WO2020244517A1 - 微流控芯片及制作方法 - Google Patents

微流控芯片及制作方法 Download PDF

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Publication number
WO2020244517A1
WO2020244517A1 PCT/CN2020/094011 CN2020094011W WO2020244517A1 WO 2020244517 A1 WO2020244517 A1 WO 2020244517A1 CN 2020094011 W CN2020094011 W CN 2020094011W WO 2020244517 A1 WO2020244517 A1 WO 2020244517A1
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Prior art keywords
flow channel
detection
storage tank
liquid
liquid storage
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PCT/CN2020/094011
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English (en)
French (fr)
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张歆
王毅
张莉
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利多(香港)有限公司
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Priority to EP20819566.9A priority Critical patent/EP3978117A4/en
Priority to US17/617,284 priority patent/US20220226813A1/en
Publication of WO2020244517A1 publication Critical patent/WO2020244517A1/zh

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502746—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the means for controlling flow resistance, e.g. flow controllers, baffles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502707—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the manufacture of the container or its components
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/50273—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the means or forces applied to move the fluids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/02—Adapting objects or devices to another
    • B01L2200/026—Fluid interfacing between devices or objects, e.g. connectors, inlet details
    • B01L2200/027—Fluid interfacing between devices or objects, e.g. connectors, inlet details for microfluidic devices
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0621—Control of the sequence of chambers filled or emptied
    • 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
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    • B01L2200/0684—Venting, avoiding backpressure, avoid gas bubbles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01L2200/0689—Sealing
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/12—Specific details about manufacturing devices
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/16—Reagents, handling or storing thereof
    • 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
    • B01L2300/04—Closures and closing means
    • 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
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    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0832—Geometry, shape and general structure cylindrical, tube shaped
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • 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
    • B01L2300/0864—Configuration of multiple channels and/or chambers in a single devices comprising only one inlet and multiple receiving wells, e.g. for separation, splitting
    • 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
    • B01L2300/0867—Multiple inlets and one sample wells, e.g. mixing, dilution
    • 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
    • B01L2300/0874—Three dimensional network
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • 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
    • 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
    • B01L2400/0409—Moving fluids with specific forces or mechanical means specific forces centrifugal forces
    • 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
    • B01L2400/0457—Moving fluids with specific forces or mechanical means specific forces passive flow or gravitation

Definitions

  • the invention belongs to the field of medical diagnostic equipment, and relates to a microfluidic chip with a liquid storage function and a method for manufacturing, detecting and using it.
  • microfluidic detection technology In the field of biomedical analysis and disease diagnosis, the emergence of microfluidic technology has promoted the development of the portable rapid diagnosis industry. The biggest advantage of the microfluidic detection technology is that it can perform automatic and rapid detection of multiple indicators at the same time and obtain accurate results under the consumption of other samples.
  • the microfluidic chip can contain all the functional units of routine laboratories such as calibration, quantitative injection, reagent storage, detection, and waste collection.
  • Fluid control is the core of microfluidic chip design.
  • the fluid power of the microfluidic chip can come from air pump (such as US8986527B2), syringe (such as US7842234), external force extrusion (such as US5821399A), and centrifugal force (such as US20110124128A1).
  • air pumps For chips powered by air pumps, for more than two fluid control, air pumps require more complex chip microchannel network design and more valve designs to achieve sequential flow control of fluids. This leads to the characteristics of large instrument volume, high chip processing requirements and high cost.
  • the air pump is used as a power to increase the probability of bubbles in the fluid, which can hinder the normal operation of the sensor.
  • a syringe-powered chip requires a sealed connection between the syringe and the chip's sample injection port in operation, which easily introduces human error and leads to the risk of sample or instrument contamination.
  • the centrifugal force-driven chip can achieve high integration detection to the greatest extent, and achieve the advantages of sample purification and equal sampling in the chip.
  • the surface tension of the material can be very large To a certain extent, it affects the flow rate, resulting in relatively high technical barriers, and making industrialization difficult.
  • the present invention uses gravity as the fluid power to design a new type of microfluidic chip.
  • the invention provides a microfluidic chip capable of controlling flow under the action of gravity.
  • the microfluidic chip can complete the automatic transmission and detection of multiple fluids without additional power equipment such as micropumps, syringe pumps, extrusion devices, centrifugal force devices, etc.
  • the microfluidic detection chip includes a substrate and a detection area on the substrate.
  • the substrate is provided with a first liquid storage tank and a second liquid storage tank.
  • the first liquid storage tank and the second liquid storage tank are respectively connected to the liquid in the detection area.
  • the first liquid storage tank and the second liquid storage tank are respectively provided with a first opening and a second opening for the liquid to flow out, the first opening is caused to flow out under the action of gravity before the second opening by rotating the microfluidic chip Liquid, and the liquid rear end of the first liquid storage tank reaches the detection area earlier than the liquid front end of the second liquid storage tank.
  • the first opening reaches the downward position before the second opening, so that the liquid in the first storage tank flows out of the first opening under its own gravity before the liquid in the second storage tank Flow out from the second opening under its own gravity; and make the liquid rear end of the first liquid storage tank reach the detection area earlier than the liquid front end of the second liquid storage tank.
  • the liquid in the first storage tank flows out from the first opening under the action of gravity and reaches the detection area, and then rotate the microfluidic chip to make the second opening reach the downward position.
  • the liquid in the second liquid storage tank flows out from the second opening under the action of gravity and reaches the detection area; and the liquid front end of the second liquid storage tank does not touch the liquid rear end of the first liquid storage tank before leaving the detection area.
  • the microfluidic detection chip also includes a waste liquid tank on the substrate, and the waste liquid tank is in communication with the detection area.
  • the liquid in the second liquid storage tank flows out from the second opening under the action of gravity and reaches the detection area
  • the liquid in the first liquid storage tank in the detection area flows to the waste liquid tank under the action of gravity.
  • the position of the first opening when the first opening flows out of liquid, the position of the first opening is higher than the position of the detection zone; when the second opening flows out of liquid, the position of the second opening is higher than the position of the detection zone.
  • the first liquid storage tank, the second liquid storage tank and the waste liquid tank may or may not penetrate the substrate.
  • the first liquid storage tank, the second liquid storage tank and the waste liquid tank do not penetrate the substrate, the first liquid storage tank, the second liquid storage tank and the waste liquid tank are located on the same surface of the substrate, or on both sides of the substrate.
  • the microfluidic chip also includes a first flow channel connected to the first opening, a second flow channel connected to the second opening, a third flow channel connected to the front end of the detection area, and a fourth flow channel connected to the back end of the detection area. And the fifth flow channel connected to the waste liquid tank; the first flow channel and the second flow channel are connected with the third flow channel; the fourth flow channel is connected with the fifth flow channel.
  • the detection zone is provided with a detection flow channel and a signal acquisition channel, and the two ends of the detection flow channel are respectively connected to the third flow channel and the fourth flow channel.
  • the detection area includes electrode sensors.
  • the microfluidic chip also includes a cover sheet for covering the substrate, and the cover sheet seals the first and second liquid storage tanks and the waste liquid tank on the substrate, as well as the first, second, third, fourth and fifth flow channels.
  • the first liquid storage tank, the second liquid storage tank and the waste liquid tank are sealed.
  • first, second and third vent holes are respectively provided on the cover sheets at the corresponding positions of the first liquid storage tank, the second liquid storage tank and the waste liquid tank.
  • the first, second and third vent holes are all sealed or can be opened. Furthermore, the first, second and third vent holes are provided with seals.
  • the first reservoir, the second reservoir, and the waste reservoir are sealed; the second and third vents are sealed or opened to control the first reservoir and the second reservoir. Liquid flow in the liquid tank.
  • the first storage tank stores reagents such as detection reagents or calibrators
  • the second storage tank stores samples.
  • a microfluidic detection chip which controls the flow speed of the liquid through the difference in hydrophilicity and hydrophobicity of the flow channel and makes the detection more accurate. That is, the difference in surface affinity and hydrophobicity of different areas is used to control the flow rate and diffusion of blood and other liquids in different areas to ensure that the liquid can flow through the detection area in order to achieve detection under the condition of gravity. That is, when the liquid is in the circulating flow channel, use the hydrophobic flow channel to slow down the flow rate to avoid excessively fast flow rate and generate bubbles. When the liquid is in the detected flow channel, use the hydrophilic flow channel to spread the liquid to the entire flow channel surface to ensure Full contact with testing equipment.
  • a microfluidic chip includes a substrate and a detection area on the substrate.
  • the substrate is provided with a first liquid storage tank, a second liquid storage tank and a waste liquid tank.
  • the substrate is also provided with a connection between the first liquid storage tank and the detection area. Zone, the second storage tank and the detection zone, and the flow channels of the detection zone and the waste liquid tank, the hydrophilic and hydrophobic surfaces of different areas of the flow channel are different.
  • the flow channel includes a first flow channel connected to the first liquid storage tank, a second flow channel connected to the second liquid storage tank, a third flow channel connected to the front end of the detection zone, a fourth flow channel connected to the back end of the detection zone, and Connect the fifth flow channel of the waste liquid tank; the first flow channel and the second flow channel are connected with the third flow channel; the fourth flow channel is connected with the fifth flow channel.
  • the detection zone is provided with a detection flow channel; the two ends of the detection flow channel are respectively connected with the third flow channel and the fourth flow channel.
  • first flow channel, the second flow channel and the fifth flow channel are hydrophobic flow channels; the third and fourth flow channels and the detection flow channel are hydrophilic flow channels.
  • the microfluidic chip also includes two cover sheets covering both sides of the substrate.
  • the substrate is made of hydrophobic material or treated, one cover sheet is made of hydrophobic material or treated, and the other cover sheet is made of hydrophilic material or treated.
  • the first flow channel, the second flow channel and the fifth flow channel are located on one side of the substrate, and the third and fourth flow channels and the detection flow channel are located on the other side of the substrate.
  • the surface of the substrate provided with the first flow channel, the second flow channel and the fifth flow channel is covered with a hydrophobic cover sheet; the substrate surface with the third, fourth flow channels and the detection flow channel is covered with a hydrophilic cover sheet.
  • the front and back sides of the substrate are provided with flow channels, and the upper and lower cover sheets with different hydrophilic and hydrophobic properties are watertightly pasted on the front and back sides of the substrate.
  • the hydrophobicity of the substrate flow channel will be due to the hydrophobicity of the cover sheet. And the corresponding changes. In this way, it is easy to manufacture detection chips with different affinity in different regions.
  • the microfluidic chip can also be connected to flow channels through perforations through the substrate, and the perforation connection between the flow channels can prevent liquid from flowing back, thereby ensuring that the liquid flows in one direction in one direction.
  • the first flow channel and the second flow channel are connected to the third flow channel through perforations, and the fourth flow channel and the fifth flow channel are also connected through perforations.
  • the first flow channel and the second flow channel are respectively connected with the third flow channel through two different perforations.
  • different upstream flow channels are respectively connected to the same downstream flow channel through separate perforations.
  • This multiple perforation connection design can prevent subsequent incoming liquid from passing through the detection flow channel (the same The probability of failure in the channel) enhances fluid handling, such as reducing the generation of bubbles.
  • first perforation connects the first flow channel and the third flow channel
  • second perforation connects the second flow channel and the third flow channel.
  • the first perforation and the second perforation have a certain distance. For example, the distance between the first perforation and the second perforation is greater than 2 mm.
  • the first perforation is located downstream of the second perforation, and the aperture of the first perforation located downstream is smaller than the aperture of the second perforation located upstream thereof.
  • the present invention also provides a method for manufacturing a microfluidic chip, which includes the following steps:
  • Step 1 Select a hydrophobic material as the substrate, and form the flow channel, first and second liquid storage tanks, detection flow channel, signal acquisition channel, etc. on the substrate by chemical etching, physical engraving, hot pressing or injection molding. Structures of waste liquid tank and perforation;
  • a first liquid storage tank, a second liquid storage tank, a detection flow channel, and first, second and third perforations are formed on the substrate; a third flow channel and a third flow channel connected to the front end of the detection flow channel are formed on one side of the substrate.
  • Step 2 Obtain the electrode sensor, paste it on the detection flow channel, place the sensor's electrode in the detection flow channel, and simultaneously seal the surface of the detection flow channel with water tightness.
  • the electrode pins of the sensor are located in the signal acquisition channel of the detection area;
  • Step 3 Obtain a cover sheet of hydrophobic material; or treat the side of the cover sheet in contact with the substrate with a hydrophobic material, that is, a hydrophobic coating is provided to make the contact surface of the cover sheet hydrophobic; the hydrophobic side of the cover sheet is watertight Ground paste on the side of the substrate with the first, second and fifth flow channels;
  • Step 4 Inject a calibration solution as a detection reagent into the first storage tank
  • Step 5 Obtain a cover sheet of hydrophilic material; or treat the side of the cover sheet in contact with the substrate with a hydrophilic material, that is, a hydrophilic coating is provided to make the contact surface of the cover sheet hydrophilic;
  • the hydrophilic side is watertightly attached to the side of the substrate with the third and fourth flow channels;
  • Step 6 Set the first, second and third vent holes at the positions of the first and second liquid storage tanks and the waste liquid tank on the cover sheet;
  • Step 7 If there is no step 4, the detection reagent is injected into the first liquid storage tank through the first vent of the upper cover sheet, and then the small hole is sealed with a seal.
  • the present invention also provides a method for detecting a sample with a microfluidic chip, which includes a microfluidic chip for detection.
  • the microfluidic chip includes a substrate and a cover sheet, and a detection zone, a first and a second reservoir on the substrate And the waste liquid tank, the first and second liquid storage tanks are respectively connected with the detection area, and the detection area is connected with the waste liquid tank; the first liquid storage tank and the second liquid storage tank are respectively provided with a first opening and a first opening for the liquid to flow out Two openings; the first storage tank includes detection reagents; the specific steps are as follows:
  • Step 1 Inject the sample into the second storage tank
  • Step 2 Place the microfluidic detection chip vertically or vertically in the instrument
  • Step 3 Connect the first liquid storage tank and the waste liquid tank to the atmosphere;
  • Step 4 Rotate the microfluidic detection chip until the first opening is facing downwards, so that the detection reagent in the first storage tank flows out of the first opening under its own gravity and flows into the detection area;
  • Step 5 Perform reagent detection
  • Step 6 Rotate the microfluidic detection chip until the second opening faces downwards, so that the sample in the second storage tank flows out of the second opening and into the detection area under its own gravity; at the same time, the detection reagent in the detection area is Flow into the waste liquid tank under gravity;
  • Step 7. Perform sample detection and obtain the detection result.
  • the microfluidic chip further includes an electrode sensor, the detection area is provided with a detection flow channel and a signal acquisition channel, the electrode sensor is provided in the detection flow channel and the signal acquisition channel; the cover sheet is located in the first reservoir There is a first vent hole at the position, a second vent hole at the position of the second liquid storage tank, and a third vent hole at the position of the waste liquid tank; the specific steps are as follows:
  • step 1 inject the sample to be tested into the second liquid storage tank through the second vent on the second liquid storage tank;
  • step 2 fix the microfluidic detection chip vertically in the instrument and rely on the components in the instrument to drive the chip to rotate to control the fluid flow direction;
  • step 3 open the first vent hole and the third vent hole
  • Step 4 Rotate the microfluidic detection chip until the first opening is facing downwards, so that the detection reagent in the first storage tank flows out of the first opening under its own gravity and flows into the detection area;
  • Step 5 Perform reagent detection
  • Step 6 Rotate the microfluidic chip until the second opening faces downwards, so that the sample in the second reservoir flows out of the second opening under its own gravity and flows into the detection area; at the same time, the detection reagent in the detection area is under its own gravity. Flow into the waste liquid tank under the action;
  • Step 7. Perform sample detection and obtain the detection result.
  • steps 5 and 7 the detection reagents and samples staying in the detection flow channel react with the sensor, and the probe of the instrument is connected to the sensor in the signal acquisition channel and collects the reaction signal.
  • it further includes a first flow channel connected to the first opening, a second flow channel connected to the second opening, a third flow channel connected to the front end of the detection zone, and a fourth flow channel connected to the back end of the detection zone, Connect the fifth flow channel of the waste liquid tank; the first flow channel and the second flow channel are connected with the third flow channel; the fourth flow channel is connected with the fifth flow channel.
  • step 4 the detection reagent in the first storage tank flows out from the first opening, flows through the first flow channel to the third flow channel, and reaches the detection flow channel.
  • step 6 the sample in the second storage tank flows out from the second opening, flows through the second flow channel to the third flow channel, and reaches the detection flow channel.
  • step 6 the detection reagent after detection is completed from the detection flow channel to the waste liquid tank through the fourth flow channel and the fifth flow channel.
  • the first flow channel, the second flow channel and the fifth flow channel are located on one side of the substrate, and the third and fourth flow channels and the detection flow channel are located on the other side of the substrate; the first flow channel and the third flow channel pass through the first The second flow channel is connected with the third flow channel through the second perforation, and the fourth flow channel is connected with the fifth flow channel through the third perforation. Then in step 4, the detection reagent in the first reservoir flows out from the first opening, flows through the first flow channel through the first perforation to the third flow channel on the other side of the substrate, and reaches the detection flow channel.
  • step 6 the sample in the second storage tank flows out from the second opening, flows through the second flow channel through the second perforation to the third flow channel on the other side of the substrate, and reaches the detection flow channel.
  • the detection reagent flows from the detection flow channel through the fourth flow channel through the third perforation to the fifth flow channel on the other side of the substrate to the waste liquid tank.
  • the microfluidic detection chip of the present invention ingeniously uses the principle of gravity in fluid driving to complete the automatic transmission of multiple fluids in the microfluidic chip. Reduce or even eliminate the need for external power equipment such as micro pumps, syringe pumps, extrusion devices, centrifugal force devices, etc. This simplifies the structure of the detection instrument, saves energy, and avoids air bubbles in the fluid due to the use of an external power source.
  • the difference in surface affinity and hydrophobicity of different areas in the microfluidic chip is used to control the flow rate and diffusion of the liquid sample in different areas. For example, when the flow rate of the blood sample flowing out of the second reservoir in the hydrophobic second flow channel is slower than the flow rate of the blood sample in the hydrophilic detection flow channel, and the hydrophilic treatment of the detection flow channel can assist the fluid Diffusion at multiple detection sites avoids the generation of bubbles.
  • Figure 1 A three-dimensional view of the first microfluidic detection chip.
  • Fig. 2 is a front view of Fig. 1.
  • the solid line indicates that the structure is on the front side of the substrate
  • the dashed line indicates that the structure is on the reverse side of the substrate.
  • Figure 2-1 is another schematic diagram of the angle of Figure 2 after rotating.
  • Figure 3 is an exploded view of Figure 1, showing the front side of the substrate.
  • Figure 4 is an exploded view of Figure 1, showing the reverse side of the substrate.
  • Fig. 5 is a schematic view of the front side of the substrate of Fig. 1.
  • Fig. 6 is a schematic view of the reverse side of the substrate of Fig. 1.
  • Figure 7-1 to Figure 7-4 are schematic diagrams of the fluid flow of the microfluidic detection chip.
  • Figure 8-1 to Figure 8-6 are schematic diagrams of the fluid flow of another microfluidic detection chip.
  • Fig. 9 is a schematic diagram of a microfluidic detection chip with four liquid storage tanks.
  • Figure 10 is a schematic diagram of a substrate with two fluid control systems.
  • Figure 11-A is a schematic diagram of the first and second flow channels being located on the same plane as the third flow channel, and the liquid in the first flow channel is gradually flowing into the third flow channel.
  • Fig. 11-B is a schematic diagram of the liquid in the first flow channel flowing into the third flow channel.
  • Figure 11-C is a schematic diagram of the liquid flowing in the second flow channel.
  • the microfluidic detection chip 1000 shown in FIGS. 1 to 6 includes a substrate 100, an upper cover sheet 200, a lower cover sheet 300 and an electrode sensor 400.
  • the substrate 100 is provided with a first liquid storage tank 11, a second liquid storage tank 12, a detection area 2 and a waste liquid tank 3, and the electrode sensor 400 is provided in the detection area 2.
  • the microfluidic detection chip is made of transparent material. Specifically, only the upper cover sheet and the lower cover sheet may be made of transparent material.
  • the liquid storage tank, the detection area and the waste liquid tank are connected by a flow channel, thereby forming a complete flow path in which the reagents and the sample to be tested sequentially flow out of the liquid storage tank, flow through the detection area and are stored in the waste liquid tank.
  • the upper cover sheet 200 and the lower cover sheet 300 are respectively watertightly adhered to the front and back surfaces of the substrate, so that the liquid storage tank, the waste liquid tank, and the flow channel are sealed in the substrate.
  • the positions and directions of the openings through the first liquid storage tank 11 and the second liquid storage tank 12 through which the liquid flows are different on the chip, and the gravity of the liquid is used to realize the first liquid storage tank 11 and the second liquid storage tank.
  • the liquid in the tank 12 successively flows to the detection area 2 to realize the detection function of the chip. Specifically, first make the opening direction of the first liquid storage tank face down, so that the liquid in the first liquid storage tank flows out of the first liquid storage tank under its own gravity and continues to flow to the detection area under the action of gravity. Then make the opening direction of the second liquid storage tank face downwards, so that the liquid in the second liquid storage tank flows out of the second liquid storage tank under its own gravity and continues to flow to the detection area under the action of gravity.
  • the opening direction of the first opening 51 connecting the first liquid storage tank 11 and the first flow passage 41 and the opening direction of the second opening 52 connecting the second liquid storage tank 12 and the second flow passage 42 In the opposite arrangement, at this time, the first liquid storage tank and the second liquid storage tank are generally in a parallel position; for example, the opening direction of the first opening is to the left, and the opening direction of the second opening is to the right.
  • the opening of the first opening 51 faces downwards
  • the liquid in the first liquid storage tank 11 can flow out from the first opening
  • the opening of the second opening 52 faces upwards.
  • the liquid in the second liquid storage tank 12 cannot flow out from the second opening.
  • the opening of the second opening 52 faces downward, and the liquid in the second liquid storage tank 12 flows out from the second opening.
  • the liquid stored in the first reservoir and the second reservoir of the chip flows out in sequence along with the rotation of the chip, and enters the flow channel through the flow channel to detect the flow channel in contact with the electrode sensor, and the electrode sensor is used to obtain the analysis signal.
  • the material of the substrate 100 is a hydrophobic material, or the surface of the substrate is subjected to a hydrophobic treatment, or the surface of the substrate in contact with a liquid is subjected to a hydrophobic treatment.
  • the surface of the upper cover sheet 200 in contact with the substrate 100 is made of a hydrophilic material or the surface is treated with a hydrophilic material.
  • the surface of the lower cover 300 in contact with the substrate 100 is made of hydrophobic material or the surface has been subjected to hydrophobic treatment.
  • the hydrophobic material can be made of any one or two of the following materials, such as silicon, ceramics, glass and plastic, etc., wherein the plastic is selected from: acrylonitrile-butadiene-styrene copolymer ( ABS), cycloolefin polymer (COP), polyamide (PA), polybutylene terephthalate (PBT), polycarbonate (PC), polydimethylsiloxane (PDMS), polyethylene (PE), polyether ether ketone (PEEK), polyethylene terephthalate (PET), polymethyl methacrylate (PMMA), polyoxymethylene (POM), polypropylene (PP), polystyrene Diethyl ether (PPE), polystyrene (PS), polysulfone (PSU), polytetrafluoroethylene (PTFE), etc.
  • ABS acrylonitrile-butadiene-styrene copolymer
  • COP cycloolefin polymer
  • PA polyamide
  • the hydrophilic material may be a material that is treated with a hydrophilic group on the surface of the hydrophobic material, and finally exhibits hydrophilic properties, such as plasma treatment or a hydrophilic coating. It is also possible to directly select hydrophilic materials, such as adding hydrophilic substances to the raw materials during injection molding.
  • the detection zone 2 is provided with a detection flow channel 21 and a signal acquisition channel 22.
  • the detection flow channel 21 and the signal acquisition channel 22 pass through the front and back of the substrate.
  • the entire electrode sensor is adhered to the detection area on the back of the substrate, thereby sealing the detection area on the back of the substrate.
  • the detection site of the electrode sensor is exposed in the detection flow channel 21, and the electrode pins of the sensor are exposed in the signal acquisition channel 22.
  • the third flow channel 44 and the fourth flow channel 45 are respectively connected to the front and rear ends of the detection flow channel, and are located on the front side of the substrate together.
  • the first flow channel 41, the second flow channel 42, the fifth flow channel 43 and the waste liquid tank 3 are arranged on the reverse side of the substrate.
  • the hydrophobic lower cover sheet When the hydrophobic lower cover sheet is watertightly adhered to the reverse side of the substrate, the first flow channel and the second The second flow channel, the fifth flow channel and the waste liquid tank form a closed pipeline or cavity, and the formed pipeline and cavity surface are hydrophobic surfaces.
  • the upper cover sheet with a hydrophilic surface When the upper cover sheet with a hydrophilic surface is watertightly adhered to the front surface of the substrate, the third flow channel, the fourth flow channel and the detection flow channel form a closed pipeline.
  • the hydrophobicity of the detection flow channel pipeline The hydrophobicity is weaker than that of the pipeline formed by the first flow channel, the second flow channel, and the fifth flow channel with the lower cover sheet pasted.
  • the blood sample flows in the detection flow channel and comes into contact with the hydrophilic surface, effectively adjusting the diffusion performance of the fluid in the area, for example, under the action of hydrophilic
  • the blood sample is more conducive to completely covering the electrode area of the sensor in the flow channel during the fluid flow. Even if there are multiple detection sites with different surface tensions in the channel, the blood can diffuse more fully, avoiding the generation of bubbles, and ensuring detection Accuracy. If the detection flow channel is completely hydrophobic, when the blood sample flows in the flow channel, some areas of the sensor electrode may have different surface tensions and be bypassed by the blood, forming bubbles, which affects the detection. accuracy.
  • the first flow channel, the second flow channel and the fifth flow channel have strong hydrophobicity (relative to the hydrophobicity of the detection flow channel).
  • the fluid is adjusted in the first flow channel, the second flow channel, and the second flow channel.
  • the first flow channel 41 and the second flow channel 42 of the microfluidic detection chip on the reverse side of the substrate 100 are respectively connected to the third flow channel 44 on the front side of the substrate through perforations.
  • the first flow channel and the second flow channel share a perforation to communicate with the third flow channel 44.
  • the liquid that flows through the first reservoir of the perforation first will form a liquid film on the hole wall, which may affect the subsequent liquid (such as the second reservoir
  • the controllability of the liquid) flowing through the perforation for example, the hole produces a hydrophilic effect after the first fluid is infiltrated, and loses the ability to control the flow rate of the fluid, so that bubbles are easily generated.
  • the liquid in the first liquid storage tank that flows through the perforation first forms a liquid film at the perforation to block the perforation, which prevents the liquid in the second liquid storage tank from flowing through the perforation to reach the detection area.
  • the first flow channel and the second flow channel are connected to the detection flow channel but do not share a perforation.
  • one end of the first flow channel 41 provided on the reverse side of the substrate 100 communicates with the first liquid storage tank 11, and the other end communicates with the third flow channel 44 in the detection area on the front side of the substrate through the first through hole 61 on the substrate.
  • One end of the second flow channel 42 provided on the reverse side of the substrate communicates with the second liquid storage tank 12, and the other end communicates with the third flow channel 44 in the detection area on the front side of the substrate through the second perforation 62 on the substrate.
  • the fourth flow passage 45 communicates with the waste liquid tank 3 through the third perforation 63 and the third flow passage 43.
  • the first flow channel and the second flow channel are on the same plane, but are not on the same plane as the third flow channel and the detection flow channel.
  • the first flow channel and the second flow channel are connected to the third flow channel through their respective perforations. .
  • This design has at least the following effects compared to the first, second, and third flow channels being arranged on the same plane (as shown in Figure 11-A to Figure 11-C): it can reduce the subsequent entry of liquid The probability of failure when passing through the inspection flow channel. Even if the liquid in the first liquid storage tank forms a liquid film at the first perforation to block the first perforation, it will not affect the liquid in the second liquid storage tank to flow into the detection flow channel through the second perforation. Enhance fluid handling and reduce bubbles.
  • the first flow channel, the second flow channel and the detection flow channel are arranged on the same plane.
  • FIG. 11-A when the first liquid 501 in the first flow channel is first allowed to flow into the third flow channel 44, a little of the first liquid will enter the second flow channel 42.
  • FIG. 11-B when the first liquid completely flows into the third flow channel 44, the first liquid 501 that has previously entered the second flow channel will stay in the second flow channel.
  • FIG. 11-C when the second liquid 502 enters the second flow channel, there will be a part of the air column 600 between the second liquid and the first liquid retained in the second flow channel.
  • the first perforation and the second perforation have a certain distance, for example, the distance between the two is greater than 2 mm. This ensures that when the liquid in the first storage tank flows through the detection flow channel, the liquid will not flow to the second perforation in the opposite direction.
  • the first flow channel and the second flow channel pass through the first perforation and the second flow channel respectively.
  • the perforation is connected with the third flow channel, and the liquid in the first flow channel first flows into the third flow channel and the detection flow channel through the first perforation.
  • the first perforation is located downstream of the second perforation (liquid flow direction), and the aperture of the first perforation located downstream is smaller than the aperture of the second perforation located upstream, and when the second liquid flows through the first perforation When the first pore size is small, a liquid film is formed at the perforation.
  • this design prevents the second liquid from flowing out of the third flow channel from the first perforation and entering the first flow channel.
  • the second perforation has a large opening, which can speed up the flow of the second liquid into the third flow channel and speed up the detection process.
  • the opening width of the first flow channel and the second flow channel on the substrate is 0.2-0.8 mm
  • the depth is 0.2-0.6 mm
  • the opening width of the waste liquid tank is 0.2-3 mm. More specifically, the thickness of the substrate is 0.4-5mm, the opening width of the first flow channel and the second flow channel on the substrate is 0.4mm, the depth is 0.3mm, the opening width of the waste liquid tank is 1.5mm, and the depth is 0.2-0.6 mm.
  • microfluidic detection chip of the present invention can realize the automatic transmission of multiple fluids without additional power equipment in terms of fluid driving.
  • the flow channel may not penetrate the substrate. In other designs, the runner can penetrate the substrate.
  • the microfluidic detection chip shown in Figures 7-1 to 7-4 includes a substrate, an upper cover sheet, a lower cover sheet and an electrode sensor.
  • the substrate 100 is provided with a first liquid storage tank 11, a second liquid storage tank 12, a detection area 2 and a waste liquid tank 3, and the electrode sensor is provided in the detection area 2.
  • the liquid storage tank, the detection area and the waste liquid tank are connected by a flow channel, and the upper cover sheet and the lower cover sheet are respectively watertightly adhered to the front and back of the substrate, thereby sealing the liquid storage tank, waste liquid tank, and flow channel.
  • the substrate is provided with a first liquid storage tank 11, a second liquid storage tank 12, a detection area 2 and a waste liquid tank 3, and the electrode sensor is provided in the detection area 2.
  • the liquid storage tank, the detection area and the waste liquid tank are connected by a flow channel, and the upper cover sheet and the lower cover sheet are respectively watertightly adhered to the front and back of the substrate, thereby sealing the liquid storage tank, waste liquid tank, and
  • the substrate is made of hydrophobic material
  • the surface where the upper cover sheet is attached to the substrate is made of hydrophilic material
  • the surface where the lower cover sheet is attached to the substrate is made of hydrophobic material.
  • the opening direction of the first opening 51 connecting the first liquid storage tank 11 and the first flow passage 41 and the opening direction of the second opening 52 connecting the second liquid storage tank 12 and the second flow passage 42 are substantially opposite. Specifically, when the first opening direction is downward, the second opening direction is upward or diagonally upward. More specifically, when the first opening direction is downward, the angle of the second opening direction toward the oblique upward direction is vertical upward and between plus or minus 30 degrees.
  • the upper cover sheet is provided with a first vent 110 at the position of the first liquid storage tank, a second vent 120 is provided at the position of the second liquid storage tank, and a second vent 120 is provided at the position of the waste liquid tank.
  • the vent hole is sealed with a seal. After the seal is removed, the detection reagent in the first liquid storage tank is injected into the first liquid storage tank through the first vent hole, and the test sample is injected into the second liquid storage tank through the second vent hole. During the detection operation, the gas in the pipeline is removed from the chip through the third vent.
  • the specific operations are shown in Figure 7-1 to Figure 7-4.
  • the first storage tank 11 is used to store a detection reagent 501, such as a calibration solution
  • the second storage tank 12 is used to store a sample 502 to be tested, such as a blood sample.
  • the chip in operation is vertically fixed in the instrument and the components in the instrument drive the chip to rotate to control the direction of fluid flow, so as to achieve the purpose of sequentially transmitting the detection reagent and the sample to be tested to the detection flow channel. When the chip is in the position shown in Fig.
  • the opening direction of the first opening 51 connecting the first reservoir 11 and the first flow channel 41 is downward so that the detection reagent 501 in the first reservoir under its own gravity and The capillary force provided by the flow channel 41 flows into the first flow channel 41.
  • the opening direction of the second opening 52 connecting the second liquid storage tank 12 and the second flow channel 42 is inclined upward, and the liquid 502 in the second liquid storage tank cannot flow out from the second opening 52.
  • the detection reagent in the first flow channel 41 flows from the reverse side of the substrate to the third flow channel 44 and the detection flow channel 21 on the front side of the substrate through the first perforation 61, staying The detection reagent in the detection flow channel 21 reacts with the sensor, and the probe of the instrument is connected to the pin of the sensor in the signal acquisition channel 22 and collects the reaction signal.
  • the second opening of the second liquid storage tank reaches a position facing downward, and the sample in the second liquid storage tank flows out of the opening into the second flow channel 42.
  • the second flow channel 42 includes a section of elbow, when the chip is in the position of FIG. 7-3, part of the liquid flowing out of the second liquid storage tank will remain in the elbow.
  • the chip continues to rotate to position 7-4, the detection reagent has flowed out of the detection flow path into the waste tank, and the volume of the waste tank is large, the detection reagent 501 can completely enter the waste tank (there is a third vent with the outside),
  • the fluid located in the second liquid storage tank flows out of the liquid storage tank under its own gravity, and flows into the third flow channel 44 and the detection flow channel 21 on the front of the substrate through the second flow channel 42 and the second perforation 62 on the back of the substrate.
  • the sample staying in the detection flow channel reacts with the sensor.
  • the instrument collects the signal of the sample to be tested through the sensor pin.
  • the microfluidic detection chip includes a substrate, an upper cover sheet, a lower cover sheet and an electrode sensor.
  • the substrate 100 is provided with a first liquid storage tank 11, a second liquid storage tank 12, a detection area 2 and a waste liquid tank 3, and the electrode sensor is provided in the detection area 2.
  • the liquid storage tank, the detection area and the waste liquid tank are connected by a flow channel, and the upper cover sheet and the lower cover sheet are respectively watertightly adhered to the front and back of the substrate, thereby sealing the liquid storage tank, waste liquid tank, and flow channel.
  • the substrate is provided with a first liquid storage tank 11, a second liquid storage tank 12, a detection area 2 and a waste liquid tank 3, and the electrode sensor is provided in the detection area 2.
  • the liquid storage tank, the detection area and the waste liquid tank are connected by a flow channel, and the upper cover sheet and the lower cover sheet are respectively watertightly adhered to the front and back of the substrate,
  • the first storage tank 11 is used to store a detection reagent 501, such as a calibration solution, a quality control solution, or an enzyme and other reaction reagents.
  • the second storage tank 12 is used to store a sample 502 to be tested, such as a blood sample.
  • the liquid level in the second liquid storage tank is lower than the opening of the second opening 52, and the direction of the first opening 51 is downward so that the liquid level in the first liquid storage tank Under the action of its own gravity, the liquid flows into the first flow channel 41, and flows through the first perforation 61 from the back of the substrate to the basic front of the third flow channel 44 and finally reaches the detection flow channel 21, and in the reserved time Inside, the detection reagent in the detection flow channel reacts with the sensor.
  • the instrument probe is connected to the pin of the sensor in the signal acquisition channel 22 and collects the response signal.
  • the detection reagent in the detection flow channel 21 enters the fifth flow channel 43 through the fourth flow channel and the third perforation, and then enters the waste liquid tank 3. At this time, the liquid in the second liquid storage tank continues to remain in the second liquid storage tank.
  • the detection chip further rotates to the position shown in Figure 8-5, the second opening of the second liquid storage tank faces downwards and is in the liquid outflow position. The liquid in the second liquid storage tank flows into the second flow channel under its own gravity. 42, and flow into the third flow channel 44 and the detection flow channel 21 on the front of the substrate through the second through hole 62.
  • the chip continues to rotate to the position shown in Figure 8-6, so that the liquid in the second storage tank completely enters the detection flow channel 21, and the sample staying in the detection flow channel 21 reacts with the sensor. At this time, the instrument collects through the sensor pins The signal of the sample to be tested.
  • the microfluidic detection chip shown in FIG. 9 is provided with a first reservoir 11, a second reservoir 12, a third reservoir 13, and a fourth reservoir 14 on the substrate, and is correspondingly connected to The first flow channel to the fourth flow channel (410-440), the first detection flow channel 21 and the second detection flow channel 23, the fifth flow channel 450 and the sixth flow channel 460 located at the front and rear ends of the first detection flow channel, The seventh flow channel 470 and the eighth flow channel 480, the first waste liquid tank 31 and the second waste liquid tank 32 are located at the front and rear ends of the second detection flow path.
  • the first waste liquid tank 31 communicates with the sixth flow path 460 and the first detection flow path 21 through the ninth flow path 490 and the perforation 65
  • the second waste liquid tank 32 communicates with the eighth flow path through the tenth flow path 491 and the perforation 66.
  • 480 communicates with the second detection flow channel 23.
  • the first liquid storage tank, the first flow channel, the first perforation, the fifth flow channel, the first detection flow channel, the sixth flow channel, the perforation 65, the ninth flow channel and the first waste liquid tank form a flow channel.
  • the second liquid storage tank, the second flow channel, the second perforation, the fifth flow channel, the first detection flow channel, the sixth flow channel, the perforation 65, the ninth flow channel and the first waste liquid tank form a flow channel.
  • the third liquid storage tank, the third flow channel, the third perforation, the seventh flow channel, the second detection flow channel, the eighth flow channel, the perforation 66, the tenth flow channel 491 and the second waste liquid tank form a flow channel.
  • the fourth liquid storage tank, the fourth flow channel, the fourth perforation, the seventh flow channel, the second detection flow channel, the eighth flow channel, the perforation 66, the tenth flow channel 491 and the second waste liquid tank form a flow channel.
  • the microfluidic test chip shown in Figure 10 has two fluid control systems on one substrate.
  • the first fluid control system includes a first liquid storage tank 11, a second liquid storage tank 12, a first flow channel 41, a second flow channel 42, a detection flow channel 21 and a first waste liquid tank 31 provided in the reaction zone 2 .
  • the second fluid control system includes a third liquid storage tank 13, a fourth liquid storage tank 14, a third flow channel 43, a fourth flow channel 44, a detection flow channel 23 provided in the reaction zone 2, and a first waste liquid tank 32.
  • the first liquid storage tank, the second liquid storage tank, the first flow channel, the second flow channel detection flow channel, the third flow channel and the waste liquid tank are all opened on the front surface of the substrate. Both the first flow channel and the second flow channel are the same as the detection flow channel.
  • Step 1 Select hydrophobic material as the substrate, and form the flow channel, liquid storage tank, detection flow channel, signal acquisition channel, waste liquid tank, perforation and other structures on the substrate by chemical etching, physical engraving, hot pressing or injection molding. .
  • Step 2 Obtain an electrode sensor, and paste it on the detection flow channel on the lower surface of the substrate, so that the electrode of the sensor is located in the detection flow channel, and at the same time, seal the lower surface of the detection flow channel watertightly. At the same time, the electrode pins of the sensor are located in the signal acquisition channel of the detection area.
  • Step 3 Obtain a hydrophobic lower cover sheet (or treat the contact surface between the lower cover sheet and the back surface of the substrate with hydrophobic material to be hydrophobic), and the lower cover sheet is water-tightly pasted on the back surface of the substrate.
  • Step 4 obtaining a hydrophilic upper cover sheet (or treating the contact surface of the upper cover sheet with the front surface of the substrate with a hydrophilic material to be hydrophilic). Attach the cover sheet to the front surface of the substrate watertightly.
  • the detection reagent is injected into the first reservoir through the first vent hole of the upper cover sheet, and then the small hole is sealed with a seal.
  • the above step 4 is to inject a calibration solution as a detection reagent into the first reservoir, and then the hydrophilic upper cover sheet or the front surface of the substrate The upper cover sheet with the hydrophilic treatment on the contact surface is water-tightly attached to the front surface of the substrate, thereby sealing the detection reagent in the first storage tank.
  • a small hole is broken in the upper cover sheet above the first storage tank to allow air to enter the first storage tank. But the liquid will not flow out of the first storage tank through the small hole, and the flow channel detects the outside of the chip.
  • the method for sample detection using the microfluidic chip of the present invention has the following steps:
  • Step 1 Obtain the microfluidic detection chip described in the present invention.
  • Step 2 Inject the blood sample to be tested into the second liquid storage tank through the second vent hole of the upper cover sheet on the second liquid storage tank.
  • Step 3 Fix the detection chip vertically in the instrument and rely on the components in the instrument to drive the chip to rotate to control the fluid flow direction.
  • the chip When the chip is in the position shown in Figure 7-1, open the first vent on the first storage tank of the upper cover sheet, and open the third vent at the same time.
  • the calibration liquid in the first liquid storage tank 11 flows into the first flow channel 41.
  • the opening direction of the second opening 52 connecting the second liquid storage tank 12 and the second flow channel 42 is inclined upward, and the liquid 502 in the second liquid storage tank cannot flow out from the second interface.
  • Step 4 The chip rotates from Figure 7-1 to the position shown in Figure 7-2.
  • the detection reagent in the first flow channel 41 flows from the reverse side of the substrate to the detection flow channel on the front side of the substrate through the first perforation 61, staying in the detection flow channel for detection.
  • the reagent reacts with the sensor, and the contact pin of the instrument is connected with the pin of the sensor in the contact pin contact port 22 and collects the response signal.
  • Step 5 The chip rotates from FIG. 7-2 to the position shown in FIG. 7-3, and the detection reagent in the detection flow channel 21 flows into the third flow channel 43 on the reverse side of the substrate through the third hole 63 until it flows into the waste liquid tank 13.
  • Step 6 the chip continues to rotate to the 7-4 position, the detection reagent has flowed out of the detection flow channel into the waste liquid tank, and the blood sample to be tested in the second liquid storage tank flows out of the liquid storage tank and passes through the second flow channel 42 on the substrate.
  • the second perforation 62 flows into the detection flow channel 21 on the front of the substrate, and the sample staying in the detection flow channel reacts with the sensor.
  • the instrument collects the signal of the sample to be tested through the sensor pins. In order to obtain the test results.
  • the detection method in the detection zone of the present invention may be a biosensor with electrodes, or may be an optical detection method such as turbidimetry, fluorescence, chemiluminescence, scattering, etc., or other detection methods.
  • the microfluidic detection chip of the present invention can perform quantitative, semi-quantitative or qualitative detection. For example, fix one or more test papers (which can be blank test papers, or test papers with pre-added reagents) in the detection area, and after the test reagents or samples flow through the test flow channel and contact the test papers, the reagents react with the sample The color changes, and then the test results can be obtained through instrumental or human observation.
  • test papers which can be blank test papers, or test papers with pre-added reagents

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Abstract

一种微流控芯片（1000）及其制作方法，包括基板（100）和位于基板（100）上的检测区（2），基板（100）上设有第一储液槽（11）和第二储液槽（12），第一储液槽（11）、第二储液槽（12）分别与检测区（2）液体连通，第一储液槽（11）设有供液体流出的第一开口（51），第二储液槽（12）设有供液体流出的第二开口（52）；当微流控芯片（1000）用于样本检测时，随着微流控芯片（1000）转动，从第一储液槽（11）流出的液体后端比从第二储液槽（12）流出的液体前端更早到达检测区（2）。

Description

微流控芯片及制作方法 技术领域
本发明属于医用诊断设备领域，涉及具有储液功能的微流控芯片及制造、检测和使用方法。
背景技术
在生物医学分析及疾病诊断领域，微流控技术的出现推动了便携式快速诊断产业的发展。微流控检测技术最大的优势是在微升级别的样品消耗下可以同时进行多个指标的全自动快速检测并得出准确的结果。微流控芯片上可以包含定标、定量进样、试剂储存、检测、废液收集等常规实验室所有的功能单元。
流体控制是微流控芯片设计的核心。根据流体动力来划分，微流控芯片的流体动力可以来自气泵(如US8986527B2)、注射器(如US7842234)、外力挤压(如US5821399A)，离心力(如US20110124128A1)。
以气泵为动力的芯片，对于两个以上的流体控制，气泵要求更为复杂的芯片微通道网络设计和更多的阀门设计来实现流体的依次流动控制。这就导致仪器体积往往比较大，芯片加工要求高、成本高的特点。气泵作为动力还会增加流体内气泡产生的概率，产生的气泡可以阻碍传感器正常工作。
以注射器为动力的芯片，其在操作上要求注射器与芯片加样口密封对接，这容易引入人为误差，导致样品或仪器污染的风险。
以外力挤压方式为动力的芯片，因为挤压形变产生的力本身比较小，因此要求芯片尺寸相对较小，这样“微型”的变化，会直接导致芯片加工及组装的难度，造成经济损失。
以离心力为驱动力的芯片，原理上离心力驱动芯片可最大程度实现高集成检测，实现芯片内样本提纯、等量分样的优势，但由于其结构相对更复杂和精细，材料表面张力可以很大程度上影响流速，造成技术壁垒比较高，导致产业化难度。
随着体外诊断市场需求的激增，微流控技术在体外诊断应用中的优势逐渐突显出来，受到工业界越来越多的关注。微流控芯片应用中，多种流体的次序性流动及测试片内置液体的保存和流动控制是目前急需解决和提高技术问题。
发明内容
为解决所述技术问题，本发明以重力作用为流体动力，设计出新型的微流控芯片。
本发明提供了一种重力作用下可控制流动的微流控芯片。该微流控芯片可以无需外加动力设备如微泵，注射泵，挤压装置，离心力装置等，完成多个流体的自动传送和检测。
所述微流控检测芯片，包括基板和位于基板上的检测区，基板上设有第一储液槽和第二储液槽，第一储液槽、第二储液槽分别与检测区液体连通，第一储液槽和第二储液槽分别设有供液体流出的第一开口和第二开口，所述通过转动微流控芯片使第一开口先于第二开口在重力作用下流出液体，并且，第一储液槽的液体后端早于第二储液槽的液体前端到达检测区。
通过转动微流控芯片使第一开口先于第二开口到达向下位置，从而使第一储液槽的液体在自身重力作用下从第一开口流出先于第二储液槽中的液体在自身重力作用下从第二开口流出；并且使第一储液槽的液体后端早于第二储液槽的液体前端到达检测区。
转动微流控芯片使第一开口到达向下位置，第一储液槽的液体在重力作用下从第一开口流出并到达检测区，再转动微流控芯片使第二开口到达向下位置，第二储液槽的液体在重力作用下从第二开口流出并到达检测区；并且，第二储液槽的液体前端在离开检测区之前未触碰到第一储液槽的液体后端。
微流控检测芯片还包括位于基板上的废液槽，废液槽与检测区连通。第二储液槽的液体在重力作用下从第二开口流出并到达检测区时，位于检测区的第一储液槽液体在重力作用下流向废液槽。
在一种设计中，第一开口流出液体时，第一开口位置高于检测区位置；第二开口流出液体时，第二开口位置高于检测区位置。
使用微流控芯片检测时，将微流控芯片垂直放置，或者垂直置于仪器内，转动微流控芯片使第一开口在转动过程中逐渐到达向下位置，且第二开口在此转动过程中不会出现向下的情况，液体在自身重力作用下从第一开口流出并流至检测区。再转动微流控芯片使第二开口在转动过程中逐渐到达向下位置，液体在自身重力作用下从第二开口流出并流至检测区；并且，在检测区的第一储液槽液体在自身重力作用下流向废液槽。在两次转动过程中，第一开口流出的液体末端先于第二开口流出的液体前端到达检测区。
第一储液槽和第二储液槽以及废液槽可以贯穿基板，也可以不贯穿基板。当第一储液槽和第二储液槽以及废液槽不贯穿基板时，第一储液槽和第二储液槽以及废液槽位于基板的同一面，或分别位于基板的两面。
微流控芯片还包括设于基板上的连接第一开口的第一流道、连接第二开口的第二流道、连接在检测区前端的第三流道、连接在检测区后端的第四流道和连接废液槽的第五流道；第一流道、第二流道与第三流道连接；第四流道与第五流道连接。
所述检测区设有检测流道和信号采集通道，检测流道两端分别连接第三流道和第四流道。检测区内包括电极传感器。
微流控芯片还包括用于覆盖基板的盖片，盖片封闭位于基板上的第一、第二储液槽和废液槽，以及第一、二、三、四和五流道。
微流控芯片在使用前，第一储液槽、第二储液槽和废液槽被密封。
在一个优选方案中，第一储液槽、第二储液槽和废液槽对应处的盖片上分别设有第一、第二和第三通气孔。第一、第二和第三通气孔均被密封或可被打开。更进一步的，第一、第二和第三通气孔上设有密封件。
微流控芯片在使用前，第一储液槽、第二储液槽和废液槽被密封；通过第二和第三通气孔被密封或被打开来控制第一储液槽和第二储液槽的液体流动。
第一储液槽存储检测试剂或校准品等试剂，第二储液槽内存储样品。
本发明中，提供一种微流控检测芯片，通过流道的亲疏水性差异来控制液体的流动速度并使检测更准确。即通过不同区域表面亲疏水性的差异，以此来控制血液等液体在不同区域的流速及扩散状况，以保证在自重力情况下液体能依次流道检测区域实现检测。即，当液体在流通 的流道中时，使用疏水流道使其流速减缓，避免流速过快产生气泡，当液体在检测的流道中时，使用亲水流道使液体扩散至整个流道表面，保证与检测仪器的充分接触。
一种微流控芯片，包括基板和位于基板上的检测区，基板上设有第一储液槽、第二储液槽和废液槽，基板上还设有连接第一储液槽与检测区、第二储液槽与检测区，以及检测区和废液槽的流道，所述流道不同区域表面的亲疏水性存在差异。
所述流道包括连接第一储液槽的第一流道，连接第二储液槽的第二流道，连接在检测区前端的第三流道，连接在检测区后端的第四流道以及连接废液槽的第五流道；第一流道、第二流道与第三流道连接；第四流道与第五流道连接。
所述检测区设有检测流道；检测流道两端分别与第三流道和第四流道连接。
进一步的，第一流道、第二流道和第五流道为疏水性流道；第三、四流道和检测流道为亲水性流道。
微流控芯片还包括盖合基板两面的两个盖片。基板为疏水材质或做疏水处理，一个盖片为疏水材质或做疏水处理，一个盖片为亲水材质或做亲水处理。第一流道、第二流道和第五流道位于基板一面，第三、四流道和检测流道位于基板另一面。设有第一流道、第二流道和第五流道的基板面覆盖有疏水盖片；设有第三、四流道和检测流道的基板面覆盖有亲水盖片。
在一个实施例中，基板的正反面分别开设流道，并且利用不同亲疏水性的上下盖片水密性地粘贴在基板的正反面上后，基板流道的亲疏水性就会因为盖片的亲疏性而相应的变化。利用这样的方式很容易制造出在不同区域具有不同亲疏性的检测芯片。
所述微流控芯片还可通过贯通基板的穿孔连接流道，流道之间通过穿孔连接可以防止液体回流，从而保证液体朝一个方向单向流动。第一流道与第二流道通过穿孔与第三流道连接，第四流道与第五流道也通过穿孔连接。第一流道与第二流道分别与第三流道通过两个不同的穿孔连接。
本发明所述微流控芯片，其上游不同的流道分别通过单独的穿孔连接到下游的同一个流道上，这种多个穿孔连接的设计，可以避免后续进入的液体通过检测流道(同一通道)时的失败概率，强化了流体操控性，例如可减少气泡的产生等。
进一步的，第一穿孔连接第一流道和第三流道，第二穿孔连接第二流道和第三流道。第一穿孔和第二穿孔具有一定的距离。例如第一穿孔和第二穿孔的距离大于2毫米。
一些实施方式中，沿液体流动方向，第一穿孔位于第二穿孔的下游，且位于下游的第一穿孔的孔径小于位于其上游的第二穿孔的孔径。
另一方面，本发明还提供一种制作微流控芯片的方法，包括以下步骤：
步骤1，选取疏水性材料作为基板，并且通过化学刻刻蚀、物理雕刻、热压或注塑成型在基板上形成的流道、第一、第二储液槽、检测流道、信号采集通道、废液槽、穿孔等结构；
具体的，在基板上形成第一储液槽，第二储液槽，检测流道，以及第一、第二和第三穿孔；在基板一面形成连接在检测流道前端的第三流道和连接在检测流道后端的第四流道；在基板另一面形成第一、第二和第五流道以及废液槽，其中，第一流道连接第一储液槽和第一穿孔，第一穿孔连接第一流道和第三流道，第二流道连接第二储液槽和第二穿孔，第二穿孔同时与第三流道连接，第四流道与第五流道通过第三穿孔连接，第五流道末端连接废液槽；
步骤2，获得电极传感器，将其粘贴在的检测流道处，让传感器的电极位于检测流道内， 并同时水密性的封住检测流道的表面。同时传感器的电极接脚位于检测区的信号采集通道内；
步骤3，获得疏水性材质的盖片；或用疏水材料处理盖片与基板接触的那一面，即设有疏水涂层，使盖片的接触面为疏水性；将盖片疏水性一面水密性地粘贴在基板设有第一、第二和第五流道的一面；
步骤4，向第一储液槽中注入作为检测试剂的定标液；
步骤5，获得亲水性材质的盖片；或用亲水性材料处理盖片与基板接触的那一面，即设有亲水涂层，使盖片的接触面为亲水性；将盖片亲水性的一面水密性地贴在基板设有第三、第四流道的一面；
步骤6，在盖片上第一、第二储液槽和废液槽位置处设置第一、第二和第三通气孔；
步骤7，若无步骤4时，将检测试剂通过上盖片的第一通气孔注入第一储液槽内，随后用密封件密封住小孔。
通过步骤1-7的方法最终获得可用于检测的微流体检测芯片。
本发明还提供一种微流控芯片检测样品的方法，包括用于检测的微流体芯片，该微流体芯片包括基板和盖片，以及位于基板上的检测区、第一、第二储液槽和废液槽，第一、第二储液槽分别与检测区连通，检测区与废液槽连通；第一储液槽和第二储液槽分别设有供液体流出的第一开口和第二开口；第一储液槽中包括检测试剂；具体步骤如下：
步骤1，将样品注入第二储液槽中；
步骤2，将微流体检测芯片垂直放置或垂直置于仪器内；
步骤3，使第一储液槽及废液槽与大气连通；
步骤4，旋转微流体检测芯片至第一开口朝下，使第一储液槽中的检测试剂在自身重力作用下从第一开口流出并流入到检测区；
步骤5，进行试剂检测；
步骤6，旋转微流体检测芯片至第二开口朝下，使第二储液槽中的样品在自身重力作用下从第二开口流出并流入到检测区；同时，位于检测区的检测试剂在自身重力作用下流入废液槽；
步骤7，进行样品检测，获取检测结果。
更为具体的实施方式中，微流体芯片还包括电极传感器，检测区设有检测流道和信号采集通道，电极传感器设于检测流道和信号采集通道内；盖片在第一储液槽的位置上设有第一通气孔，在第二储液槽的位置设有第二通气孔，在废液槽的位置设有第三通气孔；具体步骤如下：
步骤1中，通过第二储液槽上的第二通气孔将待检测的样品注入第二储液槽中；
步骤2中，将微流体检测芯片竖直固定在仪器中并依靠仪器中的部件带动芯片旋转来控制流体流动方向；
步骤3中，打开第一通气孔和第三通气孔；
步骤4，旋转微流体检测芯片至第一开口朝下，使第一储液槽中的检测试剂在自身重力作用下从第一开口流出并流入到检测区；
步骤5，进行试剂检测；
步骤6，旋转微流体芯片至第二开口朝下，使第二储液槽中的样品在自身重力作用下从第二开口流出并流入到检测区；同时，位于检测区的检测试剂在自身重力作用下流入到废液槽；
步骤7，进行样品检测，获取检测结果。
在步骤5和步骤7中，停留在检测流道内的检测试剂和样品与传感器发生反应，仪器的探针在信号采集通道内与传感器连接并采集反应信号。
一些优选的实施方式中，还包括连接第一开口的第一流道，连接第二开口的第二流道，连接在检测区前端的第三流道，连接在检测区后端的第四流道，连接废液槽的第五流道；第一流道、第二流道与第三流道连接；第四流道与第五流道连接。
则在步骤4中，第一储液槽中检测试剂从第一开口流出，经第一流道流至第三流道，到达检测流道。步骤6中，第二储液槽中样品从第二开口流出，经第二流道流至第三流道，到达检测流道。
步骤6中，检测完成后的检测试剂从检测流道经第四流道和第五流道到达废液槽。
一些优选的实施方式中，第一流道、第二流道和第五流道位于基板一面，第三、四流道和检测流道位于基板另一面；第一流道与第三流道通过第一穿孔连接，第二流道通过第二穿孔与第三流道连接，第四流道与第五流道通过第三穿孔连接。则步骤4中，第一储液槽中检测试剂从第一开口流出，经第一流道通过第一穿孔流至基板另一面的第三流道，到达检测流道。步骤6中，第二储液槽中样品从第二开口流出，经第二流道流通过第二穿孔流至基板另一面的第三流道，到达检测流道。检测完成后的检测试剂从检测流道经第四流道通过第三穿孔流至基板另一面的第五流道到达废液槽。
有益效果
(1)利用本发明所述微流控检测芯片在流体驱动方面巧妙的利用了重力学原理完成多个流体的在微流控芯片内的自动传送。减少甚至无需外加动力设备如微泵、注射泵、挤压装置、离心力装置等。这即简化了检测仪器的结构、节约能源，又避免因外部动力源的使用在流体中内产生气泡。
(2)通过微流控芯片内不同区域表面亲疏水性的差异，以此来控制液体样本在不同区域的流速及扩散状况。例如当从第二储液槽中流出的血液样品在疏水性的第二流道中的流速要慢于血液样品在亲水的检测流道中的流速，并且检测流道的亲水处理，可以协助流体在多个检测位点上的扩散，避免了气泡的产生。
(3)在微流控芯片基板的正反面分别开设流道，并且利用不同亲疏水性的上下盖片水密性地粘贴在基板的正反面上后，基板流道的亲疏水性就会因为盖片的亲疏性而相应的变化。利用这样的方式很容易制造出在不同区域具有不同亲疏性的检测芯片。
(4)同一通道内，多个穿孔连接的设计，可以避免后续进入的液体通过检测流道(同一通道)时的失败概率，强化了流体操控性，例如可减少气泡的产生等。
附图说明
图1第一款微流体检测芯片的立体图。
图2为图1的正面视图，图中实线表示该结构在基板的正面，虚线表示该结构在基板的反面。
图2-1为图2旋转后的另一个角度示意图。
图3为图1的分解图，显示的是基板的正面这一侧。
图4为图1的分解图，显示的是基板的反面这一侧。
图5是图1基板的正面一侧示意图。
图6是图1基板反面一侧示意图。
图7-1至图7-4微流体检测芯片流体流动的过程示意图。
图8-1至图8-6是另一款微流体检测芯片流体流动的过程示意图。
图9是具有四个储液槽的微流体检测芯片示意图。
图10是一个基板设有两个流体控制系统的示意图。
图11-A是第一流道和第二流道与第三流道位于同一平面上，且第一流道中的液体正在逐步流入第三流道的示意图。
图11-B是第一流道中的液体流入第三流道的示意图。
图11-C是第二流道中的液体正在流动的示意图。
具体实施方式
在以下的详细描述中，图例附带的参考文字是这里的一个部分，它以举例说明本发明可能实行的特定具体方案的方式来说明。我们并不排除本发明还可以实行其它的具体方案和在不违背本发明的使用范围的情况下改变本发明的结构。
如图1至6所示的微流控检测芯片1000，包括基板100、上盖片200、下盖片300和电极传感器400。基板100上设有第一储液槽11、第二储液槽12、检测区2和废液槽3，电极传感器400设于检测区2内。一些实施例中，微流控检测芯片为透明材料，具体的，也可以仅仅上盖片和下盖片为透明材质。
储液槽、检测区和废液槽之间通过流道连通，从而构成试剂、待测样品依次从储液槽流出，流经检测区并保存于废液槽的完整流路。上盖片200和下盖片300分别水密性地粘附在基板的正反面，从而使储液槽、废液槽、流道密闭于基板内。
本发明中，通过第一储液槽11和第二储液槽12液体流出的开口在芯片上的位置和方向不同，以及通过液体自身重力，来实现第一储液槽11和第二储液槽12的液体依次先后流动到检测区2，实现该芯片的检测功能。具体的，先使第一储液槽的开口方向朝下，从而使第一储液槽的液体在自身重力下从第一储液槽中流出，并在重力作用下继续流动到检测区。再使第二储液槽的开口方向朝下，从而使第二储液槽的液体在自身重力下从第二储液槽中流出，并在重力作用下继续流动到检测区。
如图1和2所示，第一储液槽11与第一流道41连接的第一开口51的开口方向和第二储液槽12与第二流道42连接的第二开口52的开口方向为相反设置，此时，第一储液槽与第二储液槽大体处于平行位置；例如第一开口的开口方向向左，第二开口的开口方向向右。如图2所示，当芯片处于竖立放置的位置时，第一开口51的开口朝下，第一储液槽11中的液体能从第一开口流出，第二开口52的开口朝上，第二储液槽12中液体无法从第二开口流出。当芯片旋转至图2-1所示位置时，第二开口52的开口朝下，第二储液槽12中液体从第二开口流出。存放在芯片第一储液槽和第二储液槽中的液体随着芯片的旋转按序依次流出，经流道依次进入 检测流道与电极传感器接触，利用电极传感器获得分析信号。
如图1-6所示，基板100的材料为疏水性材料，或者基板表面做了疏水处理，或者与液体接触的基板表面做了疏水处理。上盖片200与基板100接触的这面为亲水性材料或表面经亲水材料处理。下盖片300与基板100接触的这面为疏水性材料或表面经疏水处理。疏水性材料均可由下述任意一种或两种混合型的材料制成，如硅、陶瓷、玻璃和塑料等，其中所述塑料选自：丙烯腈-丁二烯-苯乙烯共聚合物(ABS)、环烯烃聚合物(COP)、聚酰胺(PA)、聚对苯二甲酸丁二醇酯(PBT)、聚碳酸酯(PC)、聚二甲基硅氧烷(PDMS)、聚乙烯(PE)、聚醚醚酮(PEEK)、聚对苯二甲酸乙二醇酯(PET)、聚甲基丙烯酸甲酯(PMMA)、聚甲醛(POM)、聚丙烯(PP)、聚苯乙烯二乙醚(PPE)、聚苯乙烯(PS)、聚砜(PSU)、聚四氟乙烯(PTFE)等。所述亲水性材料可以是将疏水性材料的表面处理成具有亲水基团，最终表现出亲水性能的材料，例如等离子体处理或者亲水涂层。也可以是直接选用具有亲水性的材料，例如在注塑时在原料中加入亲水物质。
检测区2设有检测流道21和信号采集通道22，检测流道21和信号采集通道22穿过基板正反面，整片电极传感器粘附在基板反面检测区，从而密闭住基板反面检测区，并将电极传感器的检测位点暴露在检测流道21内，传感器的电极接脚暴露在信号采集通道22内。第三流道44和第四流道45分别连接在检测流道的前端和后端，一起位于基板的正面。第一流道41、第二流道42、第五流道43和废液槽3设于基板的反面，当疏水性的下盖片水密性地粘附在基板的反面后，第一流道、第二流道、第五流道和废液槽形成了封闭的管路或腔体，所形成的管路和腔体表面为疏水性表面。当具有亲水表面的上盖片水密性地粘附在基板的正面后，第三流道、第四流道和检测流道形成了封闭的管路，此时检测流道管路的疏水性比粘贴了下盖片的第一流道、第二流道、第五流道所形成管路的疏水性弱。通过不同区域表面亲疏水性的差异，以此来控制血液等液体在不同区域的流速以及调节流体的扩散性能。
当具有亲水表面的上盖片水密性地粘附在基板的正面后，血液样品在检测流道中流动并与亲水表面接触，有效调节了该区域流体的扩散性能，例如在亲水作用下，血液样品更有利于在流体流动过程中完全覆盖流道中传感器的电极区域，即使通道内有多个表面张力不同的检测位点，血液也可以扩散更充分，避免了气泡的产生，保证了检测的准确性。如果检测流道完全都是疏水性的，则血液样品在该流道中流动时，有可能会出现传感器的电极的某些区域表面张力不同而被血液绕过的现象，形成气泡，影响了检测的准确性。
第一流道、第二流道和第五流道具有较强的疏水性(相对检测流道的疏水性而言)，通过疏水性的处理，调节流体在第一流道，第二流道，第三流道这些区域的扩散性能，比如在这些区域，流体的扩散速度变得缓慢，防止流动过程中气泡的产生。
微流控检测芯片位于基板100反面的第一流道41和第二流道42分别通过穿孔与位于基板正面的第三流道44相连接。
在一个方案中，第一流道和第二流道共用一个穿孔与第三流道44相通。不过由于流道的孔径较小，若穿孔只有一个时，首先流过穿孔的第一储液槽的液体会在孔壁上形成液膜，可能会影响后续液体(如第二储液槽中的液体)流过穿孔时的可控性，如孔在第一流体浸润后产生亲水效果，失去流体流速控制的能力，从而极易产生气泡。也可能首先流过穿孔的第一储液槽中的液体在穿孔处形成液膜堵塞了穿孔，则阻碍了第二储液槽中的液体流过穿孔到达检测区。
如图1至图6所示的方案中，第一流道和第二流道与检测流道相连通但不共用一个穿孔。具体的，设于基板100反面的第一流道41的一端与第一储液槽11连通，另一端通过基板上的第一穿孔61与基板正面检测区域的第三流道44连通。设于基板反面的第二流道42的一端与第二储液槽12连通，另一端通过基板上的第二穿孔62与基板正面检测区域的第三流道44连通。第四流道45通过第三穿孔63和第三流道43与废液槽3连通。
第一流道和第二流道位于同一平面，与第三流道和检测流道不在同一平面上，并分别通过各自的穿孔将第一流道和第二流道分别与第三流道连接在一起。这样的设计相比于第一流道、第二流道与第三流道设置在同一个平面上(如图11-A至图11-C所示)至少具有以下效果：可以降低后续进入的液体通过检测流道时的失败概率。即使第一储液槽中的液体在第一穿孔处形成了液膜堵住了第一穿孔，也不会影响第二储液槽中的液体通过第二穿孔流入检测流道中。增强流体操控性，减少气泡的产生。
如图11-A和图11-B所示是第一流道、第二流道与检测流道设置在同一个平面上。如图11-A所示，首先让第一流道的第一液体501流入第三流道44时，会引起少许第一液体进入第二流道42中。如图11-B所示，当第一液体完全流入第三流道44后，之前进入第二流道的第一液体501会滞留在第二流道内。如图11-C所示，当第二液体502进入第二流道时，第二液体和滞留在第二流道内的第一液体之间会有一部分的空气柱600。由于芯片中液体的流动并不依赖外加的动力源的，所以这段空气柱的存在就会阻碍第二液体继续流动进入第三流道44，最终导致第二流体无法经第三流道44到达检测流道完成检测。
在优选的设计中，第一穿孔和第二穿孔具有一定的距离，例如两者的距离大于2毫米。这保证第一储液槽的液体流过检测流道时，液体不会反方向流到第二穿孔处。
在一个设计中，基于第一流道、第二流道位于同一平面，并与第三流道和检测流道不在同一个平面上，第一流道、第二流道分别通过第一穿孔和第二穿孔与第三流道连接，且第一流道中的液体首先通过第一穿孔流入第三流道和检测流道。在优化设计中，第一穿孔位于第二穿孔的下游(液体流动方向)，且位于下游的第一穿孔的孔径小于位于其上游的第二穿孔的孔径，且当第二液体流经第一穿孔时，由于第一孔径小而在穿孔处形成液膜。该设计一方面避免第二液体从第一穿孔流出第三流道而进入第一流道。另一方面第二穿孔开口大，可以加速第二液体流入第三流道的速度，加快检测进程。
一些实施例中，第一流道和第二流道在基板上的开口宽度为0.2-0.8mm，深度为0.2-0.6mm，废液槽的开口宽度为0.2-3mm。更具体的，基板的厚度为0.4-5mm，第一流道和第二流道在基板上的开口宽度为0.4mm，深度为0.3mm，废液槽的开口宽度为1.5mm，深度为0.2-0.6mm。
利用本发明所述微流控检测芯片在流体驱动方面可实现无需外加动力设备，完成多个流体的自动传送。
在一些设计中，流道可以为不贯穿基材。在另一些设计方案中，流道可以贯穿基材。
如图7-1至图7-4所示的微流控检测芯片包括基板、上盖片、下盖片和电极传感器。基板100上设有第一储液槽11、第二储液槽12、检测区2和废液槽3，电极传感器设于检测区2内。储液槽、检测区和废液槽之间通过流道连通，上盖片和下盖片分别水密性地粘附在基板的正反面，从而使储液槽、废液槽、流道等密闭于基板内。基板为疏水性材料，上盖片与基板贴合的一面为亲水性材料，下盖片与基板贴合的一面为疏水性材料。第一储液槽11与第一流道41连 接的第一开口51的开口方向和第二储液槽12与第二流道42连接的第二开口52的开口方向为大致相反设置。具体的，当第一开口方向朝下时，第二开口方向朝上或朝斜向上方向。更为具体的，第一开口方向朝下时，第二开口方向朝斜向上方向的角度是垂直向上及其正负30度之间。
在该实施例中，上盖片位于第一储液槽的位置上设有第一通气孔110，在第二储液槽的位置设有第二通气孔120，在废液槽的位置设有第三通气孔310。并且通气孔处用密封件密闭。去除密封件后，第一储液槽中的检测试剂通过第一通气孔注入至第一储液槽中，检测样品通过第二通气孔注入第二储液槽中。在检测运行时，管道内的气体通过第三通气孔排除芯片之外。
具体操作如图7-1至图7-4所示。第一储液槽11用于储存检测试剂501，例如定标液，第二储液槽12用于存放待检测样品502，例如血液样品。运行中的芯片竖直固定在仪器中并依靠仪器中的部件带动芯片旋转来控制流体流动方向，从而实现依次传送检测试剂和待检测样本至检测流道的目的。当芯片处于图7-1的位置时，第一储液槽11与第一流道41连接的第一开口51的开口方向向下使第一储液槽中的检测试剂501在自身重力和由第一流道41提供的毛细力的作用下，流入第一流道41中。于此同时，第二储液槽12与第二流道42连接的第二开口52的开口方向斜向上，第二储液槽中的液体502无法从第二开口52流出。芯片从图7-1旋转到图7-2的位置时，第一流道41中的检测试剂经过第一穿孔61从基板的反面流向位于基板正面的第三流道44和检测流道21，停留在检测流道21内的检测试剂与传感器发生反应，仪器的探针在信号采集通道22内与传感器的接脚连接并采集反应信号。在图7-2位置时，由于第一储液槽中的液体先于第二储液槽中的液体流出进入检测流道，这时第二储液槽12中的待测样本与检测流道检测试剂之间形成气柱，储存在第二储液槽中的待测样本受到的气压不对等，所以会滞留在第二储液槽12中。当检测试剂的检测结束后，芯片旋转到图7-3的位置，检测流道21内的检测试剂经第四流道45和第三穿孔63流入基板反面的第五流道43直至流入废液槽13内。在此旋转过程中，第二储液槽的第二开口到达方向朝下的位置，第二储液槽中的样品流出开口到第二流道42中。更优的实施例中，由于第二流道42包括了一段弯管，当芯片位于图7-3的位置时，从第二储液槽中流出的部分液体会保留在弯管内。芯片继续旋转至7-4位置，检测试剂已流出检测流道进入废液槽，且废液槽的体积较大，检测试剂501可完全进入废液槽(与外界有个第三通气孔)，位于第二储液槽的流体在自身重力的作用下，流出储液槽，经基板反面的第二流道42、第二穿孔62流入基板正面的第三流道44和检测流道21中，停留在检测流道中的样品与传感器发生反应，此时仪器通过传感器的接脚采集待测样品的信号。
如图8-1至图8-6所示的微流控检测芯片及具体操作步骤。微流控检测芯片包括基板、上盖片、下盖片和电极传感器。基板100上设有第一储液槽11、第二储液槽12、检测区2和废液槽3，电极传感器设于检测区2内。储液槽、检测区和废液槽之间通过流道连通，上盖片和下盖片分别水密性地粘附在基板的正反面，从而使储液槽、废液槽、流道等密闭于基板内。当第一储液槽11中的液体流出第一开口51时，第二储液槽中的液面位置低于第二开口，从而不会从第二开口流出。第一储液槽11用于储存检测试剂501，例如定标液，质控液或者酶等反应试剂。第二储液槽12用于存放待检测样品502，例如血液样品。
当芯片处于图8-1至图8-3的位置时，第二储液槽中的液面低于第二开口52的开口处，第一开口51的方向向下使第一储液槽中的液体在自身重力的作用下，流入第一流道41中，并 经过第一穿孔61从基板的反面流向基本的正面的第三流道44内最终到达检测流道21，并在预留的时间内，检测流道中的检测试剂与传感器发生反应。仪器探针在信号采集通道22内与传感器的接脚连接并采集反应信号。当检测芯片旋转至图8-4所示的位置时，检测流道21中的检测试剂通过第四流道和第三穿孔进入第五流道43后入废液槽3。此时第二储液槽中的液体继续保留在第二储液槽内。当检测芯片进一步旋转至图8-5所示位置时，第二储液槽的第二开口朝下，处于液体流出位置，第二储液槽中的液体在自身重力作用下流入第二流道42中，并通过第第二穿孔62流入基板正面的第三流道44和检测流道21中。芯片继续旋转至图8-6的位置，使得第二储液槽中的液体完全进入检测流道21，停留在检测流道21中的样品与传感器发生反应，此时仪器通过传感器的接脚采集待测样品的信号。
如图9所示的微流控检测芯片，在基板上设置有第一储液槽11、第二储液槽12、第三储液槽13和第四储液槽14，并对应的连接于第一流道至第四流道(410-440)，第一检测流道21和第二检测流道23，位于第一检测流道前端和后端的第五流道450和第六流道460，位于第二检测流道前端和后端的第七流道470和第八流道480以及第一废液槽31和第二废液槽32。第一废液槽31通过第九流道490和穿孔65与第六流道460和第一检测流道21连通，第二废液槽32通过第十流道491和穿孔66与第八流道480和第二检测流道23连通。第一储液槽、第一流道、第一穿孔、第五流道、第一检测流道、第六流道、穿孔65、第九流道和第一废液槽形成流路。第二储液槽、第二流道、第二穿孔、第五流道、第一检测流道、第六流道、穿孔65、第九流道和第一废液槽形成流路。。第三储液槽、第三流道、第三穿孔、、第七流道、第二检测流道、第八流道、穿孔66、第十流道491和第二废液槽形成流路。第四储液槽、第四流道、第四穿孔、第七流道、第二检测流道、第八流道、穿孔66、第十流道491和第二废液槽形成流路。通过旋转芯片，储液槽中的液体在自身重力的作用下依次流出并在流路中流动。
如图10所示的微流控测试芯片，在一个基板上设有两个流体控制系统。第一流体控制系统包括第一储液槽11、第二储液槽12、第一流道41，、第二流道42、设于反应区2内的检测流道21和第一废液槽31。第二流体控制系统包括第三储液槽13、第四储液槽14、第三流道43，、第四流道44、设于反应区2内的检测流道23和第一废液槽32。
在另外的微流控检测芯片的基板，第一储液槽、第二储液槽、第一流道、第二流道检测流道和第三流道和废液槽均开设于基板的正面，第一流道和第二流道均与检测流道相同。通过旋转芯片，储液槽中的液体在自身重力的作用下依次流出并在流路中流动。
以图1至图7的芯片为例，说明芯片的制造方法。
步骤1，选取疏水性材料作为基板，通过化学刻蚀、物理雕刻、热压或注塑成型在基板上形成的流道、储液槽、检测流道、信号采集通道、废液槽、穿孔等结构。
步骤2，获得电极传感器，将其粘贴在基板下表面的检测流道处，以让传感器的电极位于检测流道内，并同时水密性的封住检测流道的下表面。同时传感器的电极接脚位于检测区的信号采集通道内。
步骤3，获得疏水性的下盖片(或用疏水材料处理下盖片与基板反面接触的接触面为疏水性)，下盖片水密性地粘贴在基板的反面。
步骤4，获得亲水性的上盖片(或用亲水性材料处理上盖片与基板正面接触的接触面为亲水性)。将上盖片水密性地贴在基板的正面。检测试剂通过上盖片的第一通气孔注入第一储液 槽内，随后用密封件密封住小孔。获得可用于检测的微流体检测芯片。
在另一个实施例中，若上盖片没有第一通气孔，则上述步骤4向第一储液槽中注入作为检测试剂的定标液，然后将亲水性的上盖片或与基板正面接触的表面经亲水性处理的上盖片水密性地贴在基板的正面，从而将检测试剂密封在第一储液槽中。在检测程序中，当需要使第一储液槽中的液体流出第一储液槽时，先在第一储液槽上方的上盖片破出一个小孔，让空气可以进入第一储液槽，但液体不会通过该小孔流出第一储液槽，流道检测芯片的外面。
利用本发明的微流控芯片进行样本检测的方法，其步骤如下：
步骤1，获得本发明中所述的微流控检测芯片。
步骤2，通过上盖片在第二储液槽上的第二通气孔将待检测血液样品注入第二储液槽中。
步骤3，将检测芯片竖直固定在仪器中并依靠仪器中的部件带动芯片旋转来控制流体流动方向。当芯片处于图7-1的位置时，打开上盖片位于第一储液槽上的第一通气孔，同时打开位于第三通气孔。第一储液槽11中的定标液流入第一流道41中。于此同时，第二储液槽12与第二流道42连接的第二开口52的开口方向斜向上，第二储液槽中的液体502无法从第二接口流出。
步骤4，芯片从图7-1旋转到图7-2的位置，第一流道41中的检测试剂经过第一穿孔61从基板的反面流向位于基板正面的检测流道，停留在检测流道检测试剂与传感器发生反应，仪器触脚在触脚接触口22内与传感器的接脚连接并采集反应信号。
步骤5，芯片从图7-2旋转到图7-3的位置，检测流道21内的检测试剂经第三穿孔63流入基板反面的第三流道43直至流入废液槽13内。
步骤6，芯片继续旋转至7-4位置，检测试剂已流出检测流道进入废液槽，第二储液槽内的待测血液样品流出储液槽，经基板方面的第二流道42、第二穿孔62流入基板正面的检测流道21中，停留在检测流道中的样品与传感器发生反应，此时仪器通过传感器的接脚采集待测样品的信号。从而获得检测结果。
本发明所述的检测区中的检测方法，可以是带电极的生物传感器，还可以是浊度法、荧光法、化学发光法、散射法、等光学检测法，或其他的检测方法。
本发明所述微流控检测芯片可进行定量、半定量或定性检测。例如在检测区固定一个或多个检测试纸(可以是空白的试纸，也可以是预先添加了试剂的试纸)，利用检测试剂或样本流过检测流道与检测试纸接触后，试剂与样本反应发生颜色变化，随后通过仪器或人为观察得出检测结果。

Claims (15)

  1. 微流控芯片，包括基板和位于基板上的检测区，其特征在于，基板上设有第一储液槽和第二储液槽，第一储液槽、第二储液槽分别与检测区液体连通，第一储液槽设有供液体流出的第一开口，第二储液槽设有供液体流出的第二开口；当微流控芯片用于样本检测时，从第一储液槽流出的液体后端比从第二储液槽流出的液体前端更早到达检测区。
  2. 根据权利要求1所述的微流控芯片，其特征在于，所述第一开口和第二开口的开口方向相反；或者第一开口和第二开口的开口方向基本一致，但液体从第一储液槽流出时，液体不会从第二储液槽中流出。
  3. 根据权利要求1所述的微流控芯片，其特征在于，还包括废液槽，检测区与废液槽连通。
  4. 根据权利要求1所述的微流控芯片，第一储液槽通过第一流道和第三流道与检测区连通、第二储液槽通过第二流道和第三流道与检测区连通，检测区通过第四流道和第五流道与废液槽连通；第一流道、第二流道和第五流道位于基板一个面，第三流道、第四流道以及检测流道位于基板另一面。
  5. 根据权利要求4所述的微流控芯片，其特征在于，第一流道、第二流道和第五流道与第三流道和第四流道的亲疏水性正好相反。
  6. 根据权利要求5所述的微流控芯片，其特征在于，第一流道、第二流道和第五流道为疏水性流道；第三流道、第四流道和检测流道为亲水性流道。
  7. 根据权利要求1所述的微流控芯片，其特征在于，还包括上盖片和下盖片，上盖片和下盖片分别水密性地覆盖在基板的两个面；其中一个盖片至少与基板接触的部位是疏水性的，另一个盖片至少与基板接触的部位是亲水性的。
  8. 根据权利要求4所述的微流控芯片，其特征在于，第一流道与第二流道通过穿孔与第三流道连接，第四流道通过穿孔与第五流道连接。
  9. 根据权利要求1所述的微流控芯片，其特征在于，检测区设内包括检测元件。
  10. 根据权利要求9所述的微流控芯片，所述检测元件选自电化学传感器或光学检测试纸。
  11. 微流控芯片的制作方法，包括以下步骤：
    (1)取得一基板，并在基板上形成第一储液槽、第二储液槽、检测区、废液槽和流道；
    (2)在检测区内设置检测元件；
    (3)向第一储液槽内加入试剂；
    (4)用盖片密封第一储液槽、第二储液槽、检测区、废液槽和流道。
  12. 根据权利要求11所述的制作方法，其特征在于，第一储液槽通过第一流道和第三流道与检测区连通、第二储液槽通过第二流道和第三流道与检测区连通，检测区通过第四流道和第五流道与废液槽连通；第一流道、第二流道和第五流道位于基板一个面，第三流道、第四流道以及检测流道位于基板另一面。
  13. 根据权利要求12所述的制作方法，其特征在于，第一流道通过第一穿孔与第三流道连通，第二流道通过第二穿孔与第三流道连通。
  14. 根据权利要求12所述的制作方法，其特征在于，第一流道、第二流道和第五流道进行疏水性处理；第三流道、第四流道和检测区进行亲水性处理。
  15. 根据权利要求12所述的制作方法，其特征在于，覆盖在第一储液槽、第二储液槽和废液槽的盖片上设置通气孔。
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