WO2021169785A1 - 数字微流控化学发光检测芯片及检测方法、检测装置 - Google Patents

数字微流控化学发光检测芯片及检测方法、检测装置 Download PDF

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WO2021169785A1
WO2021169785A1 PCT/CN2021/075848 CN2021075848W WO2021169785A1 WO 2021169785 A1 WO2021169785 A1 WO 2021169785A1 CN 2021075848 W CN2021075848 W CN 2021075848W WO 2021169785 A1 WO2021169785 A1 WO 2021169785A1
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substrate
driving
magnetic bead
enzyme
antibody
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PCT/CN2021/075848
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English (en)
French (fr)
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李月
姚文亮
赵楠
高涌佳
樊博麟
古乐
廖辉
赵莹莹
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京东方科技集团股份有限公司
北京京东方传感技术有限公司
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Priority to US17/434,408 priority Critical patent/US20220341925A1/en
Publication of WO2021169785A1 publication Critical patent/WO2021169785A1/zh

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54366—Apparatus specially adapted for solid-phase testing
    • G01N33/54386—Analytical elements
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/76—Chemiluminescence; Bioluminescence
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/531—Production of immunochemical test materials
    • G01N33/532—Production of labelled immunochemicals
    • G01N33/535—Production of labelled immunochemicals with enzyme label or co-enzymes, co-factors, enzyme inhibitors or enzyme substrates
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54313—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being characterised by its particulate form
    • G01N33/54326—Magnetic particles
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54366—Apparatus specially adapted for solid-phase testing
    • G01N33/54386—Analytical elements
    • G01N33/54387—Immunochromatographic test strips
    • G01N33/54388—Immunochromatographic test strips based on lateral flow

Definitions

  • the embodiments of the present disclosure relate to, but are not limited to, the technical field of chemiluminescence detection, and in particular to a digital microfluidic chemiluminescence detection chip, a detection method, and a detection device.
  • Chemiluminescence analysis is an analysis method to determine the content of substances according to the intensity of the radiant light produced by a chemical reaction.
  • Chemiluminescence immunoassay is a combination of chemiluminescence analysis and immunoreaction analysis, using chemiluminescence related substances to label antibodies or antigens, and After the reaction of the antigen or antibody to be tested, the free chemiluminescence label is separated, and other related substances of the chemiluminescence system are added to produce chemiluminescence, and quantitative or qualitative detection of the antigen or antibody is performed.
  • Chemiluminescence immunoassay technology has a high degree of accuracy and specificity, and has become one of the most important techniques in test methodology. It is currently one of the most recognized advanced label immunoassay techniques in the world. As the main method of disease diagnosis, chemiluminescence immunoassay technology has been widely used in in vitro diagnostic testing of immune function, infectious diseases, endocrine system, tumor markers, sex hormones, and thyroid function.
  • the current chemiluminescence detection device has defects such as large system volume and low consistency of detection results.
  • the embodiment of the present disclosure provides a digital microfluidic chemiluminescence detection chip, which includes a first substrate and a second substrate that are opposed to each other.
  • the cavity formed by the first substrate and the second substrate includes an antigen, a magnetic bead antibody, and The antibody-bound mixing incubation zone, the luminescence detection zone that realizes chemiluminescence and detecting light signals, and the communication path connecting the mixing incubation zone and the luminescence detection zone
  • the first substrate is provided with a device configured to drive the sample liquid to move A drive array and a light sensor array configured to collect luminescence signals of the sample liquid, the drive array corresponding to the positions of the mixing incubation area, the luminescence detection area, and the communication path, the light sensor array and the luminescence detection Corresponding to the location of the area.
  • the mixing and incubation zone includes a magnetic bead filling plate and a magnetic bead mixing channel, and the magnetic bead filling plate is configured to provide magnetic bead antibodies to the magnetic bead mixing channel.
  • Magnetic bead mixing channel the sample solution moves along the magnetic bead mixing channel under the drive of the drive array, so that the antigen in the sample solution is combined with the magnetic bead antibody to form a first incubation sample solution.
  • the incubation sample solution includes an antigen-magnetic bead antibody complex.
  • the mixing and incubation zone further includes an enzyme-labeled addition tray and an enzyme-labeled mixing channel
  • the enzyme-labeled addition tray is configured to provide an enzyme-labeled antibody to the enzyme-labeled mixing channel
  • the enzyme label mixing channel is in communication with the magnetic bead mixing channel.
  • the first incubation sample solution is driven by the drive array to move along the enzyme label mixing channel to make The first incubation sample solution is combined with the enzyme-labeled antibody to form a second incubation sample solution, and the second incubation sample solution includes an antigen-magnetic bead antibody-enzyme-labeled antibody complex.
  • the luminescence detection zone includes a substrate filling plate and a purification channel
  • the purification channel is in communication with the mixing and incubation zone
  • the substrate filling plate is configured to provide luminescence to the purification channel.
  • the second incubation sample solution moves along the purification channel under the drive of the drive array, so that the second incubation sample solution is combined with the luminescent substrate to form a third incubation sample solution
  • the third incubation sample solution includes an antigen-magnetic bead antibody-enzyme-labeled antibody-luminescent substrate complex.
  • the magnetic bead mixing channel, the enzyme-labeled mixing channel, and the purification channel are all circular channels, the sample solution and the magnetic bead antibody, the first incubation sample solution and the enzyme-labeled antibody, Both the second incubation sample solution and the luminescent substrate are mixed in a circular manner.
  • the luminescence detection zone further includes a washing and filling tray, the washing and filling tray is configured to provide a washing buffer to the purification channel, and in the purification channel, the second incubation sample solution Driven by the drive array, move along the purification channel to mix the second incubation sample solution with the washing buffer; the external magnetron device fixes the magnetic bead antibody in the second incubation sample solution, so The impurity solution in the second incubation sample solution is driven out of the purification channel by the driving array.
  • the washing and filling tray is configured to provide a washing buffer to the purification channel, and in the purification channel, the second incubation sample solution Driven by the drive array, move along the purification channel to mix the second incubation sample solution with the washing buffer; the external magnetron device fixes the magnetic bead antibody in the second incubation sample solution, so The impurity solution in the second incubation sample solution is driven out of the purification channel by the driving array.
  • the luminescence detection zone further includes a detection zone, the detection zone is in communication with the purification channel, and in the detection zone, the light sensor array collects the third incubation sample solution. Illuminate an optical signal, and convert the optical signal into an electrical signal.
  • a plurality of filling holes are provided on the second substrate, and the plurality of filling holes are respectively connected to the magnetic bead filling tray, the enzyme label filling tray, the washing filling tray, and the The position of the substrate filling tray corresponds.
  • it further includes a filling area and a waste liquid area
  • the filling area is in communication with the mixing and incubating area, and is configured to receive the sample liquid to be tested, and the waste liquid area is connected to the luminous
  • the detection area is in communication and is configured to receive waste liquid from the luminescence detection area.
  • the drive array adopts an active drive implementation manner.
  • the first substrate includes a first substrate, an array structure layer disposed on the side of the first substrate facing the second substrate, and an array structure layer disposed on the side of the array structure layer facing the second substrate.
  • the first hydrophobic layer and the second substrate include a second substrate and a second hydrophobic layer arranged on the side of the second substrate facing the first substrate; the drive array and the light sensor array are arranged in the array structure layer, and the drive The array includes a plurality of drive units, the drive unit includes a drive transistor and a drive electrode, the drive electrode is connected to the drive transistor;
  • the light sensor array includes a plurality of light sensor units, the light sensor unit includes a sensor Transistor and photodiode, the photodiode is connected to the sensing transistor.
  • the array structure layer includes:
  • the mutually adjacent ends are arranged on the driving source electrode and the driving drain electrode on the driving active layer, and the mutually adjacent ends are arranged on the sensing source electrode and the sensing drain electrode on the sensing active layer;
  • the second insulating layer and the third insulating layer covering the driving source electrode, the driving drain electrode, the sensing source electrode and the sensing drain electrode are provided with a first via hole exposing the sensing drain electrode;
  • the fourth insulating layer covering the photodiode is provided with a second via hole exposing the driving drain electrode
  • a fifth insulating layer covering the driving electrode is a fifth insulating layer covering the driving electrode.
  • the embodiment of the present disclosure also provides a digital microfluidic chemiluminescence detection device, which includes the above-mentioned digital microfluidic chemiluminescence detection chip, and also includes a pipetting device, a temperature control device, a magnetron device, and a signal processing device;
  • the pipetting device is configured to transfer the sample liquid to the digital microfluidic chemiluminescence detection chip
  • the temperature control device is configured to provide a set temperature to the digital microfluidic chemiluminescence detection chip
  • the magnetron The device is configured to provide a set magnetic field to the digital microfluidic chemiluminescence detection chip
  • the signal processing device is connected to the digital microfluidic chemiluminescence detection chip and is configured to read the electrical output of the light sensor array. Signal, analyze and process electrical signals to obtain concentration information.
  • the temperature control device is arranged on the side of the first substrate away from the second substrate or on the side of the second substrate away from the first substrate, and is arranged to face the mixing and incubating area.
  • the magnetron device is arranged on the side of the first substrate away from the second substrate or the side of the second substrate away from the first substrate, and is arranged to provide a setting for the luminescence detection area Magnetic field.
  • the embodiment of the present disclosure also provides a digital microfluidic chemiluminescence detection method using the above-mentioned digital microfluidic chemiluminescence detection chip, including:
  • the driving array driving sample solution is sequentially combined with the magnetic bead antibody, the enzyme-labeled antibody and the luminescent substrate to form an antigen-magnetic bead antibody-enzyme-labeled antibody-luminescent substrate complex;
  • the light sensor array collects the chemiluminescent light signal of the antigen-magnetic bead antibody-enzyme-labeled antibody-luminescent substrate complex, and converts the light signal into an electrical signal.
  • the drive array drive sample solution is sequentially combined with the magnetic bead antibody, the enzyme-labeled antibody, and the luminescent substrate to form an antigen-magnetic bead antibody-enzyme-labeled antibody-luminescent substrate complex, including:
  • the drive array drive sample solution is sequentially combined with the magnetic bead antibody and the enzyme-labeled antibody to form an antigen-magnetic bead antibody-enzyme-labeled antibody complex;
  • the driving array drives the antigen-magnetic bead antibody-enzyme-labeled antibody complex to bind to the luminescent substrate to form an antigen-magnetic bead antibody-enzyme-labeled antibody-luminescence substrate complex.
  • FIG. 1 is a schematic structural diagram of a digital microfluidic chemiluminescence detection device according to an embodiment of the disclosure
  • FIG. 2 is a schematic structural diagram of a digital microfluidic chemiluminescence detection chip according to an embodiment of the disclosure
  • FIG. 3 is a schematic structural diagram of an embodiment of the disclosed digital microfluidic chemiluminescence detection chip
  • FIG. 5 is a schematic structural diagram of an embodiment of a digital microfluidic chemiluminescence detection device according to an embodiment of the disclosure
  • FIG. 6 is a schematic structural diagram of a digital microfluidic chemiluminescence detection chip integrated with a light sensor array according to an embodiment of the disclosure
  • FIG. 7 is a schematic diagram of the structure of the array structure layer of the embodiment of the disclosure.
  • Point of Care Test is a bedside test or near-patient test. It is a way to obtain test results within a few minutes using portable devices. It is widely used in hospitals, nursing wards, ambulance units, and insurance companies. And family health networks are also suitable for some special environments, such as emergency relief, remote rural areas and marching. With the emergence of POCT, more work traditionally done by professional inspectors is left to non-professional inspectors.
  • the Miniaturized Total Analysis System was first proposed by Manz and Widmer of Ciba Geigy, Switzerland in 1990, and has since developed rapidly.
  • the microfluidic chip is the main development direction and the most active frontier field of the micro total analysis system. Its goal is to integrate the functions of the entire laboratory, including sampling, dilution, reagent addition, reaction, separation, and detection, on the microchip. Compared with traditional biochemical analysis laboratories, microfluidic chips have the advantages of automation, fast detection speed, small size, and low sample consumption, which will surely bring about revolutionary changes in science and technology such as biochemical analysis and medical diagnosis.
  • the driving force is applied to the discrete microdroplets to control their movement.
  • the fluid can be manipulated at the micrometer scale, which has the The basic functions of biology, chemistry and other laboratories can be scaled down to a chip of a few square centimeters, so it is also called Laboratory on a Chip (LOC), which is small in size, portable, and can be flexibly combined and integrated. High degree of advantage.
  • Digital microfluidic control is divided into active digital microfluidic control and passive digital microfluidic control. The main difference between the two is that active digital microfluidic control is an array of liquid droplets that can accurately control the liquid at a certain position.
  • the droplets move individually, while passive digital microfluidics move or stop the droplets at all positions together.
  • the digital microfluidic chip as an emerging technology for micro-liquid manipulation, has many advantages such as simple structure, small amount of samples and reagents, easy integration, parallel processing, and easy automation.
  • the related chemiluminescence detection device usually adopts the structure of liquid path system and external light detection device.
  • the liquid path system includes precision pumps such as vacuum pump, flushing pump, matrix liquid pump and peristaltic pump.
  • the external light detection device includes convex lens, Photomultiplier tube, photocell, etc. Since this structure requires complex pipelines, pumps and peripheral light paths, it not only increases the volume of the system, but also has a high signal-to-noise ratio and low consistency of detection results.
  • FIG. 1 is a schematic structural diagram of a digital microfluidic chemiluminescence detection device according to an embodiment of the disclosure.
  • the digital microfluidic chemiluminescence detection device of the embodiment of the present disclosure includes: a pipetting device 10, a temperature control device 20, a magnetron device 30, and a digital microfluidic chemiluminescence detection chip integrated with a light sensor array 40 and signal processing device 50.
  • the pipetting device 10 is configured to transfer the sample liquid to the digital microfluidic chemiluminescence detection chip 40
  • the temperature control device 20 is configured to provide a set temperature to the digital microfluidic chemiluminescence detection chip 40
  • the magnetron device 30 The digital microfluidic chemiluminescence detection chip 40 is set to provide a set magnetic field.
  • the digital microfluidic chemiluminescence detection chip 40 is set to realize the combination of antigen, magnetic bead antibody, antibody and luminescent substrate, and utilize the integrated light.
  • the sensor array collects the light signal of chemiluminescence, and converts the light signal into an electrical signal.
  • the signal processing device 50 is connected to the digital microfluidic chemiluminescence detection chip 40, and is set to read the electrical signal of the light sensor array and perform processing on the electrical signal. Analyze and process to obtain concentration information.
  • the embodiment of the present disclosure provides a digital microfluidic chemiluminescence detection device, which uses digital microfluidic technology to realize the preparation of complex sample liquids for chemiluminescence reactions, avoids complex fluid and liquid path systems, and adopts digital microfluidic chemistry
  • the light sensor array is integrated in the luminescence detection chip, which realizes the collection of light signals in the chip and avoids the complicated peripheral optical path structure.
  • the embodiments of the present disclosure have the characteristics of compact structure, small size, low power consumption, low cost, etc., which reduce the signal-to-noise ratio of signals and improve the consistency of detection results.
  • the digital microfluidic chemiluminescence detection chip 40 includes a cavity formed by a first substrate and a second substrate paired with a box.
  • the cavity is divided into multiple functional areas, and the multiple functional areas include: filling area 100.
  • the mixing and incubation area 200, the luminescence detection area 300 and the waste liquid area 400 are provided with a communication path 500 between the multiple functional areas, and the filling area 100 and the mixing and incubation area 200 are connected through a communication path 500, mixing The incubation area 200 and the luminescence detection area 300 are communicated through a communication path 500, and the luminescence detection area 300 and the waste liquid area 400 are communicated through a communication path 500.
  • the first substrate where the multiple functional areas and the communication paths are located is provided with a drive array for driving the movement of the sample liquid
  • the first substrate where the luminescence detection area 300 is located is provided with a light sensor array for collecting the luminescence signal of the sample liquid
  • the drive array A hydrophobic layer is arranged on the surface of the light sensor array.
  • the temperature control device 20 is arranged on the side of the first substrate away from the second substrate or the side of the second substrate away from the first substrate, and the position corresponds to the area where the mixing and incubating zone 200 is located, and is arranged to The uniform incubation zone 200 provides a set temperature.
  • the magnetron device 30 is arranged on the side of the first substrate away from the second substrate or the side of the second substrate away from the first substrate. The position corresponds to the area where the luminescence detection area 300 is located. magnetic field.
  • the temperature control device 20 may include a heater, a temperature sensor, a first controller, etc., such as a resistance wire or a semiconductor thermoelectric cooler, etc.
  • the heater, the temperature sensor and the first controller form a closed loop Control to accurately and effectively control the temperature of the mixing and incubation zone 200.
  • the temperature of the chemiluminescence immunoassay reaction can be controlled at 37 ⁇ 0.5°C.
  • the magnetron device 30 may include a magnet (permanent magnet or electromagnet), a second controller, etc.
  • the second controller adjusts the distance between the permanent magnet and the first substrate or the second substrate or turns on and off the electromagnet.
  • the strength of the magnetic field supplied to the light-emitting detection area 300 is controlled.
  • the temperature control device 20 and the magnetic control device 30 can be installed separately or combined together to form a temperature control and magnetic control integrated device.
  • the filling area 100 is configured to receive the sample liquid to be tested transferred by the pipetting device 10.
  • the mixing and incubation area 200 is connected to the filling area 100 through a communication path 500, and is configured to sequentially form a first incubation sample solution and a second incubation sample solution under the control of the driving array in the digital microfluidic chemiluminescence detection chip;
  • the incubation sample solution is an antigen-magnetic bead antibody complex
  • the second incubation sample solution is an antigen-magnetic bead antibody-enzyme-labeled antibody complex.
  • the luminescence detection area 300 and the mixing and incubation area 200 are connected through a communication path 500, and are arranged to complete the washing of the second incubation sample solution and the formation of the third incubation sample solution in sequence under the control of the magnetron device 30 and the drive array, using digital microfluidics
  • the light sensing unit controlling the chemiluminescence detection chip collects the light signal of the chemiluminescence of the third incubation sample liquid.
  • the third incubation sample solution is a complex of antigen-magnetic bead antibody-enzyme-labeled antibody-luminescent substrate.
  • the waste liquid area 400 communicates with the luminescence detection area 300 through a communication path 500 and is configured to store waste liquid from the luminescence detection area 300.
  • FIG. 3 is a schematic structural diagram of an embodiment of the digital microfluidic chemiluminescence detection chip of the present disclosure, and illustrates a dual-channel structure that can realize the simultaneous detection of two sample solutions (sample solutions).
  • the digital microfluidic chemiluminescence detection chip 40 includes multiple functional areas, namely: a filling area 100, a mixing and incubating area 200, and a luminescence area.
  • the purification detection area 300 and the waste liquid area 400, the filling area 100 and the mixing and incubating area 200 are connected by a communication path 500, and the mixing and incubation area 200 and the luminescence detection area 300 are connected by a communication path 500.
  • the digital microfluidic chemiluminescence detection chip 40 includes a first substrate and a second substrate for the box. A closed cavity is formed between the first substrate and the second substrate, and the formation of the cavity can achieve two Two channels for simultaneous detection of a sample liquid.
  • the first substrate includes a first substrate, an array structure layer disposed on the first substrate, and a first hydrophobic layer disposed on the array structure layer.
  • the array structure layer includes a drive array configured to drive the sample liquid to move and a drive array configured to collect the sample liquid.
  • the drive array is arranged at a position corresponding to all functional areas and communication paths, and the light sensor array is arranged at a position corresponding to the light-emitting detection area.
  • the second substrate includes a second substrate and a second hydrophobic layer disposed on the second substrate. The box is sealed between the first substrate and the second substrate by a sealant to form a closed cavity, and a plurality of functional areas and communication paths can be formed by arranging isolation columns in the cavity.
  • the filling area 100 of each channel includes a sample fluid filling tray 101, which is connected to the mixing and incubating area 200 through a communication path 500, and is configured to receive the sample fluid to be tested transferred by the pipetting device 10, and The sample solution is moved to the mixing and incubation area 200.
  • a filling hole is provided on the second substrate where the sample liquid filling tray 101 is located, so that the pipetting device 10 fills the sample liquid to the sample liquid filling tray 101.
  • the sample liquid may be a blood sample.
  • the mixing and incubation area 200 of each channel includes a magnetic bead filling plate 201, an enzyme label filling plate 202, a magnetic bead mixing channel 203 and an enzyme label mixing channel 204, a magnetic bead mixing channel 203 and an enzyme label mixing channel 204 are all annular channels, the magnetic bead filling disc 201 is connected with the magnetic bead mixing channel 203, the enzyme label filling disc 202 is connected with the enzyme label mixing channel 204, and the magnetic bead mixing channel 203 is respectively connected to the filling zone 100 and the enzyme The standard mixing channel 204 is connected, and the enzyme label mixing channel 204 is connected with the magnetic bead mixing channel 203 and the luminescence detection area 300 respectively.
  • the magnetic bead filling plate 201 and the enzyme-labeled filling plate 202 are respectively provided with corresponding filling holes on the second substrate where the magnetic bead filling plate 201 and the enzyme-labeled filling plate 202 are located, so that the external device can respectively fill the magnetic bead antibody and the enzyme-labeled antibody to the magnetic bead filling plate 201 And the enzyme label filling tray 202.
  • the magnetic bead filling tray 201 is configured to receive magnetic bead antibodies (magnetic particles) provided by an external device, so that the magnetic bead antibodies enter the magnetic bead mixing channel 203.
  • the driving array of the digital microfluidic chemiluminescence detection chip drives the sample liquid to move quickly along the annular magnetic bead mixing channel 203 through the electric field, so that the sample liquid and The magnetic bead antibody that enters the magnetic bead mixing channel 203 is mixed in a circular manner, the antigen in the sample solution is fully combined with the magnetic bead antibody to form the first incubation sample solution, and the first incubation sample solution that has been mixed is moved to the enzyme Standard mixing channel 204.
  • the first incubation sample solution includes an antigen-magnetic bead antibody complex.
  • the enzyme-labeled filling plate 202 is set to receive an enzyme-labeled antibody (enzyme-labeled antibody) provided by an external device, so that the enzyme-labeled antibody enters the enzyme-labeled mixing channel 204.
  • the driving array of the digital microfluidic chemiluminescence detection chip drives the first incubation sample solution to move quickly along the annular enzyme label mixing channel 204 through the electric field, so that the first incubation sample solution and The enzyme-labeled antibody is mixed in a circular manner, the first incubation sample solution is fully combined with the enzyme-labeled antibody to form a second incubation sample solution, and the mixed second incubation sample solution is moved to the luminescence detection area 300.
  • the second incubation sample solution includes an antigen-magnetic bead antibody-enzyme-labeled antibody complex.
  • the luminescence detection area 300 of each channel includes a washing and filling tray 301, a substrate filling tray 302, a purification channel 303, and a detection area 310.
  • the purification channel 303 is a circular channel and is respectively connected to the washing filling tray 301 and the substrate filling tray. 302 is connected.
  • the purification channel 303 is also in communication with the mixing and incubation area 200, the waste liquid area 400, and the detection area 310.
  • the washing filling tray 301 and the substrate filling tray 302 are respectively provided with corresponding filling holes on the second substrate where the washing buffer and the light-emitting substrate are respectively filled into the washing filling tray 301 and the bottom. ⁇ filling tray 302.
  • the luminescence detection area 300 is configured to wash the second incubation sample solution, that is, to realize the separation of the second incubation sample solution from the impurity solution.
  • a magnetic field is first applied through the magnetron device 30 to fix the magnetic bead antibody in the second incubation sample solution in the luminescence detection area 300.
  • the impurity solution is moved to the waste liquid area 400 by the driving of the driving array, and the separation of the second incubation sample solution and the impurity solution is completed. Subsequently, the magnetic field of the magnetron device 30 is cancelled, so that the driving array can drive the second incubation sample solution to move.
  • the impurity solution refers to a solution other than the antigen-magnetic bead antibody-enzyme-labeled antibody complex.
  • the method of fixing the magnetic bead antibody in the second incubation sample solution may be, for example, by setting the magnetron device 30 in the area where the purification channel 303 is located, controlling the magnetron device 30 to be energized, and the magnetic field generated by the magnetron device 30 attracts The magnetic bead antibody adsorbs the magnetic bead antibody on the surface of the cavity.
  • the tiny magnetic bead antibodies will gather into a very compact magnet, so they will not be taken away by the impurity solution, thus realizing the separation of the magnetic bead antibody and the impurity solution.
  • the magnetic control device 30 is controlled to be powered off, the magnetic field disappears, and the magnetic bead antibody can be driven by the electric field applied by the drive array.
  • the washing filling tray 301 is configured to receive a wash buffer provided by an external device, so that the washing buffer enters the purification channel 303.
  • the driving array of the digital microfluidic chemiluminescence detection chip drives the second incubation sample solution and washing buffer solution to move quickly along the circular purification channel 303 through an electric field, so that the second incubation sample solution and washing buffer solution are mixed in a circular manner.
  • the unreacted free substance contained in the magnetic bead antibody is released into the washing buffer.
  • the aforementioned separation and washing process can be repeated multiple times.
  • the impurity solution is transported to the waste liquid area 400 by fixing the magnetic bead antibody to complete the separation of the magnetic bead antibody and the impurity solution.
  • the luminescence detection zone 300 is configured to form an antigen-magnetic bead antibody-enzyme-labeled antibody-luminescent substrate complex.
  • the substrate filling tray 302 is configured to receive a luminescent substrate provided by an external device, so that the luminescent substrate enters the purification channel 303.
  • the driving array of the digital microfluidic chemiluminescence detection chip drives the pure second incubation sample solution to move quickly along the circular purification channel 303 through the electric field, so that the second incubation sample solution and the luminescent substrate are mixed in a circular manner.
  • the incubation sample solution and the luminescent substrate are fully combined to form a third incubation sample solution, and the mixed third incubation sample solution is moved to the detection area 310.
  • the third incubation sample solution includes an antigen-magnetic bead antibody-enzyme-labeled antibody-luminescent substrate complex.
  • the detection area 310 is located in the middle of the annular purification channel 303, communicates with the purification channel 303, and is configured to realize the light collection of the chemiluminescence of the third incubation sample liquid.
  • the light sensor array of the digital microfluidic chemiluminescence detection chip collects the chemiluminescence light signal of the third incubation sample solution, and converts the optical signal into electricity. Signal. After that, the electrical signal is transmitted to the signal processing device 50, and the signal processing device 50 obtains concentration information through analysis processing.
  • the waste liquid area 400 of each channel includes a waste liquid storage disk 401.
  • the waste liquid storage disk 401 communicates with the light-emitting detection area 300 through a communication path 500 and is configured to receive the waste liquid transferred from the light-emitting detection area 300.
  • the second substrate where the waste liquid storage tray 401 is located is provided with a liquid taking hole, so that the external device can take the waste liquid away.
  • the embodiments of the present disclosure are also applicable to a single-channel structure or a multi-channel structure that operates in parallel.
  • the mixing and incubation areas 200 of the two channels are respectively connected to each other, and the luminescence detection areas 300 of the two channels are also connected to each other, the mixing and incubation areas 200 of the two channels can share one magnetic bead for filling.
  • the tray 201 shares an enzyme-labeled filling tray 202.
  • the luminescence detection areas 300 of the two channels can share a washing filling tray 301 and a substrate filling tray 302.
  • each channel can also be individually set up with a corresponding filling plate.
  • the method of realizing mixing is not limited to the rotating method, and may be a linear oscillation method, that is, controlling the droplet to rapidly shake along a linear path. Both the rotating method and the linear oscillation method can break the equilibrium state of the substances carried in the droplets and accelerate the dispersion speed of the substances in the droplets.
  • Fig. 4 is a schematic diagram of the incubation process of the sample solution in the embodiment of the disclosure.
  • the antigen and magnetic bead antibody in the sample solution are fully mixed to form an antigen-magnetic bead antibody complex (the first incubation sample solution), and the antigen-magnetic bead antibody complex and enzyme-labeled antibody are fully mixed to form an antigen- Magnetic bead antibody-enzyme-labeled antibody complex (second incubation sample solution), antigen-magnetic bead antibody-enzyme-labeled antibody complex and luminescent substrate are fully mixed to form an antigen-magnetic bead antibody-enzyme-labeled antibody-luminescent substrate complex ⁇ (The third incubation sample solution).
  • the light sensor array of the digital microfluidic chemiluminescence detection chip can realize the content detection of the sample to be tested by collecting the light signal generated during the chemiluminescence process of the antigen-magnetic bead antibody-enzyme-labeled antibody-luminescent substrate complex .
  • FIG. 5 is a schematic structural diagram of an embodiment of a digital microfluidic chemiluminescence detection device according to an embodiment of the disclosure.
  • the pipetting device 10 uses a sample pipetting gun, which is configured to transfer the sample liquid onto the digital microfluidic chemiluminescence detection chip 40, and the temperature control device 20 and the magnetic control device 30 are combined
  • the temperature control and magnetic control module is arranged on the lower side of the digital microfluidic chemiluminescence detection chip 40, and is arranged to provide the digital microfluidic chemiluminescence detection chip 40 with a set temperature and a set magnetic field.
  • the signal processing device 50 It includes a reading module 51 and a processing display module 52.
  • the reading module 51 is electrically connected to the digital microfluidic chemiluminescence detection chip 40 and is configured to read electrical signals from the light sensor array of the digital microfluidic chemiluminescence detection chip 40,
  • the electrical signal is sent to the processing and display module 52, and the processing and display module 52 is connected to the reading module 51, and is configured to receive the electrical signal sent by the reading module 51, and analyze and process the electrical signal to obtain concentration information and display it.
  • the control unit can be integrated in the reading module.
  • the control unit realizes the timing control of the drive array in the digital microfluidic chemiluminescence detection chip, the acquisition timing of the light sensor array, the reading timing of electrical signals, and temperature control The control sequence of the magnetron device, etc.
  • the single detection process mainly involves the steps of magnetic bead incubation, enzyme label incubation, washing, luminescence mixing, and light detection.
  • the processing flow includes:
  • the blood sample is first mixed with the magnetic bead antibody in a circular manner. Under the constant temperature condition of 37°C in the temperature control system, the antigen in the blood and the magnetic bead antibody are mixed. Fully bind to form an antigen-magnetic bead antibody complex (the first incubation sample solution).
  • the antigen-magnetic bead antibody complex and the enzyme-labeled antibody are mixed and incubated in the same manner to form an antigen-magnetic bead antibody-enzyme-labeled antibody complex (second incubation sample solution).
  • the antigen-magnetic bead antibody-enzyme-labeled antibody complex is controlled by a magnetron device.
  • the substance is fixed at a certain position in the luminescence detection area, and the driving array of the digital microfluidic chemiluminescence detection chip is used to move the impurity solution except the complex to the waste area, and then manipulate the washing buffer and antigen-magnetic bead antibody-enzyme
  • the labeled antibody complexes are mixed and mixed in a circle to form a suspension solution of the antigen-magnetic bead antibody-enzyme-labeled antibody complex, and then the complex is fixed again, and the impurity solution is moved to the waste liquid area. After multiple washings, a pure antigen-magnetic bead antibody-enzyme-labeled antibody complex can be obtained.
  • pipetting is to pass a series of pre-programmed voltage sequences to the driving array of the digital microfluidic chemiluminescence detection chip, and the droplets will move on the surface of the chip according to a predetermined path to achieve orderly work.
  • the luminescent substrate and the antigen-magnetic bead antibody-enzyme-labeled antibody complex are mixed in a circular manner to form an antigen-magnetic bead antibody-enzyme-labeled antibody-luminescent substrate complex (section Three incubation sample solution).
  • Adding samples is to add the required sample, magnetic bead antibody, enzyme-labeled antibody, cleaning solution, luminescent substrate, etc., to the corresponding filling hole of the digital microfluidic chemiluminescence detection chip through the pipetting device.
  • the digital microfluidic chemiluminescence detection chip of the embodiment of the present disclosure includes a first substrate and a second substrate that are opposed to each other.
  • the second substrate includes a second base 21 and a second hydrophobic layer 22 arranged on the side of the second base facing the first substrate.
  • the array structure layer 12 includes a driving array 121 and a light sensor array 122.
  • the driving array 121 includes a plurality of driving units, each driving unit is configured to drive the incubation sample liquid 32 to move, and each driving unit includes a driving transistor and a driving electrode connected to the driving transistor.
  • the light sensor array 122 includes a plurality of light sensor units, and each light sensor unit is configured to collect light signals generated during the chemiluminescence process of the incubation sample liquid 32 and convert the light signals into electrical signals.
  • Each light sensor unit It includes a sensing transistor and a photodiode connected to the sensing transistor.
  • FIG. 7 is a schematic diagram of the structure of the array structure layer of the embodiment of the disclosure. As shown in FIG. 7, the array structure layer 12 includes:
  • the driving gate electrode 1221 and the sensing gate electrode 1231 provided on the first substrate 11;
  • the first insulating layer 1212 covering the driving gate electrode 1221 and the sensing gate electrode 1231;
  • the driving source electrode 1223, the driving drain electrode 1224, the sensing source electrode 1233 and the sensing drain electrode 1234, the ends of the driving source electrode 1223 and the driving drain electrode 1224 adjacent to each other are respectively arranged on the driving active layer 1222 (including; driving source electrode One end of 1223 adjacent to the driving drain electrode 1224 is disposed on the driving active layer 1222, and the end of the driving drain electrode 1224 adjacent to the driving source electrode 1223 is disposed on the driving active layer 1222), and a gap is formed between the driving source electrode 1223 and the driving drain electrode 1224.
  • the ends of the sensing source electrode 1233 and the sensing drain electrode 1234 adjacent to each other are respectively arranged on the sensing active layer 1232 (including: the end of the sensing source electrode 1233 adjacent to the sensing drain electrode 1234 is arranged in the sensing area On the source layer 1232, one end of the sensing drain electrode 1234 adjacent to the sensing source electrode 1233 is disposed on the sensing active layer 1232), and a sensing channel is formed between the sensing source electrode 1233 and the sensing drain electrode 1234;
  • the second insulating layer 1213 and the third insulating layer 1214 covering the driving source electrode 1223, the driving drain electrode 1224, the sensing source electrode 1233 and the sensing drain electrode 1234, the second insulating layer 1213 and the third insulating layer 1214 are provided with exposed Out the first via hole of the sensing drain electrode 1234;
  • the fourth insulating layer 1215 covering the photodiode 1235 is provided with a second via hole exposing the driving drain electrode 1224;
  • the driving electrode 1225 disposed on the fourth insulating layer 1215, the driving electrode 1225 is connected to the driving drain electrode 1224 through the second via hole;
  • the driving gate electrode 1221, the driving active layer 1222, the driving source electrode 1223, and the driving drain electrode 1224 constitute a driving transistor
  • the driving transistor and the driving electrode 1225 constitute a driving unit
  • the sensing gate electrode 1231, the sensing active layer 1232, the sensing source electrode 1233, and the sensing drain electrode 1234 constitute a sensing transistor
  • the sensing transistor and the photodiode 1235 constitute a light sensing unit.
  • the photodiode 1235 may be a PIN type photodiode, which includes a P-type semiconductor layer, an N-type semiconductor layer, and an intrinsic semiconductor layer disposed between the P-type semiconductor layer and the N-type semiconductor layer.
  • a first metal film is deposited on the substrate 11, and the first metal film is patterned through a patterning process to form patterns of the driving gate electrode 1221 and the sensing gate electrode 1231.
  • the driving source electrode 1223 and the driving drain electrode 1224 The ends distant from each other are respectively disposed on the first insulating layer 1212 (including: the end of the driving source electrode 1223 away from the driving drain electrode 1224 is disposed on the first insulating layer 1212, and the end of the driving drain electrode 1224 away from the driving source electrode 1223 is disposed on the first insulating layer 1212.
  • the ends of the sensing source electrode 1233 and the sensing drain electrode 1234 adjacent to each other are respectively arranged on the sensing active layer 1232, and a sensing groove is formed between the sensing source electrode 1233 and the sensing drain electrode 1234
  • the ends of the sensing source electrode 1233 and the sensing drain electrode 1234 far away from each other are respectively arranged on the first insulating layer 1212 (including: the end of the sensing source electrode 1233 away from the sensing drain electrode 1234 is arranged on the first insulating layer 1212 , The end of the sensing drain electrode 1234 away from the sensing source electrode 1233 is disposed on the first insulating layer 1212).
  • the layer 1213 and the third insulating layer 1214 are provided with a first via hole exposing the sensing drain electrode 1234 thereon.
  • the fourth insulating film is coated on the substrate with the aforementioned structure, and the second insulating film is patterned through a patterning process to form a fourth insulating layer 1215 covering the photodiode 1235, on which a driving drain electrode is exposed.
  • the second via of 1224 The fourth insulating film is coated on the substrate with the aforementioned structure, and the second insulating film is patterned through a patterning process to form a fourth insulating layer 1215 covering the photodiode 1235, on which a driving drain electrode is exposed.
  • the second via of 1224 The fourth insulating film is coated on the substrate with the aforementioned structure, and the second insulating film is patterned through a patterning process to form a fourth insulating layer 1215 covering the photodiode 1235, on which a driving drain electrode is exposed.
  • a transparent conductive film is deposited, and the transparent conductive film is patterned through a patterning process to form a pattern of driving electrodes 1225 on the fourth insulating layer 1215.
  • a fifth insulating film is coated on the substrate having the foregoing structure to form a fifth insulating layer 1216 covering the driving electrode 1225.
  • the first insulating layer and the second insulating layer may be silicon oxide (SiOx), silicon nitride (SiNx), or silicon oxynitride (SiON), etc., and may have a single-layer structure or a multilayer composite structure.
  • One insulating layer is called a gate insulating (GI) layer
  • the second insulating layer is called an interlayer insulating (ILD) layer.
  • the third insulating layer, the fourth insulating layer, and the fifth insulating layer may use organic materials, which are called planarization (PLN) layers.
  • the first metal film and the second metal film can be made of metal materials, such as silver (Ag), copper (Cu), aluminum (Al), or molybdenum (Mo), etc., or can be made of metal alloy materials, and can be a single layer The structure, or may be a multilayer composite structure.
  • the transparent conductive film can be indium tin oxide (ITO) or indium zinc oxide (IZO).
  • the active layer film can use amorphous indium gallium zinc oxide (a-IGZO), zinc oxynitride (ZnON), indium zinc tin oxide (IZTO), amorphous silicon (a-Si), polysilicon (p-Si) , Hexathiophene or polythiophene and other materials, that is, the embodiments of the present disclosure are applicable to thin film transistors manufactured based on oxide technology, silicon technology or organic technology.
  • a-IGZO amorphous indium gallium zinc oxide
  • ZnON zinc oxynitride
  • IZTO indium zinc tin oxide
  • a-Si amorphous silicon
  • p-Si polysilicon
  • Hexathiophene or polythiophene Hexathiophene or polythiophene and other materials
  • the aforementioned structure and the preparation process thereof are merely exemplary.
  • the corresponding structure can be changed and the patterning process can be increased or decreased according to actual needs.
  • the thin film transistor may be a top gate structure, or may be a bottom gate structure, may be a single gate structure, or may be a double gate structure.
  • Other electrodes, leads, and structural film layers may also be provided in the array structure layer, which is not specifically limited in the embodiment of the present disclosure.
  • the embodiments of the present disclosure provide a digital microfluidic chemiluminescence detection chip and a detection device, which use digital microfluidics technology to realize the preparation of complex sample liquids for chemiluminescence reactions, avoid complex fluid and liquid path systems, and realize the test
  • the automatic and high-precision pretreatment of the sample liquid can ensure the accurate ratio of the sample liquid and the reagent, and ensure the repeatability and stability of the experimental results. It has the characteristics of compact structure, small size, low power consumption, and low cost. POCT rapid and accurate detection of trace substances.
  • the optical signal is collected in the chip, the complicated peripheral optical path structure is avoided, the signal-to-noise ratio of the signal is reduced, and the consistency of the detection result is improved.
  • the embodiment of the present disclosure minimizes the volume of the system, improves the consistency of the detection result, and effectively solves the defects of the existing chemiluminescence detection device such as large system volume and low consistency of the detection result, and has a wide range of application scenarios.
  • the embodiments of the present disclosure also provide a digital microfluidic chemiluminescence detection method, which adopts the aforementioned digital microfluidic chemiluminescence detection chip.
  • the digital microfluidic chemiluminescence detection method of the embodiment of the present disclosure includes:
  • the drive array drive sample solution is sequentially combined with the magnetic bead antibody, the enzyme-labeled antibody and the luminescent substrate to form an antigen-magnetic bead antibody-enzyme-labeled antibody-luminescent substrate complex;
  • the light sensor array collects the chemiluminescent light signal of the antigen-magnetic bead antibody-enzyme-labeled antibody-luminescent substrate complex, and converts the light signal into an electrical signal.
  • step S1 includes:
  • the drive array drive sample solution is sequentially combined with the magnetic bead antibody and the enzyme-labeled antibody to form an antigen-magnetic bead antibody-enzyme-labeled antibody complex;
  • the drive array drives the antigen-magnetic bead antibody-enzyme-labeled antibody complex to bind to the luminescent substrate to form an antigen-magnetic bead antibody-enzyme-labeled antibody-luminescence substrate complex.
  • step S11 includes:
  • the driving array drives the sample solution to combine with the magnetic bead antibody to form an antigen-magnetic bead antibody complex
  • the driving array drives the antigen-magnetic bead antibody complex to combine with the enzyme-labeled antibody to form an antigen-magnetic bead antibody-enzyme-labeled antibody complex.
  • step S12 includes:
  • the drive array drives the antigen-magnetic bead antibody-enzyme-labeled antibody complex to mix with the washing buffer, and the impurity solution is discharged out of the purification channel;
  • the drive array drives the antigen-magnetic bead antibody-enzyme-labeled antibody complex to bind to the luminescent substrate to form an antigen-magnetic bead antibody-enzyme-labeled antibody-luminescent substrate complex .
  • step S2 includes:
  • the light sensor array collects the chemiluminescence light signal of the antigen-magnetic bead antibody-enzyme-labeled antibody-luminescent substrate complex, and converts the light signal into an electrical signal .
  • the embodiment of the present disclosure provides a digital microfluidic chemiluminescence detection method, which uses digital microfluidic technology to realize the preparation of complex sample liquids for chemiluminescence reactions, avoids complex fluid and liquid path systems, and adopts digital microfluidic chemistry
  • the light signal is collected in the luminescence detection chip, which avoids the complicated peripheral light path structure.
  • the method of the embodiment of the present disclosure reduces the signal-to-noise ratio of the signal and improves the consistency of the detection result.
  • connection should be interpreted broadly. For example, they may be fixed connections or Removable connection or integral connection; it can be mechanical connection or electrical connection; it can be directly connected or indirectly connected through an intermediate medium, and it can be the internal communication between two components.
  • connection should be interpreted broadly. For example, they may be fixed connections or Removable connection or integral connection; it can be mechanical connection or electrical connection; it can be directly connected or indirectly connected through an intermediate medium, and it can be the internal communication between two components.

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Abstract

一种数字微流控化学发光检测芯片及检测方法、检测装置。数字微流控化学发光检测芯片包括相对设置的第一基板和第二基板，所述第一基板和第二基板形成的腔体包括实现抗原、磁珠抗体和抗体结合的混匀孵育区、实现化学发光并检测光信号的发光检测区以及连通所述混匀孵育区和发光检测区的连通路径，所述第一基板上设置有设置为驱动样液移动的驱动阵列和设置为采集样液发光信号的光传感阵列，所述驱动阵列与所述混匀孵育区、发光检测区和连通路径的位置相对应，所述光传感阵列与所述发光检测区的位置相对应。

Description

数字微流控化学发光检测芯片及检测方法、检测装置
本申请要求于2020年2月25日提交中国专利局、申请号为202010114438.8、发明名称为“数字微流控化学发光检测芯片及检测方法、检测装置”的中国专利申请的优先权，其内容应理解为通过引用的方式并入本申请中。
技术领域
本公开实施例涉及但不限于化学发光检测技术领域，具体涉及一种数字微流控化学发光检测芯片及检测方法、检测装置。
背景技术
化学发光分析是根据化学反应产生的辐射光的强度来确定物质的含量的分析方法，化学发光免疫分析是将化学发光分析与免疫反应分析相结合，用化学发光的相关物质标记抗体或者抗原，与待测的抗原或抗体反应后，经过分离游离态的化学发光标记物，加入化学发光系统的其他相关物质产生化学发光，进行抗原或抗体的定量或定性检测。
化学发光免疫分析技术具有高度的准确性和特异性，成为检验方法学中最为重要的技术之一，是目前世界上公认的先进的标记免疫测定技术之一。化学发光免疫分析技术作为疾病诊断的主要手段已被广泛用于机体免疫功能、传染性疾病、内分泌系统、肿瘤标志物、性激素、甲状腺功能等方面的体外诊断检测中。
目前的化学发光检测装置存在系统体积大、检测结果一致性低等缺陷。
发明内容
以下是对本文详细描述的主题的概述。本概述并非是为了限制权利要求的保护范围。
本公开实施例提供了一种数字微流控化学发光检测芯片，包括相对设置 的第一基板和第二基板，所述第一基板和第二基板形成的腔体包括实现抗原、磁珠抗体和抗体结合的混匀孵育区、实现化学发光并检测光信号的发光检测区以及连通所述混匀孵育区和发光检测区的连通路径，所述第一基板上设置有设置为驱动样液移动的驱动阵列和设置为采集样液发光信号的光传感阵列，所述驱动阵列与所述混匀孵育区、发光检测区和连通路径的位置相对应，所述光传感阵列与所述发光检测区的位置相对应。
在一些可能的实现方式中，所述混匀孵育区包括磁珠加注盘和磁珠混匀通道，所述磁珠加注盘设置为向磁珠混匀通道提供磁珠抗体，在所述磁珠混匀通道，所述样液在所述驱动阵列驱动下沿着所述磁珠混匀通道移动，使样液中抗原与磁珠抗体结合，形成第一孵育样液，所述第一孵育样液包括抗原-磁珠抗体复合物。
在一些可能的实现方式中，所述混匀孵育区还包括酶标加注盘和酶标混匀通道，所述酶标加注盘设置为向酶标混匀通道提供酶标抗体，所述酶标混匀通道与所述磁珠混匀通道连通，在所述酶标混匀通道，所述第一孵育样液在所述驱动阵列驱动下沿着所述酶标混匀通道移动，使第一孵育样液与酶标抗体结合，形成第二孵育样液，所述第二孵育样液包括抗原-磁珠抗体-酶标抗体复合物。
在一些可能的实现方式中，所述发光检测区包括底物加注盘和纯化通道，所述纯化通道与所述混匀孵育区连通，所述底物加注盘设置为向纯化通道提供发光底物，在所述纯化通道中，所述第二孵育样液在所述驱动阵列驱动下沿着所述纯化通道移动，使第二孵育样液与发光底物结合，形成第三孵育样液，所述第三孵育样液包括抗原-磁珠抗体-酶标抗体-发光底物复合物。
在一些可能的实现方式中，所述磁珠混匀通道、酶标混匀通道和纯化通道均为环形通道，所述样液与磁珠抗体、所述第一孵育样液与酶标抗体、所述第二孵育样液与发光底物均通过转圈方式实现混匀。
在一些可能的实现方式中，所述发光检测区还包括洗涤加注盘，所述洗涤加注盘设置为向纯化通道提供洗涤缓冲液，在所述纯化通道中，所述第二孵育样液在所述驱动阵列驱动下沿着所述纯化通道移动，使第二孵育样液与洗涤缓冲液实现混匀；外设的磁控装置固定所述第二孵育样液中的磁珠抗体， 所述第二孵育样液中的杂质溶液在所述驱动阵列驱动下排出所述纯化通道。
在一些可能的实现方式中，所述发光检测区还包括检测区，所述检测区与所述纯化通道连通，在所述检测区，所述光传感阵列采集所述第三孵育样液化学发光的光信号，并将所述光信号转化为电信号。
在一些可能的实现方式中，所述第二基板上设置有多个加注孔，所述多个加注孔分别与所述磁珠加注盘、酶标加注盘、洗涤加注盘和底物加注盘的位置相对应。
在一些可能的实现方式中，还包括加注区和废液区，所述加注区与所述混匀孵育区连通，设置为接收待检测的样液，所述废液区与所述发光检测区连通，设置为接收来自所述发光检测区的废液。
在一些可能的实现方式中，所述驱动阵列采用有源驱动实现方式。
在一些可能的实现方式中，所述第一基板包括第一基底、设置在所述第一基底朝向第二基板一侧的阵列结构层和设置在所述阵列结构层朝向第二基板一侧的第一疏水层，第二基板包括第二基底和设置在第二基底朝向第一基板一侧的第二疏水层；所述驱动阵列和光传感阵列设置在所述阵列结构层中，所述驱动阵列包括多个驱动单元，所述驱动单元包括驱动晶体管和驱动电极，所述驱动电极与驱动晶体管连接；所述光传感阵列包括多个光传感单元，所述光传感单元包括传感晶体管和光电二极管，所述光电二极管与传感晶体管连接。
在一些可能的实现方式中，所述阵列结构层包括：
第一基底；
设置在所述第一基底上的驱动栅电极和传感栅电极；
覆盖所述驱动栅电极和传感栅电极的第一绝缘层；
设置在所述第一绝缘层上的驱动有源层和传感有源层；
相互邻近的端设置在所述驱动有源层上的驱动源电极和驱动漏电极，相互邻近的端设置在所述传感有源层上传感源电极和传感漏电极；
覆盖所述驱动源电极、驱动漏电极、传感源电极和传感漏电极的第二绝 缘层和第三绝缘层，其上开设有暴露出所述传感漏电极的第一过孔；
设置在所述第三绝缘层上的光电二极管，所述光电二极管的第一极通过所述第一过孔与所述传感漏电极连接；
覆盖所述光电二极管的第四绝缘层，其上开设有暴露出所述驱动漏电极的第二过孔；
设置在所述第四绝缘层上的驱动电极，所述驱动电极通过所述第二过孔与所述驱动漏电极连接；
覆盖所述驱动电极的第五绝缘层。
本公开实施例还提供了一种数字微流控化学发光检测装置，包括上述的数字微流控化学发光检测芯片，还包括移液装置、温控装置、磁控装置和信号处理装置；所述移液装置设置为将样液转移到所述数字微流控化学发光检测芯片上，所述温控装置设置为向所述数字微流控化学发光检测芯片提供设定的温度，所述磁控装置设置为向所述数字微流控化学发光检测芯片提供设定的磁场，所述信号处理装置与所述数字微流控化学发光检测芯片连接，设置为读取所述光传感阵列的电信号，对电信号进行分析处理，获得浓度信息。
在一些可能的实现方式中，所述温控装置设置在所述第一基板远离第二基板的一侧或所述第二基板远离第一基板的一侧，设置为向所述混匀孵育区提供设定的温度；所述磁控装置设置在所述第一基板远离第二基板的一侧或所述第二基板远离第一基板的一侧，设置为向所述发光检测区提供设定的磁场。
本公开实施例还提供了一种采用上述的数字微流控化学发光检测芯片的数字微流控化学发光检测方法，包括：
所述驱动阵列驱动样液依次与磁珠抗体、酶标抗体和发光底物结合，形成抗原-磁珠抗体-酶标抗体-发光底物复合物；
所述光传感阵列采集所述抗原-磁珠抗体-酶标抗体-发光底物复合物化学发光的光信号，并将所述光信号转化为电信号。
在一些可能的实现方式中，所述驱动阵列驱动样液依次与磁珠抗体、酶标抗体和发光底物结合，形成抗原-磁珠抗体-酶标抗体-发光底物复合物，包 括：
在所述混匀孵育区，所述驱动阵列驱动样液依次与磁珠抗体和酶标抗体结合，形成抗原-磁珠抗体-酶标抗体复合物；
在所述发光检测区，所述驱动阵列驱动所述抗原-磁珠抗体-酶标抗体复合物与发光底物结合，形成抗原-磁珠抗体-酶标抗体-发光底物复合物。
当然，实施本公开的任一产品或方法并不一定需要同时达到以上所述的所有优点。本公开的其它特征和优点将在随后的说明书实施例中阐述，并且，部分地从说明书实施例中变得显而易见，或者通过实施本公开实施例而了解。本公开实施例的目的和其他优点可通过在说明书、权利要求书以及附图中所特别指出的结构来实现和获得。
在阅读并理解了附图和详细描述后，可以明白其他方面。
附图说明
附图用来提供对本公开技术方案的进一步理解，并且构成说明书的一部分，与本公开的实施例一起用于解释本公开的技术方案，并不构成对本公开技术方案的限制。附图中部件的形状和大小不反映真实比例，目的只是示意说明本公开内容。
图1为本公开实施例数字微流控化学发光检测装置的结构示意图；
图2为本公开实施例数字微流控化学发光检测芯片的结构示意图；
图3为本公开数字微流控化学发光检测芯片一实施例的结构示意图；
图4为本公开实施例样液孵育过程的示意图；
图5为本公开实施例数字微流控化学发光检测装置一实施例的结构示意图；
图6为本公开实施例集成有光传感阵列的数字微流控化学发光检测芯片的结构示意图；
图7为本公开实施例阵列结构层的结构示意图。
具体实施方式
以下实施例用于说明本公开，但不用来限制本公开的范围。需要说明的是，在不冲突的情况下，本公开中的实施例及实施例中的特征可以相互任意组合。
近年来，随着临床检验医学的发展，小型化、便携式即时检测仪器成为目前临床诊断仪器的发展趋势之一。注意点检测(Point of Care Test，POCT)即床边检验或近患者检验，是利用便携式设备在数分钟内得出检验结果的一种方式，广泛适用于医院、护理病房、救护单位、保险公司及家庭健康网络，也适用于一些特殊环境，如抢险救灾、边远农村及行军途中等。POCT的出现，使传统上由专业检验人员完成的工作更多地交给非专业检验人员完成。
微全分析系统(Miniaturized Total Analysis System,μ-TAS)是1990年首先由瑞士Ciba Geigy公司的Manz与Widmer提出，之后得到了迅猛的发展。微流控芯片是微型全分析系统的主要发展方向和最为活跃的前沿领域，其目标是把整个实验室的功能，包括采样、稀释、加试剂、反应、分离、检测等集成在微芯片上。与传统的生化分析实验室相比，微流控芯片具有自动、检测速度快、体积小以及样品消耗低等优点，必将会带来生化分析与医学诊断等科学技术的革命性变革。对于最早发展起来的流道式微流控芯片而言，由于流道式微流控芯片需要借助外围的微泵、微阀以及复杂管路实现液体的驱动控制，流道内易存在气泡和“死区效应”。流道一旦成型不可更改，只能针对特定应用，缺少灵活性，这些问题限制了流道式微流控芯片的广泛应用。在1993年，Berge通过实验发现了介电润湿现象，并对介电润湿实现液滴操纵的原理及影响因素进行了充分的验证。自此之后，数字微流控(Micro Fluidics)技术得到了蓬勃的发展。数字微流控芯片是利用介电润湿的原理，通过改变液滴的亲疏水性，实现对离散的微液滴施加驱动力从而对其运动进行操控，可在微米尺度对流体进行操控，具有将生物、化学等实验室的基本功能微缩到一个几平方厘米的芯片上的能力，因此又被称芯片实验室(Laboratory on a Chip,简称LOC)，具有尺寸小、便携、功能可灵活组合以及集成度高等优势。数字微流控分为有源数字微流控和无源数字微流控，两者的主要区别在于，有源数字微流控是阵列化驱动液滴，可以精确地控制 某个位置上的液滴单独移动，而无源数字微流控是所有位置上的液滴一起动或一起停。近些年来，数字微流控芯片作为一种微量液体操控的新兴技术，凭借其结构简单、所需要的样品和试剂量小、易于集成、可并行处理及易实现自动化等诸多优势，在生物、化学、医学领域，尤其是POCT领域展现出巨大的发展潜力和应用前景。
目前，相关的化学发光检测装置通常采用液路系统和外置光检测器件的结构，液路系统包括真空泵、冲洗泵、基质液泵和蠕动泵等精密度泵，外置光检测装置包括凸透镜、光电倍增管、光电池等。由于该结构需要配套复杂的管路、泵和外围光路，不仅增加了系统的体积，而且信号信噪比较高，检测结果一致性比较低。
本公开实施例提供了一种数字微流控化学发光检测装置。图1为本公开实施例数字微流控化学发光检测装置的结构示意图。如图1所示，本公开实施例数字微流控化学发光检测装置包括：移液装置10、温控装置20、磁控装置30、集成有光传感阵列的数字微流控化学发光检测芯片40和信号处理装置50。其中，移液装置10设置为将样液转移到数字微流控化学发光检测芯片40上，温控装置20设置为向数字微流控化学发光检测芯片40提供设定的温度，磁控装置30设置为向数字微流控化学发光检测芯片40提供设定的磁场，数字微流控化学发光检测芯片40设置为实现抗原、磁珠抗体、抗体和发光底物的结合，并利用所集成的光传感阵列采集化学发光的光信号，将光信号转化为电信号，信号处理装置50与数字微流控化学发光检测芯片40连接，设置为读取光传感阵列的电信号，对电信号进行分析处理，获得浓度信息。
本公开实施例提供的一种数字微流控化学发光检测装置，利用数字微流控技术实现了化学发光反应复杂样液的制备，避免了复杂的流体液路系统，通过在数字微流控化学发光检测芯片中集成光传感阵列，实现了在芯片内采集光信号，避免了复杂的外围光路结构。本公开实施例具有结构紧凑、体积小、功耗低、成本低等特点，降低了信号的信噪比，提高了检测结果的一致性。
图2为本公开实施例数字微流控化学发光检测芯片的结构示意图。如图2所示，数字微流控化学发光检测芯片40包括由第一基板和第二基板对盒形 成的腔体，腔体被划分成多个功能区，多个功能区包括：加注区100、混匀孵育区200、发光检测区300和废液区400，多个功能区之间设有连通路径500，加注区100和混匀孵育区200之间通过连通路径500连通，混匀孵育区200和发光检测区300之间通过连通路径500连通，发光检测区300和废液区400之间通过连通路径500连通。多个功能区和连通路径所在的第一基板上设置有用于驱动样液移动的驱动阵列，发光检测区300所在的第一基板上设置有用于采集样液发光信号的光传感阵列，驱动阵列和光传感阵列的表面上设置有疏水层。
如图2所示，温控装置20设置在第一基板远离第二基板的一侧或第二基板远离第一基板的一侧，位置与混匀孵育区200所在区域相对应，设置为向混匀孵育区200提供设定的温度。磁控装置30设置在第一基板远离第二基板的一侧或第二基板远离第一基板的一侧，位置与发光检测区300所在区域相对应，设置为向发光检测区300提供设定的磁场。本公开实施例中，温控装置20可以包括加热器(heater)、温度传感器和第一控制器等，如电阻丝或半导体热电致冷器等，加热器与温度传感器和第一控制器形成闭环控制以精确有效的控制混匀孵育区200的温度。化学发光免疫分析反应的温度可以控制在37±0.5℃。磁控装置30可以包括磁铁(永磁铁或电磁铁)、第二控制器等，第二控制器通过调整永磁铁与第一基板或第二基板之间的距离或通过电磁铁的通断电，控制向发光检测区300提供磁场的强弱。实际实施时，温控装置20和磁控装置30既可以单独设置，也可以组合在一起形成温控磁控集成装置。
如图2所示，加注区100设置为接收移液装置10转移的待检测的样液。混匀孵育区200与加注区100通过连通路径500连通，设置为在数字微流控化学发光检测芯片中驱动阵列的控制下，依次形成第一孵育样液和第二孵育样液；第一孵育样液为抗原-磁珠抗体的复合物，第二孵育样液为抗原-磁珠抗体-酶标抗体的复合物。发光检测区300与混匀孵育区200通过连通路径500连通，设置为在磁控装置30和驱动阵列的控制下，依次完成洗涤第二孵育样液和形成第三孵育样液，利用数字微流控化学发光检测芯片的光传感单元采集第三孵育样液化学发光的光信号。第三孵育样液为抗原-磁珠抗体-酶 标抗体-发光底物的复合物。废液区400与发光检测区300通过连通路径500连通，设置为存储来自发光检测区300的废液。
图3为本公开数字微流控化学发光检测芯片一实施例的结构示意图，示意了可以实现两个样液(样本溶液)同时检测的双通道结构。如图3所示，在平行于芯片的平面内，数字微流控化学发光检测芯片40包括多个功能区，分别为：加注区100、混匀孵育区(mixing and incubating area)200、发光检测区(purification detection area)300和废液区400，加注区100和混匀孵育区200之间通过连通路径500连通，混匀孵育区200和发光检测区300之间通过连通路径500连通，发光检测区300和废液区400之间通过连通路径500连通。在垂直于芯片的平面内，数字微流控化学发光检测芯片40包括对盒的第一基板和第二基板，第一基板和第二基板之间形成封闭的腔体，腔体形成能够实现两个样液同时检测的两个通道。第一基板包括第一基底、设置在第一基底上的阵列结构层和设置在阵列结构层上的第一疏水层，阵列结构层包括设置为驱动样液移动的驱动阵列和设置为采集样液光信号的光传感阵列，驱动阵列设置在与所有功能区和连通路径相对应的位置，光传感阵列设置在与发光检测区相对应的位置。第二基板包括第二基底和设置在第二基底上的第二疏水层。第一基板和第二基板之间通过密封剂对盒封装，形成封闭的腔体，腔体内可以通过设置隔离柱形成多个功能区和连通路径。
每个通道的加注区100包括样液加注盘101，样液加注盘101与混匀孵育区200通过连通路径500连通，设置为接收移液装置10转移的待检测的样液，并将样液移动到混匀孵育区200。样液加注盘101所在位置的第二基板上设置有加注孔，使移液装置10将样液加注到样液加注盘101。其中，样液可以是血液样本(blood sampel)。
每个通道的混匀孵育区200包括磁珠加注盘201、酶标加注盘202、磁珠混匀通道203和酶标混匀通道204，磁珠混匀通道203和酶标混匀通道204均为环形通道，磁珠加注盘201与磁珠混匀通道203连通，酶标加注盘202与酶标混匀通道204连通，磁珠混匀通道203分别与加注区100和酶标混匀通道204连通，酶标混匀通道204分别与磁珠混匀通道203和发光检测区300连通。磁珠加注盘201和酶标加注盘202所在位置的第二基板上分别设置有 相应的加注孔，使外部装置将磁珠抗体和酶标抗体分别加注到磁珠加注盘201和酶标加注盘202。
磁珠加注盘201设置为接收外部装置提供的磁珠抗体(magnetic particles)，使磁珠抗体进入磁珠混匀通道203。在温控装置20提供的温度(如37℃恒温)条件下，数字微流控化学发光检测芯片的驱动阵列通过电场驱动样液沿着环形的磁珠混匀通道203快速移动，使样液与进入磁珠混匀通道203的磁珠抗体通过转圈方式实现混匀，样液中抗原与磁珠抗体充分结合，形成第一孵育样液，并将完成混匀的第一孵育样液移动到酶标混匀通道204。其中，第一孵育样液包括抗原-磁珠抗体复合物。
酶标加注盘202设置为接收外部装置提供的酶标抗体(enzyme labeled antibody)，使酶标抗体进入酶标混匀通道204。在温控装置20提供的温度条件下，数字微流控化学发光检测芯片的驱动阵列通过电场驱动第一孵育样液沿着环形的酶标混匀通道204快速移动，使第一孵育样液与酶标抗体通过转圈方式实现混匀，第一孵育样液与酶标抗体充分结合，形成第二孵育样液，并将完成混匀的第二孵育样液移动到发光检测区300。其中，第二孵育样液包括抗原-磁珠抗体-酶标抗体复合物。
每个通道的发光检测区300包括洗涤加注盘301、底物加注盘302、纯化通道303和检测区310，纯化通道303为环形通道，分别与洗涤加注盘301和底物加注盘302连通。此外，纯化通道303还与混匀孵育区200、废液区400和检测区310连通。洗涤加注盘301和底物加注盘302所在位置的第二基板上分别设置有相应的加注孔，使外部装置将洗涤缓冲液和发光底物分别加注到洗涤加注盘301和底物加注盘302。
发光检测区300一方面设置为洗涤第二孵育样液，即实现第二孵育样液与杂质溶液的分离。在完成混匀的第二孵育样液从混匀孵育区200移动到发光检测区300后，先通过磁控装置30施加磁场使第二孵育样液中的磁珠抗体固定在发光检测区300，后通过驱动阵列的驱动将杂质溶液移动到废液区400，完成第二孵育样液和杂质溶液的分离。随后，取消磁控装置30的磁场，使驱动阵列能够驱动第二孵育样液移动。其中，杂质溶液是指除了抗原-磁珠抗体-酶标抗体复合物外的溶液。本实施例中，固定第二孵育样液中的磁珠抗体的 方式例如可以是：将磁控装置30设置在纯化通道303所在区域，控制磁控装置30通电，磁控装置30产生的磁场吸引磁珠抗体，将磁珠抗体吸附在腔体内的表面上。在适宜的磁场下，微小的磁珠抗体会聚集成非常紧密的磁体，因而不会被杂质溶液带走，这样就实现了磁珠抗体和杂质溶液的分离。杂质溶液清除后，控制磁控装置30断电，磁场消失，磁珠抗体即可在驱动阵列施加的电场驱动下移动。
洗涤加注盘301设置为接收外部装置提供的洗涤缓冲液(wash buffer)，使洗涤缓冲液进入纯化通道303。数字微流控化学发光检测芯片的驱动阵列通过电场驱动第二孵育样液和洗涤缓冲液沿着环形的纯化通道303快速移动，使第二孵育样液和洗涤缓冲液通过转圈方式实现混匀，将磁珠抗体中夹杂的未反应的游离物质释放到洗涤缓冲液中。本公开实施例中，前述的分离和洗涤过程可以重复多次进行，通过固定磁珠抗体，将杂质溶液运送到废液区400，完成磁珠抗体与杂质溶液的分离，通过在纯化通道303快速移动第二孵育样液和洗涤缓冲液，完成第二孵育样液的洗涤。经过多次分离和洗涤，即可获得纯净的第二孵育样液，即抗原-磁珠抗体-酶标抗体复合物。
发光检测区300另一方面设置为形成抗原-磁珠抗体-酶标抗体-发光底物复合物。底物加注盘302设置为接收外部装置提供的发光底物(substrate)，使发光底物进入纯化通道303。数字微流控化学发光检测芯片的驱动阵列通过电场驱动纯净的第二孵育样液沿着环形的纯化通道303快速移动，使第二孵育样液与发光底物通过转圈方式实现混匀，第二孵育样液和发光底物充分结合，形成第三孵育样液，并将完成混匀的第三孵育样液移动到检测区310。其中，第三孵育样液包括抗原-磁珠抗体-酶标抗体-发光底物复合物。
本公开实施例中，检测区310位于环形的纯化通道303的中部，与纯化通道303连通，设置为实现第三孵育样液化学发光的光采集。其中，完成混匀的第三孵育样液移动到检测区310后，数字微流控化学发光检测芯片的光传感阵列采集第三孵育样液化学发光的光信号，并将光信号转化为电信号。之后，电信号被传输至信号处理装置50，信号处理装置50通过分析处理获得浓度信息。
每个通道的废液区400包括废液存储盘401，废液存储盘401与发光检 测区300通过连通路径500连通，设置为接收发光检测区300转移的废液。废液存储盘401所在位置的第二基板上设置有取液孔，使外部装置取走废液。
虽然前述以双通道结构的数字微流控化学发光检测芯片进行了说明，但本公开实施例同样适用于单通道结构，或者适用于并行操作的多通道结构。本公开实施例中，由于分别设置两个通道的混匀孵育区200相互连通，两个通道的发光检测区300也相互连通，因此两个通道的混匀孵育区200可以共用一个磁珠加注盘201，共用一个酶标加注盘202，两个通道的发光检测区300可以共用一个洗涤加注盘301，共用一个底物加注盘302。实际实施时，每个通道也可以单独设置相应的加注盘。此外，实现混匀的方式不限于转圈方式，可以是直线振荡方式，即控制液滴沿着直线路径快速震挡。转圈方式和直线振荡方式均可以实现打破液滴中所携带物质的平衡状态，加快物质在液滴中的分散速度。
图4为本公开实施例样液孵育过程的示意图。如图4所示，样液中抗原与磁珠抗体充分混匀形成抗原-磁珠抗体复合物(第一孵育样液)，抗原-磁珠抗体复合物与酶标抗体充分混匀形成抗原-磁珠抗体-酶标抗体复合物(第二孵育样液)，抗原-磁珠抗体-酶标抗体复合物与发光底物充分混匀形成抗原-磁珠抗体-酶标抗体-发光底物复合物(第三孵育样液)。这样，数字微流控化学发光检测芯片的光传感阵列通过采集抗原-磁珠抗体-酶标抗体-发光底物复合物化学发光过程中产生的光信号，即可实现待测样本的含量检测。
图5为本公开实施例数字微流控化学发光检测装置一实施例的结构示意图。如图5所示，本实施例中，移液装置10采用加样移液枪，设置为将样液转移数字微流控化学发光检测芯片40上，温控装置20和磁控装置30采用组合的温控和磁控模块，设置在数字微流控化学发光检测芯片40的下侧，设置为向数字微流控化学发光检测芯片40提供设定的温度和设定的磁场，信号处理装置50包括读取模块51和处理显示模块52，读取模块51与数字微流控化学发光检测芯片40电连接，设置为从数字微流控化学发光检测芯片40的光传感阵列读取电信号，并将电信号发送给处理显示模块52，处理显示模块52与读取模块51连接，设置为接收读取模块51发送的电信号，对电信号进行分析处理获得浓度信息并显示。实际实施时，可以将控制单元集成在读取 模块中，控制单元实现数字微流控化学发光检测芯片中驱动阵列的时序控制、光传感阵列的采集时序、电信号的读取时序以及温控磁控装置的控制时序等。
本实施例数字微流控化学发光检测装置应用于检测时，单次检测流程主要涉及磁珠孵育、酶标孵育、洗涤、发光混合和光检测等步骤。以检测血液样本为例，处理流程包括：
(1)在数字微流控化学发光检测芯片的混匀孵育区，血液样本首先与磁珠抗体通过转圈方式实现混匀，在温控系统37℃的恒温条件下，血液中抗原与磁珠抗体充分结合，形成抗原-磁珠抗体复合物(第一孵育样液)。
(2)同在混匀孵育区，抗原-磁珠抗体复合物与酶标抗体进行相同方式的混匀孵育操作，形成抗原-磁珠抗体-酶标抗体复合物(第二孵育样液)。
(3)在数字微流控化学发光检测芯片的发光检测区，抗原-磁珠抗体-酶标抗体复合物进入发光检测区后，先通过磁控装置控制抗原-磁珠抗体-酶标抗体复合物固定在发光检测区的某一位置，利用数字微流控化学发光检测芯片的驱动阵列将除了复合物外的杂质溶液移动到废液区，然后操纵洗涤缓冲液与抗原-磁珠抗体-酶标抗体复合物混合，转圈混匀，形成抗原-磁珠抗体-酶标抗体复合物的悬浮溶液，随后再次固定复合物，移动杂质溶液到废液区。经过多次洗涤，即可获得纯净的抗原-磁珠抗体-酶标抗体复合物。其中，移液是向数字微流控化学发光检测芯片的驱动阵列通入一系列预编程的电压序列，液滴会按预定的路径在芯片表面移动，实现有序工作。
(4)同在发光检测区，将发光底物与抗原-磁珠抗体-酶标抗体复合物通过转圈方式实现混匀，形成抗原-磁珠抗体-酶标抗体-发光底物复合物(第三孵育样液)。
(5)将抗原-磁珠抗体-酶标抗体-发光底物复合物移至检测区，通过数字微流控化学发光检测芯片的光传感阵列采集化学发光的光信号，并将光信号转化为电信号。光传感阵列的电信号被读取模块读取并传输至显示模块(如PC)，通过对电信号进行分析处理，最终输出检测物质的浓度。
实际实施时，还可以包括加样等步骤。加样是通过移液装置将所需的样本、磁珠抗体、酶标抗体、清洗液、发光底物等加注到数字微流控化学发光 检测芯片的相应加注孔内。
图6为本公开实施例集成有光传感阵列的数字微流控化学发光检测芯片的结构示意图，示意了数字微流控化学发光检测芯片中检测区所在位置的剖面结构，驱动阵列采用有源驱动实现方式，能够精确地控制某个位置上的液滴单独移动。如图6所示，本公开实施例数字微流控化学发光检测芯片包括相对设置的第一基板和第二基板，第一基板包括第一基底11、设置在第一基底朝向第二基板一侧的阵列结构层12和设置在阵列结构层朝向第二基板一侧的第一疏水层13，第二基板包括第二基底21和设置在第二基底朝向第一基板一侧的第二疏水层22。第一基板和第二基板之间通过密封剂(sealant)31对盒封装，在第一基板的第一疏水层13和第二基板的第二疏水层22之间形成封闭的腔体。其中，阵列结构层12包括驱动阵列121和光传感阵列122。驱动阵列121包括多个驱动单元，每个驱动单元设置为驱动孵育样液32移动，每个驱动单元包括驱动晶体管和与驱动晶体管连接的驱动电极。光传感阵列122包括多个光传感单元，每个光传感单元设置为采集孵育样液32化学发光过程中产生的光信号，并将光信号转化为电信号，每个光传感单元包括传感晶体管和与传感晶体管连接的光电二极管。
图7为本公开实施例阵列结构层的结构示意图。如图7所示，阵列结构层12包括：
第一基底11；
设置在第一基底11上的驱动栅电极1221和传感栅电极1231；
覆盖驱动栅电极1221和传感栅电极1231的第一绝缘层1212；
设置在第一绝缘层1212上的驱动有源层1222和传感有源层1232；
驱动源电极1223、驱动漏电极1224、传感源电极1233和传感漏电极1234，驱动源电极1223和驱动漏电极1224相互邻近的端分别设置在驱动有源层1222上(包括；驱动源电极1223邻近驱动漏电极1224的一端设置在驱动有源层1222上，驱动漏电极1224邻近驱动源电极1223的一端设置在驱动有源层1222上)，驱动源电极1223和驱动漏电极1224之间形成驱动沟道；传感源电极1233和传感漏电极1234相互邻近的端分别设置在传感有源层1232 上(包括：传感源电极1233邻近传感漏电极1234的一端设置在传感有源层1232上，传感漏电极1234邻近传感源电极1233的一端设置在传感有源层1232上)，传感源电极1233和传感漏电极1234之间形成传感沟道；
覆盖驱动源电极1223、驱动漏电极1224、传感源电极1233和传感漏电极1234的第二绝缘层1213和第三绝缘层1214，第二绝缘层1213和第三绝缘层1214上开设有暴露出传感漏电极1234的第一过孔；
设置在第三绝缘层1214上的光电二极管1235，光电二极管1235的第一极通过第一过孔与传感漏电极1234连接；
覆盖光电二极管1235的第四绝缘层1215，其上开设有暴露出驱动漏电极1224的第二过孔；
设置在第四绝缘层1215上的驱动电极1225，驱动电极1225通过第二过孔与驱动漏电极1224连接；
覆盖驱动电极1225的第五绝缘层1216。
其中，驱动栅电极1221、驱动有源层1222、驱动源电极1223和驱动漏电极1224组成驱动晶体管，驱动晶体管和驱动电极1225组成驱动单元。传感栅电极1231、传感有源层1232、传感源电极1233和传感漏电极1234组成传感晶体管，传感晶体管和光电二极管1235组成光传感单元。这样，驱动单元和光传感单元可通过同一次制备工艺形成在第一基底11上。本公开实施例中，光电二极管1235可以采用PIN型光电二极管，包括P型半导体层、N型半导体层以及设置在P型半导体层和N型半导体层之间的本征半导体层。
本公开实施例阵列结构层的制备过程可以包括：
(1)在基底11上沉积第一金属薄膜，通过构图工艺对第一金属薄膜进行构图，形成驱动栅电极1221和传感栅电极1231图案。
(2)在完成前述结构的基底上，依次沉积第一绝缘薄膜和有源层薄膜，通过构图工艺对有源层薄膜进行构图，形成覆盖基底11的第一绝缘层1212以及设置在第一绝缘层1212上的驱动有源层1222和传感有源层1232图案。
(3)在完成前述结构的基底上，沉积第二金属薄膜，通过构图工艺对第二金属薄膜进行构图，形成驱动源电极1223、驱动漏电极1224、传感源电极 1233和传感漏电极1234图案，驱动源电极1223和驱动漏电极1224相互邻近的端分别设置在驱动有源层1222上，驱动源电极1223和驱动漏电极1224之间形成驱动沟道，驱动源电极1223和驱动漏电极1224相互远离的端分别设置在第一绝缘层1212上(包括：驱动源电极1223远离驱动漏电极1224的一端设置在第一绝缘层1212上，驱动漏电极1224远离驱动源电极1223的一端设置在第一绝缘层1212上)；传感源电极1233和传感漏电极1234相互邻近的端分别设置在传感有源层1232上，传感源电极1233和传感漏电极1234之间形成传感沟道，传感源电极1233和传感漏电极1234相互远离的端分别设置在第一绝缘层1212上(包括：传感源电极1233远离传感漏电极1234的一端设置在第一绝缘层1212上，传感漏电极1234远离传感源电极1233的一端设置在第一绝缘层1212上)。
(4)在完成前述结构的基底上，先沉积第二绝缘薄膜，然后涂覆第三绝缘薄膜，通过构图工艺对第二绝缘薄膜和第三绝缘薄膜进行构图，形成覆盖基底11的第二绝缘层1213和第三绝缘层1214，其上开设有暴露出传感漏电极1234的第一过孔。
(5)在完成前述结构的基底上，依次沉积P型半导体层、本征半导体层和N型半导体层，通过构图工艺形成光电二极管1235图案，光电二极管1235的P型半导体层通过第一过孔与传感漏电极1234连接。
(6)在完成前述结构的基底上，涂覆第四绝缘薄膜，通过构图工艺对第二绝缘薄膜进行构图，形成覆盖光电二极管1235的第四绝缘层1215，其上开设有暴露出驱动漏电极1224的第二过孔。
(7)在完成前述结构的基底上，沉积透明导电薄膜，通过构图工艺对透明导电薄膜进行构图，在第四绝缘层1215上形成驱动电极1225图案。
(8)在完成前述结构的基底上，涂覆第五绝缘薄膜，形成覆盖驱动电极1225的第五绝缘层1216。
其中，第一绝缘层和第二绝缘层可以采用硅氧化物(SiOx)、硅氮化物(SiNx)或氮氧化硅(SiON)等，可以是单层结构，或者可以是多层复合结构，第一绝缘层称为栅绝缘(GI)层，第二绝缘层称为层间绝缘(ILD)层。第三绝缘层、第四绝缘层和第五绝缘层可以采用有机材料，称为平坦化(PLN) 层。第一金属薄膜和第二金属薄膜可以采用金属材料，如银(Ag)、铜(Cu)、铝(Al)或钼(Mo)等，或者可以采用由金属组成的合金材料，可以是单层结构，或者可以是多层复合结构。透明导电薄膜可以采用氧化铟锡(ITO)或氧化铟锌(IZO)。有源层薄膜可以采用非晶态氧化铟镓锌材料(a-IGZO)、氮氧化锌(ZnON)、氧化铟锌锡(IZTO)、非晶硅(a-Si)、多晶硅(p-Si)、六噻吩或者聚噻吩等材料，即本公开实施例适用于基于氧化物(Oxide)技术、硅技术或者有机物技术制造的薄膜晶体管。
需要说明的是，前述所示结构及其制备过程仅仅是一种示例性说明。在示例性实施方式中，可以根据实际需要变更相应结构以及增加或减少构图工艺。例如，薄膜晶体管可以是顶栅结构，或者可以是底栅结构，可以是单栅结构，或者可以是双栅结构。阵列结构层中还可以设置其它电极、引线和结构膜层，本公开实施例在此不做具体的限定。
本公开实施例提供了一种数字微流控化学发光检测芯片和检测装置，利用数字微流控技术实现了化学发光反应复杂样液的制备，避免了复杂的流体液路系统，实现了待测样液的自动化、高精度预处理，可以保证样液与试剂的准确配比，保证了实验结果的重复性及稳定性，具有结构紧凑、体积小、功耗低、成本低等特点，可实现痕量物质的POCT快速精准检测。通过在数字微流控化学发光检测芯片中集成光传感阵列，实现了在芯片内采集光信号，避免了复杂的外围光路结构，降低了信号的信噪比，提高了检测结果的一致性。本公开实施例最大限度地降低了系统体积，提高了检测结果一致性，有效解决了现有化学发光检测装置存在系统体积大、检测结果一致性低等缺陷，具有广泛的应用场景。
基于本公开实施例的技术构思，本公开实施例还提供了一种数字微流控化学发光检测方法，采用前述的数字微流控化学发光检测芯片。本公开实施例数字微流控化学发光检测方法包括：
S1、所述驱动阵列驱动样液依次与磁珠抗体、酶标抗体和发光底物结合，形成抗原-磁珠抗体-酶标抗体-发光底物复合物；
S2、所述光传感阵列采集所述抗原-磁珠抗体-酶标抗体-发光底物复合物化学发光的光信号，并将所述光信号转化为电信号。
其中，步骤S1包括：
S11、在所述混匀孵育区，所述驱动阵列驱动样液依次与磁珠抗体和酶标抗体结合，形成抗原-磁珠抗体-酶标抗体复合物；
S12、在所述发光检测区，所述驱动阵列驱动所述抗原-磁珠抗体-酶标抗体复合物与发光底物结合，形成抗原-磁珠抗体-酶标抗体-发光底物复合物。
其中，步骤S11包括：
在所述混匀孵育区的磁珠混匀通道，所述驱动阵列驱动所述样液与磁珠抗体结合，形成抗原-磁珠抗体复合物；
在所述混匀孵育区的酶标混匀通道，所述驱动阵列驱动所述抗原-磁珠抗体复合物与酶标抗体结合，形成抗原-磁珠抗体-酶标抗体复合物。
其中，步骤S12包括：
在所述发光检测区的纯化通道，所述驱动阵列驱动所述抗原-磁珠抗体-酶标抗体复合物与洗涤缓冲液混匀，并将杂质溶液排出所述纯化通道；
在所述发光检测区的纯化通道，所述驱动阵列驱动所述抗原-磁珠抗体-酶标抗体复合物与发光底物结合，形成抗原-磁珠抗体-酶标抗体-发光底物复合物。
其中，步骤S2包括：
在所述发光检测区的检测区，所述光传感阵列采集所述抗原-磁珠抗体-酶标抗体-发光底物复合物化学发光的光信号，并将所述光信号转化为电信号。
本公开实施例提供的一种数字微流控化学发光检测方法，利用数字微流控技术实现了化学发光反应复杂样液的制备，避免了复杂的流体液路系统，通过在数字微流控化学发光检测芯片内采集光信号，避免了复杂的外围光路结构。本公开实施例方法降低了信号的信噪比，提高了检测结果的一致性。
在本公开实施例的描述中，需要理解的是，术语“中部”、“上”、“下”、“前”、“后”、“竖直”、“水平”、“顶”、“底”“内”、“外”等指示的方位或位置关系为基于附图所示的方位或位置关系，仅是为了便于描述本公开和简化描述，而不是指示或暗示所指的装置或元件必须具有特定的方位、以特定的方位构造和 操作，因此不能理解为对本公开的限制。
在本公开实施例的描述中，需要说明的是，除非另有明确的规定和限定，术语“安装”、“相连”、“连接”应做广义理解，例如，可以是固定连接，也可以是可拆卸连接，或一体地连接；可以是机械连接，也可以是电连接；可以是直接相连，也可以通过中间媒介间接相连，可以是两个元件内部的连通。对于本领域的普通技术人员而言，可以具体情况理解上述术语在本公开中的具体含义。
虽然本公开所揭露的实施方式如上，但所述的内容仅为便于理解本公开而采用的实施方式，并非用以限定本公开。任何本公开所属领域内的技术人员，在不脱离本公开所揭露的精神和范围的前提下，可以在实施的形式及细节上进行任何的修改与变化，但本公开的专利保护范围，仍须以所附的权利要求书所界定的范围为准。

Claims (16)

  1. 一种数字微流控化学发光检测芯片，包括相对设置的第一基板和第二基板，所述第一基板和第二基板形成的腔体包括实现抗原、磁珠抗体和抗体结合的混匀孵育区、实现化学发光并检测光信号的发光检测区以及连通所述混匀孵育区和发光检测区的连通路径，所述第一基板上设置有设置为驱动样液移动的驱动阵列和设置为采集样液发光信号的光传感阵列，所述驱动阵列与所述混匀孵育区、发光检测区和连通路径的位置相对应，所述光传感阵列与所述发光检测区的位置相对应。
  2. 根据权利要求1所述的数字微流控化学发光检测芯片，其中，所述混匀孵育区包括磁珠加注盘和磁珠混匀通道，所述磁珠加注盘设置为向磁珠混匀通道提供磁珠抗体，在所述磁珠混匀通道，所述样液在所述驱动阵列驱动下沿着所述磁珠混匀通道移动，使样液中抗原与磁珠抗体结合，形成第一孵育样液，所述第一孵育样液包括抗原-磁珠抗体复合物。
  3. 根据权利要求2所述的数字微流控化学发光检测芯片，其中，所述混匀孵育区还包括酶标加注盘和酶标混匀通道，所述酶标加注盘设置为向酶标混匀通道提供酶标抗体，所述酶标混匀通道与所述磁珠混匀通道连通，在所述酶标混匀通道，所述第一孵育样液在所述驱动阵列驱动下沿着所述酶标混匀通道移动，使第一孵育样液与酶标抗体结合，形成第二孵育样液，所述第二孵育样液包括抗原-磁珠抗体-酶标抗体复合物。
  4. 根据权利要求3所述的数字微流控化学发光检测芯片，其中，所述发光检测区包括底物加注盘和纯化通道，所述纯化通道与所述混匀孵育区连通，所述底物加注盘设置为向纯化通道提供发光底物，在所述纯化通道中，所述第二孵育样液在所述驱动阵列驱动下沿着所述纯化通道移动，使第二孵育样液与发光底物结合，形成第三孵育样液，所述第三孵育样液包括抗原-磁珠抗体-酶标抗体-发光底物复合物。
  5. 根据权利要求4所述的数字微流控化学发光检测芯片，其中，所述磁珠混匀通道、酶标混匀通道和纯化通道均为环形通道，所述样液与磁珠抗体、所述第一孵育样液与酶标抗体、所述第二孵育样液与发光底物均通过转圈方式实现混匀。
  6. 根据权利要求4所述的数字微流控化学发光检测芯片，其中，所述发光检测区还包括洗涤加注盘，所述洗涤加注盘设置为向纯化通道提供洗涤缓冲液，在所述纯化通道中，所述第二孵育样液在所述驱动阵列驱动下沿着所述纯化通道移动，使第二孵育样液与洗涤缓冲液实现混匀；外设的磁控装置固定所述第二孵育样液中的磁珠抗体，所述第二孵育样液中的杂质溶液在所述驱动阵列驱动下排出所述纯化通道。
  7. 根据权利要求4所述的数字微流控化学发光检测芯片，其中，所述发光检测区还包括检测区，所述检测区与所述纯化通道连通，在所述检测区，所述光传感阵列采集所述第三孵育样液化学发光的光信号，并将所述光信号转化为电信号。
  8. 根据权利要求6所述的数字微流控化学发光检测芯片，其中，所述第二基板上设置有多个加注孔，所述多个加注孔分别与所述磁珠加注盘、酶标加注盘、洗涤加注盘和底物加注盘的位置相对应。
  9. 根据权利要求1所述的数字微流控化学发光检测芯片，还包括加注区和废液区，所述加注区与所述混匀孵育区连通，设置为接收待检测的样液，所述废液区与所述发光检测区连通，设置为接收来自所述发光检测区的废液。
  10. 根据权利要求1至9任一所述的数字微流控化学发光检测芯片，其中，所述驱动阵列采用有源驱动实现方式。
  11. 根据权利要求1至9任一所述的数字微流控化学发光检测芯片，其中，所述第一基板包括第一基底、设置在所述第一基底朝向第二基板一侧的阵列结构层和设置在所述阵列结构层朝向第二基板一侧的第一疏水层，第二基板包括第二基底和设置在第二基底朝向第一基板一侧的第二疏水层；所述驱动阵列和光传感阵列设置在所述阵列结构层中，所述驱动阵列包括多个驱动单元，所述驱动单元包括驱动晶体管和驱动电极，所述驱动电极与驱动晶体管连接；所述光传感阵列包括多个光传感单元，所述光传感单元包括传感晶体管和光电二极管，所述光电二极管与传感晶体管连接。
  12. 根据权利要求11所述的数字微流控化学发光检测芯片，其中，所述阵列结构层包括：
    第一基底；
    设置在所述第一基底上的驱动栅电极和传感栅电极；
    覆盖所述驱动栅电极和传感栅电极的第一绝缘层；
    设置在所述第一绝缘层上的驱动有源层和传感有源层；
    相互邻近的端分别设置在所述驱动有源层上的驱动源电极和驱动漏电极，相互邻近的端设置在所述传感有源层上传感源电极和传感漏电极；
    覆盖所述驱动源电极、驱动漏电极、传感源电极和传感漏电极的第二绝缘层和第三绝缘层，其上开设有暴露出所述传感漏电极的第一过孔；
    设置在所述第三绝缘层上的光电二极管，所述光电二极管的第一极通过所述第一过孔与所述传感漏电极连接；
    覆盖所述光电二极管的第四绝缘层，其上开设有暴露出所述驱动漏电极的第二过孔；
    设置在所述第四绝缘层上的驱动电极，所述驱动电极通过所述第二过孔与所述驱动漏电极连接；
    覆盖所述驱动电极的第五绝缘层。
  13. 一种数字微流控化学发光检测装置，包括如权利要求1至12任一所述的数字微流控化学发光检测芯片，还包括移液装置、温控装置、磁控装置和信号处理装置；所述移液装置设置为将样液转移到所述数字微流控化学发光检测芯片上，所述温控装置设置为向所述数字微流控化学发光检测芯片提供设定的温度，所述磁控装置设置为向所述数字微流控化学发光检测芯片提供设定的磁场，所述信号处理装置与所述数字微流控化学发光检测芯片连接，设置为读取所述光传感阵列的电信号，对电信号进行分析处理，获得浓度信息。
  14. 根据权利要求13所述的数字微流控化学发光检测装置，其中，所述温控装置设置在所述第一基板远离第二基板的一侧或所述第二基板远离第一基板的一侧，设置为向所述混匀孵育区提供设定的温度；所述磁控装置设置在所述第一基板远离第二基板的一侧或所述第二基板远离第一基板的一侧，设置为向所述发光检测区提供设定的磁场。
  15. 一种采用如权利要求1至12任一所述的数字微流控化学发光检测芯片的数字微流控化学发光检测方法，包括：
    所述驱动阵列驱动样液依次与磁珠抗体、酶标抗体和发光底物结合，形成抗原-磁珠抗体-酶标抗体-发光底物复合物；
    所述光传感阵列采集所述抗原-磁珠抗体-酶标抗体-发光底物复合物化学发光的光信号，并将所述光信号转化为电信号。
  16. 根据权利要求15所述的数字微流控化学发光检测方法，其中，所述驱动阵列驱动样液依次与磁珠抗体、酶标抗体和发光底物结合，形成抗原-磁珠抗体-酶标抗体-发光底物复合物，包括：
    在所述混匀孵育区，所述驱动阵列驱动样液依次与磁珠抗体和酶标抗体结合，形成抗原-磁珠抗体-酶标抗体复合物；
    在所述发光检测区，所述驱动阵列驱动所述抗原-磁珠抗体-酶标抗体复合物与发光底物结合，形成抗原-磁珠抗体-酶标抗体-发光底物复合物。
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