WO2023039938A1 - 一种微流控血型检测芯片 - Google Patents

一种微流控血型检测芯片 Download PDF

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Publication number
WO2023039938A1
WO2023039938A1 PCT/CN2021/120949 CN2021120949W WO2023039938A1 WO 2023039938 A1 WO2023039938 A1 WO 2023039938A1 CN 2021120949 W CN2021120949 W CN 2021120949W WO 2023039938 A1 WO2023039938 A1 WO 2023039938A1
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Prior art keywords
chamber
blood type
sample
reaction
blood
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PCT/CN2021/120949
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English (en)
French (fr)
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许行尚
陈·杰弗瑞
陈亚宝
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南京岚煜生物科技有限公司
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Priority to EP21930597.6A priority Critical patent/EP4174494A4/en
Priority to KR1020227023021A priority patent/KR20230042200A/ko
Priority to JP2022537195A priority patent/JP7399518B2/ja
Publication of WO2023039938A1 publication Critical patent/WO2023039938A1/zh

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/80—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood groups or blood types or red blood cells
    • 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
    • B01L3/50273—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
    • 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
    • B01L3/502738—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 integrated valves
    • 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
    • B01L2200/0605—Metering of fluids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—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
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0803—Disc shape
    • 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
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0867—Multiple inlets and one sample wells, e.g. mixing, dilution
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • 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
    • B01L2400/0406—Moving fluids with specific forces or mechanical means specific forces capillary forces
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0409—Moving fluids with specific forces or mechanical means specific forces centrifugal forces
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/06—Valves, specific forms thereof
    • B01L2400/0677—Valves, specific forms thereof phase change valves; Meltable, freezing, dissolvable plugs; Destructible barriers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N2021/752—Devices comprising reaction zones
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/01—Arrangements or apparatus for facilitating the optical investigation
    • G01N21/03—Cuvette constructions
    • G01N21/07—Centrifugal type cuvettes

Definitions

  • the invention relates to the field of microfluidic chips, in particular to a microfluidic blood type detection chip.
  • Microfluidic chip is an emerging technology industry. Microfluidic detection chip technology integrates the basic operation units such as sample preparation, reaction, separation, and detection in the process of biological, chemical, and medical analysis into a micron-scale chip, which is automatically completed. the whole process of analysis. It has great potential in the fields of biology, chemistry and medicine.
  • Blood type is a method of classifying blood, among which the ABO and Rh blood group systems are most closely related to human blood transfusion.
  • ABO blood group system A blood type system divided according to the presence or absence of specific antigens (agglutinogens) A and B on the surface of red blood cells.
  • the ABO blood group system is the first human blood group system discovered and determined. According to the distribution of agglutinogens A and B, blood is divided into four types: A, B, AB, and O.
  • Type A blood with only agglutinogen A on red blood cells has anti-B lectin in its plasma; type B blood with only agglutinogen B on red blood cells has anti-A lectin in its plasma; Type AB blood that has both agglutinogens has no anti-A and anti-B agglutinins in its plasma; type O blood that has neither A nor B agglutinogens on red blood cells has both anti-A and anti-B agglutinins in its plasma .
  • Red blood cells with agglutinogen A can be agglutinated by anti-A lectin; anti-B lectin can agglutinate red blood cells with agglutinogen B.
  • Rh blood group system According to the presence or absence of Rh factor, it is divided into Rh negative and Rh positive blood types. Clinically, human red blood cells contain five antigens of the Rh system, antigens D, C, c, E, and e, among which D antigen is the most antigenic. According to the presence or absence of D antigen on red blood cells, that is, the lack of D antigen on red blood cells is RhD negative blood, the presence of D antigen on the red blood cells is RhD positive blood.
  • Hematocrit generally refers to hematocrit (PCV), also known as hematocrit (Hct).
  • PCV hematocrit
  • Hct hematocrit
  • the clinical significance of PCV determination is basically the same as that of red blood cell count or hemoglobin determination. It is often used as an index for the diagnosis and classification of anemia. Baseline data for mean hemoglobin concentrations.
  • the present invention provides a microfluidic blood type detection chip to overcome the defects of the existing blood type detection technology, simple operation, small sample usage, automatic detection, positive and negative blood type identification at the same time, The cost is lower, the detection result is more accurate, and the hematocrit can be directly detected while performing blood type identification, which provides an important basis for blood matching.
  • An anti-typing blood type identification area which is equipped with a second sample injection chamber, a quantitative separation chamber, and an anti-typing reaction chamber;
  • Breathing holes respectively connected to the positive-setting reaction chamber and the reverse-setting reaction chamber;
  • the first sample injection chamber and the second sample injection chamber can be used to inject the samples to be tested, and are respectively connected to the quantitative mixing chamber and the quantitative separation chamber through micro-channels, and the reaction samples can be injected from the first sample injection chamber and the second sample injection chamber.
  • the cavity enters the quantitative mixing cavity and the quantitative separation cavity;
  • the diluent is preset in the first sampling chamber, and the diluent enters the quantitative mixing chamber from the first sampling chamber;
  • the blood cell sample After the reaction sample and diluent in the first sample injection chamber are mixed uniformly in the quantitative mixing chamber, the blood cell sample enters the positive reaction chamber through the micro flow channel to react with the reaction reagent therein for detection;
  • the plasma sample separated in the quantitative separation chamber enters the anti-setting reaction chamber through the micro-channel to react with the reaction reagent therein for detection.
  • the positive-type reaction chamber includes several blood group antibody reagent reaction chambers and a positive-type quality control reaction chamber and an overflow tank
  • the reverse-type reaction chamber includes several blood-group red blood cell reagent reaction chambers and a reverse-type quality control reaction chamber and an overflow tank.
  • the anti-typing blood type identification area also includes a sample overflow chamber, the sample overflow chamber is connected to the quantitative separation chamber, and more reaction samples than the quantitative separation chamber enter the sample overflow chamber.
  • the sample overflow chamber is connected to the vent hole that communicates with the positive-type reaction chamber.
  • the microfluidic channel between the sample injection chamber and the quantitative mixing chamber, the microfluidic channel between the quantitative mixing chamber and the positive stereotyped reaction chamber, and the pre-preparation in the microfluidic channel between the quantitative separation chamber and the reverse stereotyped reaction chamber Filled with solid phase change material.
  • phase change material is a single-component alkane solid phase change material.
  • the chip further includes a phase change material filling port.
  • the phase change material filling port is a vent hole.
  • the chip further includes a hematocrit detection tube groove, which is connected to the quantitative separation chamber and located on the side of the quantitative separation chamber close to the positive blood type identification area.
  • the volumes of the positive stereotyped reaction chamber and the reversed stereotyped reaction chamber are both 20-40 ⁇ L.
  • the volume of the first sample injection chamber is 100-200 ⁇ L.
  • the volume of the second sample injection chamber is 250-350 ⁇ L.
  • the present invention has following advantage:
  • microfluidic chip technology is adopted, and full-automatic blood type identification can be realized only by adding a whole blood sample to the chip; and the chip has both positive and negative typing blood type identification areas, and one chip can simultaneously complete positive and negative typing
  • the positive and negative typing results can be mutually verified, making the blood type identification results more accurate, and the reverse typing review can make up for the lack of positive typing.
  • the positive and negative typing results are inconsistent, it is easy to find and correct blood type misidentification.
  • the blood sampling volume in the present invention is small, the volume of the first sampling cavity is 100-200 ⁇ L, and the sample sampling volume is 5-20 ⁇ L, that is, the positive blood type detection can be completed with one drop of blood, which can well solve the problem of blood sampling difficulties, especially Is the applicability of newborns.
  • the microfluidic channel between the first sampling cavity and the quantitative mixing cavity is pre-filled with a phase change material, and the liquid diluent is directly encapsulated in the first sampling cavity by using the phase change material, and then passes through the
  • the matching detection instrument adjusts the temperature to reach a suitable temperature range, so that the phase change material pre-filled in the microchannel undergoes a phase change due to the temperature change in the detection room of the instrument.
  • the specific process is from solid to liquid, realizing liquid samples and reagents. flow, the chip structure is simple, and the cost is low.
  • the micro-flow channel between the quantitative mixing chamber and the positive-setting reaction chamber, and the micro-flow channel between the quantitative separation chamber and the reverse-setting reaction chamber are pre-filled with phase change materials, and the liquid reaction reagents are directly charged by using the phase change materials.
  • Encapsulated in the reaction chamber it overcomes the problems of high cost and poor repeatability of results caused by solid reagent packaging; the most important thing is that it can well maintain the integrity of the blood cell reagent in the anti-typing reaction chamber and solve the problem of blood type
  • the problem that the blood cells are easy to break when the red blood cell reagent is solidified simplifies the structure of the chip, reduces the cost and further improves the accuracy of the detection result.
  • Fig. 1 is an exploded schematic diagram of the overall structure of the microfluidic blood type detection chip of the present invention
  • Figure 2 is a schematic diagram of the front structure of the chip body in the microfluidic blood type detection chip of the present invention
  • Figure 3 is a schematic diagram of the back structure of the chip body in the microfluidic blood type detection chip of the present invention
  • Figure 4 is a schematic diagram of the three-dimensional structure of the chip body in the microfluidic blood type detection chip of the present invention
  • Figure 5 is a schematic diagram of the back structure of the overall structure of the microfluidic blood type detection chip of the present invention
  • Fig. 6 is an exploded schematic diagram of the overall structure of the chip in another embodiment of the microfluidic blood type detection chip of the present invention
  • Fig. 7 is a schematic diagram of the front structure of the chip body in another embodiment of the microfluidic blood type detection chip of the present invention
  • Fig. 8 is a schematic perspective view of the three-dimensional structure of the chip body in another embodiment of the microfluidic blood type detection chip of the present invention
  • Fig. 9 is a schematic diagram of the back structure of the chip body in another embodiment of the microfluidic blood type detection chip of the present invention
  • Figure 10 is a schematic diagram of the back structure of another embodiment of the microfluidic blood type detection chip of the present invention.
  • Fig. 11 is an exploded schematic diagram of the overall structure of the chip provided with two sets of positive blood type identification areas in the microfluidic blood type detection chip of the present invention
  • Fig. 12 is a schematic diagram of the front structure of the chip body provided with two groups of positive blood type identification areas in the microfluidic blood type detection chip of the present invention
  • Fig. 13 is a schematic diagram of the three-dimensional structure of the chip body provided with two groups of positive blood type identification areas in the microfluidic blood type detection chip of the present invention
  • Fig. 14 is a schematic diagram of the back structure of the chip body provided with two groups of positive blood type identification areas in the microfluidic blood type detection chip of the present invention
  • Fig. 15 is a schematic diagram of the structure of the back of the microfluidic blood type detection chip provided with two groups of positive blood type identification areas
  • fifth microchannel 221.
  • first upper layer 222. The through hole of the second sample chamber on the upper layer; 23.
  • the window of the sample chamber; 24. The window of the hematocrit detection tube slot; 25.
  • the window of the reaction chamber; 271. The first reverse flow channel; Two opposite runners.
  • the invention provides a microfluidic blood type detection chip, which is manufactured by mold injection and can be used in conjunction with detection equipment.
  • the detection chip can be in a fan-shaped structure, or be designed according to needs.
  • the microfluidic blood type detection chip in the present invention includes a chip upper layer 1 and a chip body 2 as a lower chip.
  • Chip upper layer 1 as shown in Figure 1 can be a transparent sticking film, is provided with upper strata first sampling cavity through hole 221 and upper strata second sampling cavity through hole 222, upper strata first sampling cavity through hole 221 and upper strata second sampling cavity through hole 221
  • the through-holes 222 of the second sample injection cavity are used for adding whole blood samples, and are respectively located on the left and right sides of the upper layer 1 of the chip near the center.
  • the chip body 2 is shown in Figure 1-5, and the chip body 2 comprises a positive type blood type identification area, is provided with the first sampling chamber 41, quantitative mixing chamber 8, positive type reaction chamber and the first vent hole 191;
  • the stereotyped blood type identification area is provided with a second sample injection chamber 42 , a quantitative separation chamber, a sample overflow chamber 11 , an anti-typing reaction chamber and a second air hole 192 .
  • the first sample injection cavity 41 and the second sample injection cavity 42 are respectively located near the left and right sides of the center of the chip body 2, and the tops of the first sample injection cavity 41 and the second sample injection cavity 42 are provided with injection ports, specifically , the first sampling chamber through hole 221 is located directly above the first sampling chamber 41, and the second sampling chamber through hole 222 is located directly above the second sampling chamber 42, through which the sampling chamber can be connected to the sampling chamber. Inject the reaction sample to be detected;
  • the volume of the first sample injection chamber 41 is fixed and can be set to 100-200 ⁇ L.
  • the sample injection volume is 5-20 ⁇ L.
  • the diluent is preset in it and connected to the quantitative mixing chamber 8 through a microchannel.
  • the quantitative mixing chamber 8 is farther away from the center of the chip body 2 than the first sample injection chamber 41. Therefore, when the chip body 2 is rotated by centrifugal driving, the mixed sample and diluent in the first sample injection chamber 41 will move toward the quantitative mixing chamber due to centrifugal action.
  • the flow in the uniform chamber 8 is specifically through the port on the bottom surface of the first sample injection chamber 41, then through the first reverse flow channel 271, and then through the first micro flow channel 211 towards the quantitative mixing chamber 8, the first reverse flow channel 271 inlet Located at the bottom of the first sampling chamber 41 near the quantitative mixing chamber 8, the outlet of the first micro flow channel 211 is located at the side of the quantitative mixing chamber 8 near the center of the chip body 2, the first reverse flow channel 271 is connected to the first micro flow channel 211.
  • the flow channel 211 is connected by an up and down vertical flow channel; the first reverse flow channel 271 is provided with a sealing film 20 to prevent the sample from flowing out; the sample is put into the first sample injection chamber 41 and initially mixed with the diluent, and then the sample is mixed with the diluent
  • the mixed liquid of the liquid is further mixed during the flow process into the quantitative mixing chamber 8, and there is no need to perform reciprocating movement in the quantitative mixing chamber 8 for mixing, thereby preventing the mixed liquid from entering the reaction chamber during the mixing process.
  • the risk of the microchannel; the mixture of the sample and the diluent is fully mixed in the quantitative mixing chamber 8 to form a blood cell suspension for detection.
  • the volume of the second sample injection chamber 42 is fixed and can be set to 250-350 ⁇ L.
  • the sample injection volume is 100-200 ⁇ L. It is connected to the quantitative separation chamber through a micro-flow channel.
  • the quantitative separation chamber includes a separation chamber 19 and a separation chamber.
  • the separation chamber II 12 and the separation chamber I 9 are successively farther away from the center of the chip body 2 than the second sample injection chamber 42; wherein the two ends of the separation chamber I 9 are respectively connected to the second sample injection chamber 42 and the separation chamber through micro-flow channels II 12 is connected, and the micro flow channel connected between the separation chamber I 9 and the separation chamber II 12 is narrow, so that when the plasma enters the reaction chamber after stratification, it can ensure that the plasma enters the reaction chamber, and blood cells will not enter the reaction chamber.
  • the reaction chamber is located inside the edge of the outer ring of the chip body 2, including positive-setting reaction chambers and reverse-setting reaction chambers.
  • the volume of the reaction chambers is 20-40 ⁇ L, and the positive-setting reaction chambers include several equidistant and uniformly distributed blood group antibody reagent reaction chambers.
  • the blood group antibody reagent reaction chamber 14 and the positive quality control reaction chamber 16 are respectively provided with the blood group antibody reagents and quality control blood type required for the reaction Antibody reagent;
  • the anti-typing reaction chamber includes several equidistant evenly distributed blood group red blood cell reagent reaction chambers 15 and an anti-typing quality control reaction chamber 17 and an overflow tank 18 positioned at the end of the flow channel.
  • the stereotyped quality control reaction chamber 17 is respectively provided with blood group red blood cell reagents and quality control blood group red blood cell reagents required for the reaction.
  • Quantitative mixing chamber 8 in the positive blood type identification area is connected to the positive type reaction chamber through the second micro flow channel 212 and the third micro flow channel 213;
  • the fifth micro-channel 215 is connected with the anti-typing reaction chamber;
  • the entrance of the fourth micro-channel 214 is located on the upper surface of the micro-channel between the separation chamber I 9 and the separation chamber II 12 near the side of the anti-typing blood group identification area, and the fourth
  • the flow channel height of the micro-channel 214 is 1/5-1/2 of the height of the micro-channel flow channel between the separation chamber I9 and the separation chamber II12, preferably 1/5-1/3, which further ensures that the blood After the sample is stratified in the quantitative separation chamber, it is plasma that enters the reaction chamber, and blood cells will not enter the reaction chamber to affect the detection structure;
  • the blood cell suspension in the quantitative mixing chamber 8 and the plasma in the quantitative separation chamber can pass through the microchannel Enter the corresponding reaction chambers to react with the reaction reagents therein for detection, and the excess blood cell
  • the quantitative mixing chamber 8 , the positively shaped reaction chamber and the reversely shaped reaction chamber communicate with the first vent hole 191 and the second vent hole 192 via microfluidic channels, respectively.
  • the vent hole runs through the chip body 2 located at the lower layer of the chip, and the setting of the vent hole makes the liquid flow in the chip smoother.
  • the sample overflow chamber 11 communicates with the first air hole 191 through a micro flow channel, and the first air hole 191 can serve as the air hole of the positive blood type identification area and the negative blood type identification area at the same time, which simplifies the chip structure and makes the inside of the chip Sample flow is smoother.
  • the micro flow channel between the first sample injection chamber 41 and the quantitative mixing chamber 8, the micro flow channel between the quantitative mixing chamber 8 and the positive stereotyped reaction chamber, and the microflow channel between the quantitative separation chamber and the reverse stereotyped reaction chamber can be pre-filled with solid phase-change materials, preferably single-component alkane-based solid phase-change materials.
  • the filling of the solid phase change material can make the chip when not in use, as shown in Figure 2, the micro flow path between the first sample injection chamber 41 and the quantitative mixing chamber 8, the quantitative mixing chamber 8 and the positive setting reaction chamber
  • the micro-channel between the quantitative separation chamber and the anti-setting reaction chamber is always in a closed state, which plays the role of packaging and protecting the liquid reagent in the chip body 2; during the reaction process, by adjusting the detection chamber of the instrument
  • the temperature makes it reach a suitable temperature range, so that the phase change material prefilled in the microchannel will undergo a phase change due to the temperature change in the detection chamber of the instrument, specifically from solid to liquid, so that the flow of liquid reagents in the chip can be realized.
  • the phase-change material that becomes liquid during the reaction will enter the chamber.
  • phase-change material When the liquid reagent or sample enters, the phase-change material will return to the microchannel due to its small specific gravity and form a layer with the lower liquid, especially for the reaction chamber.
  • the oil seal function prevents the reaction liquid in the reaction chamber from volatilizing and forming bubbles to affect the accuracy of the test results; in addition, due to the oil seal function of the phase change material, the reaction waste liquid in the chip will not leak after the test, effectively reducing the risk of biological safety; More importantly, the use of phase-change material packaging can well maintain the integrity of the blood cell reagent in the anti-setting reaction chamber, and solve the problem that blood cells are easily broken when the blood group red blood cell reagent is freeze-dried or dried.
  • the microfluidic blood type detection chip of the present invention also includes a phase-change material filling port, which is respectively used to fill the first phase-change material connected to the quantitative mixing chamber 8, the positive-setting reaction chamber, and the reverse-setting reaction chamber through micro-channels. Port 13, the second phase change material filling port and the third phase change material filling port.
  • the phase-change material filling port can be a vent hole, and the aforementioned first vent hole 191 and the second vent hole 192 can also be used as the second phase-change material filling port and the third phase-change material filling port; chip production , after the upper sealing film is sealed to the chip body 2, inject a single group through the first phase-change material filling port 13, the second phase-change material filling port and the third phase-change material filling port For alkane-based liquid phase-change materials, due to the action of capillary force, the phase-change materials enter the flow channel to be sealed, so that the micro-channel between the first sample injection chamber 41 and the quantitative mixing chamber 8, the quantitative mixing chamber 8 and the The third micro-channel 213 between the positive-setting reaction chambers and the fifth micro-channel 215 between the quantitative separation chamber and the reverse-setting reaction chamber are pre-filled with single-component alkane-based solid phase-change materials.
  • the microfluidic blood type detection chip of the present invention can also include a hematocrit detection tube groove 10, which is located on the microflow channel between the quantitative separation chamber and the sample overflow chamber 11 in the anti-typing blood type identification area, and is a radial straight tube Groove, the marking scale on the surface of the tube groove is divided into 10 equidistant segments, and each segment is further subdivided, specifically to use the effect of the standard centrifugal force on the spilled blood, so that the hematocrit can be directly detected, and the percentage of the volume can be manually interpreted to provide blood for matching blood supply.
  • Important basis reference range of normal hematocrit: female: 37% to 48%; male: 40% to 50%).
  • the microfluidic blood type detection chip of the present invention can also include an anti-interference groove 5, which is located between each reaction chamber.
  • the anti-interference groove 5 is to prevent light interference between two adjacent reaction chambers during microscopic imaging detection, which affects the detection. the accuracy of the results.
  • a positioning structure 6 is also provided inside the anti-interference groove 5, and the positioning structure 6 is a triangular column structure inside the anti-interference groove, which plays a role of detection and positioning when detecting in the matching detection instrument.
  • the microfluidic blood type detection chip in the present invention can also include an opaque film 3, which covers the upper surface of the upper layer 1 of the chip, and the opaque film 3 is provided with a plurality of through holes to play a role Observe the function of the window.
  • each through hole is arranged in order from near to far: the sample injection cavity window 23, the hematocrit detection tube slot window 24 and the reaction cavity window 25, wherein the sample injection cavity window 23 is connected with the reaction cavity window 25.
  • the through hole 221 of the first sampling chamber on the upper layer 1 of the chip corresponds to the through hole 222 of the second sampling chamber on the upper layer
  • the hematocrit detection tube slot window 24 corresponds to the hematocrit detection tube slot 10 on the chip body 2.
  • the chamber windows 25 correspond to the reaction chambers on the chip body 2 one by one. During the test, the staff can record the sample number and related information on the opaque film 3, without additional labeling, which is convenient and practical.
  • microfluidic blood type detection chip of the present invention can also be pre-prepared with a diluent in the second sample injection chamber 42 of the anti-type blood type identification area, and the blood sample is diluted after being added, and then enters the subsequent detection process.
  • the addition of the phase change material can also be carried out in the following manner, before the transparent sealing film of the upper layer 1 of the chip is sealed to the chip body 2, and after the sealing film 20 is sealed to the chip body 2 , anti-typing blood type identification area: inject a single-component alkane liquid phase change material through the outlet of the second reverse flow channel 272, and seal the diluent in the second sample injection chamber 42 along the second reverse flow channel 272;
  • the chip reaction chamber Blood type antibody reagent reaction chamber 14, blood type erythrocyte reagent reaction chamber 15, positive type quality control reaction chamber 16, negative type quality control reaction chamber 17
  • the reaction reagent is added to the reaction chamber Then directly add a single-component alkane liquid phase change material, the temperature change makes the phase change material change from liquid to solid, and seal the micro flow channel entering the reaction chamber;
  • the single-component alkane liquid phase change material inject a single-component alkane liquid phase change material through the outlet of the second reverse flow channel 272, and seal the dilu
  • the specific process is: the whole blood sample enters the first sampling cavity 41 and the second sampling cavity through the upper first sampling port 221 and the upper second sampling cavity port 222 respectively 42.
  • the chip of the present invention in a matching detection instrument, and the instrument operates according to the set program according to the detection requirements.
  • Positive type blood type identification area the phase change material pre-filled in the micro flow channel between the first sample injection chamber 41 and the quantitative mixing chamber 8 changes from solid to liquid due to the temperature change in the instrument detection chamber.
  • the mixed sample and liquid diluent in the sample injection chamber 41 flow out, and flow into the quantitative mixing chamber 8 through the micro flow channel; the mixed solution of the sample to be tested and the diluent is fully mixed in the flow process and in the quantitative mixing chamber 8 to form blood cells Suspension; the pre-filled phase change material in the third micro flow channel 213 also changes from solid to liquid due to the temperature change in the instrument detection chamber; under the action of centrifugal force, the blood cell suspension in the quantitative mixing chamber 8 passes through the second micro flow
  • the flow channel 212 and the third micro-flow channel 213 enter the positive-setting reaction chamber, and are not compatible with the anti-A antibody reagent, anti-B antibody reagent, anti-D antibody reagent in the blood group antibody reagent reaction chamber 14 and the positive-setting quality control reaction chamber 16.
  • the quality control antibody reagents containing anti-A, anti-B and anti-D are mixed and fully reacted, and the excess blood cell suspension flows into the overflow tank 18 .
  • Anti-type blood type identification area when the samples in the positive type blood type identification area enter the reaction chamber reaction process, under the action of centrifugal force, the samples in the second sample injection chamber 42 flow into the separation chamber 19 and the separation chamber sequentially through the micro flow channel II 12, hematocrit detection tube groove 10, excess sample flows into sample overflow chamber 11.
  • the blood cells and plasma in the separation chamber I 9 and the separation chamber II 12 are layered, the lower layer of blood cells is deposited, and the upper layer is plasma;
  • the change changes from solid to liquid;
  • the upper layer plasma in the quantitative separation chamber enters the anti-setting reaction chamber through the fourth micro-channel 214 and the fifth micro-channel 215 in sequence, and is mixed with the red blood cell reagent reaction chamber 15.
  • Type A erythrocyte reagent, B type erythrocyte reagent and the quality control erythrocyte reagent (generally O type erythrocyte reagent) that do not contain A and B blood type erythrocytes in the anti-type quality control reaction chamber 17 are mixed and fully reacted, and excess plasma flows into the overflow In slot 18.
  • the microscopic camera is used to take pictures, and the blood type identification results are automatically analyzed and displayed, and the results can also be reviewed with manual images, and the data can also be automatically transmitted to the company's platform. Experts review the judgment results. See Table 1 below for blood type identification results:
  • Fig. 6-10 it is a combined detection chip of ABO blood type and Rh blood type system, and the quantitative mixing chamber 8 is connected with the third air hole 193 through another micro flow channel, The setting of the vent hole makes the liquid flow in the chip more smooth.
  • This chip is especially suitable for the blood type identification of newborns. This is because newborns have few blood group antigen sites and low antibody titers. It is generally believed that there is basically no blood type antibodies within 3 months. It is often the IgG blood type antibody from the mother, which will lead to false positive results in neonatal anti-typing blood group identification;
  • the specific process is as follows: the whole blood sample enters the first sampling chamber 41 through the through hole 221 of the first sampling chamber on the upper layer, the chip of the present invention is placed in the detection instrument, and the instrument operates according to the set program according to the detection requirements;
  • the phase change material pre-filled in the micro flow channel between the sample chamber 41 and the quantitative mixing chamber 8 changes from solid to liquid due to the temperature change in the detection chamber of the instrument.
  • the mixed sample in the first sample injection chamber 41 and the liquid diluent flow out, and flow into the quantitative mixing chamber 8 through the micro flow channel; the sample and the diluent are fully mixed in the flow process and the quantitative mixing chamber 8 to form a blood cell suspension; the pre-filled phase in the third micro flow channel 213
  • the variable material also changes from solid to liquid due to the temperature change in the detection chamber of the instrument; under the action of centrifugal force, the blood cell suspension in the quantitative mixing chamber 8 enters the positive setting reaction through the second microchannel 212 and the third microchannel 213 in sequence
  • the quality control blood type antibody reagents that do not contain the above blood type antibodies in the control reaction chamber 16 are mixed and fully reacted, and the excess blood cell
  • two groups of ABO positive blood type identification areas can be set on the chip body 2 at the same time, that is, double ABO positive blood type detection chips, which can detect two different blood types at the same time. samples; and the three chip bodies 2 can also be assembled into a circular detection chip, which can detect six different samples at the same time, increasing the throughput of detection samples.
  • the specific process is as follows: the whole blood sample enters the first sampling chamber 41 through the through hole 221 of the first sampling chamber on the upper layer, the chip of the present invention is placed in the detection instrument, and the instrument operates according to the set program according to the detection requirements;
  • the phase change material pre-filled in the micro flow channel between the sample chamber 41 and the quantitative mixing chamber 8 changes from solid to liquid due to the temperature change in the detection chamber of the instrument.
  • the mixed sample in the first sample injection chamber 41 and the liquid diluent flow out, and flow into the quantitative mixing chamber 8 through the micro flow channel; the sample and the diluent are fully mixed in the flow process and the quantitative mixing chamber 8 to form a blood cell suspension; the pre-filled phase in the third micro flow channel 213
  • the variable material also changes from solid to liquid due to the temperature change in the detection chamber of the instrument; under the action of centrifugal force, the blood cell suspension in the quantitative mixing chamber 8 enters the positive setting reaction through the second microchannel 212 and the third microchannel 213 in sequence
  • the anti-A antibody reagent, anti-B antibody reagent, anti-D antibody reagent in the reaction cavity 14 and the positive quality control reaction cavity 16 do not contain anti-A, anti-B, anti-D quality control blood type antibodies
  • the reagents are mixed and fully reacted, the excess blood cell suspension flows into the overflow tank 18, and the microscopic camera is used to take pictures, and the blood type identification results
  • the volume of the first sample injection chamber 41 in the positive blood type identification area of the microfluidic blood type detection chip of the present invention is 100-200 ⁇ L, the sample injection volume is 5-20 ⁇ L, and the blood collection volume is small, which can well solve blood collection difficulties, especially Is the applicability of newborns.

Abstract

一种微流控血型检测芯片，该芯片包括芯片本体（2），芯片本体（2）包括正定型血型鉴定区和反定型血型鉴定区，正定型血型鉴定区设第一进样腔（41）、定量混匀腔（8）、正定型反应腔和第一透气孔（191）；反定型血型鉴定区设第二进样腔（42）、定量分离腔、反定型反应腔及第二透气孔（192）；第一进样腔（41）注入样本，第一进样腔（41）内样本和预设稀释液经微流道入定量混匀腔（8）；样本与稀释液在定量混匀腔（8）中混匀后，入正定型反应腔与反应试剂反应以待检测；第二进样腔（42）注入样本，经微流道入定量分离腔，样本在定量分离腔内被分离，分离出的血浆入反定型反应腔与反应试剂反应以待检测。该微流控血型检测芯片能够实现正、反定型血型鉴定同时进行，使血型鉴定结果更加准确。

Description

一种微流控血型检测芯片 技术领域
本发明涉及微流控芯片领域，尤其涉及一种微流控血型检测芯片。
背景技术
微流控芯片是一个新兴的科技产业，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，自动完成分析的全过程。在生物、化学、医学等领域有着巨大的潜力。
血型是对血液分类的方法，其中ABO和Rh血型系统与人类输血关系最密切。ABO血型系统：根据红细胞表面有无特异性抗原(凝集原)A和B来划分的血液类型系统。ABO血型系统是发现和确定的人类第一个血型系统。根据凝集原A、B的分布把血液分为A、B、AB、O四型。红细胞上只有凝集原A的为A型血，其血浆中有抗B凝集素；红细胞上只有凝集原B的为B型血，其血浆中有抗A的凝集素；红细胞上A、B两种凝集原都有的为AB型血，其血浆中无抗A、抗B凝集素；红细胞上A、B两种凝集原皆无者为O型，其血浆中抗A、抗B凝集素皆有。具有凝集原A的红细胞可被抗A凝集素凝集；抗B凝集素可使含凝集原B的红细胞发生凝集。所谓的正定型是指用标准抗A抗B分型血浆来测定红细胞上有无相应的A抗原或(和)B抗原；所谓的反定型，是指用标准的A型、B型细胞来测定血浆中有无抗A和(或)抗B凝集素，正反定型结合鉴定，可作 为验证，提高检测结果的准确性。Rh血型系统：根据Rh因子的有无，区分为Rh阴性和Rh阳性两种血型。临床上人体红细胞上含有Rh系统的五种抗原，抗原D、C、c、E、e，其中D抗原的抗原性最强，根据红细胞上D抗原的有无，即红细胞上缺乏D抗原的是RhD阴性血，红细胞上存在D抗原的是RhD阳性血。
由于ABO血型系统不相容输血，必然会导致溶血性输血反应症状(弥漫性血管内凝血、肾衰甚至死亡)的发生，因此，ABO血型的准确鉴定至关重要。此外，虽然在我国人群中Rh阴性率仅为0.34％，因Rh血型不合而发生的免疫现象很少见，但因Rh阴性的人输入Rh阳性的血液后，在其血浆中可以出现抗Rh抗体，当再输入Rh阳性血，就会发生凝集，造成溶血性反应；另外，一般人血浆中虽然没有Rh抗体，但Rh阴性妇女若孕育Rh阳性胎儿，胎儿的红细胞一旦进入母体，也可刺激母体产生Rh抗体，即使第一次给母体输血，也可引起溶血反应。因此，我国卫生部明确规定，输血科要逐项核对输血申请单、受血者和供血者血样，复查受血者和供血者ABO血型(正反定型)，并常规检查患者的Rh血型，正确无误时方可进行交叉配血。
血球压积一般指红细胞压积(PCV)，亦称红细胞比容(Hct)，是指一定量的抗凝全血经离心沉淀后，测得下沉的红细胞占全血的容积比，是一种间接反映红细胞数量大小及体积的简单方法。PCV测定的临床意义基本同红细胞计数或血红蛋白测定，常用作贫血诊断和分类的指标，还可作真性红细胞增多症、临床输血及输液治疗疗效观察的一 项指标，同时也是计算红细胞平均体积和红细胞平均血红蛋白浓度的基础数据。
目前普遍使用的血型鉴定方法有：纸板法、玻片法、试管法、微柱凝胶法。但是纸板法、玻片法、试管法几种方法均存在以下缺陷：1)正反定型血型系统的鉴定需要分别进行；2)均需进行样本前处理，费时费力；3)不能自动化检测，对实验人员熟练程度要求高；4)所需血液样本量大；另外，虽然微柱凝胶法可实现自动化，但该方法对待测标本、试剂质量及仪器要求极高，成本较高；与此同时，血球压积的检测也是配供血的一项重要依据，目前还未有人将其应用到血型鉴定芯片上。
发明内容
为了解决现有技术中的不足，本发明提供一种微流控血型检测芯片，以克服现有血型检测技术的缺陷，操作简单、样本使用量小、自动化检测、正反定型血型鉴定同时进行、成本较低、检测结果更准确且在进行血型鉴定的同时能够直接检测血球压积，为配供血提供重要依据。
为实现上述的技术目的，本发明采取如下的技术方案：
一种微流控血型检测芯片，该芯片包括芯片本体，芯片本体包括一正定型血型鉴定区，设置有第一进样腔、定量混匀腔、正定型反应腔；
一反定型血型鉴定区，设置有第二进样腔、定量分离腔、反定型反应腔；
分别与正定型反应腔、反定型反应腔相连通的透气孔；
第一进样腔和第二进样腔可供注入待检测的样本，分别通过微流道与定量混匀腔和定量分离腔对应相连，反应样本能从第一进样腔和第二进样腔进入定量混匀腔和定量分离腔；
第一进样腔内预设有稀释液，稀释液从第一进样腔进入定量混匀腔；
第一进样腔的反应样本和稀释液在定量混匀腔内混匀之后，血球样本经微流道进入正定型反应腔与其中的反应试剂进行反应以待检测；
定量分离腔中分离出的血浆样本通过微流道进入反定型反应腔与其中的反应试剂进行反应以待检测。
优选地，正定型反应腔包括若干个血型抗体试剂反应腔和一个正定型质控反应腔以及一个溢流槽；反定型反应腔包括若干个血型红细胞试剂反应腔和一个反定型质控反应腔以及一个溢流槽。
更优选地，若干个血型抗体试剂反应腔和若干个血型红细胞试剂反应腔分别等距分布。
优选地，第二进样腔内预设有稀释液，稀释液从第二进样腔进入定量分离腔。
优选地，反定型血型鉴定区还包括样本溢流腔，样本溢流腔与定量分离腔相连，多于定量分离腔的反应样本进入样本溢流腔。
优选地，定量分离腔包括分离腔I和分离腔II，样本溢流腔和分离腔I分别通过不同的微流道与分离腔II相连，多于分离腔I的反应 样本依次进入分离腔II和样本溢流腔。
优选地，样本溢流腔和与正定型反应腔相连通的透气孔相连。
优选地，进样腔与定量混匀腔之间的微流道、定量混匀腔与正定型反应腔之间的微流道，以及定量分离腔与反定型反应腔之间的微流道内预填充有固体相变材料。
更优选地，相变材料为单一组分烷烃类固体相变材料。
优选地，芯片还包括相变材料加注口。
更优选地，相变材料加注口是透气孔。
优选地，芯片还包括血球压积检测管槽，血球压积检测管槽与定量分离腔相连，位于定量分离腔靠近正定型血型鉴定区一侧。
优选地，正定型反应腔和反定型反应腔的容积均为20～40μL。
优选地，第一进样腔的容积为100～200μL。
优选地，第二进样腔的容积为250～350μL。
根据上述的技术方案，本发明具有如下优点：
本发明中采用微流控芯片技术，只需在芯片上加入全血样本，就可以实现全自动血型鉴定；且该芯片同时具备正反定型血型鉴定区，一张芯片可同时完成正反定型的血型检测，正反定型结果可相互验证，使血型鉴定结果更加准确，用反定型复查可弥补正定型的不足，在正反定型结果出现不一致时，易于发现和纠正血型错误鉴定。
本发明中的采血量小，第一进样腔的容积为100～200μL，样本进样量为5-20μL，即采用一滴血即可完成正定型血型检测，能够很好的解决采血困难者尤其是新生儿的适用性问题。
本发明中内设血球压积检测管槽，能在进行血型鉴定的同时直接检测血球压积，为配供血提供重要依据。
本发明中第一进样腔与定量混匀腔之间的微流道内预填充有相变材料，利用相变材料将液体稀释液直接封装在了第一进样腔内，血型鉴定时再通过配套检测仪器调整温度使其达到一个合适的温度范围，使得微流道内预填充的相变材料因仪器检测室内温度变化而发生相变，具体过程为由固态变为液态，实现了液体样本与试剂的流动，芯片结构简单、成本低。
本发明中定量混匀腔与正定型反应腔之间的微流道，以及定量分离腔与反定型反应腔之间的微流道内预填充有相变材料，利用相变材料将液态反应试剂直接封装在反应腔内，克服了采用固体试剂封装所带来的高成本、结果重复性不好等问题；最重要的是能够很好地保持反定型反应腔中血球试剂的完整性，解决了血型红细胞试剂固态化时血球易破裂的问题，简化了芯片结构、降低了成本并进一步提高了检测结果的准确性。
附图说明：
图1为本发明的微流控血型检测芯片的整体结构分解示意图
图2为本发明的微流控血型检测芯片中芯片本体的正面结构示意图
图3为本发明的微流控血型检测芯片中芯片本体的背面结构示意图
图4为本发明的微流控血型检测芯片中芯片本体的立体结构示 意图
图5为本发明的微流控血型检测芯片的整体结构的背面结构示意图
图6为本发明的微流控血型检测芯片中另一实施方式的芯片整体结构分解示意图
图7为本发明的微流控血型检测芯片中另一实施方式的芯片本体的正面结构示意图
图8为本发明的微流控血型检测芯片中另一实施方式的芯片本体的立体结构示意图
图9为本发明的微流控血型检测芯片中另一实施方式的芯片本体的背面结构示意图
图10为本发明的微流控血型检测芯片中另一实施方式的芯片的背面结构示意图
图11为本发明的微流控血型检测芯片中设置有两组正定型血型鉴定区的芯片的整体结构分解示意图
图12为本发明的微流控血型检测芯片中设置有两组正定型血型鉴定区的芯片本体的正面结构示意图
图13为本发明的微流控血型检测芯片中设置有两组正定型血型鉴定区的芯片本体的立体结构示意图
图14为本发明的微流控血型检测芯片中设置有两组正定型血型鉴定区的芯片本体的背面结构示意图
图15为本发明的微流控血型检测芯片中设置有两组正定型血型 鉴定区的芯片的背面结构示意图
附图标号说明：
1.芯片上层；2.芯片本体；3.不透明贴膜；41.第一进样腔；42.第二进样腔；5.防干扰凹槽；6.定位结构；8.定量混匀腔；9.分离腔I；10.血球压积检测管槽；11.样本溢流腔；12.分离腔II；13.第一相变材料加注口；14.血型抗体试剂反应腔；15.血型红细胞试剂反应腔；16.正定型质控反应腔；17.反定型质控反应腔；18.溢流槽；191.第一透气孔；192.第二透气孔；193：第三透气孔；20.密封膜；211.第一微流道；212.第二微流道；213.第三微流道；214.第四微流道；215.第五微流道；221.上层第一进样腔通孔；222.上层第二进样腔通孔；23.进样腔窗口；24血球压积检测管槽窗口；25.反应腔窗口；271.第一反面流道；272.第二反面流道。
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。
本发明提供了一种微流控血型检测芯片，该芯片通过模具注塑的方式制作而成，可配合检测设备使用。检测芯片可呈扇形结构，或根 据需要进行设计。
如图1-5所示，本发明中的微流控血型检测芯片包括芯片上层1以及作为下层芯片的芯片本体2。
芯片上层1如图1所示，可以为透明贴膜，其上设有上层第一进样腔通孔221和上层第二进样腔通孔222，上层第一进样腔通孔221及上层第二进样腔通孔222用于加入全血样本，分别位于芯片上层1靠近中心左右两侧的位置。
芯片本体2如图1-5所示，芯片本体2包括一正定型血型鉴定区，设置有第一进样腔41、定量混匀腔8、正定型反应腔以及第一透气孔191；一反定型血型鉴定区，设置有第二进样腔42、定量分离腔、样本溢流腔11、反定型反应腔及第二透气孔192。
第一进样腔41和第二进样腔42，分别位于靠近芯片本体2中心左右两侧的位置，第一进样腔41和第二进样腔42顶部均设有进样口，具体的，第一进样腔通孔221位于第一进样腔41的正上方，第二进样腔通孔222位于第二进样腔42的正上方，通过进样腔通孔可向进样腔中注入待检测的反应样本；
第一进样腔41容积固定，可设定为100～200μL，样本进样量为5～20μL，其内预设有稀释液，通过微流道与定量混匀腔8相连，定量混匀腔8较第一进样腔41远离芯片本体2的中心位置，因此，当芯片本体2被离心驱动而旋转时，第一进样腔41内混合的样本及稀释液会因离心作用而朝向定量混匀腔8流动，具体的是经第一进样腔41底面端口，然后经第一反面流道271，再经第一微流道211朝向定 量混匀腔8流动，第一反面流道271入口位于第一进样腔41靠近定量混匀腔8的一侧底部，第一微流道211出口位于定量混匀腔8靠近芯片本体2中心位置一侧，第一反面流道271与第一微流道211通过一上下垂直的流道相连接；第一反面流道271设置有密封膜20，防止样本流出；样本加入第一进样腔41中，与稀释液初步混匀，随后样本与稀释液的混合液在进入定量混匀腔8的流动过程中进一步混匀，无需在定量混匀腔8内进行往复运动进行混匀，从而避免了混匀液在混匀过程中进入通向反应腔的微流道的风险；样本及稀释液的混合液在定量混匀腔8内充分混匀形成血球悬液以待检测之用。
第二进样腔42容积固定，可设定为250～350μL，样本进样量为100～200μL，通过微流道与定量分离腔相连，优选地，定量分离腔包括分离腔I 9和分离腔II 12，分离腔II 12和分离腔I 9依次较第二进样腔42远离芯片本体2的中心位置；其中分离腔I 9两端通过微流道分别与第二进样腔42和分离腔II 12相连，分离腔I 9和分离腔II 12之间连通的微流道较窄，作用是血浆分层后进入反应腔时能够确保进入反应腔的是血浆，血细胞不会进入反应腔对检测结果造成干扰；分离腔II 12通过另一侧的微流道与样本溢流腔11相连，样本溢流腔11位于定量分离腔靠近正定型血型鉴定区的一侧；因此，当芯片本体2被离心驱动而旋转时，第二进样腔42内的样本会因离心作用经第二进样腔42底面端口，经第二反面流道272朝向分离腔I 9流动，第二反面流道272入口位于第二进样腔42靠近定量分离腔一侧底部，第二反面流道272出口位于分离腔I 9远离芯片本体2中心位置一侧； 第二反面流道272设置有密封膜20，防止样本流出；多于分离腔I 9容量的样本依次进入分离腔II 12和样本溢流腔11，在定量分离腔内血细胞与血浆分层，下层血细胞沉积，上层血浆供待检测之用。
反应腔位于芯片本体2外圈边缘内侧，包括正定型反应腔和反定型反应腔，反应腔容积大小均为20～40μL，其中正定型反应腔包括若干个等距均匀分布的血型抗体试剂反应腔14和一个正定型质控反应腔16以及一个位于流道尾端的溢流槽18，血型抗体试剂反应腔14和正定型质控反应腔16内分别设有反应所需的血型抗体试剂及质控血型抗体试剂；反定型反应腔包括若干个等距均匀分布的血型红细胞试剂反应腔15和一个反定型质控反应腔17以及一个位于流道尾端的溢流槽18，血型红细胞试剂反应腔15和反定型质控反应腔17内分别设有反应所需的血型红细胞试剂及质控血型红细胞试剂。
正定型血型鉴定区中定量混匀腔8依次通过第二微流道212、第三微流道213与正定型反应腔相连；反定型血型鉴定区中定量分离腔通过第四微流道214、第五微流道215与反定型反应腔相连；第四微流道214入口位于分离腔I 9和分离腔II 12之间的微流道靠近反定型血型鉴定区一侧的上表面，第四微流道214的流道高度为分离腔I 9和分离腔II 12之间的微流道流道高度的1/5-1/2，优选为1/5-1/3，进一步保证了血液样本在定量分离腔分层后进入反应腔室的是血浆，血细胞不会进入反应腔对检测结构造成影响；定量混匀腔8内的血球悬液及定量分离腔内的血浆可以经微流道分别进入相应的反应腔以便与其中的反应试剂进行反应以待检测，多余的血球悬液和血浆分别 进入相应的溢流槽18；一个芯片可同时完成正定型和反定型两个不同的分离反应体系的血型检测，两者鉴定结果可相互验证，使血型鉴定结果更加准确，在正定型和反定型血型检测结果出现不一致时，易于发现和纠正血型错误鉴定。
如图1-5所示，定量混匀腔8，正定型反应腔以及反定型反应腔经由微流道分别与第一透气孔191以及第二透气孔192相连通。透气孔贯穿位于芯片下层的芯片本体2，透气孔的设置使芯片内液体流动更顺畅。
样本溢流腔11通过一微流道与第一透气孔191相连通，第一透气孔191可以同时充当正定型血型鉴定区和反定型血型鉴定区的透气孔，精简了芯片结构，使芯片内样本的流动更加顺畅。
第一进样腔41与定量混匀腔8之间的微流道、定量混匀腔8与正定型反应腔之间的微流道，以及定量分离腔与反定型反应腔之间的微流道内可预填充固体相变材料，优选为单一组分烷烃类固体相变材料。固体相变材料的填充可使得芯片在未使用时，如图2中所示，第一进样腔41与定量混匀腔8之间的微流道、定量混匀腔8与正定型反应腔之间的微流道，以及定量分离腔与反定型反应腔之间的微流道始终处于封闭状态，起到封装并保护芯片本体2内液体试剂的作用；反应过程中，通过调整仪器检测室内温度使其达到一个合适的温度范围，使得微流道内预填充的相变材料因仪器检测室内温度变化而发生相变，具体由固态变为液态，从而能够实现芯片中液体试剂的流动。反应过程中变为液态的相变材料会进入腔室，当液态试剂或样本进入 时，相变材料由于比重小，会重新回到微流道中，与下部液体形成分层，尤其对于反应腔起到了油封作用，避免了反应腔内反应液体挥发形成气泡影响检测结果的准确性；此外，由于相变材料的油封作用，检测后芯片内的反应废液不会泄露，有效降低了生物安全风险；更重要的是使用相变材料封装，能够很好地保持反定型反应腔内血球试剂的完整性，解决了血型红细胞试剂冻干或干燥时血球易破裂的问题。
本发明的微流控血型检测芯片还包括相变材料加注口，其分别为与定量混匀腔8、正定型反应腔以及反定型反应腔经微流道相连的第一相变材料加注口13、第二相变材料加注口和第三相变材料加注口。优选的，相变材料加注口可以是透气孔，前述的第一透气孔191、第二透气孔192可以兼做第二相变材料加注口和第三相变材料加注口；芯片生产时，当上层密封膜密封到芯片本体2后，从芯片本体2的背面通过第一相变材料加注口13、第二相变材料加注口和第三相变材料加注口注入单一组分烷烃类液体相变材料，由于毛细管力的作用，相变材料进入需密封的流道，使得第一进样腔41与定量混匀腔8之间的微流道、定量混匀腔8与正定型反应腔之间的第三微流道213以及定量分离腔与反定型反应腔之间的第五微流道215内预填充有单一组分烷烃类固体相变材料。
本发明的微流控血型检测芯片还可以包括血球压积检测管槽10，其位于反定型血型鉴定区中定量分离腔和样本溢流腔11之间的微流道上，为一径向直管槽，管槽表面标识刻度按10等距分段，每段再进行细分，具体为利用溢出血液在标准离心力的作用，从而能够直接 检测血球压积，人工判读压积百分比，为配供血提供重要依据(血球压积正常值参考范围：女：37％～48％；男：40％～50％)。
本发明的微流控血型检测芯片还可以包括防干扰凹槽5，其位于各个反应腔之间，防干扰凹槽5是为了防止显微摄像检测时相邻两反应腔的光线干扰，影响检测结果的准确性。在防干扰凹槽5内部还设有定位结构6，定位结构6为防干扰凹槽内部的三角形柱体结构，在配套检测仪器中检测时起到检测定位的作用。
优选地，如图1所示，本发明中的微流控血型检测芯片还可以包括不透明贴膜3，其盖合在芯片上层1的上表面，不透明贴膜3上设置有多个通孔，起到观察窗口的作用，各个通孔相较于不透明贴膜3中心由近及远依次排布：进样腔窗口23、血球压积检测管槽窗口24和反应腔窗口25，其中进样腔窗口23与芯片上层1上上层第一进样腔通孔221和上层第二进样腔通孔222相对应，血球压积检测管槽窗口24与芯片本体2上血球压积检测管槽10相对应，反应腔窗口25与芯片本体2上各反应腔一一对应。检测时工作人员可在不透明贴膜3上记录样本编号及相关信息，无需另外粘贴标签，方便实用。
本发明的微流控血型检测芯片，也可在反定型血型鉴定区的第二进样腔42中预设有稀释液，血液样本加入后被稀释，再进入后续检测流程。
本发明的微流控血型检测芯片，在芯片生产时，相变材料的加入还可以通过以下方式进行，在芯片上层1透明密封膜密封到芯片本体2之前，密封膜20密封到芯片本体2之后，反定型血型鉴定区：通 过第二反面流道272出口注入单一组分烷烃类液体相变材料，沿第二反面流道272将稀释液密封在第二进样腔42中；芯片反应腔：血型抗体试剂反应腔14、血型红细胞试剂反应腔15、正定型质控反应腔16、反定型质控反应腔17在芯片上层1透明密封膜密封到芯片本体2之前，在向反应腔加入反应试剂后直接加入单一组分烷烃类液体相变材料，温度变化使相变材料由液态变为固态，密封住进入反应腔的微流道；正定型血型鉴定区：通过第一微流道211的竖直进液通道注入单一组分烷烃类液体相变材料，沿第一反面流道271将稀释液密封在第一进样腔41中。
使用本发明的微流控血型检测芯片时，具体过程为：全血样本经上层第一进样口221和上层第二进样腔口222分别进入第一进样腔41和第二进样腔42，将本发明的芯片置于配套检测仪器中，根据检测需求，仪器按照设定程序运转。正定型血型鉴定区：第一进样腔41与定量混匀腔8之间的微流道内部预填充的相变材料因仪器检测室内温度变化由固态变为液态，在离心力作用下，使第一进样腔41中混合的样本和液体稀释液流出，经微流道流入定量混匀腔8；待测样本和稀释液的混合液在流动过程及在定量混匀腔8内充分混合形成血球悬液；第三微流道213内预填充的相变材料也因仪器检测室内温度变化由固态变为液态；在离心力的作用下，定量混匀腔8内的血球悬液依次经第二微流道212和第三微流道213进入正定型反应腔中，与血型抗体试剂反应腔14内的抗A抗体试剂、抗B抗体试剂、抗D抗体试剂以及正定型质控反应腔16内不含抗A、抗B、抗D的质控 抗体试剂混合并充分反应，多余的血球悬液流入溢流槽18中。
反定型血型鉴定区：在正定型血型鉴定区的样本进入反应腔反应的过程中，在离心力的作用下，第二进样腔42内的样本经微流道依次流入分离腔I 9、分离腔II 12，血球压积检测管槽10，多余的样本流入样本溢流腔11。随后，在高速离心作用下，分离腔I 9和分离腔II 12内血细胞和血浆分层，血细胞下层沉积，上层为血浆；第五微流道215内预填充的相变材料因仪器检测室内温度变化由固态变为液态；在离心力的作用下，定量分离腔内的上层血浆依次经第四微流道214和第五微流道215进入反定型反应腔中，与血型红细胞试剂反应腔15内的A型红细胞试剂、B型红细胞试剂以及反定型质控反应腔17内不含A、B血型红细胞的质控红细胞试剂(一般为O型红细胞试剂)混合并充分反应，多余的血浆流入溢流槽18内。
在正定型血型鉴定区和反定型血型鉴定区反应结束后，用显微摄像头摄像，自动分析显示血型鉴定结果，也可配合人工图像复核判断结果，还可以将数据自动传输到公司平台，由平台专家复核判断结果。血型鉴定结果判断见下表一：
Figure PCTCN2021120949-appb-000001
Figure PCTCN2021120949-appb-000002
在本发明的另一实施方式中，如图6-10所示，为ABO血型与Rh血型系统正定型联合检测芯片，定量混匀腔8通过另一微流道与第三透气孔193相连，透气孔的设置使芯片内液体流动更顺畅。该芯片尤其适用于新生儿的血型鉴定，这是由于新生儿自身血型抗原位点少，抗体效价又低，一般认为在3个月以内基本上没有血型抗体，其血清中可检测出的抗体常是来自母体的IgG型血型抗体，会导致新生儿反定型血型鉴定出现假阳性性结果；所以，新生儿用反定型检测血清中抗体意义不大，一般只做正定型血型鉴定。
具体过程为：全血样本经上层第一进样腔通孔221进入第一进样腔41，将本发明的芯片置于检测仪器中，根据检测需求，仪器按照设定程序运转；第一进样腔41与定量混匀腔8之间的微流道内部预填充的相变材料因仪器检测室内温度变化由固态变为液态，在离心力作用下，使第一进样腔41中混合的样本及液体稀释液流出，经微流道流入定量混匀腔8；样本和稀释液在流动过程和定量混匀腔8内充分混匀形成血球悬液；第三微流道213内预填充的相变材料也因仪器 检测室内温度变化由固态变为液态；在离心力的作用下，定量混匀腔8内的血球悬液依次经第二微流道212和第三微流道213进入正定型反应腔中，与血型抗体试剂反应腔14内的抗A抗体试剂、抗B抗体试剂、抗D抗体试剂、抗C抗体试剂、抗c抗体试剂、抗E抗体试剂、抗e抗体试剂以及正定型质控反应腔16内不含以上血型抗体的质控血型抗体试剂混合并充分反应，多余的血球悬液流入溢流槽18中，利用显微摄像头摄像，自动分析显示血型鉴定结果，也可配合人工图像复核判断结果，还可以将数据自动传输到公司平台，由平台专家复核判断结果。
在本发明的又一实施方式中，如图11-15所示，可以在芯片本体2上同时设置两组ABO正定型血型鉴定区，即双ABO正定型血型检测芯片，可同时检测2份不同样本；且3个芯片本体2也可拼装为1个圆形的检测芯片，可同时检测6份不同样本，增大检测样本通量。
具体过程为：全血样本经上层第一进样腔通孔221进入第一进样腔41，将本发明的芯片置于检测仪器中，根据检测需求，仪器按照设定程序运转；第一进样腔41与定量混匀腔8之间的微流道内部预填充的相变材料因仪器检测室内温度变化由固态变为液态，在离心力作用下，使第一进样腔41中混合的样本及液体稀释液流出，经微流道流入定量混匀腔8；样本和稀释液在流动过程和定量混匀腔8内充分混匀形成血球悬液；第三微流道213内预填充的相变材料也因仪器检测室内温度变化由固态变为液态；在离心力的作用下，定量混匀腔8内的血球悬液依次经第二微流道212和第三微流道213进入正定型 反应腔中，与血型抗体试剂反应腔14内的抗A抗体试剂、抗B抗体试剂、抗D抗体试剂以及正定型质控反应腔16内不含抗A、抗B、抗D的质控血型抗体试剂混合并充分反应，多余的血球悬液流入溢流槽18中，利用显微摄像头摄像，自动分析显示血型鉴定结果，也可配合人工图像复核判断结果，还可以将数据自动传输到公司平台，由平台专家复核判断结果。
本发明微流控血型检测芯片的正定型血型鉴定区中的第一进样腔41容积为100～200μL，样本进样量为5～20μL，采血量小，能够很好的解决采血困难者尤其是新生儿的适用性问题。
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 (15)

  1. 一种微流控血型检测芯片，其特征在于：所述芯片包括芯片本体，芯片本体包括一正定型血型鉴定区，设置有第一进样腔、定量混匀腔、正定型反应腔；
    一反定型血型鉴定区，设置有第二进样腔、定量分离腔、反定型反应腔；
    分别与所述正定型反应腔，所述反定型反应腔相连通的透气孔；
    所述第一进样腔和第二进样腔可供注入待检测的样本，分别通过微流道与所述定量混匀腔和所述定量分离腔相连，反应样本从所述第一进样腔和所述第二进样腔分别进入所述定量混匀腔和所述定量分离腔；
    所述第一进样腔内预设有稀释液，稀释液从所述第一进样腔进入所述定量混匀腔；
    所述第一进样腔的反应样本和稀释液在所述定量混匀腔内混匀之后，血球样本经微流道进入所述正定型反应腔与其中的反应试剂进行反应以待检测；
    所述定量分离腔中分离出的血浆样本通过微流道进入所述反定型反应腔与其中的反应试剂进行反应以待检测。
  2. 根据权利要求1所述的微流控血型检测芯片，其特征在于：所述正定型反应腔包括若干个血型抗体试剂反应腔和一个正定型质控反应腔以及一个溢流槽；
    所述反定型反应腔包括若干个血型红细胞试剂反应腔和一个反 定型质控反应腔以及一个溢流槽。
  3. 根据权利要求2所述的微流控血型检测芯片，其特征在于：所述若干个血型抗体试剂反应腔和所述若干个血型红细胞试剂反应腔分别等距分布。
  4. 根据权利要求1所述的微流控血型检测芯片，其特征在于：所述第二进样腔内预设有稀释液，稀释液从所述第二进样腔进入所述定量分离腔。
  5. 根据权利要求1所述的微流控血型检测芯片，其特征在于：所述反定型血型鉴定区还包括样本溢流腔，所述样本溢流腔与所述定量分离腔相连，多于所述定量分离腔的反应样本进入所述样本溢流腔。
  6. 根据权利要求5所述的微流控血型检测芯片，其特征在于：所述定量分离腔包括分离腔I和分离腔II，所述样本溢流腔和所述分离腔I分别通过不同的微流道与所述分离腔II相连，多于所述分离腔I的反应样本依次进入所述分离腔II和所述样本溢流腔。
  7. 根据权利要求5所述的微流控血型检测芯片，其特征在于：所述样本溢流腔和与所述正定型反应腔相连通的透气孔相连。
  8. 根据权利要求1所述的微流控血型检测芯片，其特征在于：所述第一进样腔与所述定量混匀腔之间的微流道、所述定量混匀腔与所述正定型反应腔之间的微流道，以及所述定量分离腔与所述反定型反应腔之间的微流道内预填充有固体相变材料。
  9. 根据权利要求8所述的微流控血型检测芯片，其特征在于：所述相变材料为单一组分烷烃类固体相变材料。
  10. 根据权利要求8所述的微流控血型检测芯片，其特征在于：所述芯片还包括相变材料加注口。
  11. 根据权利要求10所述的微流控血型检测芯片，其特征在于：所述相变材料加注口是透气孔。
  12. 根据权利要求1所述的微流控血型检测芯片，其特征在于：所述芯片还包括血球压积检测管槽，所述血球压积检测管槽与所述定量分离腔相连，位于所述定量分离腔靠近所述正定型血型鉴定区一侧。
  13. 根据权利要求1所述的微流控血型检测芯片，其特征在于：所述正定型反应腔和所述反定型反应腔的容积均为20～40μL。
  14. 根据权利要求1所述的微流控血型检测芯片，其特征在于：所述第一进样腔的容积为100～200μL。
  15. 根据权利要求1所述的微流控血型检测芯片，其特征在于：所述第二进样腔的容积为250～350μL。
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