10—Integrating sample preparation and analysis in single entity, e.g. lab-on-a-chip concept
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0627—Sensor or part of a sensor is integrated
    • 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
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0681—Filter
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0832—Geometry, shape and general structure cylindrical, tube shaped
    • 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
    • B01L2300/18—Means for temperature control
    • B01L2300/1805—Conductive heating, heat from thermostatted solids is conducted to receptacles, e.g. heating plates, blocks

Definitions

  • This application relates to the field of digital PCR technology, and in particular to a microfluidic chip.
  • the existing droplet digital PCR technology route uses droplet generation, and the PCR reaction and droplet detection are performed on different instruments. This technical route results in cumbersome operation steps, and the samples are not closed, which does not meet the requirements of clinical diagnosis and analysis; and the manual transfer of samples or chips between different instruments increases the overall operation time and cost, restricting the popularization and application of this technology.
  • the present application provides a microfluidic chip, which is used to realize the whole process of droplet generation, droplet storage, temperature control, PCR reaction, droplet detection, and waste liquid treatment.
  • the microfluidic chip described in the present application includes an upper layer of the chip, a lower layer of the chip, a sealing layer, and a droplet generation area, a droplet storage area, a droplet detection area and a waste liquid collection area provided on the microfluidic chip,
  • the droplet generation area, the droplet storage area, the droplet detection area, and the waste liquid collection area are all connected through a channel;
  • the droplet generation area is used to form tens of thousands to millions of droplets through the continuous phase of the sample phase.
  • the droplet detection area is used for PCR
  • the droplets after the reaction are optically detected, and the waste liquid collection area is used to collect and store the droplets and the continuous phase after the detection.
  • the upper layer of the chip is provided with a sample injection hole penetrating the upper and lower surfaces of the upper layer of the chip, a continuous phase injection hole, a continuous phase injection hole, and a waste liquid discharge hole.
  • a sample cell connected to the sample injection hole, a generated continuous phase cell connected to the generated continuous phase injection hole, a detected continuous phase cell connected to the detected continuous phase injection hole, and a waste liquid connected to the waste liquid discharge hole
  • the lower layer of the chip is provided with droplet transfer holes and droplet discharge holes that penetrate the upper and lower surfaces of the lower layer of the chip.
  • the lower surface of the upper layer of the chip is bonded to the upper surface of the lower layer of the chip, and the lower surface of the lower layer of the chip is bonded to the upper surface of the sealing layer;
  • the droplet storage area is provided on the lower surface of the lower layer of the chip, and the droplet generation area is provided on any surface of the lower surface of the upper layer of the chip, the upper surface of the lower layer of the chip, and the lower surface of the lower layer of the chip.
  • the droplet detection area and the waste liquid collection area are provided on the lower surface of the upper layer of the chip or the upper surface of the lower layer of the chip.
  • the microfluidic chip has multiple independent sets of the droplet generation area, droplet storage area, droplet detection area and waste liquid collection area arranged side by side, respectively corresponding to multiple samples, each group of The droplet generation area, the droplet storage area, the droplet detection area, and the waste liquid collection area form a full-process processing path for a sample, and the microfluidic chip can independently generate droplets for a plurality of the samples, Droplet storage, temperature control and PCR reaction, drop detection, waste liquid collection.
  • the droplet generation area includes a continuous generation inlet, a continuous generation channel communicating with the continuous generation inlet, a sample inlet, and a sample phase channel communicating with the sample inlet.
  • the generating continuous phase injection hole is in communication, the sample inlet is in communication with the sample injection hole, the sample phase channel is connected to at least one sample phase branch channel, and each of the sample phase branch channels is connected to the Generate continuous phase channels;
  • the droplet is generated at the bell mouth and enters the generation continuous phase channel, and is pushed to the end of the droplet generation area by the generation continuous phase.
  • the depth dimension of the generated continuous phase channel depth is greater than or equal to 5 times the depth dimension of the trumpet, and the depth of the trumpet and the branch channel of the sample phase are the same.
  • the droplet storage area includes a droplet storage tank, the droplet storage tank penetrates the droplet transfer hole and the droplet discharge hole communicating with the droplet detection area, the droplet storage tank It includes a dome surface and an inner wall.
  • the dome surface is a dome design. The top of the dome communicates with the droplet discharge hole, and the bottom of the inner wall communicates with the droplet transfer hole.
  • the droplet detection area includes a detection continuous phase inlet, a detection continuous phase channel communicating with the detection continuous phase inlet, a droplet inlet, a droplet channel communicating with the droplet inlet, a detection channel, the detection The continuous phase inlet communicates with the detection continuous phase injection hole, and the droplet inlet communicates with the droplet discharge hole;
  • the waste liquid collection area includes a waste liquid channel corresponding to the detection channel and the waste liquid Waste liquid outlet connected to the channel;
  • the detection continuous phase channel connects the detection continuous phase inlet and the detection channel
  • the droplet channel connects the droplet entrance and the detection channel
  • the detection continuous phase channel and the droplet channel The detection channels cross at the same point, and the detection channels communicate with the waste liquid channel.
  • the lower layer of the chip is provided with a droplet transfer channel communicating with the droplet transfer hole, the liquid The droplet transfer channel communicates with the droplet transfer hole and the droplet storage tank.
  • the end of the droplet generation area directly communicates with the droplet storage area, and at the same time, the lower layer of the chip is provided with communication with the sample inlet
  • the sample injection hole of the sample the generated continuous phase injection hole communicating with the generated continuous phase inlet
  • the sample injection hole and the continuous phase injection hole penetrate the upper and lower surfaces of the lower layer of the chip, and communicate with the sample injection hole and the continuous phase injection hole of the upper layer of the chip, respectively.
  • a filtering area is provided between the sample inlet and the sample phase channel, between the generated continuous phase inlet and the generated continuous phase channel, and between the detected continuous phase inlet and the detected continuous phase channel.
  • the sealing layer serves to seal the lower surface of the lower layer of the chip and to transfer heat with the droplet storage area.
  • the droplet storage area includes a sealing ring and a PCR tube.
  • the lower surface of the sealing layer is provided with a PCR tube installation groove.
  • the PCR tube installation groove includes a dome surface, a sealing surface, an inner wall, and a droplet entry hole penetrating the sealing layer is provided within the range of the dome surface And droplet discharge holes.
  • One end of the droplet transfer channel is connected to the droplet transfer hole, the other end is communicated with the droplet entry hole, and the droplet discharge hole is communicated with the droplet discharge hole under the chip.
  • the sealing ring and the PCR tube are installed between the inner walls of the PCR tube installation groove, and the sealing surface and the PCR tube are sealed by the sealing ring.
  • the microfluidic chip provided by the present application is used to realize the whole process of droplet generation, droplet storage, temperature control, PCR reaction and droplet detection, and waste liquid treatment. This process does not need to manually transfer samples, and the samples are independently closed, which realizes the automated process of sample entry and experiment results.
  • the microfluidic chip has a high degree of integration. The autonomous transfer of droplets in various areas can simplify the operation process and reduce Operation difficulty, improve operation rate.
  • FIG. 1 is a schematic diagram of a first embodiment of a microfluidic chip described in this application.
  • FIG. 2 is a schematic plan view of the microfluidic chip shown in FIG. 1.
  • FIG. 3 is a schematic cross-sectional view of a full-process processing path for a single sample of the microfluidic chip shown in FIG. 1.
  • FIG. 4 is a schematic diagram of the upper surface and lower surface of the chip of the microfluidic chip shown in FIG.
  • FIG. 5 is a partially enlarged schematic view of the droplet generation area of the microfluidic chip shown in FIG. 1.
  • FIG. 6 is a schematic diagram of the lower layer of the microfluidic chip shown in FIG.
  • FIG. 7 is a partial enlarged schematic view and a cross-sectional schematic view of the lower layer of the chip of the microfluidic chip shown in FIG. 1.
  • FIG. 8 is a partially enlarged schematic view of the droplet detection area of the microfluidic chip shown in FIG. 1.
  • FIG. 9 is a schematic diagram of a single sample full-process processing path of the second embodiment of the microfluidic chip described in this application.
  • FIG. 10 is a schematic diagram of the lower layer of the chip of the second embodiment of the microfluidic chip shown in FIG. 9.
  • FIG. 11 is a schematic view of the sealing layer of the second embodiment of the microfluidic chip shown in FIG. 9.
  • FIG. 12 is a schematic diagram of a seal ring of the second embodiment of the microfluidic chip shown in FIG. 9.
  • FIG. 13 is a schematic diagram of the lower layer of the chip of the third embodiment of the microfluidic chip described in this application.
  • FIG. 14 is a schematic diagram of the lower layer of the chip of the fourth embodiment of the microfluidic chip described in this application.
  • FIG. 15 is a schematic diagram of a droplet generation area of the fourth embodiment of the microfluidic chip shown in FIG. 14.
  • FIGS. 1-8 are presented in a perspective manner so that the internal structure can be seen clearly.
  • This application provides a microfluidic chip for droplet generation, droplet storage, temperature control, PCR reaction, droplets
  • the waste liquid collection is completed in the waste liquid collection area 90.
  • the microfluidic chip includes an upper chip layer 10, a lower chip layer 20, a sealing layer 30, and a droplet generation area 60, a droplet storage area 70, a droplet detection area 80 and a waste liquid provided on the microfluidic chip
  • the collection area 90, the droplet generation area 60, the droplet storage area 70, the droplet detection area 80, and the waste liquid collection area 90 are all connected through a channel.
  • the droplet generation area 60 is used to form tens of thousands to millions of droplets through the continuous phase of the sample phase.
  • the droplet detection area 80 is used for the optical detection of the droplets after the PCR reaction, the waste liquid collection area 90 is used to collect and store the detected droplets and the continuous phase.
  • the microfluidic chip of this embodiment has multiple sets of independent, side-by-side arrangement of droplet generation area 60, droplet storage area 70, droplet detection area 80, and waste liquid collection area 90, respectively corresponding to multiple samples, each
  • the group droplet generation area 60, the droplet storage area 70, the droplet detection area 80, and the waste liquid collection area 90 form a full-process processing path for a sample, and the microfluidic chip can perform liquid for multiple samples independently of each other.
  • Drop generation, drop storage, temperature control and PCR reaction, drop detection, and waste liquid collection The following description mainly clarifies the full flow processing path of a single sample. Obviously, the structural principle of the full flow processing path of each sample is the same.
  • the chip upper layer 10 includes an upper surface 11 and a lower surface 12
  • the chip lower layer 20 includes an upper surface 21 and a lower surface 22
  • the sealing layer 30 includes an upper surface 31 and a lower surface 32
  • the chip The lower surface 12 of the upper layer 10 is bonded to the upper surface 21 of the chip lower layer 20, and the lower surface 22 of the chip lower layer 20 is bonded to the upper surface 31 of the sealing layer 30.
  • the bonding is carried out by means of bonding, welding, bonding, etc. to ensure a firm and tight bonding.
  • the droplet storage area 70 is provided on the lower surface 12 of the chip lower layer 10, and the droplet generation area 60 is provided on the lower surface 12 of the chip upper layer 10, the upper surface 21 of the chip lower layer 20, and the chip lower layer 20 On either surface of the lower surface 22, the droplet detection area 80 and the waste liquid collection area 90 are provided on the lower surface 12 of the chip upper layer 10 or the upper surface 21 of the chip lower layer 20.
  • the droplet generation area 60 is provided on the lower surface 12 of the upper layer 10 of the chip near one end.
  • the droplet detection area 80 and the waste liquid collection area 90 are provided on the lower surface 12 of the chip upper layer 10 at an end away from the droplet generation area 60, and the droplet storage area 70 is provided on the chip lower layer 20 Of the lower surface 22.
  • the chip upper layer 10 is provided with a sample injection hole 13 penetrating the upper and lower surfaces of the chip upper layer 10, a continuous phase injection hole 14, a continuous phase injection hole 15 and a waste liquid discharge ⁇ 16.
  • the upper surface 11 of the upper layer 10 of the chip is provided with a sample cell 131 communicating with the sample injection hole 13, a generation continuous phase cell 141 communicating with the generation continuous phase injection hole 14, and a detection continuous phase injection hole 15
  • the lower chip layer 20 is provided with a droplet transfer hole 23 penetrating the upper and lower surfaces of the lower chip layer 20, and the droplet discharge
  • the hole 24 is a droplet transfer channel 231 communicating with the droplet transfer hole 23.
  • the droplet generation area 60 includes a generation continuous phase inlet 64, a generation continuous phase channel 66 communicating with the generation continuous phase inlet 64, a sample inlet 61, and a communication with the sample inlet 61
  • Sample phase channel 63 the generated continuous phase inlet 64 communicates with the generated continuous phase injection hole 14
  • the sample inlet 61 communicates with the sample injection hole 13
  • the sample phase channel 63 connects at least one of the samples Phase branch channels 631
  • each of the sample phase branch channels 631 is connected to the generated continuous phase channel 66 through a bell mouth 632; the droplet is generated at the bell mouth 632 and enters the generated continuous phase channel 66, And is pushed to the end 661 of the droplet generation area 60 by the generation continuous phase.
  • the depth dimension of the generated continuous phase channel 66 is greater than or equal to twice the depth dimension of the bell mouth 632, and the depth of the bell mouth 632 is the same as the depth of the sample phase branch channel 631.
  • the sample inlet 61, the sample phase channel 63, the continuous phase generation inlet 64, and the continuous phase generation channel 66 are all eight.
  • the sample inlet 61, the sample phase channel 63, the generation continuous phase inlet 64, and the generation continuous phase channel 66 are all recessed on the lower surface 12 of the chip upper layer 10 and packaged by the chip lower layer 20.
  • 8 sample inlets 61 are arranged in a row, and 8 generation continuous phase inlets 64 are arranged in a row and arranged in parallel with the row where the sample inlets 61 are located.
  • the sample inlet 61 is located on a side far from the droplet detection area 80 relative to the generated continuous phase inlet 64.
  • a sample filter area 62 is provided between the sample inlet 61 and the sample phase channel 63, and the sample filter area 62 includes a chamber and a plurality of chambers on the side of the sample inlet 61 that communicate with the sample inlet 61 An array of micropillars 621 arranged in the chamber.
  • a generation continuous phase filter area 65 is provided between the generation continuous phase inlet 64 and the generation continuous phase channel 66, and the generation continuous phase filter area 65 includes a generation continuous phase filtering area 65 on the side of the generation continuous phase inlet 64.
  • the cavity in communication with the inlet 64 and a plurality of microcolumns 651 arranged in the cavity.
  • the distance between the plurality of microcolumns 621 and the microcolumns 651 is 10-100 microns, and their function is to intercept impurities.
  • the generated continuous phase enters from the generated continuous phase inlet 64, enters and fills the generated continuous phase channel 66 after passing through the generated continuous phase filter area 65.
  • the sample phase channel 63 has a symmetrical structure on both sides, and the sample phase enters from the sample inlet 61, passes through the sample filter area 62, and is divided into two strands to enter the two sides of the sample phase channel 63, respectively.
  • the sample phase channel 63 and the generated continuous phase channel 66 are connected through the sample phase branch channel 631, and the sample phase branch channel 631 and the generated continuous phase channel 66 are connected through the bell mouth 632.
  • the multiple sample phase branch channels 631 are connected to the symmetrical sides of the continuous phase channel 66.
  • six sample phase branch channels 631 are taken as an example.
  • the six sample phase branch channels 631 are located on symmetrical sides of the continuous phase channel 66 to communicate with the sample phase channel 61.
  • the number of the sample phase branch channels 631 is 1-100. The more the sample phase branch channels 631, the higher the efficiency of droplet generation.
  • the bell mouth 632 is a “ ⁇ ” shape with symmetric openings on both sides or a “ ⁇ ” shape with single bevel openings.
  • the depth dimension of the generated continuous phase channel 66 is greater than or equal to twice the depth dimension of the sample phase branch channel 631 and the bell mouth 632.
  • the width of the sample phase branch channel 631 is 10-200 ⁇ m, and the depth is 2-100 ⁇ m.
  • the ratio of the width and depth of the sample phase branch channel 631 is greater than or equal to 1.
  • the width of the generated continuous phase channel 66 is 10-2000 microns, and the depth is 10-500 microns.
  • the droplet storage area 70 is provided on the lower surface 22 of the lower layer 20 of the chip, which is offset from the position of the droplet generation area 60.
  • the sample injection hole 13 and the generation continuous phase injection hole 14 penetrate the upper surface 11 and the lower surface 12 of the chip upper layer 10 and communicate with the sample inlet 61 and the generation continuous phase inlet 64 to inject the sample phase and the continuous phase.
  • the end of the generation continuous phase channel 66 away from the generation continuous phase inlet 64 communicates with the droplet transfer hole 23, and the droplet transfer hole 23 is used to communicate with the droplet storage area 70.
  • the droplet storage area 70 includes a droplet storage tank 71 that penetrates the droplet transfer hole 23 and communicates with the droplet
  • the droplet discharge hole 24 of the detection area 80, the droplet storage tank 71 includes a dome surface 72 and an inner wall 73, the dome surface 72 is a dome design, the top of the dome communicates with the droplet discharge hole 24
  • the bottom of the inner wall 73 communicates with the droplet transfer hole 23.
  • the droplet transfer hole 23 communicates with the bottom of the inner wall 73 of the droplet storage tank 71 through the droplet transfer channel 231.
  • the droplet storage tank 71 is formed by the dome surface 72 and the inner wall 73 The enclosed space.
  • the droplet storage area 70 is described by taking eight as an example.
  • the droplet storage tank 71, the droplet transfer hole 23 and the droplet discharge hole 24 are all eight, and the eight droplet storage areas 70 include eight There are two droplet storage grooves 71 arranged in the same row, and the droplet transfer holes 23 and the droplet discharge holes 24 of each droplet storage area 70 are spaced apart.
  • the microfluidic chip of the present application is placed horizontally during application, so the dome surface 72 is actually the upper surface of the droplet storage tank 71.
  • the dome surface 72 is a conical surface, and the point where it connects with the droplet discharge hole 24 is the highest point.
  • the droplet in the droplet storage tank 71 approaches The top of the dome surface 72 floats up, and the shape of the dome surface 72 causes the droplets to float up and concentrate to the droplet discharge hole 24, which facilitates the rapid and complete droplet discharge.
  • the droplet generation area 60 After the droplet generation area 60 generates droplets, it passes through the end 661 of the droplet generation area 60 and then passes through the droplet transfer hole 23 communicating with the droplet storage area 70.
  • the droplet transfer channel 231 connecting the droplet transfer hole 23 and the droplet storage tank 71 enters the droplet storage tank 71, and a PCR reaction is performed in the droplet storage tank 71. After the PCR reaction is completed
  • the droplet enters the droplet detection area 80 through the droplet discharge hole 24 of the droplet storage tank 71.
  • the liquid droplet storage tank 71 has a good sealing property, ensuring the storage and circulation of liquid droplets.
  • the lower surface 22 of the lower chip layer 20 is bonded to the upper surface 31 of the sealing layer 30, so that the droplet storage area 70 forms a closed droplet storage space.
  • the sealing layer 30 serves to seal the droplet storage area 70 of the lower surface 22 of the chip lower layer 20 and to transfer heat with the droplet storage area 70.
  • the thickness of the sealing layer 30 is 0.1-5 mm. In order to make the heat conduction during the PCR reaction more rapid, the sealing layer 30 should be as thin as possible.
  • the droplet detection area 80 includes a detection continuous phase inlet 81, a detection continuous phase channel 83 communicating with the detection continuous phase inlet 81, a droplet inlet 84, and a liquid communicating with the droplet inlet 84
  • a drop channel 85 and a detection channel 86 the detection continuous phase inlet 81 communicates with the detection continuous phase injection hole 15, the droplet inlet 84 communicates with the droplet discharge hole 24;
  • the waste liquid collection area 90 includes A waste liquid channel 91 corresponding to the detection channel 86 and a waste liquid outlet 92 communicating with the waste liquid channel 91;
  • the detection continuous phase channel 83 connects the detection continuous phase inlet 81 and the detection channel 86, and the droplet channel 85 connects the droplet entrance 84 and the detection channel 86, and the detection continuous phase channel 83 is The droplet channel 85 and the detection channel 86 cross at the same point, and the detection channel 86 communicates with the waste liquid channel 91.
  • the droplet detection area 80 and the waste liquid collection area 90 are described by taking 8 as examples.
  • the droplet detection area 80 and the waste liquid collection area 90 are provided on the lower surface 12 of the chip upper layer 10, and the detection continuous phase injection hole 15
  • the waste liquid discharge hole 16 penetrates the upper surface 11 and the lower surface 12 of the chip upper layer 10 and communicates with the detection continuous phase inlet 81 and the waste liquid outlet 92.
  • the droplet generation area 60, the droplet detection area 80, and the waste liquid collection area 90 are sequentially arranged from one end to the other end of the lower surface 12 of the chip upper layer 10.
  • the position corresponding to the droplet inlet 84 on the lower layer 20 of the chip is the droplet transfer hole 23, and the droplet inlet 84 is docked with the droplet transfer hole 23.
  • a filtering area is provided between the detection continuous phase inlet 81 and the detection continuous phase channel 83.
  • a detection continuous phase filter area 82 is provided between the detection continuous phase inlet 81 and the detection continuous phase channel 83, and the detection continuous phase filter area 82 includes a A chamber communicating with the continuous phase inlet 81 and a plurality of microcolumns 821 arranged in the chamber are detected.
  • the distance between the plurality of microcolumns 821 is 10 to 100 microns, and their function is to intercept impurities.
  • the detection continuous-phase channel 83 has a bifurcated structure, and the branches on both sides intersect the droplet channel 85 and the detection channel 86 at the same point.
  • the detection continuous phase enters the detection continuous phase filtration zone 82 from the detection continuous phase inlet 81, is filtered by the microcolumn 821, enters the detection continuous phase channel 83, and shunts to both sides, and droplets flow from the droplets
  • the inlet 84 enters the droplet channel 85, and the droplet enters the detection channel 86 when it is the same as the detection continuity. To be tested.
  • the eight detection channels 86 arranged in parallel are concentrated and arranged side by side, which facilitates the detection of other optical detection systems.
  • the detection channel 86 communicates with the waste liquid channel 91, and the detected droplets and the detection continuous phase flow through the waste liquid channel 91 to the waste liquid outlet 92.
  • the detection continuous phase inlet 81 is located on the side close to the droplet generation region 60, and the droplet inlet 84 is located on the side far from the droplet generation region 60.
  • the detection continuous phase channel 83 is bent from two directions and extends on both sides of the droplet channel 85 until it converges at the end of the detection channel 86.
  • the detection continuous phase channel 83 communicates with the detection continuous phase inlet 81 and the detection channel 86, and the detection continuous phase channel 83 intersects and communicates with the droplet channel 85 from two directions at an angle.
  • the droplet channel 85 connects the droplet inlet 84 and the detection channel 86, and merges with the detection continuous phase channel 83 at the same position of the detection channel 86.
  • the detection continuous phase channel 83 corresponding to the same detection continuous phase inlet 81 and the liquid droplet channel 85 corresponding to the liquid droplet inlet 84 corresponding to the detection continuous phase inlet 81 extend a distance toward the middle of the chip It gathers at an angle and finally converges at the end of the detection channel 86.
  • Eight detection channels 86 are arranged in parallel and spaced apart, and the waste liquid channel 91 extends outward from the other side of the detection channel 86 and extends to a waste liquid outlet 91 after a distance.
  • the sample injection hole 13, the generation of continuous phase injection hole 14, the detection of the continuous phase injection hole 15, and the waste liquid discharge hole 16 of the upper layer 10 of the chip are respectively connected to the sample inlet 61 and the generation of continuous phase inlet 64 of the droplet generation area 60 2. Detect the alignment of the continuous phase inlet 81 and the waste liquid outlet 92.
  • the droplet generation area end 661 is aligned with the droplet transfer hole 23, and the droplet discharge hole 24 is aligned with the droplet inlet 84 of the droplet detection area 80.
  • the container for droplet storage and PCR reaction is changed to a PCR tube 50.
  • the microfluidic chip of this embodiment includes a chip upper layer 10, a chip lower layer 20, and a sealing layer 30.
  • the chip lower layer 20 and the sealing layer 30 are different from the first embodiment, as follows
  • the droplet storage area includes a sealing ring 40 and a PCR tube 50.
  • the lower layer 20 of the chip is provided with a droplet transfer hole 23 and a droplet discharge hole 24 penetrating up and down.
  • the lower surface 22 is provided with a droplet transfer channel 231. One end is connected to the droplet transfer hole 23.
  • the lower surface 32 of the sealing layer 30 is provided with a PCR tube mounting groove 35.
  • the PCR tube mounting groove 35 includes a dome surface 351, a sealing surface 352, an inner wall 353, and a penetrating surface is provided in the range of the dome surface
  • the droplet entry hole 33 and the droplet exit hole 34 of the sealing layer is provided with a droplet transfer hole 23 and a droplet discharge hole 24 penetrating up and down.
  • the lower surface 22 is provided with a droplet transfer channel 231. One end is connected to the droplet transfer hole 23.
  • the lower surface 32 of the sealing layer 30 is provided with a PCR tube mounting groove 35.
  • the PCR tube mounting groove 35 includes a dome surface 351, a sealing surface 352, an inner wall 353, and
  • the sealing ring 40 and the PCR tube 50 are installed between the inner walls 353 of the PCR tube mounting groove 35, and the sealing surface 352 and the PCR tube 50 are sealed by the sealing ring 49.
  • the PCR tube 50 is installed in the PCR tube installation groove 35 of the lower surface 32 of the sealing layer 30, and the inner wall 353 plays a role of restraining and catching the PCR tube 50
  • a sealing ring 40 is installed between the sealing surface 352 and the PCR tube 50.
  • the droplet transfer channel 231 communicates with the droplet entry hole 33, and the droplet discharge hole 34 is aligned with the droplet discharge hole 24 of the chip lower layer 20.
  • the end 661 of the droplet generation area is aligned with the droplet transfer hole 23, the droplet discharge hole 24 of the lower chip layer 20 and the droplet inlet of the droplet detection area 80 84 aligned.
  • the dome surface 351 plays a role of discharging droplets quickly and completely.
  • the droplet generation area 60, the droplet detection area 80, and the waste liquid collection area 90 are transferred to the upper surface of the chip lower layer 20 twenty one.
  • the lower chip layer 20 is provided with a droplet transfer channel 231 communicating with the droplet transfer hole 23, and the droplet transfer channel 231 communicates with the droplet transfer hole 23 and droplet storage of the droplet storage area 70 ⁇ 71 ⁇ Groove 71.
  • the end 661 of the droplet generation area 60 is aligned with the droplet transfer hole 23 of the lower layer of the chip, and the droplet discharge hole 24 of the lower layer of the chip 20 is aligned with the droplet inlet 84 of the droplet detection area 80 .
  • the droplet generation area 60 is transferred to the lower surface 22 of the chip lower layer 20 and increased by 8
  • Two sample injection holes 25 and eight continuous-phase injection holes 26 are generated.
  • the sample injection hole 25 and the continuous phase injection hole 26 penetrate the upper surface 21 and the lower surface 22 of the chip lower layer 20 and communicate with the sample injection hole 13 and the continuous phase injection hole 14 of the chip upper layer 10, respectively .
  • the sample injection hole 25 and the continuous phase generation injection hole 26 are aligned with the sample inlet 61 and the continuous phase generation inlet 64 of the droplet generation region 60, respectively.
  • the end 661 of the droplet generation area 60 is in communication with the droplet storage tank 71, and the generated droplets directly enter the droplet storage tank 71 through the generation continuous phase channel 66 without the process of droplet transfer.
  • the sealing layer 30 functions to seal the droplet generation area 60 and the droplet storage area 70 of the lower surface 22 of the chip lower layer 20, and to transfer heat with the droplet storage area.
  • the microfluidic chip provided by this application is used to realize the whole process of droplet generation, droplet storage, temperature control, PCR reaction and droplet detection, and waste liquid treatment. It has a high degree of integration and can process multiple samples at the same time. It is closed independently. The whole process does not need to manually transfer samples to meet the needs of automated operation. In addition, the autonomous transfer of droplets in various areas can simplify the operation process, reduce the difficulty of the operation, and improve the operation efficiency.

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Abstract

一种微流控芯片，所述微流控芯片包括芯片上层（10）、芯片下层（20）、密封层（30），以及设于所述微流控芯片上的液滴生成区（60）、液滴储存区（70）、液滴检测区（80）和废液收集区（90），所述液滴生成区（60）、液滴储存区（70）、液滴检测区（80）和废液收集区（90）之间均是通过通道连通；所述液滴生成区（60）用于将样本相通过连续相形成数万个～数百万个液滴，所述液滴进入液滴储存区（70）进行PCR反应后，所述液滴检测区（80）用于对PCR反应后的液滴进行光学检测，所述废液收集区（90）用于将检测后的所述液滴、连续相进行收集、储存。

Description

微流控芯片 技术领域
本申请涉及数字PCR技术领域，特别涉及一种微流控芯片。
背景技术
现有的微滴式数字PCR技术路线采用液滴生成，PCR反应和液滴检测分别在不同的仪器上进行。这个技术路线造成操作步骤繁琐，样本非封闭，不符合临床诊断分析的要求；而且样本或芯片需要在不同仪器间手动转移增加了整体操作时间和成本，制约了该技术的普及应用。
发明内容
本申请提供一种微流控芯片，用于实现液滴生成、液滴储存、控温、PCR反应和液滴检测、废液处理等全流程过程。
本申请所述的微流孔芯片包括芯片上层、芯片下层、密封层，以及设于所述微流控芯片上的液滴生成区、液滴储存区、液滴检测区和废液收集区，所述液滴生成区、液滴储存区、液滴检测区和废液收集区之间均是通过通道连通；
所述液滴生成区用于将样本相通过连续相形成数万个～数百万个液滴，所述液滴进入液滴储存区进行PCR反应后，所述液滴检测区用于对PCR反应后的液滴进行光学检测，所述废液收集区用于将检测后的所述液滴、连续相进行收集、储存。
其中，所述芯片上层设有穿透所述芯片上层的上下表面的样本注入孔、生成连续相注入孔、检测连续相注入孔和废液排出孔，所述芯片上层的上表面设有与所述样本注入孔连通的样本池、与所述生成连续相注入孔连通的生成连续相池、与所述检测连续相注入孔连通的检测连续相池以及与所述废液排出孔连通的废液池；所述芯片下层设有穿透所述芯片下层的上下表面的液滴转移孔和液滴排出孔。
其中，所述芯片上层的下表面与所述芯片下层的上表面相贴合，所述芯片下层的下表面与所述密封层的上表面相贴合；
所述液滴储存区设于所述芯片下层的下表面上，所述液滴生成区设于所述 芯片上层的下表面、芯片下层的上表面、芯片下层的下表面的任一表面上，所述液滴检测区和废液收集区设于所述芯片上层的下表面或者芯片下层的上表面上。
其中，所述微流控芯片具有多组独立的、并排布置的所述液滴生成区、液滴储存区、液滴检测区和废液收集区，分别对应于多个样本，每一组所述液滴生成区、液滴储存区、液滴检测区和废液收集区形成一个样本的全流程处理通路，所述微流控芯片能对多个所述样本相互独立地进行液滴生成、液滴储存、控温及PCR反应、液滴检测、废液收集。
其中，所述液滴生成区包括生成连续相入口、与所述生成连续相入口连通的生成连续相通道、样本入口、与所述样本入口连通的样本相通道，所述生成连续相入口与所述生成连续相注入孔连通，所述样本入口与所述样本注入孔连通，所述样本相通道连接至少一个所述样本相分支通道，每一个所述样本相分支通道经过一个喇叭口连接所述生成连续相通道；
所述液滴在所述喇叭口处生成并进入所述生成连续相通道，并被所述生成连续相推动到所述液滴生成区的末端。
其中，在所述微流控芯片的厚度方向上，所述生成连续相通道深度尺寸大于等于5倍的喇叭口深度尺寸，所述喇叭口与所述样本相分支通道深度相同。
其中，所述液滴储存区包括液滴储存槽，所述液滴储存槽贯通有所述液滴转移孔和连通所述液滴检测区的所述液滴排出孔，所述液滴储存槽包括穹顶面和内壁，所述穹顶面为穹顶设计，穹顶的顶端与所述液滴排出孔连通，所述内壁的底部与所述液滴转移孔连通。
其中，所述液滴检测区包括检测连续相入口、与所述检测连续相入口连通的检测连续相通道、液滴入口、与所述液滴入口连通的液滴通道、检测通道，所述检测连续相入口与所述检测连续相注入孔连通，所述液滴入口与所述液滴排出孔连通；所述废液收集区包括与所述检测通道对应的废液通道以及与所述废液通道连通的废液出口；
所述检测连续相通道连接所述检测连续相入口和所述检测通道，所述液滴通道连接所述液滴入口和所述检测通道，所述检测连续相通道与所述液滴通道、所述检测通道交叉于同一点，所述检测通道与所述废液通道连通。
其中，所述液滴生成区设于所述芯片上层的下表面或者所述芯片下层的上 表面时，所述芯片下层设有与所述液滴转移孔连通的液滴转移通道，所述液滴转移通道连通所述液滴转移孔和液滴储存槽。
其中，所述液滴生成区设于所述芯片下层的下表面时，所述液滴生成区的末端与所述液滴储存区直接连通，同时所述芯片下层设有与所述样本入口连通的样本注入孔、与所述生成连续相入口连通的生成连续相注入孔；
所述样本注入孔和生成连续相注入孔穿透所述芯片下层的上下表面，并分别与所述芯片上层的样本注入孔和生成连续相注入孔连通。
其中，所述样本入口与样本相通道之间，所述生成连续相入口与生成连续相通道之间，所述检测连续相入口与检测连续相通道之间，均设有过滤区。
其中，所述密封层起到密封所述芯片下层的下表面，并起到与所述液滴储存区传递热量的作用。
其中，所述液滴储存区包括密封圈和PCR管。所述密封层的下表面设有PCR管安装槽，所述PCR管安装槽包括穹顶面、密封面、内壁以及在所述穹顶面的范围内设有穿透所述密封层的液滴进入孔和液滴排出孔。所述液滴转移通道的一端与所述液滴转移孔连接，另一端与所述液滴进入孔连通，所述液滴排出孔与所述芯片下层的液滴排出孔连通。所述密封圈和PCR管安装在所述的PCR管安装槽的内壁之间，所述密封面与所述PCR管之间通过所述密封圈密封。
本申请提供的微流控芯片用于实现液滴生成、液滴储存、控温、PCR反应和液滴检测、废液处理等全流程过程。这个流程无需手动转移样本，样本之间独立封闭，实现了样本进、实验结果出的自动化过程，微流控芯片的集成化程度高，通过液滴在各个区域的自主转移能够简化操作过程，降低操作难度，提高操作率。
附图说明
为了更清楚地说明本申请的技术方案，下面将对实施方式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一些实施方式，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，还可以如这些附图获得其他的附图。
图1是本申请所述微流控芯片第一实施例的示意图。
图2是图1所述微流控芯片的平面示意图。
图3是图1所述微流控芯片的单个样本的全流程处理通路的剖面示意图。
图4是图1所述微流控芯片的芯片上层下表面的示意图。
图5是图1所述微流控芯片液滴生成区的局部放大示意图。
图6是图1所述微流控芯片的芯片下层示意图。
图7是图1所述微流控芯片的芯片下层局部放大示意图及剖面示意图。
图8是图1所述微流控芯片液滴检测区的局部放大示意图。
图9是本申请所述微流控芯片第二实施例的单个样本全流程处理通路的示意图。
图10是图9所述微流控芯片第二实施例的芯片下层示意图。
图11是图9所述微流控芯片第二实施例的密封层示意图。
图12是图9所述微流控芯片第二实施例的密封圈示意图。
图13是本申请所述微流控芯片第三实施例的芯片下层示意图。
图14是本申请所述微流控芯片第四实施例的芯片下层示意图。
图15是图14所述微流控芯片第四实施例的液滴生成区示意图。
具体实施方式
下面将结合本申请实施例中的附图，对本申请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申请一部分实施例，而不是全部的实施例。基于本申请中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本申请保护的范围。
请参阅图1～8，图中以透视方式呈现，以便可以看清楚内部结构，本申请提供一种微流控芯片，用于实现液滴生成、液滴储存、控温及PCR反应、液滴检测、废液收集的全流程过程，其中液滴生成在液滴生成区60完成，液滴储存、控温及PCR反应在液滴储存区70完成，液滴检测在液滴检测区80完成，废液收集在废液收集区90完成。所述微流控芯片包括芯片上层10、芯片下层20、密封层30，以及设于所述微流控芯片上的液滴生成区60、液滴储存区70、液滴检测区80和废液收集区90，所述液滴生成区60、液滴储存区70、液滴检测区80和废液收集区90之间均是通过通道连通。
所述液滴生成区60用于将样本相通过连续相形成数万个～数百万个液滴， 所述液滴进入液滴储存区70进行PCR反应后，所述液滴检测区80用于对PCR反应后的液滴进行光学检测，所述废液收集区90用于将检测后的所述液滴、连续相进行收集、储存。
本实施例的微流控芯片具有多组独立的、并排布置的液滴生成区60、液滴储存区70、液滴检测区80、废液收集区90，分别对应于多个样本，每一组液滴生成区60、液滴储存区70、液滴检测区80、废液收集区90形成一个样本的全流程处理通路，所述的微流控芯片能对多个样本相互独立地进行液滴生成、液滴储存、控温及PCR反应、液滴检测、废液收集。以下描述主要阐明单个样本的全流程处理通路，显而易见的是，每一个样本的全流程处理通路的结构原理是一样的。
本实施例中，所述芯片上层10包括上表面11和下表面12，所述芯片下层20包括上表面21和下表面22，所述密封层30包括上表面31和下表面32，所述芯片上层10的下表面12与所述芯片下层20的上表面21相贴合，所述芯片下层20的下表面22与所述密封层30的上表面31相贴合。贴合采用粘接、焊接、键合等方式，以保证贴合牢固、紧密。
所述液滴储存区70设于所述芯片下层10的下表面12上，所述液滴生成区60设于所述芯片上层10的下表面12、芯片下层20的上表面21、芯片下层20的下表面22的任一表面上，所述液滴检测区80和废液收集区90设于所述芯片上层10的下表面12或者芯片下层20的上表面21上。
如图4和图7所示，本申请微流控芯片第一实施例中，所述液滴生成区60设于所述芯片上层10的下表面12上靠近一端位置。所述液滴检测区80和废液收集区90设于所述芯片上层10的下表面12上远离所述液滴生成区60的一端，所述液滴储存区70设于所述芯片下层20的下表面22上。
如图1和图3所示，所述的芯片上层10设有穿透所述芯片上层10的上下表面的样本注入孔13、生成连续相注入孔14、检测连续相注入孔15和废液排出孔16。所述芯片上层10的上表面11设有与所述样本注入孔13连通的样本池131、与所述生成连续相注入孔14连通的生成连续相池141、与所述检测连续相注入孔15连通的检测连续相池151以及与所述废液排出孔16连通的废液池161；所述芯片下层20设有穿透所述芯片下层20的上下表面的液滴转移孔23、液滴排出孔24、与所述液滴转移孔23连通的液滴转移通道231。
如图4-图6所示，所述液滴生成区60包括生成连续相入口64、与所述生成连续相入口64连通的生成连续相通道66、样本入口61、与所述样本入口61连通的样本相通道63，所述生成连续相入口64与所述生成连续相注入孔14连通，所述样本入口61与所述样本注入孔13连通，所述样本相通道63连接至少一个所述样本相分支通道631，每一个所述样本相分支通道631经过一个喇叭口632连接所述生成连续相通道66；所述液滴在所述喇叭口632处生成并进入所述生成连续相通道66，并被所述生成连续相推动到所述液滴生成区60的末端661。
所述微流控芯片的厚度方向上，所述生成连续相通道66深度尺寸大于等于2倍的喇叭口632深度尺寸，所述喇叭口632与所述样本相分支通道631深度相同。
本实施例中，液滴生成区60以8个为例进行说明，所述样本入口61、样本相通道63、生成连续相入口64、生成连续相通道66均为8个。所述样本入口61、样本相通道63、生成连续相入口64、生成连续相通道66均凹设于所述芯片上层10的下表面12上并通过芯片下层20封装。其中8个样本入口61排列成一行，8个生成连续相入口64排列成一行并与所述样本入口61所在行并列设置。所述样本入口61相对于所述的生成连续相入口64位于远离所述液滴检测区80的一侧。
所述样本入口61与样本相通道63之间，所述生成连续相入口64与生成连续相通道66之间，均设有过滤区。具体的，所述样本入口61与样本相通道63之间设有样本过滤区62，所述样本过滤区62包括位于所述样本入口61一侧的与所述样本入口61连通的腔室和多个阵列排列在腔室内的微柱621。所述生成连续相入口64与生成连续相通道66之间设有生成连续相过滤区65，所述生成连续相过滤区65包括位于所述生成连续相入口64一侧的与所述生成连续相入口64连通的腔室和多个阵列排列在腔室内的微柱651。所述多个微柱621、微柱651之间的距离为10～100微米，作用是拦截杂质。
如图5所示，生成连续相从所述生成连续相入口64进入，经过所述生成连续相过滤区65后进入并充满所述生成连续相通道66。所述样本相通道63为两边对称的结构，样本相从所述样本入口61进入，经过所述样本过滤区62后分成两股分别进入所述样本相通道63的两边。所述样本相通道63与所述生成连续相通道66之间通过所述样本相分支通道631连接，所述样本相分支通道631与所述生成连续相通道66通过所述喇叭口632连接。具体的，当所述样本相分支通道631为多个时，所述多个样本相分支通道631连接于所述生成连续相通道66的对称 两侧。本实施例中以6条样本相分支通道631为例，所述6条样本相分支通道631位于所述生成连续相通道66的对称两侧与所述样本相通道61连通。所述样本相分支通道631的数量为1～100个，所述样本相分支通道631的数量越多则液滴生成的效率越高。所述喇叭口632是两侧对称开口的“<”形或者是单斜边开口的“∠”形。样本相在经过所述喇叭口632进入所述生成连续相通道66的过程中由于压差、表面张力的作用而断裂形成一个一个的液滴，液滴被包裹在生成连续相中，然后液滴在所述生成连续相通道66中被流动的生成连续相往所述液滴生成区60的末端661推动。
进一步的，所述生成连续相通道66深度尺寸大于等于2倍的所述样本相分支通道631和喇叭口632的深度尺寸。所述样本相分支通道631的宽度为10-200微米，深度为2-100微米，所述样本相分支通道631宽度与深度比大于等于1。所述生成连续相通道66的宽度为10-2000微米，深度为10-500微米。
所述液滴储存区70设于芯片下层20的下表面22上，与所述液滴生成区60的位置错开。所述样本注入孔13、生成连续相注入孔14贯穿所述芯片上层10的上表面11和下表面12并与所述样本入口61和生成连续相入口64连通，以便注入样本相和连续相。所述生成连续相通道66远离所述生成连续相入口64的一端与所述液滴转移孔23连通，所述液滴转移孔23用于与所述液滴储存区70连通。
如图6和图7所示，本实施例中，所述液滴储存区70包括液滴储存槽71，所述液滴储存槽71贯通有所述液滴转移孔23和连通所述液滴检测区80的所述液滴排出孔24，所述液滴储存槽71包括穹顶面72和内壁73，所述穹顶面72为穹顶设计，穹顶的顶端与所述液滴排出孔24连通，所述内壁73的底部与所述液滴转移孔23连通。具体的，所述液滴转移孔23通过所述液滴转移通道231与所述液滴储存槽71的内壁73的底部连通，所述液滴储存槽71是由所述穹顶面72和内壁73所围成的空间。
所述液滴储存区70以8个为例进行说明，所述液滴储存槽71、液滴转移孔23和液滴排出孔24均为8个，所述8个液滴储存区70包括8个同一行排列的液滴储存槽71，每个所述液滴储存区70的液滴转移孔23和液滴排出孔24间隔设置。本申请的微流控芯片在应用时处于水平放置的状态，因此所述穹顶面72实际上是所述液滴储存槽71的上表面。所述穹顶面72是一个圆锥面，与所述液滴排出孔24相连接处为最高处，由于液滴比检测连续相的密度小，因此所述液滴储存 槽71里的液滴往靠近所述穹顶面72的顶端上浮，所述穹顶面72的形状使液滴上浮集中到所述液滴排出孔24，有利于液滴排出迅速、彻底。
请参阅图3，具体的，所述液滴生成区60生成液滴后通过所述液滴生成区60的末端661后通过与所述液滴储存区70连通的所述液滴转移孔23、连通所述液滴转移孔23和所述液滴储存槽71的所述液滴转移通道231进入所述液滴储存槽71，在所述液滴储存槽71内进行PCR反应，完成PCR反应后，液滴通过所述液滴储存槽71的液滴排出孔24进入所述液滴检测区80。所述液滴储存槽71的密封性良好，保证液滴的储存和流通。
本实施例中，所述芯片下层20的下表面22与所述密封层30的上表面31贴合，使所述液滴储存区70形成了封闭的液滴储存空间。所述密封层30起到密封所述芯片下层20的下表面22的所述液滴储存区70，并起到与所述液滴储存区70传递热量的作用。所述密封层30的厚度为0.1～5毫米，为了使PCR反应时的热量传导更迅速，密封层30应尽量薄。
请参照图4，所述液滴检测区80包括检测连续相入口81、与所述检测连续相入口81连通的检测连续相通道83、液滴入口84、与所述液滴入口84连通的液滴通道85、检测通道86，所述检测连续相入口81与所述检测连续相注入孔15连通，所述液滴入口84与所述液滴排出孔24连通；所述废液收集区90包括与所述检测通道86对应的废液通道91以及与所述废液通道91连通的废液出口92；
所述检测连续相通道83连接所述检测连续相入口81和所述检测通道86，所述液滴通道85连接所述液滴入口84和所述检测通道86，所述检测连续相通道83与所述液滴通道85、所述检测通道86交叉于同一点，所述检测通道86与所述废液通道91连通。
本实施例中，液滴检测区80和废液收集区90以8个为例进行说明，所述检测连续相入口81、检测连续相通道83、液滴入口84、液滴通道85、检测通道86、废液通道91、废液出口92均为8个，所述液滴检测区80和废液收集区90设于所述芯片上层10的下表面12上，所述检测连续相注入孔15和废液排出孔16贯穿所述芯片上层10的上表面11和下表面12并连通所述检测连续相入口81和废液出口92。所述液滴生成区60、液滴检测区80和废液收集区90由所述芯片上层10的下表面12一端向另一端依次排列。所述芯片下层20上对应所述液滴入口84的位置为所述液滴转移孔23，所述液滴入口84与所述液滴转移孔23对接。
所述检测连续相入口81与检测连续相通道83间设有过滤区。具体的，所述检测连续相入口81与检测连续相通道83之间设有检测连续相过滤区82，所述检测连续相过滤区82包括位于所述检测连续相入口81一侧的与所述检测连续相入口81连通的腔室和多个阵列排列在腔室内的微柱821。所述多个微柱821之间的距离为10～100微米，作用是拦截杂质。
如图4所示，所述检测连续相通道83为两边分叉的结构，两边的分支与所述液滴通道85、检测通道86交汇于同一点。检测连续相从所述检测连续相入口81进入所述检测连续相过滤区82，经所述微柱821过滤，进入所述检测连续相通道83后分流到两边，同时液滴从所述液滴入口84进入所述液滴通道85，液滴与检测连续相同时进入所述检测通道86，液滴之间的距离由于检测连续相的挤入而变大，有利于其它光学检测系统对液滴进行检测。
如图8所示，本实施例中，8个平行间隔设置的所述检测通道86，集中并排在一起，这样有利于其它光学检测系统的检测。所述检测通道86与废液通道91连通，经过检测的液滴和检测连续相经过所述废液通道91流向所述废液出口92。
具体的，所述检测连续相入口81位于靠近所述液滴生成区60的一侧，所述液滴入口84位于远离所述液滴生成区60的一侧。所述检测连续相通道83从两个方向弯折后于所述液滴通道85两侧延伸，直至在所述检测通道86的端部汇聚。所述检测连续相通道83连通所述检测连续相入口81和所述检测通道86，并且所述检测连续相通道83从两个呈夹角的方向与所述液滴通道85相交并连通。所述液滴通道85连接所述液滴入口84与所述检测通道86，并且与所述检测连续相通道83在检测通道86的同一位置汇入。
本实施例中，同一个检测连续相入口81对应的所述检测连续相通道83及与该检测连续相入口81相对应的液滴入口84对应的液滴通道85延伸一段距离后向芯片中间部位倾斜聚拢，最后在检测通道86的端部汇聚，8个检测通道86平行间隔设置，而废液通道91由检测通道86的另一侧向外展开延伸一段距离后延伸至废液出口91。所述芯片上层10的样本注入孔13、生成连续相注入孔14、检测连续相注入孔15、废液排出孔16，分别与所述液滴生成区60的样本入口61、生成连续相入口64、检测连续相入口81、废液出口92对准。所述的液滴生成区末端661与所述的液滴转移孔23对准，所述的液滴排出孔24与所述液滴检测区80的液滴入口84对准。
如图9-图12所示，本申请的第二实施例中，基于第一实施例的实施方案，将液滴储存、PCR反应的容器改为PCR管50。与第一实施例的方案大体相似，本实施例的微流控芯片包括芯片上层10、芯片下层20、密封层30，区别在于芯片下层20、密封层30与第一实施例不一样，具体如下，本实施例的液滴储存区包括密封圈40、PCR管50。
如图10-图12所示，所述的芯片下层20设有穿透上下的液滴转移孔23、液滴排出孔24，下表面22设置有液滴转移通道231，液滴转移通道231的一端与液滴转移孔23连接。所述密封层30的下表面32设有PCR管安装槽35，所述PCR管安装槽35包括穹顶面351、密封面352、内壁353以及在所述穹顶面的范围内设有穿透所述密封层的液滴进入孔33和液滴排出孔34。所述液滴转移通道231的一端与所述液滴转移孔23连接，另一端与所述液滴进入孔33连通，所述液滴排出孔34与所述芯片下层20的液滴排出孔24连通。所述密封圈40和PCR管50安装在所述的PCR管安装槽35的内壁353之间，所述密封面352与所述PCR管50之间通过所述密封圈49密封。
如图9所示，所述PCR管50安装在所述密封层30的下表面32的所述PCR管安装槽35中，所述内壁353起到限位、卡住所述PCR管50的作用，在所述密封面352和PCR管50之间安装有密封圈40。所述液滴转移通道231与所述液滴进入孔33连通，所述液滴排出孔34与所述芯片下层20的液滴排出孔24对准。与第一实施例相同，所述液滴生成区的末端661与所述液滴转移孔23对准，所述芯片下层20的液滴排出孔24与所述液滴检测区80的液滴入口84对准。所述穹顶面351起到使液滴排出迅速、彻底的作用。
如图13所示，本申请的第三实施例中，基于第一实施例的实施方案，将液滴生成区60、液滴检测区80和废液收集区90转移到芯片下层20的上表面21。
所述芯片下层20设有与所述液滴转移孔23连通的液滴转移通道231，所述液滴转移通道231连通所述液滴转移孔23和所述液滴储存区70的液滴储存槽71。所述液滴生成区60的末端661与所述芯片下层的液滴转移孔23对准，所述芯片下层20的液滴排出孔24与所述液滴检测区80的液滴入口84对准。
如图14和图15所示，本申请的第四实施例中，基于第三实施例的实施方案，将所述液滴生成区60转移到所述芯片下层20的下表面22，并增加8个样本注入孔25和8个生成连续相注入孔26。所述样本注入孔25和生成连续相注入孔26穿 透所述芯片下层20的上表面21和下表面22，并分别与所述芯片上层10的样本注入孔13和生成连续相注入孔14连通。所述样本注入孔25、生成连续相注入孔26分别与所述液滴生成区60的样本入口61、生成连续相入口64对准。所述液滴生成区60的末端661与液滴储存槽71相连通，生成的液滴通过所述生成连续相通道66直接进入所述液滴储存槽71，没有液滴转移的过程。所述密封层30起到密封所述芯片下层20的下表面22的液滴生成区60和液滴储存区70，并起到与所述液滴储存区传递热量的作用。
本申请提供的微流控芯片用于实现液滴生成、液滴储存、控温、PCR反应和液滴检测、废液处理等全流程过程，集成化程度高可同时处理多个样本，且样本之间独立封闭，整个流程无需手动转移样本，满足自动化操作的需求，另外通过液滴在各个区域的自主转移能够简化操作流程，降低操作难度，提高操作效率。
以上对本申请实施例进行了详细介绍，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，以上实施例的说明只是用于帮助理解本申请的方法及其核心思想；同时，对于本领域的一般技术人员，依据本申请的思想，在具体实施方式及应用范围上均会有改变之处，综上所述，本说明书内容不应理解为对本申请的限制。

Claims (13)

  1. 一种微流控芯片，其特征在于，所述微流控芯片包括芯片上层、芯片下层、密封层，以及设于所述微流控芯片上的液滴生成区、液滴储存区、液滴检测区和废液收集区，所述液滴生成区、液滴储存区、液滴检测区和废液收集区之间均是通过通道连通；
    所述液滴生成区用于将样本相通过连续相形成数万个～数百万个液滴，所述液滴进入液滴储存区进行PCR反应后，所述液滴检测区用于对PCR反应后的液滴进行光学检测，所述废液收集区用于将检测后的所述液滴、连续相进行收集、储存。
  2. 如权利要求1所述的微流控芯片，其特征在于，所述芯片上层设有穿透所述芯片上层的上下表面的样本注入孔、生成连续相注入孔、检测连续相注入孔和废液排出孔，所述芯片上层的上表面设有与所述样本注入孔连通的样本池、与所述生成连续相注入孔连通的生成连续相池、与所述检测连续相注入孔连通的检测连续相池以及与所述废液排出孔连通的废液池；
    所述芯片下层设有穿透所述芯片下层的上下表面的液滴转移孔和液滴排出孔。
  3. 如权利要求2所述的微流控芯片，其特征在于，所述芯片上层的下表面与所述芯片下层的上表面相贴合，所述芯片下层的下表面与所述密封层的上表面相贴合；
    所述液滴储存区设于所述芯片下层的下表面上，所述液滴生成区设于所述芯片上层的下表面、芯片下层的上表面、芯片下层的下表面之中的任一表面上，所述液滴检测区和废液收集区设于所述芯片上层的下表面或者芯片下层的上表面上。
  4. 如权利要求3所述的微流控芯片，其特征在于，所述微流控芯片具有多组独立的、并排布置的所述液滴生成区、液滴储存区、液滴检测区和废液收集区，分别对应于多个样本，每一组所述液滴生成区、液滴储存区、液滴检测区和废液收集区形成一个样本的全流程处理通路，所述微流控芯片能对多个所述样本相互独立地进行液滴生成、液滴储存、控温及PCR反应、液滴检测、废液收集。
  5. 如权利要求4所述的微流控芯片，其特征在于，所述液滴生成区包括 生成连续相入口、与所述生成连续相入口连通的生成连续相通道、样本入口、与所述样本入口连通的样本相通道，所述生成连续相入口与所述生成连续相注入孔连通，所述样本入口与所述样本注入孔连通，所述样本相通道连接至少一个所述样本相分支通道，每一个所述样本相分支通道经过一个喇叭口连接所述生成连续相通道；
    所述液滴在所述喇叭口处生成并进入所述生成连续相通道，并被所述生成连续相推动到所述液滴生成区的末端。
  6. 如权利要求5所述的微流控芯片，其特征在于，在所述微流控芯片的厚度方向上，所述生成连续相通道深度尺寸大于等于5倍的喇叭口深度尺寸，所述喇叭口与所述样本相分支通道深度相同。
  7. 如权利要求4所述的微流控芯片，其特征在于，所述液滴储存区包括液滴储存槽，所述液滴储存槽贯通有所述液滴转移孔和连通所述液滴检测区的所述液滴排出孔，所述液滴储存槽包括穹顶面和内壁，所述穹顶面为穹顶设计，穹顶的顶端与所述液滴排出孔连通，所述内壁的底部与所述液滴转移孔连通。
  8. 如权利要求4所述的微流控芯片，其特征在于，所述液滴检测区包括检测连续相入口、与所述检测连续相入口连通的检测连续相通道、液滴入口、与所述液滴入口连通的液滴通道、检测通道，所述检测连续相入口与所述检测连续相注入孔连通，所述液滴入口与所述液滴排出孔连通；所述废液收集区包括与所述检测通道对应的废液通道以及与所述废液通道连通的废液出口；
    所述检测连续相通道连接所述检测连续相入口和所述检测通道，所述液滴通道连接所述液滴入口和所述检测通道，所述检测连续相通道与所述液滴通道、所述检测通道交叉于同一点，所述检测通道与所述废液通道连通。
  9. 如权利要求2、5、6、7所述的微流控芯片，其特征在于，所述液滴生成区设于所述芯片上层的下表面或者所述芯片下层的上表面时，所述芯片下层设有与所述液滴转移孔连通的液滴转移通道，所述液滴转移通道连通所述液滴转移孔和液滴储存槽。
  10. 如权力要求2、5、6、7所述的微流控芯片，其特征在于，所述液滴生成区设于所述芯片下层的下表面时，所述液滴生成区的末端与所述液滴储存区直接连通，所述芯片下层设有与所述样本入口连通的样本注入孔、与所述生成连续相入口连通的生成连续相注入孔；
    所述样本注入孔和生成连续相注入孔穿透所述芯片下层的上下表面，并分别与所述芯片上层的样本注入孔和生成连续相注入孔连通。
  11. 如权利要求5或8所述的微流控芯片，其特征在于，所述样本入口与样本相通道之间，所述生成连续相入口与生成连续相通道之间，所述检测连续相入口与检测连续相通道之间，均设有过滤区。
  12. 如权利要求1所述的微流控芯片，其特征在于，所述密封层起到密封所述芯片下层的下表面，并起到与所述液滴储存区传递热量的作用。
  13. 如权利要求1或9所述的微流控芯片，其特征在于，所述液滴储存区包括密封圈和PCR管，所述密封层的下表面设有PCR管安装槽，所述PCR管安装槽包括穹顶面、密封面、内壁以及在所述穹顶面的范围内设有穿透所述密封层的液滴进入孔和液滴排出孔，所述液滴转移通道的一端与所述液滴转移孔连接，另一端与所述液滴进入孔连通，所述液滴排出孔与所述芯片下层的液滴排出孔连通，所述密封圈和PCR管安装在所述的PCR管安装槽的内壁之间，所述密封面与所述PCR管之间通过所述密封圈密封。
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