WO2018210104A1 - 一种生物检测芯片及其检测方法 - Google Patents

一种生物检测芯片及其检测方法 Download PDF

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WO2018210104A1
WO2018210104A1 PCT/CN2018/084088 CN2018084088W WO2018210104A1 WO 2018210104 A1 WO2018210104 A1 WO 2018210104A1 CN 2018084088 W CN2018084088 W CN 2018084088W WO 2018210104 A1 WO2018210104 A1 WO 2018210104A1
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biomolecule
chip
biodetection
microcapsules
electrode
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PCT/CN2018/084088
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English (en)
French (fr)
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耿越
蔡佩芝
庞凤春
古乐
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京东方科技集团股份有限公司
北京京东方光电科技有限公司
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Priority to US16/095,023 priority Critical patent/US11067570B2/en
Publication of WO2018210104A1 publication Critical patent/WO2018210104A1/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
    • G01N33/54373—Apparatus specially adapted for solid-phase testing involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings
    • G01N33/5438—Electrodes
    • 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
    • B01L3/502761—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 specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads, for physically stretching molecules
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502715—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 interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
    • 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
    • G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • G01N21/78—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator producing a change of colour
    • 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
    • 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
    • B01L2200/0647—Handling flowable solids, e.g. microscopic beads, cells, particles
    • B01L2200/0668—Trapping microscopic beads
    • 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
    • B01L2300/0645—Electrodes
    • 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
    • B01L2300/0819—Microarrays; Biochips
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0887—Laminated structure
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/16—Surface properties and coatings
    • B01L2300/161—Control and use of surface tension forces, e.g. hydrophobic, hydrophilic
    • B01L2300/165—Specific details about hydrophobic, oleophobic surfaces
    • 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
    • B01L2300/16—Surface properties and coatings
    • B01L2300/168—Specific optical properties, e.g. reflective coatings
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0415—Moving fluids with specific forces or mechanical means specific forces electrical forces, e.g. electrokinetic

Definitions

  • the present disclosure relates to the field of biological detection, and in particular to a biological detection chip and a detection method thereof.
  • the detection method is to first fix a large number of different probe molecules to each detection site of the chip, and then pass the fluorescently labeled biomolecule solution to be detected into the chip. If the biomolecule to be detected specifically binds to a probe at a certain site, the structure or type of the biomolecule to be detected can be determined by detecting the released fluorescent signal.
  • the detection result of the detection method has high accuracy, but the fluorescence detection process is required to determine the structure or type of the biomolecule to be detected, and the intuitiveness thereof is not high.
  • biomolecule detection chips are generally used in a single use, and each type of biomolecules to be detected can be detected each time, which leads to a substantial increase in the cost of the detected consumables, which is not conducive to the popularization and promotion of biomolecule detection technology.
  • Embodiments of the present disclosure provide a biodetection chip and a detection method thereof for simplifying a biomolecule detection process and reducing the cost of biomolecule detection.
  • inventions of the present disclosure provide a biometric detection chip.
  • the bio-detection chip includes an upper substrate and a lower substrate, a reference electrode, a driving electrode, a first dielectric layer, a second dielectric layer, a first hydrophobic layer and a second hydrophobic layer disposed opposite to each other.
  • a reference electrode is formed on a side of the upper substrate facing the lower substrate.
  • a driving electrode is formed on a side of the lower substrate facing the upper substrate.
  • the first dielectric layer, the first hydrophobic layer, the second hydrophobic layer, and the second dielectric layer are sequentially disposed between the reference electrode and the driving electrode.
  • the biodetection chip further includes a plurality of microcapsules disposed between the first hydrophobic layer and the second hydrophobic layer.
  • the microcapsules enclose a plurality of charged microspheres having a first biomolecule on a surface thereof for specifically binding to a second biomolecule entering the biodetection chip to cause a color change.
  • One of the first biomolecule and the second biomolecule is a biomolecule to be detected.
  • the charged microsphere moves closer to the upper substrate when a voltage is applied between the reference electrode and the drive electrode.
  • the biodetection chip further includes a plurality of retaining walls disposed between the first hydrophobic layer and the second hydrophobic layer.
  • the retaining wall divides the space between the upper substrate and the lower substrate into a plurality of subspaces. There is a gap between two adjacent retaining walls.
  • the microcapsules are filled in the subspace. The diameter of the microcapsule is the same as the height of the retaining wall and greater than the width of the gap.
  • the drive electrode comprises a plurality of sub-electrodes. Each sub-electrode corresponds to one or more sub-spaces of the plurality of sub-spaces.
  • the biometric detection chip further includes: a controllable switch corresponding to each of the sub-electrodes in one-to-one correspondence.
  • the switch can be a switching transistor.
  • the orthographic projections of the respective retaining walls on the lower substrate are arranged around the orthographic projections of the sub-electrodes on the lower substrate.
  • the shape of the sub-electrode may be a regular hexagon.
  • the surface of the microcapsule has a plurality of micropores.
  • the microspheres are white, and the first biomolecule is a plurality of linkers for specifically binding to the second biomolecule.
  • the microcapsules range in diameter from 50 to 200 microns.
  • the upper substrate has a set of inlets and outlets.
  • the inlet is for introduction of a sample solution comprising the second biomolecule.
  • the sample port is used for the derivation of the sample solution.
  • the upper substrate may be a transparent substrate.
  • the surface of the charged microspheres in the microcapsules filled in different subspaces has a first biomolecule arranged to specifically bind to a different biomolecule.
  • embodiments of the present disclosure provide a method of detecting using a biodetection chip as described above and elsewhere herein.
  • the method includes: introducing a sample solution of a second biomolecule with a dyed label into the biodetection chip; after the sample solution flows through the plurality of microcapsules, at the reference electrode and the drive A voltage signal is applied between the electrodes; and the information of the biomolecule to be detected is determined according to the microcapsules in which the color change occurs.
  • the method further comprises: after the sample solution flows through the plurality of microcapsules, no specific binding occurs prior to applying a voltage signal to the reference electrode and the drive electrode
  • the sample solution is derived from the biodetection chip.
  • FIG. 1 is a schematic structural diagram of a biometric detection chip according to an embodiment of the present disclosure
  • FIG. 2 is a schematic view showing the arrangement of a retaining wall according to an embodiment of the present disclosure
  • FIG. 3 is a schematic view showing the arrangement of sub-electrodes according to an embodiment of the present disclosure
  • FIG. 4 is a schematic structural view of a microcapsule according to an embodiment of the present disclosure.
  • 5a-5d are schematic views of a biomolecule detection process provided by an embodiment of the present disclosure.
  • FIG. 6 is a flowchart of a biological detection method according to an embodiment of the present disclosure.
  • FIG. 1 illustrates a biodetection chip in accordance with an embodiment of the present disclosure.
  • the biodetection chip includes: an upper substrate 01 and a lower substrate 02, a reference electrode 03, a driving electrode 04, a first dielectric layer 05, a second dielectric layer 06, a first hydrophobic layer 07, and a second hydrophobic layer disposed opposite to each other.
  • the reference electrode 03 is formed on one side of the upper substrate 01 facing the lower substrate 02.
  • the drive electrode 04 is formed on one side of the lower substrate 02 facing the upper substrate 01.
  • a first dielectric layer 05, a first hydrophobic layer 07, a second hydrophobic layer 08, and a second dielectric layer 06 are sequentially disposed between the reference electrode 03 and the driving electrode 04.
  • the first dielectric layer 05 is located on one side of the reference electrode 03 facing the lower substrate 02.
  • the first hydrophobic layer 07 is located on a side of the first dielectric layer 05 facing the lower substrate 02.
  • the second dielectric layer 06 is located on a side of the drive electrode 04 facing the upper substrate 01.
  • the second hydrophobic layer 08 is located on a side of the second dielectric layer 06 facing the upper substrate 01.
  • the material of the upper and lower substrates may be glass, silicon, or the like.
  • the drive electrode can be formed by depositing an etch on the lower substrate.
  • the material of the drive electrode may be ITO (indium tin oxide). Because of its good transparency, it is easy to observe color. Thereafter, a dielectric layer and a hydrophobic layer can be formed.
  • the material of the dielectric layer may be silicon oxide, silicon nitride or the like, and the material of the hydrophobic layer may be a low surface energy material such as PTFE (polytetrafluoroethylene).
  • the biodetection chip further includes a plurality of microcapsules disposed between the first hydrophobic layer and the second hydrophobic layer.
  • a layer of microcapsules can be placed between the first hydrophobic layer and the second hydrophobic layer.
  • the microcapsules may include a capsule wall shell formed using a natural polymeric material (eg, abbreviated, acacia, alginate, etc.) or a synthetic polymeric material (eg, polyamide, polyamino acid, etc.).
  • the biologically active substance can be encapsulated within the envelope wall shell to form, for example, spherical microcapsules.
  • the microcapsules enclose a plurality of charged microspheres having a first biomolecule (such as a known biomolecule) on the surface for specific binding to a second biomolecule (for example, a biomolecule to be detected) entering the biodetection chip to generate color Variety.
  • the charged microspheres can become the marker color of the biomolecule to be detected.
  • the charged microspheres can move closer to the upper substrate when a voltage is applied between the reference electrode and the drive electrode. Thereby, the color signal of the charged microspheres in which the color change occurs can be observed from above the chip (for example, through the upper substrate), thereby obtaining information of the biomolecule to be detected.
  • the biometric chip further includes a plurality of retaining walls.
  • Each of the retaining walls 09 is disposed between the first hydrophobic layer 07 and the second hydrophobic layer 08, and each of the retaining walls 09 is between the upper substrate 01 and the lower substrate 02 (ie, the first hydrophobic layer 07 and the second hydrophobic layer 08).
  • the space between the two is divided into multiple subspaces.
  • the retaining wall may be formed by depositing an etch over the second hydrophobic layer.
  • the material of the retaining wall may be silicon nitride, silicon oxide, resin or the like.
  • FIG. 2 shows a schematic illustration of a formed retaining wall in accordance with an embodiment of the present disclosure.
  • multiple retaining walls divide the entire space into multiple subspaces.
  • Each subspace can be filled with a plurality of microcapsules 10 that can undergo a color change by specific binding between biomolecules.
  • the diameter of the microcapsule 10 can be the same as the height of the retaining wall 09, but greater than the width of the gap a.
  • the gap between the retaining walls is smaller than the diameter of the microcapsules, which ensures that the microcapsules cannot move through the gaps in different subspaces, but can allow liquid to flow through the gaps in the subspace.
  • the microcapsule of each subspace can undergo a color change by specific binding between a known biomolecule and a biomolecule to be detected, for example, into a biomolecule to be detected. Mark color.
  • the microcapsules can be brought close to the surface of the upper substrate to exhibit a color change.
  • the color change of the microcapsules can be directly observed from above the biodetection chip, so that the biomolecule detection can realize the visual observation of the detection result, thereby determining the structure or type information of the biomolecule to be detected.
  • the scheme according to an embodiment of the present disclosure does not require fluorescence detection, which simplifies the detection process of biomolecules.
  • the microcapsules in the biodetection chip of the embodiments of the present disclosure are replaceable, so that the biodetection chip can be reused, reducing the detection cost.
  • the bio-detection chip can be fabricated by using an existing photolithography process, and the fabrication method is simple.
  • FIG. 3 illustrates an exemplary illustration of one configuration of a biometric detection chip provided in accordance with an embodiment of the present disclosure.
  • the drive electrode includes a plurality of sub-electrodes 041.
  • the sub-electrodes 041 may be arranged in a matrix.
  • the biometric detecting chip may further include: a switch 11 corresponding to each sub-electrode 041, a plurality of control lines 12 extending in the first direction, and a plurality of extending in a second direction crossing the first direction Signal line 13.
  • each control line 12 is coupled to a control terminal of one or more switches 11, each signal line 13 being coupled to an input of one or more switches 11.
  • each switch 11 is connected to a corresponding sub-electrode 041.
  • the switch 11 can input a signal on the corresponding signal line 13 to the corresponding sub-electrode 041 under the control of the corresponding control line 12 to generate a driving voltage.
  • each switch 11 can be independently controlled.
  • each of the retaining walls 09 may be disposed such that the orthographic projections of the adjacent retaining walls on the lower substrate 02 are arranged around the sub-electrodes 041 in the orthographic projection pattern of the lower substrate 02, that is, the sub-electrode 041 and the retaining wall
  • the divided subspaces correspond, for example, by a corresponding retaining wall.
  • each sub-electrode can be the area that is planned for detecting biomolecules.
  • the area of one sub-electrode can correspond to the detection area surrounded by the retaining wall.
  • biomolecule detection can be performed in the corresponding region by the power-on of the switch control sub-electrode.
  • the switches can be independently controlled such that they can precisely control each sub-electrode so that each detection zone can be precisely controlled.
  • the switch can be implemented by a switching transistor.
  • the gate of the switching transistor is connected to a corresponding control line
  • the source is connected to a corresponding signal line
  • the drain is connected to a corresponding sub-electrode.
  • the switching transistor of the one or more sub-electrodes in the corresponding detection area may be controlled to be turned on by the control line, and then the voltage signal on the signal line is output to the corresponding sub-electrode to realize the area corresponding to the sub-electrode. Biomolecular detection.
  • the shape of the sub-electrode 041 may be a regular hexagon.
  • the sub-electrode 041 can also be provided in other suitable shapes, such as a circular shape, a rectangular shape, or the like.
  • the shape of the sub-electrodes may be adapted to the shape of the detection area in practical use.
  • the cross-sectional shape of the retaining wall can also be set to a variety of shapes.
  • the orthographic shape of the retaining wall 09 on the lower substrate may be hexagonal. In practical applications, the retaining wall can also be set to other types of cross-sectional shapes without being limited thereto.
  • the surface of the microcapsule 10 has a plurality of micropores 101.
  • the microcapsule 10 has a plurality of microspheres 102 that are white in color and charged.
  • the surface of the microspheres 102 has a plurality of tabs 103 for specific binding.
  • the linker 103 can be a known biomolecule or a biomolecule to be detected.
  • the microwells are configured to allow free entry and exit of biomolecules with stained markers.
  • the surface of the white charged microspheres encased in the microcapsules can be chemically treated to link different structures and types of linkers, such as antigens, antibodies, aptamers, and the like. These linkers can and can only specifically bind to one other biomolecule.
  • microcapsules can be filled in different subspaces formed by the retaining wall, with charged microspheres with different structures and kinds of joints to detect different biomolecules.
  • a variety of known protein antigen molecules can be immobilized or adsorbed on the surface of the microspheres within the microcapsules. Thereafter, for each known protein antigen molecule, the position of the microcapsules containing its associated microspheres in the biodetection chip, such as in which subspaces, is recorded. Alternatively, the names of known protein antigen molecules immobilized or adsorbed on the surface of the microspheres in the microcapsules at different locations on the biodetection chip (eg, in which subspaces) can also be recorded.
  • the antibody to be detected can be stain-labeled, formulated into a solution, and allowed to flow into the bioassay chip.
  • the microspheres to which the known protein antigen molecule is immobilized become a marker color of the antibody to be detected.
  • an unreacted, eg, antibody solution that does not specifically bind is washed out of the bioassay chip.
  • the antibody to be detected can be determined based on the site at which the color changes.
  • the antibody to be detected can be immobilized on the surface of the microspheres within the microcapsules.
  • a variety of known protein antigen molecules are further labeled with different dyes and formulated into a bioassay chip. When the solution flows through each microcapsule, only one known protein antigen molecule will specifically bind to the antibody to be detected. Upon specific binding, the surface of the microspheres will exhibit a color change with the color of the bound protein antigen molecule. Thereafter, the unreacted solution containing the antigen molecule is washed out of the chip. The antibody to be detected can be determined based on the color developed by the microspheres.
  • FIGS 5a-5d show schematic diagrams of biomolecule detection processes provided by embodiments of the present disclosure.
  • the sample solution with the dye-labeled biomolecule to be detected is introduced into the biodetection chip.
  • the sample solution flows through all of the microcapsules.
  • the biomolecules in the sample solution can enter the microcapsules through the micropores on the microcapsules and contact the white charged microspheres in the microcapsules.
  • the surface of these charged microspheres changes from white to the mark color of the corresponding biomolecule to be detected.
  • the surface of the charged microsphere is still white.
  • the microcapsules in the subspace partitioned by the retaining wall may have charged microspheres with different joints, there may be some surface of the charged microspheres in the subspace becoming a marker color, The charged microspheres in other spaces are still white.
  • a voltage is then applied between the reference electrode and the drive electrode by, for example, switching control.
  • the charged microspheres within the microcapsules are moved into the microcapsules near the surface of the upper substrate.
  • the upper substrate is a transparent substrate, so that the color exhibited by the microspheres can be directly observed, thereby detecting the biomolecule to be detected.
  • the microcapsules may range in diameter from tens to hundreds of microns.
  • the diameter of the microcapsules can be set to 50 to 200 microns.
  • the upper substrate has a set of inlets and outlets.
  • the inlet is used for the introduction of the sample solution; the outlet is used for the extraction of the sample solution.
  • the bio-detection chip can be provided with a pair of inlets and outlets on the upper substrate for realizing the introduction and derivation of the solution to be detected.
  • the detection of the biomolecule to be detected may be similarly accomplished by immobilizing the biomolecule to be detected on the surface of the microsphere and dissolving the known biomolecule in solution.
  • FIG. 6 illustrates a method of detecting using a biometric chip provided by an embodiment of the present disclosure. As shown in FIG. 6, the method may include:
  • the biomolecule with a staining marker may be a biomolecule to be detected or a known biomolecule.
  • the biomolecule to be detected may be a biomolecule in the sample solution, or may be a biomolecule on the surface of the microsphere.
  • the color change of the microcapsules can be directly observed, and the information of the biomolecule to be detected, such as the structure or type information of the biomolecule to be detected, is determined according to the microcapsules in which the color change occurs.
  • Embodiments in accordance with embodiments of the present disclosure do not require fluorescence detection relative to the prior art. This simplifies the detection process of biomolecules.
  • the sample solution can be injected into the biodetection chip by an injection port in the substrate on the biodetection chip.
  • the method further includes: removing all unreacted sample solutions, for example, extracting the sample solution from the sample outlet Biometric chip. This will prevent unreacted sample solutions from affecting the observation of the test results.
  • the microcapsules in the biodetection chip of the present disclosure are replaceable such that the biodetection chip can be reused. This further reduces the cost of testing.

Abstract

一种生物检测芯片及其检测方法，生物检测芯片包括：相对设置的上基板（01）和下基板（02）、参比电极（03）、驱动电极（04）、第一介电层（05）、第二介电层（06）、第一疏水层（07）和第二疏水层（08）；其中，参比电极（03）形成于上基板（01）面向下基板（02）的一面；驱动电极（04）形成于下基板（02）面向上基板（01）的一面；在参比电极（03）与驱动电极（04）之间依次设置有第一介电层（05）、第一疏水层（07）、第二疏水层（08）和第二介电层（06）；生物检测芯片还包括安排于第一疏水层（07）与第二疏水层（08）之间的多个微囊（10），微囊（10）包裹多个带电微球（102），其表面具有第一生物分子，用于与进入生物检测芯片的第二生物分子进行特异性结合而发生颜色变化，其中第一生物分子和第二生物分子中的一个是待检测生物分子，且带电微球（102）在参比电极（03）和驱动电极（04）间施加电压时移动靠近上基板（01），可以直观地观察生物分子检测的检测结果。

Description

一种生物检测芯片及其检测方法
相关申请
本申请要求于2017年5月17日递交的中国专利申请No.201710348447.1的优先权，在此全文引用上述中国专利申请公开的内容作为本申请的一部分。
技术领域
本公开涉及生物检测领域，尤其涉及一种生物检测芯片及其检测方法。
背景技术
当前生物分子的检测是在相应的检测芯片上进行的，如蛋白质检测、抗原抗体检测、酶检测、基因检测等。其检测方法是先将大量不同的探针分子点样固定到芯片的各个检测位点上，再将带有荧光标记的待检测生物分子溶液通入芯片。若待检测生物分子与某一位点的探针发生特异性结合反应，通过检测释放的荧光信号即可确定待检测生物分子的结构或类型。该检测方法的检测结果准确度较高，但需要经过荧光检测过程才能确定待检测生物分子的结构或类型，其直观性不高。而且，目前现有的生物分子检测芯片一般为单次使用，每次能够检测的待检测生物分子种类较少，这会导致检测的耗材成本大幅提高，不利于生物分子检测技术的普及和推广。
因此，如何简化生物分子的检测过程，降低生物分子检测的成本，是本领域技术人员亟待解决的技术问题。
发明内容
本公开实施例提供了一种生物检测芯片及其检测方法，用以简化生物分子的检测过程，降低生物分子检测的成本。
在一个方面，本公开实施例提供了一种生物检测芯片。该生物检测芯片包括相对设置的上基板和下基板、参比电极、驱动电极、第一介电层、第二介电层、第一疏水层和第二疏水层。参比电极形成于所述上基板面向所述下基板的一面。驱动电极形成于所述下基板面向所 述上基板的一面。在所述参比电极与所述驱动电极之间依次设置有所述第一介电层、所述第一疏水层、所述第二疏水层和所述第二介电层。所述生物检测芯片还包括安排于所述第一疏水层与所述第二疏水层之间多个微囊。所述微囊包裹多个带电微球，其表面具有第一生物分子，用于与进入生物检测芯片的第二生物分子进行特异性结合而发生颜色变化。所述第一生物分子和第二生物分子中的一个是待检测生物分子。所述带电微球在所述参比电极和所述驱动电极间施加电压时移动靠近上基板。
在一些实施例中，生物检测芯片还包括设置于所述第一疏水层与所述第二疏水层之间的多个挡墙。挡墙将所述上基板与所述下基板之间的空间分割为多个子空间。相邻两个所述挡墙之间具有间隙。所述微囊被填充于所述子空间中。所述微囊的直径与所述挡墙的高度相同，且大于所述间隙的宽度。
在一些实施例中，所述驱动电极包括多个子电极。每个子电极与所述多个子空间中的一个或多个子空间对应。所述生物检测芯片还包括：与各所述子电极一一对应的可控制的开关。所述开关可以为开关晶体管。
在一些实施例中，各所述挡墙在所述下基板的正投影图形围绕各所述子电极在所述下基板的正投影图形排列。所述子电极的形状可以为正六边形。
在一些实施例中，微囊表面具有多个微孔。微球为白色，且所述第一生物分子是多个用于与所述第二生物分子进行特异性结合的接头。
在一些实施例中，微囊的直径范围为50～200微米。
在一些实施例中，所述上基板具有一组进样口和出样口。所述进样口用于包含所述第二生物分子的样本溶液的导入。所述出样口用于样本溶液的导出。所述上基板可以为透明基板。
在一些实施例中，在不同的子空间中填充的微囊中的带电微球的表面具有被安排为与不同的生物分子特异性结合的第一生物分子。
在另一方面，本公开实施例提供了一种使用如上文及本文其它地方所述的生物检测芯片进行检测的方法。该方法包括：将带有染色标记的第二生物分子的样本溶液导入所述生物检测芯片内；在所述样本溶液流经所述多个微囊后，在所述参比电极和所述驱动电极之间施加 电压信号；以及根据发生颜色变化的微囊确定所述待检测生物分子的信息。
在一些实施例中，该方法还包括：待所述样本溶液流经所述多个微囊后，在对所述参比电极和所述驱动电极施加电压信号之前，将未发生特异性结合的样本溶液导出所述生物检测芯片。
附图说明
现在将参考示出本公开的多个实施例的附图来更详细地描述本公开的上述以及其它方面。
图1为本公开实施例提供的生物检测芯片的结构示意图；
图2为本公开实施例提供的挡墙的排列示意图；
图3为本公开实施例提供的子电极的排列示意图；
图4为本公开实施例提供的微囊的结构示意图；
图5a-图5d分别为本公开实施例提供的生物分子检测过程示意图；和
图6为本公开实施例提供的生物检测方法流程图。
具体实施方式
下面结合附图，对本公开实施例提供的生物检测芯片及其检测方法的具体实施方式进行详细的说明。
图1示出了按照本公开实施例的一种生物检测芯片。该生物检测芯片包括：相对设置的上基板01和下基板02、参比电极03、驱动电极04、第一介电层05、第二介电层06、第一疏水层07、第二疏水层08。参比电极03被形成于上基板01面向下基板02的一面。驱动电极04被形成于下基板02面向上基板01的一面。在参比电极03与驱动电极04之间依次设置有第一介电层05、第一疏水层07、第二疏水层08和第二介电层06。示范性地，第一介电层05位于参比电极03面向下基板02的一面。第一疏水层07位于第一介电层05面向下基板02的一面。第二介电层06位于驱动电极04面向上基板01的一面。第二疏水层08位于第二介电层06面向上基板01的一面。
在一些实施例中，上下基板的材料可以是玻璃、硅等。可以通过在下基板上沉积刻蚀而形成驱动电极。驱动电极的材料可以是ITO(氧 化铟锡)。由于其具有较好的透明性，因此便于颜色观察。之后，可以形成介电层和疏水层。介电层的材料可以为氧化硅、氮化硅等，而疏水层的材料可以为PTFE(聚四氟乙烯)等低表面能材料。
所述生物检测芯片还包括安排于所述第一疏水层与所述第二疏水层之间多个微囊。在一些实施例中，可以在第一疏水层与所述第二疏水层之间铺置一层微囊。示例性的，微囊可以包括利用天然高分子材料(例如名叫、阿拉伯胶、海藻酸盐等)或合成高分子材料(例如聚酰胺、聚氨基酸等)形成的囊膜壁壳。在一些实施例中，可以将具有生物活性的物质包封在囊膜壁壳内，形成例如球状的微囊。
微囊包裹多个带电微球，其表面具有第一生物分子(例如已知生物分子)，用于与进入生物检测芯片的第二生物分子(例如待检测生物分子)的特异性结合而发生颜色变化。带电微球可以变为待检测生物分子的标记色。带电微球可以在所述参比电极和所述驱动电极间施加电压时移动靠近上基板。由此，可从芯片上方(例如通过上基板)观测到发生颜色变化的带电微球的颜色信号，从而得到待检测生物分子的信息。
在一些实施例中，生物检测芯片还包括多个挡墙。各挡墙09被设置于第一疏水层07与第二疏水层08之间，且各挡墙09将上基板01与下基板02之间(也即第一疏水层07与第二疏水层08之间)的空间分割为多个子空间。在一些实施例中，挡墙可以通过在第二疏水层之上沉积刻蚀而形成。挡墙的材料可以是氮化硅、氧化硅、树脂等。
图2示出了按照本公开实施例的所形成的挡墙的示意性图示。如图2所示，多个挡墙将整个空间分隔成多个子空间。包围一个子空间的相邻两个挡墙09之间具有间隙a。各子空间可以填充有多个可通过生物分子之间的特异性结合而发生颜色变化的微囊10。在一些实施例中，微囊10的直径可以与挡墙09的高度相同，但大于间隙a的宽度。这样挡墙之间的间隙小于微囊直径，可以保证微囊不能通过间隙在不同子空间移动，但可以允许液体通过挡墙间隙在子空间中流动。
在本公开实施例提供的上述的生物检测芯片中，每个子空间的微囊可通过已知生物分子与一种待检测生物分子间的特异性结合而发生颜色变化，例如变为待检测生物分子的标记色。这样，通过对驱动电极与参比电极施加电压，可以使微囊靠近上基板的表面以呈现其颜色 变化。由此，可从生物检测芯片上方直接观察到微囊的颜色变化，使得生物分子检测可以实现对检测结果的直观观察，进而确定待检测生物分子的结构或类型信息。相对于现有技术，按照本公开实施例的方案不需要进行荧光检测，简化了生物分子的检测过程。而且本公开实施例的生物检测芯片中的微囊可替换，从而该生物检测芯片可重复使用，降低了检测成本。另外，该生物检测芯片可以采用现有的光刻制作工艺来制作，其制作方法简单。
图3示出了按照本公开实施例提供的生物检测芯片的一种结构的示例性图示。如图所示，驱动电极包括多个子电极041。子电极041可以呈矩阵排列。在一些实施例中，生物检测芯片还可以包括：与各子电极041一一对应的开关11、多条沿第一方向延伸的控制线12以及多条沿与第一方向交叉的第二方向延伸的信号线13。在一个实施例中，每条控制线12与一个或多个开关11的控制端相连，每条信号线13与一个或多个开关11的输入端相连。各开关11的输出端与对应的子电极041相连。开关11可以在对应的控制线12的控制下，将对应的信号线13上的信号输入到对应的子电极041以产生驱动电压。在一个实施例中，各开关11可被独立地控制。
在本公开实施例提供的生物检测芯片中，通过将驱动电极分割为多个子电极，进而设置与子电极一一对应的开关来控制与一个或多个子电极对应的各区域的生物分子检测，可以实现分区控制。另外，如图3所示，各挡墙09可以被设置为：相邻挡墙在下基板02的正投影图形围绕各子电极041在下基板02的正投影图形排列，即子电极041可以与挡墙分割出的子空间对应，例如由相应的挡墙区分或限定。这样使得每个子电极对应的区域可以为被规划用于检测生物分子的区域。通过设置挡墙的排列，可以使一个子电极的区域对应由挡墙围绕成的检测区域。进而，通过开关控制子电极的加电，可以在对应区域进行生物分子检测。在一个实施例中，开关可被独立地控制，使得其可以精确地控制每个子电极，进而可以精确地控制每一个检测区域。
在一个实施例中，开关可以通过开关晶体管来实现。示例性地，开关晶体管的栅极与对应的控制线相连，源极与对应的信号线相连，漏极与对应的子电极相连。在进行生物分子检测时，可以通过控制线控制对应检测区域中的一个或多个子电极的开关晶体管打开，进而将 信号线上的电压信号输出到对应的子电极，以实现该子电极对应的区域的生物分子检测。
在一个实施例中，如图3所示，子电极041的形状可以为正六边形。当然子电极041也可以被设置为其他合适的形状，例如圆形、矩形等形状。在实际应用时子电极的形状可以适配于检测区域的形状。相应的，挡墙的截面形状也可以设置为多种多样的形状。如图3所示，挡墙09在下基板上的正投影形状可以为六边形。在实际应用中，挡墙也可以被设置为其他类型的截面形状，而不限于此。
图4示出了按照本公开实施例的微囊的结构示意图。如图所示，微囊10表面具有多个微孔101。微囊10内具有多个颜色为白色且带电的微球102。微球102的表面具有多个用于进行特异性结合的接头103。所述接头103可以是已知生物分子或者待检测生物分子。在一些实施例中，微孔被设置为可以允许带有染色标记的生物分子自由进出。微囊内包裹的白色带电微球的表面可以经过化学处理以连接不同结构和种类的接头，如抗原、抗体、适配体等。这些接头能且仅能与一种其他生物分子发生特异性结合。在一些实施例中，在通过挡墙形成的不同子空间中可以填充微囊，其具有带不同结构和种类的接头的带电微球，以便检测不同的生物分子。
在一个进行蛋白质检测的示例场景中，可以将多种已知蛋白抗原分子固定或吸附在微囊内的微球表面。之后，对于每种已知蛋白抗原分子，记录包含其关联的微球的微囊在生物检测芯片中的位置，例如在哪些各子空间中。替换地，也可以记录在生物检测芯片上不同位置处(例如哪些子空间内)微囊中微球表面所固定或吸附的已知蛋白抗原分子的名称。待检测抗体可以进行染色标记，配成溶液，且使之流入生物检测芯片内。溶液在流经生物检测芯片，例如流经各微囊时，只有一种已知蛋白抗原分子会与待检测抗体进行特异性结合。由此，固定有该已知蛋白抗原分子的微球会变为待检测抗体的标记色。之后，将未反应的，例如未发生特异性结合的抗体溶液清洗出生物检测芯片。可以根据颜色发生变化的位点确定待检测抗体。
替换地，在另一个进行蛋白质检测的示例场景中，可以将待检测抗体固定在微囊内的微球表面。再将多种已知蛋白抗原分子进行不同染色标记，配成溶液通入生物检测芯片内。当溶液流经各微囊时，只 有一种已知蛋白抗原分子会与待检测抗体进行特异性结合。在发生特异性结合后，微球表面将随所结合的蛋白抗原分子的颜色而显现出颜色变化。之后，未反应的含抗原分子的溶液被清洗出芯片。可以基于微球所显现的颜色判定待检测抗体。
图5a-图5d示出了本公开实施例提供的生物分子检测过程的示意图。
如图5a所示，在参比电极和驱动电极之间未施加电压时，带染色标记的待检测生物分子的样本溶液被导入生物检测芯片中。样本溶液流经所有微囊。此时，样本溶液中的生物分子可以通过微囊上的微孔进入微囊中并与微囊中的白色带电微球接触。
如图5b所示，由于待检测生物分子与带电微球上的接头发生特异性结合，这些带电微球的表面由白色变为相应待检测生物分子的标记色。如图5c所示，若待检测生物分子与带电微球上的接头未发生特异性结合，则带电微球的表面仍为白色。在一些实施例中，在通过挡墙所分割出的子空间中的微囊可以具有带不同接头的带电微球的情形中，可能有一些子空间中的带电微球的表面变为标记色，而其他的空间中的带电微球仍为白色。
之后通过例如开关控制在参比电极和驱动电极之间施加电压。如图5d所示，微囊内的带电微球会在移动到微囊中靠近上基板的表面。在一些实施例中，上基板为透明基板，因此可直接观察到微球所呈现的颜色，从而检测出待检测生物分子。
在一个实施例中，微囊的直径范围可以为几十到几百微米。示例性地，微囊的直径可以被设置为50～200微米。
在一个实施例中，上基板具有一组进样口和出样口。进样口用于样本溶液的导入；出样口用于样本溶液的导出。示例性地，该生物检测芯片在上基板可以设置一对进样口和出样口，用于实现待检测溶液的导入和导出。
可以理解，在其他的一些实施例中，可以类似地，通过将待检测生物分子固定在微球表面且将已知生物分子溶于溶液，来完成待检测生物分子的检测。
图6示出了本公开实施例提供的使用生物检测芯片进行检测的方法。如图6所示，该方法可以包括：
S101、将带有染色标记的生物分子的样本溶液导入生物检测芯片内。带有染色标记的生物分子可以是待检测生物分子，也可以是已知的生物分子。
S102、待样本溶液流经各微囊后，对参比电极和驱动电极施加电压信号；
S103、根据发生颜色变化的微囊确定待检测生物分子的信息。待检测生物分子可以是样本溶液中的生物分子，也可以是微球表面所具有的生物分子。
在本公开实施例提供的上述检测方法中，可以直接地观察微囊的颜色变化，并根据发生颜色变化的微囊确定待检测生物分子的信息，例如待检测生物分子的结构或类型信息。相对于现有技术，按照本公开实施例的方案不需要进行荧光检测。这简化了生物分子的检测过程。
在一些实施例中，可以通过生物检测芯片上基板中的进样口将样本溶液注入生物检测芯片内。在一个实施例中，待样本溶液流经各微囊后，在对参比电极和驱动电极施加电压信号之前，还包括：清除所有未反应的样本溶液，例如可以将样本溶液从出样口导出生物检测芯片。这样可以避免未反应的样本溶液影响对检测结果的观察。
在一些实施例中，本公开的生物检测芯片中的微囊是可替换的，从而该生物检测芯片可以重复使用。这进一步降低了检测成本。
显然，本领域的技术人员可以对本公开进行各种改动和变型而不脱离本公开的精神和范围。这样，倘若本公开的这些修改和变型属于本公开权利要求及其等同技术的范围之内，则本公开也意图包含这些改动和变型在内。

Claims (13)

  1. 一种生物检测芯片，包括：相对设置的上基板和下基板、参比电极、驱动电极、第一介电层、第二介电层、第一疏水层和第二疏水层；其中，
    所述参比电极形成于所述上基板面向所述下基板的一面；
    所述驱动电极形成于所述下基板面向所述上基板的一面；
    在所述参比电极与所述驱动电极之间依次设置有所述第一介电层、所述第一疏水层、所述第二疏水层和所述第二介电层；
    所述生物检测芯片还包括安排于所述第一疏水层与所述第二疏水层之间多个微囊，所述微囊包裹多个带电微球，其表面具有第一生物分子，用于与进入生物检测芯片的第二生物分子进行特异性结合而发生颜色变化，其中所述第一生物分子和第二生物分子中的一个是待检测生物分子，且所述带电微球在所述参比电极和所述驱动电极间施加电压时移动靠近上基板。
  2. 如权利要求1所述的生物检测芯片，还包括设置于所述第一疏水层与所述第二疏水层之间的多个挡墙，所述挡墙将所述上基板与所述下基板之间的空间分割为多个子空间，相邻两个所述挡墙之间具有间隙；其中，所述微囊被填充于所述子空间中，且所述微囊的直径与所述挡墙的高度相同并大于所述间隙的宽度。
  3. 如权利要求2所述的生物检测芯片，其中所述驱动电极包括多个子电极，每个子电极与所述多个子空间中的一个或多个子空间对应；所述生物检测芯片还包括：与各所述子电极一一对应的可控制的开关。
  4. 如权利要求3所述的生物检测芯片，其中各所述挡墙在所述下基板的正投影图形围绕各所述子电极在所述下基板的正投影图形排列。
  5. 如权利要求3所述的生物检测芯片，其中所述开关为开关晶体管。
  6. 如权利要求3所述的生物检测芯片，其中所述子电极的形状为正六边形。
  7. 如权利要求1所述的生物检测芯片，其中所述微囊表面具有多个微孔；所述微球为白色，其中所述第一生物分子是多个用于与所述第二生物分子进行特异性结合的接头。
  8. 如权利要求1所述的生物检测芯片，其中所述微囊的直径范围为50～200微米。
  9. 如权利要求1-8任一项所述的生物检测芯片，其中所述上基板具有一组进样口和出样口；所述进样口用于包含所述第二生物分子的样本溶液的导入；所述出样口用于样本溶液的导出。
  10. 如权利要求1-9任一项所述的生物检测芯片，其中所述上基板为透明基板。
  11. 如权利要求2所述的生物检测芯片，其中在不同的子空间中填充的微囊中的带电微球的表面具有被安排为与不同的生物分子进行特异性结合的相应的第一生物分子。
  12. 一种使用如权利要求1-11任一项所述的生物检测芯片进行检测的方法，包括：
    将带有染色标记的所述第二生物分子的样本溶液导入所述生物检测芯片内；
    在所述样本溶液流经所述多个微囊后，在所述参比电极和所述驱动电极之间施加电压信号；以及
    根据发生颜色变化的微囊确定所述待检测生物分子的信息。
  13. 如权利要求12所述的检测方法，其中待所述样本溶液流经所述多个微囊后，在对所述参比电极和所述驱动电极施加电压信号之前，还包括：
    将未发生特异性结合的样本溶液导出所述生物检测芯片。
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