WO2022116758A1 - 一种多功能微流控检测芯片 - Google Patents

一种多功能微流控检测芯片 Download PDF

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Publication number
WO2022116758A1
WO2022116758A1 PCT/CN2021/127908 CN2021127908W WO2022116758A1 WO 2022116758 A1 WO2022116758 A1 WO 2022116758A1 CN 2021127908 W CN2021127908 W CN 2021127908W WO 2022116758 A1 WO2022116758 A1 WO 2022116758A1
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Prior art keywords
chamber
sample
diluent
quantitative
reaction
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PCT/CN2021/127908
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English (en)
French (fr)
Inventor
许行尚
陈·杰弗瑞
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南京岚煜生物科技有限公司
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Application filed by 南京岚煜生物科技有限公司 filed Critical 南京岚煜生物科技有限公司
Priority to JP2022537199A priority Critical patent/JP2023509368A/ja
Priority to KR1020227023687A priority patent/KR20220113775A/ko
Priority to US18/012,653 priority patent/US20230249180A1/en
Priority to EP21899792.2A priority patent/EP4257239A1/en
Publication of WO2022116758A1 publication Critical patent/WO2022116758A1/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
    • B01L3/502723—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 venting arrangements
    • 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
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
    • B01F23/40—Mixing liquids with liquids; Emulsifying
    • B01F23/45—Mixing liquids with liquids; Emulsifying using flow mixing
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
    • B01F23/40—Mixing liquids with liquids; Emulsifying
    • B01F23/45—Mixing liquids with liquids; Emulsifying using flow mixing
    • B01F23/451—Mixing liquids with liquids; Emulsifying using flow mixing by injecting one liquid into another
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
    • B01F23/40—Mixing liquids with liquids; Emulsifying
    • B01F23/48—Mixing liquids with liquids; Emulsifying characterised by the nature of the liquids
    • B01F23/483—Mixing liquids with liquids; Emulsifying characterised by the nature of the liquids using water for diluting a liquid ingredient, obtaining a predetermined concentration or making an aqueous solution of a concentrate
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F33/00—Other mixers; Mixing plants; Combinations of mixers
    • B01F33/30—Micromixers
    • B01F33/301—Micromixers using specific means for arranging the streams to be mixed, e.g. channel geometries or dispositions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F33/00—Other mixers; Mixing plants; Combinations of mixers
    • B01F33/30—Micromixers
    • B01F33/301—Micromixers using specific means for arranging the streams to be mixed, e.g. channel geometries or dispositions
    • B01F33/3017—Mixing chamber
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/80—Forming a predetermined ratio of the substances to be mixed
    • B01F35/83—Forming a predetermined ratio of the substances to be mixed by controlling the ratio of two or more flows, e.g. using flow sensing or flow controlling devices
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F2101/00—Mixing characterised by the nature of the mixed materials or by the application field
    • B01F2101/23—Mixing of laboratory samples e.g. in preparation of analysing or testing properties of materials
    • 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
    • B01L2200/02—Adapting objects or devices to another
    • B01L2200/028—Modular arrangements
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0647—Handling flowable solids, e.g. microscopic beads, cells, particles
    • 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
    • B01L2200/0684—Venting, avoiding backpressure, avoid gas bubbles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/10—Integrating sample preparation and analysis in single entity, e.g. lab-on-a-chip concept
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • 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
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0832—Geometry, shape and general structure cylindrical, tube shaped
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—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
    • B01L2300/0861—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
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    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/087—Multiple sequential chambers
    • 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

Definitions

  • the invention belongs to the field of in vitro microfluidic detection, in particular to a multifunctional microfluidic detection chip.
  • Microfluidic detection chip technology integrates basic operation units such as sample preparation, reaction, separation, and detection in biological, chemical, and medical analysis processes into a micron-scale chip to automatically complete the entire analysis process. It has great potential in biology, chemistry, medicine and other fields.
  • the microfluidic detection chip technology in the prior art still has some defects in practical application, such as complex structure, large sample usage, inaccurate detection results, too small volume ratio between the dilution chamber and the sample chamber, production High cost.
  • the centrifugal microfluidic detection chip on the market requires a large amount of blood sample, which is not suitable for clinical blood sampling detection of infants, especially newborns and critically ill patients, and lacks effective quality control functions; therefore, it is necessary to develop a centrifugal microfluidic detection chip.
  • the detection chip has a simple structure, a small amount of samples can be injected at a time, multiple indicators can be detected in a small volume, the production cost is low, it is suitable for mass production, and the detection results are more accurate.
  • the purpose of the present invention is to provide a multifunctional microfluidic detection chip, which can overcome the defects of the existing microfluidic detection chip technology, can reduce the amount of samples and further improve the accuracy of the detection results.
  • a multifunctional microfluidic detection chip includes a chip body, and the chip body is provided with a sample injection cavity, a sample quantitative cavity, a sample overflow cavity, a diluent storage cavity, a diluent quantitative cavity, a diluent overflow cavity, Quantitative mixing chamber, reaction chamber and ventilation holes;
  • the sample injection chamber can be used to inject the reaction sample to be detected, and is connected to the sample quantitative chamber through the micro-channel, the reaction sample can enter the sample quantitative chamber from the sample injection chamber, and the excess reaction sample enters the sample overflow chamber;
  • the diluent storage cavity is connected with the diluent quantitative cavity through the micro-channel, the diluent can enter the diluent quantitative cavity from the diluent storage cavity, and the excess diluent enters the diluent overflow cavity;
  • the reaction cavity includes one or more reaction chambers and a sample blank chamber;
  • the mixed liquid After the sample in the sample quantitative chamber and the diluent in the diluent quantitative chamber are mixed in the quantitative mixing chamber, the mixed liquid enters the reaction chamber through the microfluidic channel to react with the reaction reagents therein for detection, and the mixed liquid enters the sample at the same time.
  • the blank chamber serves as a sample blank to be tested.
  • the sample quantitative chamber includes a first sample quantitative chamber and a second sample quantitative chamber.
  • the reaction chamber includes several equidistantly distributed reaction chambers.
  • the reaction chamber has the same volume as the sample blank chamber.
  • the reaction sample in the sample quantitative chamber and the diluent in the diluent quantitative chamber enter the quantitative mixing chamber through microchannel I and microchannel II respectively after mixing; the mixed solution enters the reaction through microchannel III and microchannel IV in turn.
  • the chamber and the sample blank chamber; the microfluidic channel I, the microfluidic channel II and the microfluidic channel III respectively include an inflection point which is close to the center of the chip body relative to the corresponding liquid outflow chamber.
  • the channel of the sample blank chamber is wider than the channel of the reaction chamber.
  • the quantitative mixing chamber and the reaction chamber are respectively communicated with the ventilation holes.
  • the quantitative ratio of reaction sample and diluent in the quantitative mixing chamber is less than 1:30.
  • the quantitative ratio of the reaction sample to the diluent in the quantitative mixing chamber is 1:50.
  • the reaction reagent is lyophilized beads prepared by lyophilization.
  • the lyophilized beads have a radius between 0.5mm and 1mm.
  • the microfluidic channel between the sample quantitative cavity and the sample overflow cavity is also provided with a sample ventilation channel connected to the outside of the chip, and the microfluidic channel between the diluent quantitative cavity and the diluent overflow cavity is also provided with a diluent ventilation channel. connected to the outside of the chip.
  • the chip is a fan-shaped structure.
  • the chip also includes a chip upper layer and a chip middle layer, and the chip body is located at the lower layer.
  • Each side of the chip body is provided with a splicing card position.
  • the chip body can be used to detect biochemical items, immune items, nucleic acid molecule items and blood coagulation items.
  • the present invention has the following advantages:
  • the quantitative ratio of the reaction sample and the diluent is designed to be less than 1:30, and an appropriate ratio of the reaction sample and the diluent is selected according to the needs.
  • a microfluidic detection chip with a fixed structure is designed. In the application, it is only necessary to change the reagent formula required for different detection indicators, and a chip design template can meet the clinical detection of different projects or project combination indicators.
  • reaction chambers of the present invention have the same three-dimensional size as the sample blank chamber, so the volume is the same, and the volume of the reaction sample and the diluent entered during the reaction are the same, so only one sample blank chamber needs to be set up to realize several reaction chambers
  • the effective quality control of the detection index combination simplifies the chip structure and reduces the cost.
  • the sample blank chamber of the present invention is located at the end of the reaction chamber array, shares a micro-channel with the reaction chamber, and can be used as a sample blank chamber and a mixing liquid overflow chamber at the same time, and the sample blank is the reaction sample and the diluent. Mixing the liquid, the test result will eliminate the influence of the sample itself, and the test value of the sample blank can detect whether the amount of the sample and the diluent entering the reaction chamber is sufficient, which has the dual functions of improving the accuracy of the test results and judging the validity of the test.
  • the blood collection volume of the present invention is small, only one drop of blood is needed for one injection, and simultaneous detection of multiple indicators can be realized, and the blood sample consumption is only 1/10 to 1/5 of that of ordinary products in the market, and is especially suitable for neonatal and long-term tumors. Clinical detection of patients with difficulty in blood collection due to radiotherapy, chemotherapy and other reasons.
  • the chip of the present invention has a fan-shaped structure, and a splicing card position is provided on the left and right edges of the chip for splicing two chips, and the three chips can form a circular chip, which can detect three samples at a time, which can greatly increase the Measure the throughput of the sample.
  • FIG. 1 is a schematic diagram of the overall structure of the multifunctional microfluidic detection chip of the present invention.
  • FIG. 2 is a schematic diagram of the front structure of the chip body in the multifunctional microfluidic detection chip of the present invention.
  • FIG. 3 is a schematic three-dimensional structure diagram of the chip body in the multifunctional microfluidic detection chip of the present invention.
  • FIG. 4 is a schematic front view of the overall three-dimensional structure of the multifunctional microfluidic detection chip of the present invention.
  • FIG. 5 is a schematic view of the back of the overall three-dimensional structure of the multifunctional microfluidic detection chip of the present invention.
  • FIG. 6 is a schematic diagram of the assembled structure of the disc-type multifunctional microfluidic detection chip assembled by the multifunctional microfluidic detection chip of the present invention.
  • FIG. 7 is a schematic diagram of the overall structure of a disc-type multifunctional microfluidic detection chip formed by splicing the multifunctional microfluidic detection chip of the present invention.
  • the multifunctional microfluidic detection chip of the present invention is manufactured by injection molding of a mold, and can be used with detection equipment.
  • the detection chip has a fan-shaped structure, preferably one-third of the circle, that is, the angle formed by the intersection of the left and right extension lines is 120 degrees.
  • the fan-shaped structure can be part of the circle, and the rest can be designed and added according to needs part.
  • the multifunctional microfluidic detection chip of the present invention includes three layers: upper, middle and lower layers, as shown in FIG. lower chip.
  • the upper layer 1 of the chip is provided with a through hole 261 of the upper sample injection chamber, a through hole 262 of the upper diluent storage chamber and a group of through holes 263 of the upper reaction chamber.
  • the upper sample injection chamber through holes 261 and the upper diluent storage chamber through holes 262 are located near the center of the upper layer 1 of the chip, and the upper reaction chamber through holes 263 are equally spaced and distributed inside the upper edge of the upper layer 1 of the chip.
  • the upper sample injection chamber through hole 261 is used for adding samples, and the upper diluent storage chamber through hole 262 and the upper reaction chamber through hole 263 correspond to the diluent storage chamber 12 and each reaction chamber, respectively.
  • the middle layer 2 of the chip is provided with through holes 264 in the middle layer injection chamber, through holes 265 in the middle layer diluent storage chamber, a set of ventilation through holes 266 and a set of positioning hole through holes 267 .
  • the through-hole 264 of the middle-layer injection chamber and the through-hole 265 of the middle-layer diluent storage chamber are located near the center of the middle layer 2 of the chip, and correspond to the through-hole 261 of the upper sample injection chamber of the upper layer 1 of the chip and the through-hole 262 of the upper layer of the diluent storage chamber respectively.
  • the through hole 266 and the positioning hole through hole 267 are farther from the center of the middle layer 2 of the chip than the through hole 264 of the middle layer injection chamber and the through hole 265 of the middle layer diluent storage chamber.
  • I 221 corresponds to the ventilation hole II 222
  • the positioning hole through hole 267 corresponds to a group of positioning holes 25 on the lower chip body 3 .
  • the chip body 3 is provided with a sample injection chamber 4, a sample quantitative chamber, a sample overflow chamber 11, a diluent storage chamber 12, a diluent quantitative chamber 15, a diluent overflow chamber 16, and a quantitative mixing chamber.
  • the cavity 17, the reaction cavity, the ventilation holes I 221 and the ventilation holes II 222, and the chambers are all connected by micro-channels.
  • the sample injection chamber 4 and the diluent storage chamber 12 are located near the center of the chip body 3.
  • the top of the sample injection chamber 4 is provided with a sample cover 5, and the sample cover 5 is provided with a sample inlet 6, which can be used for injecting the sample to be detected, diluting
  • the liquid storage chamber 12 is provided with a diluting liquid bag 13, and a puncturing structure 14 is provided at the bottom for injecting the diluting liquid.
  • the sample quantitative chamber includes a first sample quantitative chamber 9 and a second sample quantitative chamber 10.
  • the first sample quantitative chamber 9 and the second sample quantitative chamber 10 communicate with the sample injection chamber 4.
  • the first sample quantitative chamber 9 and the first sample quantitative chamber The two-sample quantitative chamber 10 is farther from the center of the chip body 3 than the sample injection chamber 4.
  • the sample in the sample injection chamber 4 will pass through the bottom port of the sample injection chamber 4 due to the centrifugal effect. It flows through the reverse flow channel, and then flows toward the first sample quantitative chamber 9 and the second sample quantitative chamber 10 through the front flow channel.
  • the outlet of the flow channel is located on the side of the first sample quantitative cavity 9 close to the center of the chip body 3;
  • the vertical flow channels are connected;
  • the bottom surface of the injection cavity 4 is provided with a flow channel sealing film 8 of the injection cavity to prevent the sample from overflowing when it flows through the reverse flow channel.
  • the first sample quantification chamber 9 and the second sample quantification chamber 10 are provided to achieve better separation of upper plasma and lower blood cells and quantification of plasma samples.
  • the diluent quantitative chamber 15 is communicated with the diluent storage chamber 12.
  • the diluent quantitative chamber 15 needs to be farther from the center of the chip body 3 than the diluent storage chamber 12. Therefore, when the chip body 3 is rotated by the centrifugal device, the diluent storage The diluent in the cavity 12 will flow toward the diluent dosing cavity 15 due to centrifugal action.
  • the volume ratio of the first sample quantitative chamber 9 and the second sample quantitative chamber 10 to the diluent quantitative chamber 15 determines the mixing ratio of the reaction sample and the diluent.
  • the overflow chamber includes a sample overflow chamber 11 and a diluent overflow chamber 16, which are respectively connected with the first sample quantitative chamber 9 and the diluent quantitative chamber 15.
  • the sample overflow chamber 11 is farther from the center of the chip body 3 than the first sample quantitative chamber 9 and the second sample quantitative chamber 10 . Therefore, when the chip body 3 is rotated by centrifugal driving, there are more samples than the first sample quantitative chamber 9 .
  • the sample with the capacity of the second sample quantitative chamber 10 will flow into the sample overflow chamber 11 due to the centrifugal force.
  • the diluent overflow chamber 16 is farther from the center of the chip body 3 than the diluent quantitative chamber 15. Therefore, when the chip body 3 is rotated by centrifugal driving, the diluent that is larger than the diluent quantitative chamber 15 will be driven by centrifugal force. Flow to the diluent overflow chamber 16.
  • the microfluidic channel between the first sample quantitative chamber 9 and the sample overflow chamber 11 is also connected to the outside of the chip via a sample ventilation channel 23 .
  • the microchannel between the diluent quantitative chamber 15 and the diluent overflow chamber 16 The flow channel is also connected to the outside of the chip via a diluent vent channel 24 . Vented channels are provided for smoother flow of diluents and samples.
  • the quantitative mixing chamber 17 communicates with the first sample quantitative chamber 9 and the second sample quantitative chamber 10 respectively through the microchannel I191, and communicates with the diluent quantitative chamber 15 through the microchannel II192.
  • the quantitative mixing chamber 17 needs to be relatively
  • the first sample quantification chamber 9, the second sample quantification chamber 10, and the diluent quantification chamber 15 are far from the center of the chip body 3, and the quantitative sample and the quantitative diluent can be mixed and diluted for detection.
  • the quantitative mixing chamber 17 makes the mixed liquid flow into each reaction chamber 18 in the reaction chamber through the microfluidic channel III 193 and the microfluidic channel IV194 so as to react with the detection reagent therein.
  • the reaction chamber includes several equidistantly distributed reaction chambers 18 and a sample blank chamber 21 at the end of the flow channel.
  • the volume of the reaction chambers 18 is the same, and the reaction reagents required for the reaction are contained therein.
  • the reaction reagents can be frozen.
  • the lyophilized beads produced by the dry method the radius of each lyophilized bead is between 0.5mm and 1mm, and the small volume of the reaction reagent increases the carrying capacity of the reaction chamber 18 in the same size chip, effectively improving the Detection sensitivity and detection efficiency, in addition, the use of lyophilized beads for the reaction reagents effectively increases the shelf life of the reagents in storage.
  • the channel of the sample blank chamber 21 is wider than the channels of the other reaction chambers 18 , thereby providing more storage space for the overflow of the chip mixing liquid.
  • the sample blank chamber 21 can allow the liquid in the quantitative mixing chamber 17 to enter, to eliminate the influence of different samples on the detection results and to detect whether the amount of reaction sample and diluent entering the reaction chamber 18 is sufficient, so that the detection results are more accurate.
  • the sample blank chamber 21 in the multifunctional microfluidic chip of the present invention can also be used as a mixed liquid overflow chamber. After each reaction chamber 18 has reacted, the excess mixed liquid can enter the sample blank chamber 21 .
  • the quantitative mixing chamber 17 and the sample blank chamber 21 are respectively communicated with the ventilation holes I 221 and the ventilation holes II 222 through the micro flow channel.
  • the ventilation hole I221 and the ventilation hole II222 run through the chip body 3 located in the lower layer of the chip.
  • the ventilation hole I221 and the ventilation hole II222, the ventilation hole I221 and the ventilation hole can be seen on the back of the chip body 3 The setting of II222 makes the liquid flow more smoothly.
  • the diluent stored in the aforementioned diluent storage chamber 12 is encapsulated in the diluent sac 13 in a liquid state, and the bottom surface of the diluent sac 13 is provided with a sealing film, which is made of a pierceable material, such as plastic, aluminum foil or aluminum-plastic composite material, etc.
  • the supporting detection instrument squeezes the diluent capsule 13 through the upper diluent storage chamber through hole 262 of the upper layer 1 of the chip, so that the sealing film on the bottom surface of the diluent capsule 13 is in contact with the puncturing structure 14, so that the diluent capsule 13 is ruptured. Internal diluent flows out.
  • the pipe shape design of the aforementioned microchannel I191, microchannel II192 and microchannel III193 is based on the capillary action and siphon effect, and is set according to the experimental requirements.
  • the inflection point of the microchannel I191 is closer to the chip body than the sample quantitative cavity. 3; the inflection point of the microchannel II 192 is closer to the center of the chip body 3 than the dilution quantitative chamber 15; the inflection point of the microchannel III 193 is closer to the center of the chip body 3 than the quantitative mixing chamber 17;
  • the capillary action makes the liquid flow to the inflection point of the microchannel; then centrifugal force is applied, and the liquid flows into the next chamber under the siphon action, acting as a siphon valve.
  • the multifunctional microfluidic chip of the present invention also includes a set of positioning holes 25 located on the left and right sides of the quantitative mixing chamber 17, which are specifically used to ensure the positional accuracy between the chip layers, and the positioning holes pass between the chip layers. 25 are plugged into one.
  • the multifunctional microfluidic chip of the present invention also includes splicing card positions 20 located on the left and right sides of the upper edge of the chip body 3, which are specifically used for splicing two adjacent chips; and finally three The sector-shaped chip body 3 can be spliced into a circular chip to further increase the number of samples to be tested.
  • the specific process is as follows: the whole blood sample enters the sampling cavity 4 through the upper sampling cavity through hole 261, and is put into the matching detection instrument, and the diluent of the detection instrument releases the upper diluent of the structure.
  • the storage cavity through hole 262 squeezes the diluent bag 13, so that the sealing film on the bottom surface of the diluent bag 13 contacts the puncturing structure 14, so that the diluent bag 13 is ruptured and the diluent flows out.
  • the blood and the diluent flow through different microchannel paths respectively, the blood sample enters the first sample quantitative chamber 9 and the second sample quantitative chamber 10, and the excess blood enters the sample overflow chamber 11 through the microchannel , the blood sample is centrifuged into an upper layer of plasma and a lower layer of blood cells, and the lower layer of blood cells is mainly deposited in the first sample quantification chamber 9; the diluent enters the diluent quantification chamber 15 through the microchannel, and the excess dilution in the diluent quantification chamber 15
  • the liquid enters the diluent overflow chamber 16 through the microfluidic channel; the setting of the ventilation channel makes the flow of the diluent and the blood sample smoother, and the centrifugal action can be set to different rotational speeds and centrifugation directions; after the centrifugation is stopped, the plasma and the diluent are under the capillary action.
  • the excess mixing liquid enters the sample blank chamber 21, the three-dimensional size and volume of the reaction chamber 18 and the sample blank chamber 21 are the same, the fixed reagent formulations inside the reaction chamber 18 are different, and the sample blank chamber 21 also serves as a mixing liquid overflow Flow chamber, ventilation holes I 221 and ventilation holes II 222 are arranged to make the liquid flow smoothly; the mixed liquid dissolves the preset immobilized reaction reagent (lyophilized beads) in the reaction chamber 18, fully reacts, and is equipped with the optical path detection device of the detection instrument Optical detection is performed on each reaction chamber, and the detection results are calculated.
  • the ratio of the reaction sample to the diluent in the present invention is fixed, and the ratio is designed to be less than 1:30, such as 1:40, 1:50, etc., which are designed according to actual application needs; after the ratio of the reaction sample to the diluent is determined, the design structure is fixed.
  • the microfluidic chip can realize the simultaneous detection of multiple indicators only by changing the detection reagent formula in the reaction chamber 18, and the blood collection volume is small, and only 20 ⁇ L (one drop of blood) is required for one injection, and multiple indicators can be achieved.
  • the blood sample consumption is only one-tenth to one-fifth of the ordinary products on the market, so it is especially suitable for clinical testing of neonatal and long-term tumor patients who have difficulty in blood collection due to radiotherapy, chemotherapy and other reasons.
  • the difference between the solution in the sample blank chamber 21 in the reaction chamber and the solution in the reaction chamber 18 is that it does not contain a reaction reagent, that is, the mixed solution after mixing the reaction sample and the diluent is used as the sample blank. This method can The reliability of the detection results is greatly improved.
  • the multifunctional microfluidic detection chip of the present invention can be used for detection items including biochemical items, immune items, nucleic acid molecule items and blood coagulation items.
  • biochemical indicators include total bilirubin, direct bilirubin, total bile acids, total protein, albumin, albumin/globulin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, ⁇ -glutamyl transaminase Peptidase, potassium, sodium, chloride, calcium, magnesium, phosphorus, iron, carbon dioxide, ammonia, aspartate aminotransferase mitochondrial isoenzyme (ASTm), lactate dehydrogenase (LDH), creatine kinase (CK) , ⁇ -hydroxybutyrate dehydrogenase ( ⁇ -HBD), creatine kinase isoenzyme (CK-MB), urea nitrogen (BUN), creatinine (Cr), cysteinase inhibitor
  • Immune items include cardiac troponin I, procalcitonin, N-terminal brain natriuretic peptide precursor, thyroid stimulating hormone, total triiodothyronine, free triiodothyronine, total thyroxine, free thyroxine , estradiol, anti-Mullerian hormone, brain natriuretic peptide, cardiac fatty acid-binding protein, interleukin-6, lipoprotein-associated phospholipase A2, serum amyloid A, soluble growth-stimulating gene 2 protein, creatine kinase CK-MB, myoglobin Myo, luteinizing hormone, follicle-stimulating hormone, prolactin, testosterone, progesterone, 25-hydroxyvitamin D3, 25-hydroxyvitamin D, immunoglobulin G4, cardiac troponin T , myeloperoxidase, aldosterone, renin, homocysteine, D-dimer, S100-bet
  • Nucleic acid molecule project indicators include Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella pneumophila, Influenza A virus, Influenza B virus, Bacillus pertussis, Streptococcus pneumoniae, Respiratory syncytial virus, Parainfluenza virus, Rhinovirus, Respiratory adenovirus.
  • Blood coagulation items include prothrombin time PT, thrombin time TT, activated partial thromboplastin time APTT, activated coagulation time ACT, fibrinogen FIB, fibrin degradation product FDP, coagulation factor Xa, viper venom time (RVVT) , Antithrombin III (AT III), D-dimer (D-Dimer).
  • the detection reagent is fixed in the reaction chamber 18, and the freeze-drying method is used, that is, freeze-dried beads are made, and each freeze-dried bead has a diameter of 0.5-1.0 mm and a diameter of 4-8 mm.
  • the freeze-drying method is used, that is, freeze-dried beads are made, and each freeze-dried bead has a diameter of 0.5-1.0 mm and a diameter of 4-8 mm.
  • Frozen bead preparation adjust the drop volume of the automatic bead drop machine (Xiamen Wumen Automation Technology Co., Ltd.; LC200-R) to be accurate to 2-100 microliters (preferably 4 microliters) for each drop of reagent beads, and put it into the matching container.
  • the reagents are dropped into the liquid nitrogen to quickly form frozen beads and sink to the bottom of the liquid nitrogen container. Finally, the frozen beads are poured into the freeze-drying container for further vacuum. Freeze-dried.
  • Preparation of freeze-dried beads put the above-mentioned frozen beads into a vacuum freeze-drying apparatus (Shanghai Tofflon Technology; LYO-0.5), set the instrument parameters, and the drying time is 24-28 hours, and the frozen beads are dehydrated to form freeze-dried beads. Take it out into an airtight container.
  • a vacuum freeze-drying apparatus Shanghai Tofflon Technology; LYO-0.5
  • the microfluidic detection chip of the present invention has a fixed structure, and the ratio of the reaction sample to the diluent is designed to be 1:50.
  • the diluent flows out from the diluent storage chamber 12 and enters the diluent quantitative chamber 15, and the excess diluent enters the diluent
  • the whole blood sample is centrifuged into layers, and blood cells are mainly deposited in the first sample quantitative chamber 9, and the second sample quantitative chamber 10 is plasma.
  • the quantitative plasma 4 ⁇ L and the quantitative diluent 200 ⁇ L are quantitatively mixed.
  • reaction chamber 17 After mixing in the chamber 17, it enters nine reaction chambers 18 and one sample blank chamber 21 with the same capacity.
  • the mixed solution dissolves the fixed reaction reagent in the reaction chamber 18 and reacts fully.
  • the optical path detection device of the matching detection instrument is suitable for Each reaction chamber 18 and the sample blank chamber 21 are optically detected to obtain a detection result.
  • the detection results of the 9 reaction chambers 18 are subtracted from the detection results of the sample blank chamber 21, which eliminates the influence of different samples on the results, and can also detect whether the amount of reaction samples and diluents entering the reaction chamber 18 is sufficient, which both improves The dual function of the accuracy of the test results and the judgment of the validity of the test.
  • the blood sample consumption of the present invention is only 1/10-1/5 of that of common products on the market, and the blood collection volume is small, and is especially suitable for clinical detection of neonatal and long-term tumor patients with difficulty in blood collection due to radiotherapy, chemotherapy and other reasons.
  • the structure of the microfluidic detection chip is fixed, and the ratio of reaction sample and diluent is fixed. Only by changing the reagent formula required for different detection indicators, a chip design template can be realized to meet the clinical detection of different projects or project combinations.
  • the setting of the splicing card position 20 can assemble three chip detection chips into one circular detection chip, and can detect three different samples at the same time, thereby increasing the throughput of the detection samples.
  • the volume ratio of the sample of the present invention to the detection reagent is as follows compared with the market product 1 and product 2:
  • the sample-to-reagent ratio of product 1 and product 2 is not fixed, but the present invention uses the chip as a carrier to achieve the fixed ratio of sample to reagent, and then the structure of the chip is fixed, and the three-dimensional size and volume of the reaction pool are the same, ensuring that the reaction pool enters the reaction pool.
  • the sample volume is the same, just change the reagent formula of different detection indicators, the chip structure is fixed, the cost of mold opening is reduced, and it is conducive to mass production.
  • the present invention detects 9 indicators, and roughly calculates the blood volume of each indicator to be 2.2 ⁇ L. Only 1 drop of blood can actually be used to detect 9 indicators, and the blood collection volume is small, especially suitable for the clinical detection of neonatal and long-term tumor patients who have difficulty in blood collection due to radiotherapy, chemotherapy and other reasons.
  • the product of the present invention can achieve better performance, and the product testing result is accurate and stable.

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Abstract

一种多功能微流控检测芯片，所述芯片包括芯片本体（3）；芯片本体（3）上设置有进样腔（4）、样本定量腔、样本溢流腔（11）、稀释液存储腔（12）、稀释液定量腔（15）、稀释液溢流腔（16）、定量混匀腔（17）、反应腔以及透气孔；所述样本定量腔的反应样本和所述稀释液定量腔（15）的稀释液在所述定量混匀腔（17）混匀之后，混匀液通过微流道进入反应腔室（18）与其中的反应试剂进行反应以待检测，同时混匀液进入样本空白室（21）作为样本空白待检测；所述的多功能微流控检测芯片能够有效减少样本用量，提高检测结果的准确性，同时检测多个指标。

Description

一种多功能微流控检测芯片 技术领域
本发明属于体外微流控检测领域，尤其涉及一种多功能微流控检测芯片。
背景技术
微流控检测芯片技术是把生物、化学、医学分析过程的样品制备、反应、分离、检测等基本操作单元集成到一块微米尺度的芯片上，自动完成分析全过程。在生物、化学、医学等领域有着巨大的潜力。
但现有技术中的微流控检测芯片技术在实际应用中还存在一些缺陷，如结构复杂，样本使用量大，检测结果不够精确，稀释液定量腔与样本定量腔的体积比过小、生产成本高等。目前市场上的离心式微流控检测芯片所需进血样量较大，不适用于婴幼儿尤其新生儿、重症病人的临床采血检测，且缺乏有效的质控功能；所以有必要开发一种离心式检测芯片，结构简单，一次少量进样，能够在较小体积上实现检测多个指标，生产成本低、适于大批量生产，检测结果更精确，同时经过芯片拼装可以进行多样本的检测。
发明内容
本发明的目的在于提供一种多功能微流控检测芯片，以克服现有微流控检测芯片技术的缺陷，能减少样本的用量并进一步提高检测结果的准确性。
为实现上述的技术目的，本发明采取如下的技术方案：
一种多功能微流控检测芯片，该芯片包括芯片本体，芯片本体上设置有进样腔、样本定量腔、样本溢流腔、稀释液存储腔、稀释液定量腔、稀释液溢流腔、定量混匀腔、反应腔以及透气孔；
进样腔可供注入待检测的反应样本，通过微流道与样本定量腔相连，反应样本能从进样腔进入样本定量腔，多余的反应样本进入样本溢流腔；
稀释液存储腔通过微流道与稀释液定量腔相连，稀释液能从稀释液存储腔进入稀释液定量腔，多余的稀释液进入稀释液溢流腔；反应腔包括一个或多个反应腔室以及一个样本空白室；
样本定量腔的样本和稀释液定量腔的稀释液在定量混匀腔混匀之后，混匀液通过微流道进入反应腔室与其中的反应试剂进行反应以待检测，同时混匀液进入样本空白室作为样本空白待检测。
样本定量腔包括第一样本定量腔和第二样本定量腔。
反应腔包括若干个等距分布的反应腔室。
反应腔室与样本空白室体积相同。
样本定量腔的反应样本和稀释液定量腔的稀释液分别经微流道Ⅰ、微流道Ⅱ进入定量混匀腔混匀之后；混匀液依次经微流道Ⅲ、微流道Ⅳ进入反应腔室和样本空白室；微流道Ⅰ、微流道Ⅱ和微流道Ⅲ分别包括一相对于相应液体流出腔室靠近芯片本体中心位置的拐点。
样本空白室的通道比反应腔室的通道宽。
定量混匀腔和反应腔分别与透气孔连通。
定量混匀腔中反应样本与稀释液的定量比小于1:30。
优选的，定量混匀腔中反应样本与稀释液的定量比为1:50。
反应试剂为采用冻干法制作的冻干珠。
冻干珠的半径介于0.5mm到1mm。
样本定量腔和样本溢流腔之间的微流道还设有一个样本透气通道连接到芯片外部，稀释液定量腔和稀释液溢流腔之间的微流道也设有一个稀释液透气通道连接到芯片外部。
芯片为扇形结构。
芯片还包括芯片上层和芯片中层，芯片本体位于下层。
芯片本体两侧各设有一个拼接卡位。
芯片本体可用于检测生化项目、免疫项目、核酸分子项目以及血凝项目。
根据上述的技术方案，本发明具有如下优点：
本发明将反应样本与稀释液的定量配比设计为小于1:30，根据需要选择合适的反应样本与稀释液比例，反应样本与稀释液比例确定后，设计结构固定的微流控检测芯片，应用中仅需改变不同检测指标所需试剂配方，就可以实现一个芯片设计模板满足不同项目或项目组合指标的临床检测。
本发明的若干反应腔室与样本空白室的三维大小相同，所以体积相同，反应时进入的反应样本与稀释液体积均相同，所以只需要设置1个样本空白室，即可实现若干反应腔室检测指标组合的有效质控，同时使得芯片结构简化，成本降低。
本发明的样本空白室位于反应腔室阵列的尾端，与反应腔室共用一条微流道，可以同时作为样本空白腔室以及混匀液溢流室，并且样本空白为反应样本和稀释液的混匀液，检测结果将样本自身的影响消除，同时样本空白的检测值可以检测样本和稀释液进入反应腔室的量是否足够，兼有提高检测结果精确性和判断检测有效性的双重功能。
本发明的采血量少，一次进样仅需一滴血，即可实现多项指标的同时检测，血液样本用量仅为市面普通产品的1/10～1/5，尤其适用于新生儿及长期肿瘤病人因放、化疗等原因 造成的采血困难患者的临床检测。
本发明的芯片为扇形结构，在其左右两侧边缘各设有一个拼接卡位，用于拼接两个芯片，且3个芯片可以形成一个圆形芯片，一次可以检测3份样本，可大大增加检测样本的通量。
附图说明
图1为本发明多功能微流控检测芯片的整体结构示意图。
图2为本发明多功能微流控检测芯片中芯片本体的正面结构示意图。
图3为本发明多功能微流控检测芯片中芯片本体的立体结构示意图。
图4为本发明多功能微流控检测芯片整体立体结构正面示意图。
图5为本发明多功能微流控检测芯片整体立体结构背面示意图。
图6为本发明多功能微流控检测芯片拼接成的圆盘式多功能微流控检测芯片拼装结构示意图。
图7为本发明多功能微流控检测芯片拼接成的圆盘式多功能微流控检测芯片整体结构示意图。
附图标号说明
1.芯片上层；2.芯片中层；3.芯片本体；4.进样腔；5.样本盖；6.进样口；7.进样腔流道；8.进样腔流道密封膜；9.第一样本定量腔；10.第二样本定量腔；11.样本溢流腔；12.稀释液存储腔；13.稀释液囊；14.刺破结构；15.稀释液定量腔；16.稀释液溢流腔；17.定量混匀腔；18.反应腔室；191.微流道Ⅰ；192.微流道Ⅱ；193.微流道Ⅲ；194.微流道Ⅳ；20.拼接卡位；21.样本空白室；221.透气孔Ⅰ；222.透气孔Ⅱ；23.样本透气通道；24.稀释液透气通道；25.定位孔；261.上层进样腔通孔；262.上层稀释液存储腔通孔；263.上层反应腔通孔；264.中层进样腔通孔；265.中层稀释液存储腔通孔；266.透气通孔；267.定位孔通孔。
具体实施方式
以下结合附图对本发明技术方案进行详细说明。应当理解，此处所描述的具体实施方式仅用以解释本发明，并不用于限定本发明。本申请的范围并不受这些实施方式的限定，乃以申请专利的范围为准。而为提供更清楚的描述及使熟悉该项技艺者能理解本申请的申请内容，图示内各部分并不一定依照其相对的尺寸而绘图，某些尺寸与其他相关尺度的比例会被凸显而显得夸张，且不相关或不重要的细节部分亦未完全绘出，以求图示的简洁。
如图1-4所示，本发明的多功能微流控检测芯片通过模具注塑的方式制作而成，可配合检测设备使用。检测芯片呈扇形结构，优选为圆形的三分之一大小，即左右两侧延长线相 交形成的夹角为120度，扇形结构可以是圆形的一部分，其余部分可根据需要自行设计加入其它部分。
本发明的多功能微流控检测芯片包括上中下三层，如图1所示，从上到下依次为作为壳体的芯片上层1，作为密封层的芯片中层2和作为芯片本体3的下层芯片。
芯片上层1如图1所示，设有上层进样腔通孔261、上层稀释液存储腔通孔262以及一组上层反应腔通孔263。上层进样腔通孔261及上层稀释液存储腔通孔262位于芯片上层1靠近中心的位置，上层反应腔室通孔263等距排列分布在芯片上层1上边缘内侧。上层进样腔通孔261用于加入样本，上层稀释液存储腔通孔262和上层反应腔通孔263分别与稀释液存储腔12以及各反应腔相对应。
芯片中层2如图1所示，设有中层进样腔通孔264、中层稀释液存储腔通孔265、一组透气通孔266以及一组定位孔通孔267。中层进样腔通孔264和中层稀释液存储腔通孔265位于芯片中层2靠近中心的位置，分别与芯片上层1上层进样腔通孔261和上层稀释液存储腔通孔262相对应，透气通孔266和定位孔通孔267较中层进样腔通孔264和中层稀释液存储腔通孔265依次远离芯片中层2的中心位置，透气通孔266与下层芯片本体3上的一组透气孔Ⅰ221、透气孔Ⅱ222相对应，定位孔通孔267与下层芯片本体3上的一组定位孔25相对应。
芯片本体3如图1-3所示，设置有进样腔4、样本定量腔、样本溢流腔11、稀释液存储腔12、稀释液定量腔15、稀释液溢流腔16、定量混匀腔17、反应腔以及透气孔Ⅰ221、透气孔Ⅱ222，各腔室之间均由微流道进行连接。
进样腔4以及稀释液存储腔12位于芯片本体3靠近中心的位置，进样腔4顶部设有样本盖5，样本盖5上设有一进样口6，可供注入欲检测的样本，稀释液存储腔12内设稀释液囊13，底部设刺破结构14，可供注入稀释液。样本定量腔包括第一样本定量腔9和第二样本定量腔10，第一样本定量腔9和第二样本定量腔10与进样腔4相连通，第一样本定量腔9和第二样本定量腔10较进样腔4远离芯片本体3的中心位置，因此当芯片本体3被离心设备驱动而旋转时，进样腔4内的样本会因离心作用通过进样腔4底面端口，经过反面流道，再经过正面流道朝向第一样本定量腔9和第二样本定量腔10流动，反面流道入口位于进样腔4靠近第一样本定量腔9的一侧底部，正面流道出口位于第一样本定量腔9靠近芯片本体3中心位置一侧；反面流道与正面流道于反面流道入口与正面流道出口两点之间连线的中点处通过一上下垂直的流道相连接；进样腔4底面设有进样腔流道密封膜8，防止样本流经反面流道时溢出。设置第一样本定量腔9和第二样本定量腔10是为了实现上层血浆和下 层血细胞更好的分离及血浆样本的定量。稀释液定量腔15与稀释液存储腔12相连通，稀释液定量腔15需较稀释液存储腔12远离芯片本体3的中心位置，因此当芯片本体3被离心设备驱动而旋转时，稀释液存储腔12内的稀释液会因离心作用而朝向稀释液定量腔15流动。第一样本定量腔9和第二样本定量腔10与稀释液定量腔15的体积比决定了反应样本与稀释液混合的比例。
溢流腔包括样本溢流腔11和稀释液溢流腔16，分别与第一样本定量腔9和稀释液定量腔15相连接。样本溢流腔11较第一样本定量腔9和第二样本定量腔10远离芯片本体3的中心位置，因此，当芯片本体3被离心驱动而旋转时，多于第一样本定量腔9和第二样本定量腔10容量的样本会因离心力的驱使而流入样本溢流腔11。稀释液溢流腔16较稀释液定量腔15远离芯片本体3的中心位置，因此，当芯片本体3被离心驱动而旋转时，多于稀释液定量腔15容量的稀释液会因离心力的驱使而流至稀释液溢流腔16。
第一样本定量腔9和样本溢流腔11之间的微流道还经由一个样本透气通道23连接到芯片外部，类似的，稀释液定量腔15和稀释液溢流腔16之间的微流道也经由一个稀释液透气通道24连接到芯片外部。透气通道的设置能使稀释液和样本的流动更顺畅。
定量混匀腔17分别通过微流道Ⅰ191与第一样本定量腔9和第二样本定量腔10相连通，通过微流道Ⅱ192与稀释液定量腔15相连通，定量混匀腔17需较第一样本定量腔9和第二样本定量腔10，以及稀释液定量腔15远离芯片本体3的中心位置，可将定量的样本和定量的稀释液进行混合稀释后供检测之用。
定量混匀腔17通过微流道Ⅲ193与微流道Ⅳ194使混匀液流入反应腔中的各个反应腔室18以便与其中的检测试剂进行反应。反应腔包括若干个等距分布的反应腔室18和位于流道末端的一个样本空白室21，反应腔室18的体积均相同，内设有反应所需的反应试剂，反应试剂可以为采用冻干法制作的冻干珠，每个冻干珠的半径介于0.5mm到1mm之间，体积极小的反应试剂使得在同样大小的芯片中反应腔室18的承载量加大，有效的提高检测灵敏度和检测效率，此外，反应试剂采用冻干珠有效地增加了试剂存储的有效期。
样本空白室21的通道相比其他反应腔室18的通道宽，进而可以为芯片混匀液溢流提供更多的存储空间。样本空白室21可允许定量混匀腔17的液体进入，用于消除不同样本自身对检测结果的影响及检测进入反应腔室18的反应样本与稀释液的量是否足够，使检测结果更精确。另外，本发明的多功能微流控芯片中的样本空白室21可以同时作为混匀液溢流室，各反应腔室18反应过后，多余的混匀液可进入样本空白室21中。
定量混匀腔17和样本空白室21如图2所示经由微流道分别与透气孔Ⅰ221、透气 孔Ⅱ222连通。透气孔Ⅰ221、透气孔Ⅱ222如图3所示，贯穿位于芯片下层的芯片本体3，如图5所示，芯片本体3的背面可以看到透气孔Ⅰ221和透气孔Ⅱ222，透气孔Ⅰ221以及透气孔Ⅱ222的设置使液体流动更顺畅。
前述稀释液存储腔12中存放的稀释液以液体状态包封在稀释液囊13中，稀释液囊13底面有密封膜，材质为可刺破材料，如塑料、铝箔或铝塑复合材料等，检测时，配套检测仪器通过芯片上层1的上层稀释液存储腔通孔262挤压稀释液囊13，使稀释液囊13底面的密封膜与刺破结构14相接触，使稀释液囊13破裂，内部稀释液流出。
前述微流道Ⅰ191、微流道Ⅱ192及微流道Ⅲ193的管道形状设计，是考虑到毛细作用和和虹吸作用，根据实验需求设置的，微流道Ⅰ191的拐点位置较样本定量腔靠近芯片本体3的中心位置；微流道Ⅱ192的拐点位置较稀释液定量腔15靠近芯片本体3的中心位置；微流道Ⅲ193的拐点位置较定量混匀腔17靠近芯片本体3的中心位置；当离心作用停止时，毛细作用使液体流到微流道拐点处；接着再施加离心力，液体在虹吸作用下流入下一个腔室，起到虹吸阀门作用。
本发明的多功能微流控芯片还包括位于定量混匀腔17左右两侧的一组定位孔25，具体用于保证芯片层与层之间的位置精度，芯片层与层之间通过定位孔25插接成一体。
如图6和图7所示，本发明的多功能微流控芯片还包括位于芯片本体3上边缘左右两侧的拼接卡位20，具体用于拼接相邻的两个芯片；且最终3个扇形芯片本体3可以拼接成为一个圆形芯片，进一步增大检测样本数量。
使用本发明的多功能微流控检测芯片时，具体过程为全血样本经上层进样腔通孔261进入进样腔4中，放入配套检测仪器，检测仪器的稀释液释放结构上层稀释液存储腔通孔262挤压稀释液囊13，使稀释液囊13底面的密封膜与刺破结构14相接触，使稀释液囊13破裂，稀释液流出。在离心作用下，血液与稀释液分别流经不同的微流道路径，血液样本进入第一样本定量腔9和第二样本定量腔10，多余的血液经由微流道进入样本溢流腔11中，血液样本经离心分为上层血浆和下层血细胞，下层血细胞主要沉积在第一样本定量腔9中；稀释液经由微流道进入稀释液定量腔15，稀释液定量腔15中多余的稀释液经由微流道进入稀释液溢流腔16；透气通道的设置使稀释液和血液样本的流动更顺畅，离心作用可设置不同转速与离心方向；停止离心后，血浆和稀释液在毛细作用下分别流到微流道Ⅰ191和微流道Ⅱ192的拐点处；再施加离心力，利用虹吸作用使定量的血浆和稀释液进入定量混匀腔17，通过对仪器严格的离心参数设置，使血浆与稀释液在定量混匀腔17内充分混匀；停止离心，混匀液再在毛细作用下流到微流道Ⅲ193拐点处，再施加离心力，利用虹吸作用 经微流道Ⅳ194依次进入各反应腔室18中，多余的混匀液进入样本空白室21内，反应腔室18与样本空白室21三维大小及体积相同，反应腔室18内部的固定试剂配方不同，样本空白室21兼做混匀液溢流室，透气孔Ⅰ221、透气孔Ⅱ222的设置使液体流动顺畅；混匀液在反应腔室18内溶解其中预设的固定反应试剂(冻干珠)，充分反应，配套检测仪器的光路检测装置对每个反应室进行光学检测，计算得出检测结果。
本发明的反应样本与稀释液比例固定，比例设计为小于1:30，比如设计为1:40，1:50等，根据实际应用需要设计；反应样本与稀释液比例确定后，设计结构固定的微流控芯片，只需改变反应腔室18内检测试剂配方，就可以实现多项指标的同时检测，且采血量小，一次进样量仅需20μL(一滴血)，即可实现多项指标的同时检测，血液样本用量仅为市面普通产品的十分之一到五分之一，因此尤其适用于新生儿及长期肿瘤病人因放、化疗等原因造成的采血困难患者的临床检测。而反应腔中的样本空白室21内的溶液与反应腔室18中的溶液相比，区别在于不含有反应试剂，即将反应样本和稀释液混匀后的混匀液作为样本空白，此方法可以使得检测结果的可靠性大大提高。
如图2所示，当反应样本与稀释液比例固定为1:50时，离心后，定量的血浆4μL与定量稀释液200μL混合后进入容量相同的若干个反应腔室18和样本空白室21中。因为反应腔室18内的反应样本与稀释液体积均相同，所以只需要设置1个样本空白室21，即可实现芯片若干检测指标的有效质控，同时使得芯片结构简化，成本降低。
本发明的多功能微流控检测芯片，可用于的检测项目包括生化项目、免疫项目、核酸分子项目和血凝项目。具体的生化项目指标包括总胆红素、直接胆红素、总胆汁酸、总蛋白、白蛋白、白蛋白/球蛋白、谷丙转氨酶、谷草转氨酶、碱性磷酸酶、γ-谷氨酰转肽酶、钾、钠、氯、钙、镁、磷、铁、二氧化碳、氨、天冬氨酸氨基转移酶线粒体同工酶(ASTm)、乳酸脱氢酶(LDH)、肌酸激酶(CK)、α-羟丁酸脱氢酶(α-HBD)、肌酸激酶同功酶(CK-MB)、尿素氮(BUN)、肌酐(Cr)、半胱氨酸酶抑制剂C(Cys C)、尿酸、新生儿缺血缺氧性脑病；葡萄糖、胆固醇、甘油三酯、游离脂肪酸、磷脂、CRP、甲胎蛋白、胆碱酯酶、淀粉酶。
免疫项目指标包括心肌肌钙蛋白I、降钙素原、N末端脑钠肽前体、促甲状腺激素、总三碘甲状原氨酸、游离三碘甲状原氨酸、总甲状腺素、游离甲状腺素、雌二醇、抗缪勒管激素、脑利钠肽、心脏型脂肪酸结合蛋白、白介素6、脂蛋白相关磷脂酶A2、血清淀粉样蛋白A、可溶性生长刺激表达基因2蛋白、肌酸激酶同工酶CK-MB、肌红蛋白Myo、促黄体生成素、促卵泡生成素、泌乳素、睾酮、孕酮、25-羟基维生素D3、25羟基维生素D、免疫球蛋白G4、心肌肌钙蛋白T、髓过氧化物酶、醛固酮、肾素、同型半胱氨酸、D-二聚体、 S100-β蛋白、半乳糖凝集素3、人生长分化因子15、P选择素、肾素活性、血管紧张素Ⅰ、血管紧张素Ⅱ、超敏心肌肌钙蛋白I。
核酸分子项目指标包括肺炎支原体、肺炎衣原体、嗜肺军团菌、甲型流感病毒、乙型流感病毒、百日咳杆菌、肺炎链球菌、呼吸道合胞病毒、副流感病毒、鼻病毒、呼吸道腺病毒。
血凝项目指标包括凝血酶原时间PT、凝血酶时间TT、活化部分凝血活酶时间APTT、活化凝血时间ACT、纤维蛋白原FIB、纤维蛋白降解产物FDP、凝血因子Xa、蝰蛇毒时间(RVVT)、抗凝血酶Ⅲ(ATⅢ)、D-二聚体(D-Dimer)。
在本发明的非限制性生化检测应用实施例中，首先检测试剂固定在反应腔室18中，采用冻干法，即制作冻干珠，每个冻干珠直径0.5～1.0mm，4～8℃干燥保存。具体步骤为：
冷冻珠制备：调整自动滴珠机(厦门武门自动化科技有限公司；LC200-R)液滴体积，精确到每一滴试剂珠为2～100微升(优选4微升)，装入配套的盛有液氮的保温容器，同时调整液面高度等参数，开始仪器滴珠，试剂滴入液氮中迅速形成冷冻珠并沉于液氮容器底部，最后冷冻珠倒入冻干容器中待进一步真空冷冻干燥。
冻干珠制备：将上述冷冻珠放入真空冷冻干燥仪(上海东富龙科技；LYO-0.5)，设置仪器参数，干燥时间为24～28小时，冷冻珠脱水形成冻干珠，完成后将其取出放入密闭容器中。
本发明微流控检测芯片结构固定，反应样本与稀释液比例设计为1:50。采用本发明多功能微流控检测芯片一次进样，全血仅需要20μL，放入配套检测仪器，稀释液从稀释液存储腔12流出，进入稀释液定量腔15，多余的稀释液进入稀释液溢流腔16中，全血样本经离心后分层，血细胞主要沉积在第一样本定量腔9，第二样本定量腔10中为血浆，定量的血浆4μL与定量稀释液200μL在定量混匀腔17中混合后，进入容量相同的9个反应腔室18与1个样本空白室21，混匀液在反应腔室18溶解其中的固定反应试剂，充分反应，配套检测仪器的光路检测装置对每个反应腔室18和样本空白室21进行光学检测，得出检测结果。
9个反应腔室18检测结果减掉样本空白室21的检测结果，消除了不同样本自身对结果的影响，还可以检测进入反应腔室18的反应样本与稀释液的量是否足够，兼有提高检测结果精确性和判断检测有效性的双重功能。
本发明的血液样本用量仅为市面普通产品的1/10～1/5，采血量少，尤其适用于新生儿及长期肿瘤病人因放、化疗等原因造成的采血困难患者的临床检测。微流控检测芯片结构固定，反应样本与稀释液比例固定，仅需改变不同检测指标所需试剂配方，就可以实现一个芯 片设计模板满足不同项目或项目组合的临床检测。
拼接卡位20的设置可以将3个芯片检测芯片拼装为1个圆形的检测芯片，可同时检测三份不同样本，增大检测样本通量。
1.以肝功能9项检测为例，本发明的样本与检测试剂体积比，与市面产品1与产品2相比较结果如下：
Figure PCTCN2021127908-appb-000001
产品1和产品2样本与试剂比不固定，而本发明以芯片为载体，实现了样本与试剂比的固定，继而使芯片的结构固定，反应池三维大小、体积相同，保证了进入反应池的样本量相同，只需改变不同检测指标的试剂配方即可，芯片结构固定，减少开模成本，利于大批量生产。
2.与产品3做对比，本发明检测9个指标，粗略计算每个指标用血量为2.2μL。实际进血量只需1滴血，即可检测9个指标，采血量少，尤其适用于新生儿及长期肿瘤病人因放、化疗等原因造成的采血困难患者的临床检测。
产品 产品3 本发明
进血样量 ≥120.0μL 20μL
检测指标个数 ≤16 9
用血量/指标 ≥7.5μL 2.2μL
3.以产品3为对照，本发明与其的性能参数比较如下：
对比产品3的产品性能参数，本发明产品的性能参数标准要求如下：
Figure PCTCN2021127908-appb-000002
具体实施例数据如下：
(1)准确度
Figure PCTCN2021127908-appb-000003
(2)精密度
Figure PCTCN2021127908-appb-000004
Figure PCTCN2021127908-appb-000005
(3)批间差
Figure PCTCN2021127908-appb-000006
Figure PCTCN2021127908-appb-000007
Figure PCTCN2021127908-appb-000008
Figure PCTCN2021127908-appb-000009
由以上可知，本发明产品能达到较优秀的性能，产品检测结果准确稳定。
以上所述仅是本发明的优选实施例而已，并非用以限定本发明，任何熟悉本专业的技术人员，在不脱离本发明的原理和宗旨的情况下可以对这些实施例进行多种变化、修改、替换和变型，本发明的范围由权利要求及其等同物限定。

Claims (13)

  1. 一种多功能微流控检测芯片，其特征在于：所述芯片包括芯片本体，芯片本体上设置有进样腔、样本定量腔、样本溢流腔、稀释液存储腔、稀释液定量腔、稀释液溢流腔、定量混匀腔、反应腔以及透气孔；
    所述进样腔可供注入待检测的反应样本，通过微流道与所述样本定量腔相连，反应样本能从所述进样腔进入所述样本定量腔，多余的反应样本进入所述样本溢流腔；
    所述稀释液存储腔通过微流道与所述稀释液定量腔相连，稀释液能从所述稀释液存储腔进入所述稀释液定量腔，多余的稀释液进入所述稀释液溢流腔；
    所述反应腔包括一个或多个反应腔室以及一个样本空白室；
    所述样本定量腔的反应样本和所述稀释液定量腔的稀释液在所述定量混匀腔混匀之后，混匀液通过微流道进入反应腔室与其中的反应试剂进行反应以待检测，同时混匀液进入样本空白室作为样本空白待检测，
    所述反应腔室与所述样本空白室三维大小相同；
    所述样本空白室的通道比反应腔室的通道宽；
    所述定量混匀腔中反应样本与稀释液的定量比小于1:30。
  2. 根据权利要求1所述的多功能微流控检测芯片，其特征在于：所述样本定量腔包括第一样本定量腔和第二样本定量腔。
  3. 根据权利要求1所述的多功能微流控检测芯片，其特征在于：所述反应腔包括若干个等距分布的反应腔室。
  4. 根据权利要求1所述的多功能微流控检测芯片，其特征在于：所述样本定量腔的反应样本和所述稀释液定量腔的稀释液分别经微流道Ⅰ、微流道Ⅱ进入所述定量混匀腔混匀之后；所述混匀液依次经微流道Ⅲ、微流道Ⅳ进入所述反应腔室和所述样本空白室；所述微流道Ⅰ、微流道Ⅱ和微流道Ⅲ分别包括一相对于相应液体流出腔室靠近所述芯片本体中心位置的拐点。
  5. 根据权利要求1所述的多功能微流控检测芯片，其特征在于：所述定量混匀腔和所述反应腔分别与透气孔连通。
  6. 根据权利要求1所述的多功能微流控检测芯片，其特征在于：所述定量混匀腔中反应样本与稀释液的定量比为1:50。
  7. 根据权利要求1所述的多功能微流控检测芯片，其特征在于：所述反应试剂为采用冻干法制作的冻干珠。
  8. 根据权利要求7所述的多功能微流控检测芯片，其特征在于：所述冻干珠的半径介于0.5mm到1mm。
  9. 根据权利要求1所述的多功能微流控检测芯片，其特征在于：所述样本定量腔和样本溢流腔之间的微流道还设有一个样本透气通道连接到芯片外部，所述稀释液定量腔和所述稀释液溢流腔之间的微流道也设有一个稀释液透气通道连接到芯片外部。
  10. 根据权利要求1所述的多功能微流控检测芯片，其特征在于：所述芯片为扇形结构。
  11. 根据权利要求1所述的多功能微流控检测芯片，其特征在于：所述芯片还包括芯片上层和芯片中层，所述芯片本体位于下层。
  12. 根据权利要求1所述的多功能微流控检测芯片，其特征在于：所述芯片本体两侧各设有一个拼接卡位。
  13. 根据权利要求1所述的多功能微流控检测芯片，其特征在于：所述芯片本体可用于检测生化项目、免疫项目、核酸分子项目以及血凝项目。
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