CN114505106B - Active micro-fluidic chip for optimizing magnetic uniform mixing effect and use method thereof - Google Patents

Active micro-fluidic chip for optimizing magnetic uniform mixing effect and use method thereof Download PDF

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CN114505106B
CN114505106B CN202210109921.6A CN202210109921A CN114505106B CN 114505106 B CN114505106 B CN 114505106B CN 202210109921 A CN202210109921 A CN 202210109921A CN 114505106 B CN114505106 B CN 114505106B
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cavity
waste liquid
flow channel
hole
chip
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CN114505106A (en
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许行尚
杰弗瑞·陈
王龙
刘祥
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Nanjing Lanyu Biological Technology Co Ltd
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Nanjing Lanyu Biological Technology Co Ltd
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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
    • 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
    • B01L3/502715—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
    • 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
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—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
    • 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
    • B01L2400/043—Moving fluids with specific forces or mechanical means specific forces magnetic forces

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Analytical Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Clinical Laboratory Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Automatic Analysis And Handling Materials Therefor (AREA)

Abstract

The invention discloses an active micro-fluidic chip for optimizing a magnetic uniform mixing effect and a using method thereof. The active micro-fluidic chip comprises a chip body, wherein a sample introduction cavity is arranged on the chip body, a magnetic component is preset in the sample introduction cavity, a labeled antibody is attached to the sample introduction cavity, an outlet of the sample introduction cavity is directly and integrally communicated with an output flow channel of the sample introduction cavity, the output flow channel of the sample introduction cavity is a U-shaped bent pipe flow channel, an inlet end of the U-shaped bent pipe flow channel is integrally connected with the sample introduction cavity in a tangential connection mode, and an outlet end of the U-shaped bent pipe flow channel is provided with a first backflow prevention structure. Therefore, in the process that the whole blood sample and the labeled antibody attached to the sample injection cavity are fully reacted under the driving of the rotating magnetic component, the invention effectively prevents the incompletely reacted whole blood sample from entering the sample injection cavity output flow channel, thereby ensuring the high accuracy of the detection result of the micro-fluidic chip, simplifying the flow path structure of the sample injection cavity output flow channel and effectively improving the product qualification rate of the micro-fluidic chip.

Description

Active micro-fluidic chip for optimizing magnetic uniform mixing effect and use method thereof
Technical Field
The invention relates to an active micro-fluidic chip and a using method thereof, in particular to an active micro-fluidic chip for optimizing a magnetic uniform mixing effect and a using method thereof.
Background
The microfluidic chip technology integrates basic operation units of sample preparation, reaction, separation, detection and the like in biological, chemical and medical analysis processes into a micron-scale chip, and automatically completes the whole analysis process. Due to its great potential in the fields of biology, chemistry, medicine, etc., it has been developed into a new research field across the disciplines of biology, chemistry, medicine, fluid, electronics, materials, mechanics, etc.
Chinese patent CN 113413935A discloses an active microfluidic chip based on a magnetic mixing technique, which adopts a magnetic mixing technique in a sample injection cavity to fully react and mix a whole blood sample with a labeled antibody attached in the sample injection cavity. Meanwhile, the active micro-fluidic chip in the patent is of a three-chip structure, comprises three layers of chips, needs vacuum bonding, and has a complex internal flow path, a complex overall processing technology and high cost. In addition, in order to prevent the whole blood sample and the labeled antibody from reacting in the sample injection cavity, the incompletely reacted whole blood sample enters the sample injection flow channel to influence the detection effect, the sample injection flow channel in the patent is processed on the back surface of the middle layer chip and is set to be a quite complicated flow path structure, and therefore the product qualification rate of the microfluidic chip is influenced.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides an active micro-fluidic chip for optimizing the magnetic uniform mixing effect and a using method thereof. A sample injection cavity output runner directly connected with an outlet of a sample injection cavity is set to be a U-shaped runner, and the U-shaped runner is tangentially connected with the sample injection cavity. In the process that the whole blood sample and the labeled antibody attached to the sample injection cavity are fully reacted under the driving of the rotating magnetic component, the invention effectively prevents the incompletely reacted whole blood sample from entering the sample injection cavity output flow channel, thereby ensuring the high accuracy of the detection result of the micro-fluidic chip, simplifying the flow path structure of the sample injection cavity output flow channel and effectively improving the product qualification rate of the micro-fluidic chip.
In order to achieve the technical purpose, the invention adopts the following technical scheme:
the utility model provides an optimize initiative micro-fluidic chip of magnetism mixing effect, includes the chip body, be provided with the appearance chamber on the chip body, preset magnetic member in the appearance chamber, and adhere to the mark antibody in the appearance chamber, the appearance chamber export is direct and the integrative intercommunication of appearance chamber output runner simultaneously, appearance chamber output runner be U-shaped return bend runner, the mode body coupling through the tangential connection between the entrance point of U-shaped return bend runner and the appearance chamber, and the first anti-reflux structure of U-shaped return bend runner's exit end assembly.
Preferably, the chip body is further provided with a quantitative reaction cavity, a first external liquid path interface and a second external liquid path interface;
the inlet of the quantitative reaction cavity is directly and integrally communicated with the outlet end of the input channel of the reaction cavity, and the outlet of the quantitative reaction cavity is directly and integrally communicated with the inlet end of the output channel of the reaction cavity; the coating antibody is attached to the quantitative reaction cavity;
the first external liquid path interface can be communicated with the input runner of the reaction cavity, and the second external liquid path interface can be communicated with the output runner of the reaction cavity.
Preferably, a waste liquid chamber is further included; the inlet of the waste liquid cavity is directly and integrally communicated with the outlet end of the waste liquid input flow passage;
the inlet end of the reaction cavity input flow passage is communicated with the outlet end of the U-shaped bent pipe flow passage through a first backflow prevention structure; the outlet end of the reaction cavity output flow channel is communicated with the inlet end of the waste liquid input flow channel through the second backflow prevention structure and the third backflow prevention structure in sequence.
Preferably, the first backflow prevention structure comprises a first vertical through hole, a first transverse connecting flow passage and a second vertical through hole; the second backflow prevention structure comprises a third vertical through hole, a first longitudinal connecting flow channel and a fourth vertical through hole; the third backflow prevention structure comprises a second longitudinal connecting flow passage, a second transverse connecting flow passage, a fifth vertical through hole and a sixth vertical through hole;
the first through sixth vertical through holes are all holes arranged along the thickness direction of the chip body;
one end of the first transverse connecting flow passage is in butt joint communication with the outlet end of the U-shaped bent pipe flow passage through a first vertical through hole; the other end of the first transverse connecting flow channel is arranged at the upper end of the second vertical through hole in a bypass mode and can be communicated with the upper end of the second vertical through hole, and the lower end of the second vertical through hole is directly communicated with the inlet end of the reaction cavity input flow channel; the position of the upper end of the second vertical through hole is provided with the first external liquid circuit interface;
one end of the first longitudinal connecting flow channel is in butt joint communication with the inlet end of the second transverse connecting flow channel through a third vertical through hole, the other end of the first longitudinal connecting flow channel is arranged at the upper end of the fourth vertical through hole in a bypass mode and can be communicated with the upper end of the fourth vertical through hole, and the lower end of the fourth vertical through hole is directly communicated with the outlet end of the reaction cavity output flow channel; the position of the upper end of the fourth vertical through hole is provided with the second external liquid path interface;
the outlet end of the second transverse connecting flow channel is communicated with one end of the second longitudinal connecting flow channel through a fifth vertical through hole, and the other end of the second longitudinal connecting flow channel is communicated with the inlet of the waste liquid cavity input flow channel through a sixth vertical through hole.
Preferably, the chip body is formed by laminating an upper chip and a lower chip, and a film is attached to the upper surface of the upper chip;
the sample injection cavity comprises a sample injection pool arranged on the upper surface of the lower chip and a sample injection hole which penetrates through the upper chip and is in butt joint communication with the inlet of the sample injection pool;
the quantitative reaction cavity comprises a reaction cavity lower cover arranged on the upper surface of the lower chip and a reaction cavity upper cover arranged on the lower surface of the upper chip and capable of being sealed with the reaction cavity lower cover; the reaction cavity input runner and the reaction cavity output runner are arranged on the lower surface of the upper chip and can be correspondingly communicated with an inlet and an outlet of the reaction cavity upper cover respectively;
the waste liquid cavity comprises a waste liquid pool arranged on the upper surface of the lower chip and a waste liquid cavity cover plate which is arranged on the lower surface of the upper chip and can be sealed with a pool opening of the waste liquid pool; the waste liquid input flow channel is arranged on the lower surface of the upper chip and can be communicated with the waste liquid cavity cover plate;
the first to sixth vertical through holes are all holes arranged along the thickness direction of the upper chip, and the first to sixth vertical through holes are all through holes arranged through the upper chip;
the first transverse connecting flow channel, the first longitudinal connecting flow channel and the second longitudinal connecting flow channel are uniformly distributed at corresponding positions on the upper surface of the upper chip; and the second transverse connecting flow channel is arranged at the corresponding position of the lower surface of the upper layer chip.
Preferably, the upper chip and the lower chip are spliced into a whole through the matched first positioning column and the first positioning hole, the upper chip and the lower chip are bonded through the double-sided adhesive film, and the double-sided adhesive film is provided with matched hollow holes at the positions of the cavity and the pipeline on the front side of the lower chip, so that the upper chip and the lower chip are bonded to form the required cavity and flow path.
Preferably, the waste liquid cavity comprises a rectangular waste liquid cavity and an elongated waste liquid cavity extending along one corner of the rectangular waste liquid cavity and communicated with the rectangular waste liquid cavity;
the waste liquid pool comprises a rectangular waste liquid pool and a strip-shaped waste liquid pool which extends along one corner position of the rectangular waste liquid pool and is communicated with the rectangular waste liquid pool;
the waste liquid cavity cover plate comprises a rectangular waste liquid cavity cover plate which is arranged on the lower surface of the upper chip and is sealed with the tank opening of the rectangular waste liquid tank; the rectangular waste liquid pool and the rectangular waste liquid cavity cover plate are sealed to form the rectangular waste liquid cavity;
a waste liquid overflow storage tank with an upward notch is arranged on the upper surface of the upper chip at a position corresponding to the strip-shaped waste liquid tank; the bottom of the waste liquid overflow storage tank is provided with an overflow hole which is communicated with the strip-shaped waste liquid pool; the notch of the waste liquid overflowing the storage tank is sealed by the film.
Preferably, the sample feeding cavity is arranged at the left side of the quantitative reaction cavity; the sample introduction cavity is arranged on the left side of the quantitative reaction cavity; the inner edge line of the flow path of the U-shaped bent pipe flow channel is tangent to the sample injection cavity at the point B, the outer edge line of the flow path of the U-shaped bent pipe flow channel is intersected with the sample injection cavity at the point A, and the tangential angle alpha of the sample injection cavity passing through the point A ranges from 30 degrees to 75 degrees.
Preferably, the waste liquid cavity comprises a rectangular waste liquid cavity and an elongated waste liquid cavity extending along one corner of the rectangular waste liquid cavity and communicated with the rectangular waste liquid cavity;
more than one spacer block is arranged in the rectangular waste liquid cavity;
the waste liquid cavity is divided into more than two waste liquid cavity split bodies which are communicated in a snake-shaped winding manner through the partition blocks.
The invention also aims to provide another active micro-fluidic chip for optimizing the magnetic uniform mixing effect, which comprises a chip body, wherein the chip body comprises an upper chip, a lower chip and a double-sided adhesive film arranged between the upper chip and the lower chip; wherein:
a plurality of first positioning columns are arranged on the periphery of the upper surface of the lower chip as required, and matched first positioning holes are arranged on the periphery of the lower surface of the upper chip at positions corresponding to the first positioning columns;
the upper surface of the lower chip is respectively provided with a sample feeding pool, a U-shaped bent pipe flow passage, a reaction cavity lower cover and a waste liquid pool;
the back surface of the upper chip is respectively provided with a reaction cavity upper cover, a reaction cavity input flow channel, a reaction cavity output flow channel, a rectangular waste liquid cavity cover plate, a waste liquid input flow channel and a second transverse connecting flow channel; the front surface of the upper chip is respectively provided with a first transverse connecting flow channel, a first longitudinal connecting flow channel, a second longitudinal connecting flow channel, a first external liquid path interface, a second external liquid path interface and a waste liquid overflow storage tank; meanwhile, the upper chip is provided with a sample inlet, an overflow hole and first to sixth vertical through holes along the thickness direction, and the sample inlet, the overflow hole and the first to sixth vertical through holes are all through holes which simultaneously penetrate through the upper surface and the lower surface of the upper chip;
one end of the first transverse connecting flow passage is communicated with the upper end of the first vertical through hole, the other end of the first transverse connecting flow passage is arranged at the upper end of the second vertical through hole in a bypass mode and can be communicated with the upper end of the second vertical through hole, and the upper end of the second vertical through hole is provided with the first external liquid path interface in a position flush with the upper surface of the upper chip in a matching mode; one end of the first longitudinal connecting flow passage is communicated with the upper end of the third vertical through hole, the other end of the first longitudinal connecting flow passage is arranged at the upper end of the fourth vertical through hole in a bypass mode and can be communicated with the upper end of the fourth vertical through hole, and a second external liquid path interface is arranged at the position, flush with the upper surface of the upper chip, of the upper end of the fourth vertical through hole in a matched mode; the upper end of the fifth vertical through hole is communicated with one end of the second longitudinal connecting flow channel, the lower end of the fifth vertical through hole is communicated with the outlet end of the second transverse connecting flow channel, the upper end of the sixth vertical through hole is communicated with the other end of the second longitudinal connecting flow channel, and the lower end of the sixth vertical through hole is communicated with the inlet end of the waste liquid input flow channel;
the chip body is bonded into a whole through a double-sided adhesive film under the auxiliary positioning of the first positioning column and the first positioning hole, so that the upper chip and the lower chip can be spliced to form a sample injection cavity, a quantitative reaction cavity and a waste liquid cavity, an outlet of the sample injection cavity is communicated with an input runner of the reaction cavity through a U-shaped bent pipe runner and a first backflow prevention structure in sequence, and an output runner of the reaction cavity is communicated with an input runner of the waste liquid through second and third backflow prevention structures in sequence; wherein:
the sample injection cavity is formed by butt-joint communication of a sample injection hole and a sample injection pool port; the quantitative reaction cavity is formed by splicing an upper reaction cavity cover and a lower sealing reaction cavity cover; the waste liquid cavity comprises a rectangular waste liquid cavity and a strip-shaped waste liquid cavity, the rectangular waste liquid cavity is formed by sealing a rectangular waste liquid pool through a rectangular waste liquid cavity cover plate, the strip-shaped waste liquid cavity is formed by sealing a strip-shaped waste liquid pool through the bottom of a waste liquid overflowing storage tank, and the waste liquid overflowing storage tank is communicated with the strip-shaped waste liquid pool through an overflow hole which penetrates through the bottom of the waste liquid overflowing storage tank;
the first backflow prevention structure is formed by butt joint and communication of the lower end of the first vertical through hole and the outlet end of the U-shaped elbow flow channel; the second backflow prevention structure is formed by the first longitudinal connecting flow channel and a third vertical through hole and a fourth vertical through hole which are arranged at the two ends of the first longitudinal connecting flow channel; the third backflow prevention structure is formed by a second transverse connecting flow channel, a fifth vertical through hole, a second longitudinal connecting flow channel and a sixth vertical through hole which are sequentially connected between the third vertical through hole and the waste liquid input flow channel.
The invention further aims to provide a use method of the microfluidic chip for optimizing the uniform magnetic mixing effect, which comprises the following steps:
step one, assembling a chip body
Step 1.1, according to planning, arranging a sample feeding pool, a U-shaped bent pipe flow channel, a reaction cavity lower cover and a waste liquid pool on the upper surface of a lower chip, and arranging first positioning columns on the periphery of the upper surface of the lower chip as required; the back surface of the upper chip is respectively provided with a reaction cavity upper cover, a reaction cavity input flow channel, a reaction cavity output flow channel, a rectangular waste liquid cavity cover plate, a waste liquid input flow channel and a second transverse connecting flow channel, and first positioning holes are arranged on the periphery of the back surface of the upper chip as required; a first transverse connecting flow channel, a first longitudinal connecting flow channel, a second longitudinal connecting flow channel, a first external liquid path interface, a second external liquid path interface and a waste liquid overflow storage tank are respectively arranged on the front surface of the upper layer chip, and a sample inlet hole, an overflow hole and first to sixth vertical through holes are vertically arranged on the upper surface of the upper layer chip in a penetrating manner; wherein:
one end of the first transverse connecting flow channel is communicated with the upper end of the first vertical through hole, the other end of the first transverse connecting flow channel is arranged at the upper end of the second vertical through hole in a bypass mode and can be communicated with the upper end of the second vertical through hole, and the upper end of the second vertical through hole is provided with the first external liquid path interface in a position flush with the upper surface of the upper chip; one end of the first longitudinal connecting flow channel is communicated with the upper end of the third vertical through hole, the other end of the first longitudinal connecting flow channel is arranged at the upper end of the fourth vertical through hole in a bypass mode and can be communicated with the upper end of the fourth vertical through hole, and the upper end of the fourth vertical through hole is provided with the second external liquid connecting channel interface in a position flush with the upper surface of the upper chip; the upper end of the fifth vertical through hole is in butt joint communication with one end of the second longitudinal connecting flow channel, the lower end of the fifth vertical through hole is in butt joint communication with the outlet end of the second transverse connecting flow channel, the upper end of the sixth vertical through hole is communicated with the other end of the second longitudinal connecting flow channel, and the lower end of the sixth vertical through hole is in butt joint communication with the inlet end of the waste liquid input flow channel;
step 1.2, after a magnetic component is added into a sample injection pool, an upper chip and a lower chip are assembled into a whole under the auxiliary positioning of a first positioning column and a first positioning hole through a double-sided adhesive film arranged between the upper chip and the lower chip, so that the upper chip and the lower chip can be spliced to form a sample injection cavity, a quantitative reaction cavity and a waste liquid cavity, an outlet of the sample injection cavity is communicated with an input flow channel of the reaction cavity through a U-shaped bent pipe flow channel and a first backflow prevention structure in sequence, and an output flow channel of the reaction cavity is communicated with the input flow channel of the waste liquid through a second backflow prevention structure and a third backflow prevention structure in sequence; wherein:
the sample introduction cavity is formed by connecting and communicating a sample introduction hole with a pool port of the sample introduction pool in a butt joint mode, the quantitative reaction cavity is formed by connecting and sealing an upper cover of the reaction cavity with a lower cover of the sealing reaction cavity, the waste liquid cavity comprises a rectangular waste liquid cavity and a strip-shaped waste liquid cavity, the rectangular waste liquid cavity is formed by sealing and sealing a cover plate of the rectangular waste liquid cavity with the rectangular waste liquid pool, the strip-shaped waste liquid cavity is formed by sealing and sealing a groove bottom of a waste liquid overflow storage groove with the strip-shaped waste liquid pool, and the waste liquid overflow storage groove is communicated with the strip-shaped waste liquid pool through an overflow hole; the lower end of the first vertical through hole is in butt joint communication with the outlet end of the U-shaped bent pipe flow passage, and then the first transverse connecting flow passage and the second vertical through hole form the first anti-backflow structure; the second backflow prevention structure is formed by the first longitudinal connecting flow channel and a third vertical through hole and a fourth vertical through hole which are arranged at the two ends of the first longitudinal connecting flow channel; the third prevention backflow structure is formed by a second transverse connecting flow channel, a fifth vertical through hole, a second longitudinal connecting flow channel and a sixth vertical through hole which are sequentially connected between the third vertical through hole and the waste liquid input flow channel;
step 1.3, adding coated antibody liquid into the quantitative reaction cavity through any one of the first external liquid path interface and the second external liquid path interface, after incubation, sucking out the liquid through the other external liquid path interface, and then placing the liquid in a vacuum drying oven for drying or performing ventilation drying through the first external liquid path interface or the second external liquid path interface until the coated antibody is attached to the cavity wall of the quantitative reaction cavity;
step 1.4, dropwise adding a labeled antibody liquid into a sample injection pool through a sample injection hole, and then placing the chip body in a vacuum drying oven for drying at normal temperature for a period of time until the labeled antibody liquid is dried, so that the labeled antibody is attached to the wall of the sample injection cavity;
step 1.5, pasting a film on the front surface of the upper layer chip, and ensuring that a sample inlet hole, an external liquid connection port and an overflow hole of a sample inlet cavity are exposed;
step two, testing
Step 2.1, adding the whole blood sample into a sample introduction pool;
2.2, promoting the magnetic force between the magnetic mechanism and the magnetic member through the magnetic mechanism arranged on the detection instrument to drive the magnetic member to rotate clockwise in the sample injection cavity, stopping moving the magnetic mechanism until the whole blood sample and the labeled antibody in the sample injection cavity have complete immunoreaction, and stopping rotating the magnetic member; in the process, the U-shaped bent pipe flow channel can effectively prevent the fluid in the sample feeding cavity from flowing out;
step 2.3, applying pneumatic power assistance to the sample injection cavity, and allowing the sample reaction liquid processed in the step 2.2 to flow into the quantitative reaction cavity for reaction through the U-shaped bent pipe flow channel and the first anti-backflow structure in sequence;
2.4, after the reaction is finished, adopting pneumatic assistance to sequentially push the reacted liquid in the quantitative reaction cavity into a second and a third backflow prevention structures, and finally flowing into a waste liquid cavity; according to different detection project requirements, cleaning fluid can be added from an external fluid port to clean the quantitative reaction cavity, and the cleaned waste fluid is pushed into the waste fluid cavity through pneumatic assistance;
and 2.5, detecting the sample compound processed in the step 2.4 by using a detection instrument.
Based on the technical purpose, compared with the prior art, the invention has the following advantages:
1. according to the micro-fluidic chip, in order to optimize the magnetic mixing effect (mixing of a whole blood sample and a labeled antibody) of a sample in the sample injection cavity, the output flow channel of the sample injection cavity is set to be the U-shaped bent pipe flow channel, so that the sample in the sample injection cavity is effectively prevented from flowing out from the inlet end of the U-shaped bent pipe flow channel in the magnetic stirring and mixing process, and the final detection effect of the sample is guaranteed.
2. The invention provides another idea of attaching the coated antibody in the quantitative reaction cavity by changing a micro-flow channel (comprising a first external liquid path interface and a second external liquid path interface) of the micro-fluidic chip (inputting the coated antibody liquid into the quantitative reaction cavity through any one of the external liquid path interfaces, pumping out liquid through the other external liquid path interface after incubation, and blowing the liquid to the quantitative reaction cavity or placing the liquid in a vacuum chamber for vacuum drying until the coated antibody liquid in the quantitative reaction cavity is dried, so that the coated antibody is attached to the wall of the quantitative reaction cavity).
3. The invention simplifies the micro-channel of the micro-fluidic chip, directly connects the input channel of the reaction cavity with the first external liquid channel interface, and connects the output channel of the reaction cavity with the second external liquid channel interface, thereby reducing the need of ensuring the butt joint of the second external liquid channel interface and the external liquid channel inlet distributed on the upper surface of the lower chip during the assembly of the prior chip, otherwise easily causing the assembly failure of the micro-channel and influencing the product percent of pass; meanwhile, the invention also simplifies the complexity of the arrangement of the micro-flow channels and reduces the production difficulty of the micro-flow control chip.
4. In the invention, the second backflow prevention structure and the third backflow prevention structure are formed when the upper layer chip is provided with the micro flow path, and only the splicing of the sample injection cavity, the quantitative reaction cavity and the waste liquid cavity needs to be concerned in the assembling process, so that the assembling difficulty is reduced, and the product percent of pass is further improved.
5. The upper chip is provided with the concave waste liquid overflowing storage cavity, so that the surface of the upper chip can not be polluted if waste liquid flows out along with gas in the using process of the two layers of chips, and pollution is avoided.
6. The invention provides a two-piece microfluidic chip, which is provided with an upper layer of chips and a lower layer of chips, wherein a layer of adhesive film is additionally arranged on the upper layer, and a double-sided adhesive film is arranged between the two layers of chips to replace the chip bonding assembly mode in the prior art; in addition, a plurality of dispersed magnetic components are arranged in the sample injection cavity, and the magnetic components in the sample injection cavity move by using an external magnetic driving device, so that the immune reaction of the sample and the labeled antibody is fully and uniformly mixed. The invention solves the problems of complex structure and complex processing technology of the three-chip in the prior art, ensures full reaction in the microfluidic chip by utilizing a magnetic mixing technology, and improves the accuracy of a detection result. Meanwhile, the design of the two-piece chip is adopted, the whole flow path is shortened, the coated antibody liquid contains sucrose components, the liquid presents certain adhesiveness, the sucrose components play a role in sealing and stabilizing protein, and if the flow path is longer, the blocking risk is increased; the two-piece design is higher than the three-piece design in air tightness, the liquid leakage risk is reduced, the positioning function of the positioning column positioning hole is bonded and matched in a double-sided adhesive tape mode, the process is further simplified, and the cost is reduced.
Drawings
FIG. 1 is a schematic structural diagram of a microfluidic chip according to the present invention;
FIG. 2 is a schematic diagram of a front side structure of the upper chip in FIG. 1;
FIG. 3 is a schematic diagram of the front structure of the upper chip in FIG. 1 (labeled vertical through holes);
FIG. 4 is a schematic diagram of a backside structure of the upper chip in FIG. 1;
FIG. 5 is a schematic diagram of the front side structure of the lower chip in FIG. 1;
FIG. 6 is a schematic diagram of a backside structure of the lower chip in FIG. 1;
FIG. 7 is a partially enlarged schematic view of the sample cell of FIG. 5;
in FIGS. 1-5: 1-a chip body; 11-a sample injection cavity; 12-the waste liquid overflows the storage cavity; 13-a first external liquid path; 14-a second external liquid path; 15-a second anti-backflow structure; 16-a first backflow prevention structure; 17-a third backflow prevention structure;
10-upper chip; 101-a sample inlet hole; 102-a waste liquid overflow storage tank; 103-a first external liquid path interface; 104-a second longitudinal connecting flow channel; 105-a second external fluid path interface; 106-reaction chamber input flow channel; 107-a second transverse connecting runner; 108-a waste liquid input channel; 109-rectangular waste liquid chamber cover plate; 110-a reaction chamber output flow channel; 111-reaction chamber upper cover; 112-overflow holes; 113-a first vertical through hole; 114-a first positioning post; 115-a first transverse connecting runner; 116-a first longitudinal connecting flow channel; 118-a second vertical through hole; 119-a third vertical through hole; 120-a fourth vertical through hole; 121-a fifth vertical through hole; 122-sixth vertical through hole;
20-lower chip; 201-sample introduction pool; 202-a lower cover of the reaction chamber; 203-a first positioning hole; 204-rectangular waste liquid pool; 2041-first waste liquid cavity split; 2042-second waste liquid cavity split; 205-spacer blocks; 206-strip waste liquid pool; 207-sample cavity output flow channel; 2071-the inner edge line of the flow path of the U-shaped elbow channel; 2072-the outer edge line of the flow path of the U-shaped elbow flow channel; the connection site of the flow path outer edge line of the A-U-shaped elbow flow channel and the sample injection pool; and the connection site of the inner edge line of the flow path of the flow passage of the B-U-shaped bent pipe and the sample injection pool.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. The following description of at least one exemplary embodiment is merely illustrative in nature and is in no way intended to limit the invention, its application, or uses. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention. The relative arrangement of the components and steps, expressions and numerical values set forth in these embodiments do not limit the scope of the present invention unless it is specifically stated otherwise. Techniques, methods, and apparatus known to those of ordinary skill in the relevant art may not be discussed in detail but are intended to be part of the specification where appropriate. In all examples shown and discussed herein, any particular value should be construed as exemplary only and not as limiting. Thus, other examples of the exemplary embodiments may have different values.
As shown in fig. 1 to 7, the microfluidic chip of the present invention includes a chip body 1, which is rectangular in overall configuration, and includes a sample injection cavity 11, a quantitative reaction cavity and a waste liquid cavity, which are sequentially arranged along a length direction of the chip body 1, specifically, the sample injection cavity 11 is located at a left side of the chip body 1, the waste liquid cavity is located at a right side, the quantitative reaction cavity is located between the two cavities, and the sample injection cavity 11, the quantitative reaction cavity and the waste liquid cavity are all located at a middle position of the chip body 1 in a width direction. The chip body 1 is further provided with two external liquid paths, namely a first external liquid path 13 and a second external liquid path 14.
In order to facilitate the production and assembly of the chip body 1 and simplify the micro flow channel, the chip body 1 of the invention is integrally of a two-piece structure, and comprises an upper chip 10 and a lower chip 20, wherein a film is pasted on the upper surface of the upper chip 10, the film does not cover the sample injection cavity 11, the external liquid connection port and the overflow hole 112, and the upper chip 10 and the lower chip 20 are pasted through a double-sided adhesive film.
As shown in fig. 1 to 4, the front surface of the upper chip 10 is respectively provided with a first transverse connecting channel 115, a first longitudinal connecting channel 116, a second longitudinal connecting channel 104, a first external liquid path interface 103, a second external liquid path interface 105, and a waste liquid overflow storage tank 102, while the back surface of the upper chip 10 is respectively provided with a reaction chamber upper cover 111, a reaction chamber input channel 106, a reaction chamber output channel 110, a rectangular waste liquid chamber cover plate 109, a waste liquid input channel 108, and a second transverse connecting channel 107, and the periphery of the back surface of the upper chip 10 is provided with first positioning pillars 114 as required; meanwhile, the upper chip 10 is provided with a sample inlet 101, an overflow hole 112 and first to sixth vertical through holes along the thickness direction, and the sample inlet 101, the overflow hole 112 and the first to sixth vertical through holes are all through holes which simultaneously penetrate through the upper surface and the lower surface of the upper chip 10; in the upper chip 10, one end of the first transverse connecting flow channel 115 is communicated with the upper end of the first vertical through hole 113, the other end of the first transverse connecting flow channel 115 is arranged by-pass with the upper end of the second vertical through hole 118 and can be communicated with the upper end of the second vertical through hole 118, and the upper end of the second vertical through hole 118 is provided with the first external liquid path interface 103 at a position flush with the upper surface of the upper chip 10; one end of the first longitudinal connecting flow passage 116 is communicated with the upper end of the third vertical through hole 119, the other end of the first longitudinal connecting flow passage 116 is arranged by-pass with the upper end of the fourth vertical through hole 120 and can be communicated with the upper end of the fourth vertical through hole 120, and the second external liquid-receiving path interface 105 is arranged at the position of the upper end of the fourth vertical through hole 120, which is flush with the upper surface of the upper chip 10; the upper end of the fifth vertical through hole 121 is in butt communication with one end of the second longitudinal connecting flow channel 104, the lower end of the fifth vertical through hole 121 is in butt communication with the outlet end of the second transverse connecting flow channel 107, the upper end of the sixth vertical through hole 122 is in butt communication with the other end of the second longitudinal connecting flow channel 104, and the lower end of the sixth vertical through hole 122 is in butt communication with the inlet end of the waste liquid input flow channel 108. The first external liquid path interface 103 is communicated with the reaction chamber upper cover 111 through the second vertical through hole 118 and the reaction chamber input flow channel 106 in sequence, so as to form the first external liquid path 13. The second external liquid path interface 105 is sequentially communicated with the reaction chamber upper cover 111 through the fourth vertical through hole 120 and the reaction chamber output flow channel 110, so as to form the second external liquid path 14.
As shown in fig. 1 and fig. 5 to 7, the upper surface of the lower chip 20 of the present invention is provided with a sample inlet cell 201, a U-shaped elbow channel (a sample inlet cavity output channel 207), a reaction cavity lower cover 202 and a waste liquid cell, and first positioning holes 203 are arranged around the upper surface of the lower chip 20 as required.
After a magnetic member (nickel rod) is added into the sample injection pool 201, the upper chip 10 and the lower chip 20 are assembled into a whole through a double-sided adhesive film arranged between the upper chip 10 and the lower chip 20 under the auxiliary positioning of the first positioning column 114 and the first positioning hole 203, so that the upper chip 10 and the lower chip 20 can be spliced to form a sample injection cavity 11, a quantitative reaction cavity and a waste liquid cavity, an outlet of the sample injection cavity is communicated with the reaction cavity input flow channel 106 through a U-shaped bent pipe flow channel and a first backflow prevention structure 16 in sequence, and the reaction cavity output flow channel 110 is communicated with the waste liquid input flow channel 108 through a second backflow prevention structure 15 and a third backflow prevention structure 17 in sequence; wherein:
the sample introduction cavity 11 is formed by connecting and communicating the sample introduction hole 101 with the pool port of the sample introduction pool 201, the quantitative reaction cavity is formed by connecting and communicating the reaction cavity upper cover 111 and the sealing reaction cavity lower cover 202, the waste liquid cavity comprises a rectangular waste liquid cavity and a strip-shaped waste liquid cavity, the rectangular waste liquid cavity is formed by connecting and sealing a rectangular waste liquid pool 204 with a rectangular waste liquid cavity cover plate 109, the strip-shaped waste liquid cavity is formed by sealing and communicating a strip-shaped waste liquid pool 206 with the bottom of the waste liquid overflow storage pool 102, and the waste liquid overflow storage pool 102 is communicated with the strip-shaped waste liquid pool 206 through an overflow hole 112; the lower end of the first vertical through hole 113 is in butt joint communication with the outlet end of the U-shaped elbow flow passage, and then the first transverse connecting flow passage 115 and the second vertical through hole 118 form the first backflow prevention structure 16; the second backflow prevention structure 15 is formed by the first longitudinal connection flow channel 116, and a third vertical through hole 119 and a fourth vertical through hole 120 provided at both ends thereof; the third backflow prevention structure 17 is formed by a second transverse connecting flow channel 107, a fifth vertical through hole 121, a second longitudinal connecting flow channel 104 and a sixth vertical through hole 122 which are sequentially connected between the third vertical through hole 119 and the waste liquid input flow channel 108.
Therefore, in the invention, the sample injection cavity output flow channel 207 directly communicated with the outlet of the sample injection pool 201 is set to be a U-shaped bent pipe flow channel, so that the magnetic mixing effect (mixing of the whole blood sample and the labeled antibody) of the sample in the sample injection cavity 11 is optimized, the sample in the sample injection cavity 11 is effectively prevented from flowing out from the inlet end of the U-shaped bent pipe flow channel in the magnetic stirring and mixing process, and the final detection effect of the sample is ensured.
Specifically, as shown in fig. 7, in the U-bend flow channel according to the present invention, under the condition that the pipe diameter of the flow channel is constant, an inner edge line 2071 of the flow channel of the U-bend flow channel is tangent to the sample injection cavity 11 (the sample injection pool 201 in the drawing), the tangent point is a point B, the external magnetic driving device makes the nickel rod clockwise drive the reaction liquid to rotate, and the liquid in the sample injection cavity 11 is not easy to flow into the U-bend flow channel at this angle.
In the invention, the outer edge line 2072 of the flow path of the U-shaped elbow flow channel intersects with the sample injection cavity 11 (the sample injection pool 201 in the drawing) at the point a, and the tangential angle alpha of the sample injection cavity 11 (the sample injection pool 201 in the drawing) passing through the point a ranges from 30 degrees to 75 degrees. In the drawing, the included angle β represents the inclination angle of the straight line OA, and the point O represents the center of the sample introduction chamber 11.
Specifically, in the present invention, the inner side of the rectangular waste liquid cavity is close to the side wall of the chip and extends to communicate with the elongated waste liquid pool 206, so as to increase the volume of the waste liquid cavity, and can contain more waste liquid, the elongated waste liquid pool 206 is covered by the upper chip 10, wherein the upper chip 10 is provided with an exhaust hole (overflow hole 112) at the position covering the elongated waste liquid pool 206, so that the liquid path flows smoothly, and the upper chip 10 is recessed in the position corresponding to the elongated waste liquid pool 206 to form the waste liquid overflow storage cavity 12, and is communicated with the elongated waste liquid pool 206 only through the exhaust hole. The purpose that sets up like this is in the exhaust gas time, if some waste liquid spills over the exhaust hole along with the gas, can keep in the waste liquid of upper chip 10 and spill over storage chamber 12, avoids polluting the upper surface of upper chip 10 (if do not lay the waste liquid and spill over storage chamber 12 in exhaust hole setting position, it directly is infected with on upper chip 10 when the exhaust hole is spilled over along with the gas to part waste liquid and lead to polluting the chip upper surface to probably appear).
In addition, in the invention, more than one spacer block 205 is arranged in the rectangular waste liquid cavity, so that the waste liquid cavity is divided into more than two waste liquid cavity split bodies which are communicated in a snake-shaped winding manner through the spacer blocks 205. In the present invention, there is only one spacer 205, and the waste liquid chamber is divided into two parts, namely, a first waste liquid chamber and a second waste liquid chamber according to the flow direction of the fluid. Therefore, the partition block 205 in the waste liquid cavity is convenient to fill the first waste liquid cavity split 2041 first after the waste liquid enters the waste liquid cavity, and then enters the second waste liquid cavity split 2042 through the communication flow channel between the first waste liquid cavity and the second waste liquid cavity split 2041, so that the induced waste liquid is filled with the absorbent paper in the first waste liquid cavity split 2041 first and then flows into the second waste liquid cavity split 2042, the absorbent paper in the waste liquid cavity can absorb the waste liquid completely, and waste of positions is avoided. If the partition block 205 is not arranged, the waste liquid flows irregularly after entering the waste liquid cavity, part of the absorbent paper does not absorb the waste liquid, the waste liquid enters the strip-shaped waste liquid cavity, and even enters the waste liquid overflow storage cavity 12 on the upper layer of the chip through the exhaust hole, so that the waste liquid overflow is possibly caused to pollute the chip, and the detection result is inaccurate; another function is to facilitate efficient venting of gases within the chip.
The principle of chip preparation:
adding a magnetic component such as a nickel rod into the sample injection pool 201 of the lower chip 20, adhering the upper chip 20 and the lower chip 20 by a double-sided adhesive tape under the assistance of positioning holes of the positioning columns, adding a coated antibody liquid into a liquid inlet hole at one end of an external liquid path, enabling the coated antibody liquid to flow into a quantitative-reaction cavity, sucking out the liquid from the other side after incubation, and drying in a vacuum drying oven or ventilating and drying at a sample injection port of the external liquid path. Then, the labeled antibody liquid is dripped into the sample injection cavity 11, and then the sample injection cavity is placed into a vacuum drying oven to be dried for 0.5h at the normal temperature of 20-27 ℃. Finally, the front surface of the upper layer chip 10 is pasted with a film without covering the sample injection cavity 11 and the external liquid inlet.
The chip detection principle is as follows: after a whole blood sample is added into the sample inlet hole 101, the sample and a labeled antibody preset in the sample inlet cavity 11 fully react under the uniform mixing action of a magnetic part, an external air circuit is applied to the sample inlet cavity 11, the sample is further pushed into the quantitative reaction cavity by air pressure to react with the coated antibody, air pressure is applied after the reaction, waste liquid after the reaction is blown into a waste liquid cavity, cleaning liquid can be added from an external liquid intersection according to different detection item requirements to clean the quantitative reaction cavity, finally, a chip detects a fluorescence signal through a light path detection device of a matched detection instrument, and a data processing system obtains a detection result.
Based on the microfluidic chip, the invention provides a use method of the microfluidic chip, which comprises the following steps:
step one, assembling a chip body 1
Step 1.1, preparing an upper chip 10 and a lower chip 20 with specific structure configurations as shown in figures 1-7 according to a plan;
step 1.2, after a magnetic component is added into a sample injection pool 201, an upper chip 10 and a lower chip 20 are assembled into a whole through a double-sided adhesive film arranged between the upper chip 10 and the lower chip 20 under the auxiliary positioning of a first positioning column 114 and a first positioning hole 203, so that the upper chip 10 and the lower chip 20 can be spliced to form a sample injection cavity 11, a quantitative reaction cavity and a waste liquid cavity, an outlet of the sample injection cavity 11 is communicated with a reaction cavity input flow channel 106 sequentially through a U-shaped bent pipe flow channel and a first backflow prevention structure 16, and a reaction cavity output flow channel 110 is communicated with a waste liquid input flow channel 108 sequentially through a second backflow prevention structure 17 and a third backflow prevention structure 17; wherein:
the sample introduction cavity 11 is formed by connecting and communicating the sample introduction hole 101 with the pool port of the sample introduction pool 201, the quantitative reaction cavity is formed by connecting and communicating the reaction cavity upper cover 111 and the sealing reaction cavity lower cover 202, the waste liquid cavity comprises a rectangular waste liquid cavity and a strip-shaped waste liquid cavity, the rectangular waste liquid cavity is formed by connecting and sealing a rectangular waste liquid pool 204 with a rectangular waste liquid cavity cover plate 109, the strip-shaped waste liquid cavity is formed by sealing and communicating a strip-shaped waste liquid pool 206 with the bottom of the waste liquid overflow storage pool 102, and the waste liquid overflow storage pool 102 is communicated with the strip-shaped waste liquid pool 206 through an overflow hole 112; the lower end of the first vertical through hole 113 is in butt joint communication with the outlet end of the U-shaped elbow flow channel, and then the first transverse connecting flow channel 115 and the second vertical through hole 118 are connected to form the first backflow prevention structure 16; the second backflow prevention structure 15 is formed by the first longitudinal connection flow channel 116, and a third vertical through hole 119 and a fourth vertical through hole 120 provided at both ends thereof; the third backflow prevention structure 17 is formed by a second transverse connecting flow channel 107, a fifth vertical through hole 121, a second longitudinal connecting flow channel 104 and a sixth vertical through hole 122 which are sequentially connected between the third vertical through hole 119 and the waste liquid input flow channel 108;
step 1.3, inputting coated antibody liquid into the quantitative reaction cavity through any one of the first external liquid path interface and the second external liquid path interface 105, and then blowing air into the quantitative reaction cavity through the other external liquid path interface until the coated antibody liquid in the quantitative reaction cavity is dried, so that the coated antibody is attached to the cavity wall of the quantitative reaction cavity; or inputting the coated antibody liquid into the quantitative reaction cavity through any one of the external liquid path interfaces for incubation and drying, and then sucking out the coated antibody liquid through the other external liquid path interface until the coated antibody liquid in the quantitative reaction cavity is dried, so that the coated antibody is attached to the wall of the quantitative reaction cavity;
step 1.4, dropwise adding a labeled antibody liquid into a sample injection pool 201 through a sample injection hole 101, and then placing the chip body 1 in a vacuum drying oven for drying at normal temperature for a period of time until the labeled antibody liquid is dried, so that the labeled antibody is attached to the wall of a sample injection cavity 11;
step 1.5, pasting a film on the front surface of the upper layer chip 10, and ensuring that the sample inlet hole 101, the external liquid inlet and the overflow hole 112 of the sample inlet cavity 11 are exposed;
step two, testing
Step 2.1, adding the whole blood sample into a sample inlet cell 201;
2.2, the magnetic force between the magnetic mechanism and the magnetic member is promoted through the magnetic mechanism arranged on the detection instrument, so that the magnetic member is driven to rotate clockwise in the sample injection cavity 11, the magnetic mechanism is stopped moving after the whole blood sample and the labeled antibody in the sample injection cavity 11 have complete immunoreaction, and the magnetic member stops rotating; in the process, the U-shaped elbow flow channel can effectively prevent the fluid in the sample introduction cavity 11 from flowing out;
step 2.3, applying pneumatic assistance to the sample injection cavity 11, and allowing the sample reaction liquid processed in the step 2.2 to flow into the quantitative reaction cavity for reaction through the U-shaped bent pipe flow channel and the first anti-backflow structure 16 in sequence;
2.4, after the reaction is finished, adopting pneumatic assistance to sequentially push the reacted liquid in the quantitative reaction cavity into a second and a third backflow prevention structures 17, and finally flowing into a waste liquid cavity; according to different detection project requirements, cleaning fluid can be added from an external fluid port to clean the quantitative reaction cavity, and the cleaned waste fluid is pushed into the waste fluid cavity through pneumatic assistance;
and 2.5, detecting the sample compound processed in the step 2.4 by using a detection instrument.

Claims (11)

1. An active micro-fluidic chip for optimizing a magnetic mixing effect comprises a chip body, wherein a sample injection cavity is arranged on the chip body, a magnetic component is preset in the sample injection cavity, a labeled antibody is attached to the sample injection cavity, and meanwhile, an outlet of the sample injection cavity is directly and integrally communicated with an output runner of the sample injection cavity; the U-shaped elbow flow channel can effectively prevent fluid in the sample feeding cavity from flowing out.
2. The active micro-fluidic chip for optimizing the uniform magnetic mixing effect according to claim 1, wherein a quantitative reaction cavity, a first external liquid path interface and a second external liquid path interface are further arranged on the chip body;
the inlet of the quantitative reaction cavity is directly and integrally communicated with the outlet end of the reaction cavity input flow channel, and the outlet of the quantitative reaction cavity is directly and integrally communicated with the inlet end of the reaction cavity output flow channel; the coating antibody is attached to the quantitative reaction cavity;
the first external liquid path interface can be communicated with the input runner of the reaction cavity, and the second external liquid path interface can be communicated with the output runner of the reaction cavity.
3. The active microfluidic chip for optimizing the uniform magnetic mixing effect according to claim 2, further comprising a waste liquid chamber; the inlet of the waste liquid cavity is directly communicated with the outlet end of the waste liquid input flow channel integrally;
the inlet end of the reaction cavity input flow passage is communicated with the outlet end of the U-shaped bent pipe flow passage through a first backflow prevention structure; the outlet end of the reaction cavity output flow channel is communicated with the inlet end of the waste liquid input flow channel through the second backflow prevention structure and the third backflow prevention structure in sequence.
4. The active micro-fluidic chip for optimizing the uniform magnetic mixing effect according to claim 3, wherein the first backflow prevention structure comprises a first vertical through hole, a first transverse connecting flow channel and a second vertical through hole; the second backflow prevention structure comprises a third vertical through hole, a first longitudinal connecting flow channel and a fourth vertical through hole; the third backflow prevention structure comprises a second longitudinal connecting flow passage, a second transverse connecting flow passage, a fifth vertical through hole and a sixth vertical through hole;
the first through sixth vertical through holes are all holes arranged along the thickness direction of the chip body;
one end of the first transverse connecting flow passage is in butt joint communication with the outlet end of the U-shaped bent pipe flow passage through a first vertical through hole; the other end of the first transverse connecting flow channel is arranged at the upper end of the second vertical through hole in a bypass mode and can be communicated with the upper end of the second vertical through hole, and the lower end of the second vertical through hole is directly communicated with the inlet end of the reaction cavity input flow channel; the position of the upper end of the second vertical through hole is provided with the first external liquid circuit interface;
one end of the first longitudinal connecting flow channel is communicated with the inlet end of the second transverse connecting flow channel through a third vertical through hole, the other end of the first longitudinal connecting flow channel is arranged at the upper end of the fourth vertical through hole in a bypass mode and can be communicated with the upper end of the fourth vertical through hole, and the lower end of the fourth vertical through hole is directly communicated with the outlet end of the reaction cavity output flow channel; the position of the upper end of the fourth vertical through hole is provided with the second external liquid path interface in a matching way;
the outlet end of the second transverse connecting flow channel is communicated with one end of the second longitudinal connecting flow channel through a fifth vertical through hole, and the other end of the second longitudinal connecting flow channel is communicated with the inlet of the waste liquid cavity input flow channel through a sixth vertical through hole.
5. The active micro-fluidic chip for optimizing the uniform magnetic mixing effect according to claim 3, wherein the chip body is formed by laminating an upper chip and a lower chip, and a film is attached to the upper surface of the upper chip;
the sample injection cavity comprises a sample injection pool arranged on the upper surface of the lower chip and a sample injection hole which penetrates through the upper chip and is in butt joint communication with the inlet of the sample injection pool;
the quantitative reaction cavity comprises a reaction cavity lower cover arranged on the upper surface of the lower chip and a reaction cavity upper cover arranged on the lower surface of the upper chip and capable of being sealed with the reaction cavity lower cover; the reaction cavity input runner and the reaction cavity output runner are arranged on the lower surface of the upper chip and can be correspondingly communicated with an inlet and an outlet of the reaction cavity upper cover respectively;
the waste liquid cavity comprises a waste liquid pool arranged on the upper surface of the lower chip and a waste liquid cavity cover plate which is arranged on the lower surface of the upper chip and can be sealed with a pool opening of the waste liquid pool; the waste liquid input flow channel is arranged on the lower surface of the upper chip and can be communicated with the waste liquid cavity cover plate;
the first through sixth vertical through holes are all through holes arranged along the thickness direction of the upper chip, and the first through sixth vertical through holes are all through holes arranged through the upper chip;
the first transverse connecting flow channel, the first longitudinal connecting flow channel and the second longitudinal connecting flow channel are uniformly distributed at corresponding positions on the upper surface of the upper chip; and the second transverse connecting flow channel is arranged at the corresponding position of the lower surface of the upper layer chip.
6. The active micro-fluidic chip for optimizing the uniform magnetic mixing effect according to claim 5, wherein the upper chip and the lower chip are inserted into a whole through the first positioning column and the first positioning hole which are matched with each other, the upper chip and the lower chip are bonded through the double-sided adhesive film, and meanwhile, the double-sided adhesive film is provided with the hollow holes which are matched with each cavity and each pipeline position arranged on the front surface of the lower chip, so that the upper chip and the lower chip are bonded to form the required cavity and flow path.
7. The active micro-fluidic chip for optimizing the uniform magnetic mixing effect according to claim 5, wherein the waste liquid cavity comprises a rectangular waste liquid cavity and an elongated waste liquid cavity extending along one corner position of the rectangular waste liquid cavity and communicated with the rectangular waste liquid cavity;
the waste liquid pool comprises a rectangular waste liquid pool and a strip-shaped waste liquid pool which extends along one corner of the rectangular waste liquid pool and is communicated with the rectangular waste liquid pool;
the waste liquid cavity cover plate comprises a rectangular waste liquid cavity cover plate which is arranged on the lower surface of the upper chip and is sealed with the tank opening of the rectangular waste liquid tank; the rectangular waste liquid pool and the rectangular waste liquid cavity cover plate are sealed to form the rectangular waste liquid cavity;
a waste liquid overflow storage tank with an upward notch is arranged on the upper surface of the upper chip at a position corresponding to the strip-shaped waste liquid tank; the bottom of the waste liquid overflow storage tank is provided with an overflow hole which is communicated with the strip-shaped waste liquid pool; the notch of the waste liquid overflowing the storage tank is sealed by the film.
8. The active micro-fluidic chip for optimizing the magnetic uniform mixing effect according to claim 2 or 3, wherein the sample injection cavity is arranged at the left side of the quantitative reaction cavity; the flow path inner edge line of the U-shaped bent pipe flow channel is tangent to the sample injection cavity at the point B, the flow path outer edge line of the U-shaped bent pipe flow channel is intersected with the sample injection cavity at the point A, and the tangential angle alpha of the sample injection cavity passing through the point A ranges from 30 degrees to 75 degrees.
9. The active micro-fluidic chip for optimizing the uniform magnetic mixing effect according to claim 3, wherein the waste liquid cavity comprises a rectangular waste liquid cavity and an elongated waste liquid cavity extending along one corner position of the rectangular waste liquid cavity and communicated with the rectangular waste liquid cavity;
more than one spacer block is arranged in the rectangular waste liquid cavity;
the waste liquid cavity is divided into more than two waste liquid cavity split bodies which are communicated in a snake-shaped winding manner through the partition blocks.
10. An active micro-fluidic chip for optimizing a magnetic uniform mixing effect comprises a chip body, and is characterized in that the chip body comprises an upper chip, a lower chip and a double-sided adhesive film arranged between the upper chip and the lower chip; wherein:
a plurality of first positioning columns are arranged on the periphery of the upper surface of the lower chip as required, and matched first positioning holes are arranged on the periphery of the lower surface of the upper chip at positions corresponding to the first positioning columns;
the upper surface of the lower chip is respectively provided with a sample feeding pool, a U-shaped bent pipe flow passage, a reaction cavity lower cover and a waste liquid pool;
the back surface of the upper chip is respectively provided with a reaction cavity upper cover, a reaction cavity input flow channel, a reaction cavity output flow channel, a rectangular waste liquid cavity cover plate, a waste liquid input flow channel and a second transverse connecting flow channel; the front surface of the upper chip is respectively provided with a first transverse connecting flow channel, a first longitudinal connecting flow channel, a second longitudinal connecting flow channel, a first external liquid path interface, a second external liquid path interface and a waste liquid overflow storage tank; meanwhile, the upper chip is provided with a sample inlet, an overflow hole and first to sixth vertical through holes along the thickness direction, and the sample inlet, the overflow hole and the first to sixth vertical through holes are all through holes which simultaneously penetrate through the upper surface and the lower surface of the upper chip;
one end of the first transverse connecting flow channel is communicated with the upper end of the first vertical through hole, the other end of the first transverse connecting flow channel is arranged at the upper end of the second vertical through hole in a bypass mode and can be communicated with the upper end of the second vertical through hole, and the upper end of the second vertical through hole is provided with the first external liquid circuit interface in a position flush with the upper surface of the upper chip; one end of the first longitudinal connecting flow passage is communicated with the upper end of the third vertical through hole, the other end of the first longitudinal connecting flow passage is arranged in a bypass way with the upper end of the fourth vertical through hole and can be communicated with the upper end of the fourth vertical through hole, and the upper end of the fourth vertical through hole is provided with the second external liquid connecting channel interface at a position flush with the upper surface of the upper chip; the upper end of the fifth vertical through hole is communicated with one end of the second longitudinal connecting flow channel, the lower end of the fifth vertical through hole is communicated with the outlet end of the second transverse connecting flow channel, the upper end of the sixth vertical through hole is communicated with the other end of the second longitudinal connecting flow channel, and the lower end of the sixth vertical through hole is communicated with the inlet end of the waste liquid input flow channel;
the chip body is bonded into a whole through a double-sided adhesive film under the auxiliary positioning of a first positioning column and a first positioning hole, so that the upper chip and the lower chip can be spliced to form a sample feeding cavity, a quantitative reaction cavity and a waste liquid cavity, an outlet of the sample feeding cavity is communicated with an input flow channel of the reaction cavity sequentially through a U-shaped bent pipe flow channel and a first backflow prevention structure, and an output flow channel of the reaction cavity is communicated with an input flow channel of the waste liquid sequentially through a second backflow prevention structure and a third backflow prevention structure; wherein:
the sample feeding cavity is formed by butt joint and communication of a sample feeding hole and a sample feeding pool port; the quantitative reaction cavity is formed by splicing an upper reaction cavity cover and a lower sealing reaction cavity cover; the waste liquid cavity comprises a rectangular waste liquid cavity and a strip-shaped waste liquid cavity, the rectangular waste liquid cavity is formed by sealing a rectangular waste liquid pool through a rectangular waste liquid cavity cover plate, the strip-shaped waste liquid cavity is formed by sealing a strip-shaped waste liquid pool through the bottom of a waste liquid overflowing storage tank, and the waste liquid overflowing storage tank is communicated with the strip-shaped waste liquid pool through an overflow hole which penetrates through the bottom of the waste liquid overflowing storage tank;
the first backflow prevention structure is formed by butt joint and communication of the lower end of the first vertical through hole and the outlet end of the U-shaped bent pipe flow channel; the second backflow prevention structure is formed by the first longitudinal connecting flow channel and a third vertical through hole and a fourth vertical through hole which are arranged at the two ends of the first longitudinal connecting flow channel; the third backflow prevention structure is formed by a second transverse connecting flow channel, a fifth vertical through hole, a second longitudinal connecting flow channel and a sixth vertical through hole which are sequentially connected between the third vertical through hole and the waste liquid input flow channel.
11. The use method of the active microfluidic chip for optimizing the magnetic uniform mixing effect of claim 10 is characterized by comprising the following steps of:
step one, assembling a chip body
Step 1.1, according to the planning, a sample injection pool, a U-shaped bent pipe flow channel, a reaction cavity lower cover and a waste liquid pool are respectively arranged on the upper surface of a lower chip, and first positioning columns are arranged on the periphery of the upper surface of the lower chip as required; the back surface of the upper chip is respectively provided with a reaction cavity upper cover, a reaction cavity input flow channel, a reaction cavity output flow channel, a rectangular waste liquid cavity cover plate, a waste liquid input flow channel and a second transverse connecting flow channel, and first positioning holes are arranged on the periphery of the back surface of the upper chip as required; a first transverse connecting flow channel, a first longitudinal connecting flow channel, a second longitudinal connecting flow channel, a first external liquid path interface, a second external liquid path interface and a waste liquid overflow storage tank are respectively arranged on the front surface of the upper layer chip, and a sample inlet hole, an overflow hole and first to sixth vertical through holes are vertically arranged on the upper surface of the upper layer chip in a penetrating manner; wherein:
one end of the first transverse connecting flow passage is communicated with the upper end of the first vertical through hole, the other end of the first transverse connecting flow passage is arranged at the upper end of the second vertical through hole in a bypass mode and can be communicated with the upper end of the second vertical through hole, and the upper end of the second vertical through hole is provided with the first external liquid path interface in a position flush with the upper surface of the upper chip in a matching mode; one end of the first longitudinal connecting flow passage is communicated with the upper end of the third vertical through hole, the other end of the first longitudinal connecting flow passage is arranged in a bypass way with the upper end of the fourth vertical through hole and can be communicated with the upper end of the fourth vertical through hole, and the upper end of the fourth vertical through hole is provided with the second external liquid connecting channel interface at a position flush with the upper surface of the upper chip; the upper end of the fifth vertical through hole is communicated with one end of the second longitudinal connecting flow channel, the lower end of the fifth vertical through hole is communicated with the outlet end of the second transverse connecting flow channel, the upper end of the sixth vertical through hole is communicated with the other end of the second longitudinal connecting flow channel, and the lower end of the sixth vertical through hole is communicated with the inlet end of the waste liquid input flow channel in a butt joint way;
step 1.2, after a magnetic component is added into a sample injection pool, an upper chip and a lower chip are assembled into a whole through a double-sided adhesive film arranged between the upper chip and the lower chip under the auxiliary positioning of a first positioning column and a first positioning hole, so that the upper chip and the lower chip can be spliced to form a sample injection cavity, a quantitative reaction cavity and a waste liquid cavity, an outlet of the sample injection cavity is communicated with an input flow channel of the reaction cavity sequentially through a U-shaped bent pipe flow channel and a first backflow prevention structure, and an output flow channel of the reaction cavity is communicated with an input flow channel of the waste liquid sequentially through a second backflow prevention structure and a third backflow prevention structure; wherein:
the sample introduction cavity is formed by connecting and communicating a sample introduction hole with a pool port of the sample introduction pool in a butt joint mode, the quantitative reaction cavity is formed by connecting and sealing an upper cover of the reaction cavity with a lower cover of the sealing reaction cavity, the waste liquid cavity comprises a rectangular waste liquid cavity and a strip-shaped waste liquid cavity, the rectangular waste liquid cavity is formed by sealing and sealing a cover plate of the rectangular waste liquid cavity with the rectangular waste liquid pool, the strip-shaped waste liquid cavity is formed by sealing and sealing a groove bottom of a waste liquid overflow storage groove with the strip-shaped waste liquid pool, and the waste liquid overflow storage groove is communicated with the strip-shaped waste liquid pool through an overflow hole; the lower end of the first vertical through hole is in butt joint communication with the outlet end of the U-shaped bent pipe flow passage, and then the first transverse connecting flow passage and the second vertical through hole form the first anti-backflow structure; the second backflow prevention structure is formed by the first longitudinal connecting flow channel and a third vertical through hole and a fourth vertical through hole which are arranged at the two ends of the first longitudinal connecting flow channel; the third backflow prevention structure is formed by a second transverse connecting flow channel, a fifth vertical through hole, a second longitudinal connecting flow channel and a sixth vertical through hole which are sequentially connected between the third vertical through hole and the waste liquid input flow channel;
step 1.3, adding coated antibody liquid into the quantitative reaction cavity through any one of the first external liquid path interface and the second external liquid path interface, after incubation, sucking out the liquid through the other external liquid path interface, and then placing the liquid in a vacuum drying oven for drying or performing ventilation drying through the first external liquid path interface or the second external liquid path interface until the coated antibody is attached to the cavity wall of the quantitative reaction cavity;
step 1.4, dropwise adding a labeled antibody liquid into a sample injection pool through a sample injection hole, and then placing the chip body in a vacuum drying oven for drying at normal temperature for a period of time until the labeled antibody liquid is dried, so that the labeled antibody is attached to the wall of the sample injection cavity;
step 1.5, pasting a film on the front surface of the upper layer chip, and ensuring that a sample inlet hole, an external liquid connection port and an overflow hole of a sample inlet cavity are exposed;
step two, testing
Step 2.1, flowing the whole blood sample into a sample introduction pool;
2.2, promoting the magnetic force between the magnetic mechanism and the magnetic member through the magnetic mechanism arranged on the detection instrument to drive the magnetic member to rotate clockwise in the sample injection cavity, stopping moving the magnetic mechanism until the whole blood sample and the labeled antibody in the sample injection cavity have complete immunoreaction, and stopping rotating the magnetic member; in the process, the U-shaped bent pipe flow channel can effectively prevent the fluid in the sample feeding cavity from flowing out;
step 2.3, applying pneumatic power assistance to the sample injection cavity, and allowing the sample reaction liquid processed in the step 2.2 to flow into the quantitative reaction cavity for reaction through the U-shaped bent pipe flow channel and the first anti-backflow structure in sequence;
2.4, after the reaction is finished, pushing the reacted liquid in the quantitative reaction cavity into a second and a third backflow prevention structures in sequence by adopting pneumatic assistance, and finally flowing into a waste liquid cavity; according to different detection project requirements, cleaning fluid can be added from an external fluid port to clean the quantitative reaction cavity, and the cleaned waste fluid is pushed into the waste fluid cavity through pneumatic assistance;
and 2.5, detecting the sample compound processed in the step 2.4 by using a detection instrument.
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