WO2021068912A1 - 一种多标志物检测的磁微粒发光微流控芯片以及检测装置 - Google Patents

一种多标志物检测的磁微粒发光微流控芯片以及检测装置 Download PDF

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Publication number
WO2021068912A1
WO2021068912A1 PCT/CN2020/120087 CN2020120087W WO2021068912A1 WO 2021068912 A1 WO2021068912 A1 WO 2021068912A1 CN 2020120087 W CN2020120087 W CN 2020120087W WO 2021068912 A1 WO2021068912 A1 WO 2021068912A1
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Prior art keywords
magnetic particle
detection
zone
storage part
ligand
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PCT/CN2020/120087
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English (en)
French (fr)
Inventor
王东
江荣香
范玉霞
李泉
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深圳华迈兴微医疗科技有限公司
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Application filed by 深圳华迈兴微医疗科技有限公司 filed Critical 深圳华迈兴微医疗科技有限公司
Priority to EP20874443.3A priority Critical patent/EP4012411A4/en
Publication of WO2021068912A1 publication Critical patent/WO2021068912A1/zh
Priority to US17/685,368 priority patent/US20220184619A1/en

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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
    • B01L3/502715—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54313—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being characterised by its particulate form
    • G01N33/54326—Magnetic particles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502761—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads, for physically stretching molecules
    • 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
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/531—Production of immunochemical test materials
    • G01N33/532—Production of labelled immunochemicals
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54366—Apparatus specially adapted for solid-phase testing
    • 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
    • G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
    • G01N33/582—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances with fluorescent label
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0627—Sensor or part of a sensor is integrated
    • B01L2300/0654—Lenses; Optical fibres
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0681—Filter
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0819—Microarrays; Biochips
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/043—Moving fluids with specific forces or mechanical means specific forces magnetic forces
    • 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
    • B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
    • B01L2400/0481—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure squeezing of channels or chambers
    • 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
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • G01N2021/6439—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" with indicators, stains, dyes, tags, labels, marks

Definitions

  • the invention belongs to the technical field of microfluidic chip luminescence immunodetection, and in particular relates to a magnetic particle luminescence microfluidic chip for multi-marker detection and a detection device.
  • in vitro diagnostics has two main development trends: one is automation and integration, that is, the use of fully automated, highly sensitive large-scale instruments and equipment in the central laboratory supporting large hospitals to achieve high-precision disease analysis and diagnosis. ; Another kind of miniaturization, bedside, that is, through the palm of the small simple device, to achieve rapid on-site analysis and diagnosis.
  • bedside Another kind of miniaturization, bedside, that is, through the palm of the small simple device, to achieve rapid on-site analysis and diagnosis.
  • small hospitals have insufficient funds and small sample sizes, making them unsuitable for purchasing expensive large-scale equipment. Therefore, the rapid detection equipment used by most hospitals at this stage is mainly test strips and its supporting equipment, but the test strips can only achieve qualitative or semi-quantitative detection, with low detection sensitivity, poor specificity, poor repeatability, and obvious interference. Due to the large population of China, the increasing ageing, and the sharp increase in the incidence rate, relying solely on large hospitals has become overwhelmed. Therefore, it is extremely urgent to develop rapid detection methods and equipment with simple
  • Chemiluminescence refers to the phenomenon in which reaction intermediates, reaction products or external luminescent reagents convert chemical energy into light energy in the process of chemical reactions. Compared with fluorescence and absorption of light, chemiluminescence has no background signal interference from external excitation light sources, small cross-interference, and has the advantages of high sensitivity and wide linear range. The chemiluminescence analysis thus established has been widely used in clinical diagnosis and other fields. Chemiluminescence analyzer is the main large-scale IVD analysis and testing equipment.
  • Microfluidic chip technology integrates basic operation units such as sample preparation, reaction, separation, and detection in biological, chemical, and medical analysis processes onto a micron-scale chip to automatically complete the entire analysis process. Because of its great potential in the fields of biology, chemistry, medicine, etc., it has developed into a multidisciplinary research field of biology, chemistry, medicine, fluids, materials, machinery, etc., and has been applied to biomedical research, biochemical testing, forensic appraisal, etc. field.
  • the sample and the labeled ligand enter the reaction area where it reacts with the magnetic particle ligand after the sample is mixed. After the reaction, the sample enters the sample for quantitative analysis and detection. Detection area. However, all the magnetic particle ligands are placed in the same reaction zone. Because different magnetic particle ligands have different magnetic particle volume, weight, and nuclear-to-mass ratio, by controlling the moving speed of the external magnet, different magnetic particles can be driven in sequence. Move to enter the detection area.
  • Magnetic particle ligand mixing has the problem of poor stability, which greatly reduces the accuracy of the detection results.
  • the embodiment of the present invention provides a magnetic particle luminescent microfluidic chip for multi-marker detection and a detection device, which aims to solve the problem that the magnetic particles are easy to cross interfere with each other during the detection of the existing magnetic particle luminescent microfluidic chip, and the stability is relatively high. Poor, greatly reducing the accuracy of the test results.
  • the embodiment of the present invention is achieved in this way, and provides a magnetic particle luminescent microfluidic chip for multi-marker detection, comprising: a top plate, the top plate is provided with at least one sample application portion and a mixing area communicating with the sample application portion , And a plurality of labeling ligands arranged in the mixing zone, each labeling ligand is different from each other; a bottom plate, the bottom plate includes a diversion zone communicating with the mixing zone, and a plurality of mutually communicating with the diversion zone Connected reaction zones, a plurality of detection zones connected to the corresponding reaction zones, a cleaning solution storage part and a luminescent solution storage part connected to the detection zone; each reaction zone is provided with a magnetic particle ligand, and each magnetic particle is equipped with The ligands of the body are different; the cleaning liquid storage section is provided with a cleaning liquid, and the luminescent liquid storage section is stored with a luminescent liquid; it is arranged on the top plate and used to drive the sample in the sample addition
  • the mixing zone is provided with a labeled ligand storage section, and the labeled ligand is stored inside the labeled ligand storage section.
  • the number of the sample application part and the number of the labeled ligand storage part are consistent with each other.
  • the sample application part includes a sample application port and a cover for opening or closing the sample application port, and the sample application part further includes a rubber ring provided on the sample application port.
  • the top plate is provided with a first buckle or a first groove
  • the bottom plate is provided with a second buckle or a second buckle
  • the first buckle and the second buckle pass through , Or through the mutual cooperation of the first slot and the second buckle, so that the top plate and the bottom plate are buckled with each other.
  • the top plate is provided with magnetic attraction holes on the corresponding communication tracks with the reaction zone and the detection zone.
  • the top plate is provided with a cleaning liquid yield hole and a luminescent liquid yield hole at corresponding positions of the cleaning liquid storage part and the luminescent liquid storage part.
  • a groove with a height lower than the bottom wall of the reaction zone and a flow guide part arranged on the groove and connected to the reaction zone are arranged inside the diversion zone.
  • the detection area includes a cleaning area and a light-emitting area that are connected to each other, the cleaning area and the light-emitting area are each provided with multiple, and the reaction area, the cleaning area and the light-emitting area are one by one. Corresponding settings.
  • the present invention also provides a magnetic particle luminescence microfluidic detection device for multi-marker detection, comprising: the magnetic particle luminescence microfluidic chip as described above; a magnet unit for driving the magnetic particles to move; The cleaning liquid storage part, the luminescence liquid storage part and the squeezing unit of the air pump; a detection unit for detecting the luminescence signal in the detection area.
  • the beneficial effects achieved by the present invention are compared with the prior art.
  • the present invention provides a magnetic particle luminescent microfluidic chip for multi-marker detection and a detection device.
  • the sample enters from the sample loading part of the top plate, and the sample is matched with each label.
  • the body mixes in the mixing zone, then enters the diversion zone, enters the different reaction zones of the bottom plate from the diversion zone, and enters different detection zones from the reaction zone.
  • the external magnet drives the magnetic particles of the magnetic particle ligand into different In the detection zone, luminescence detection is realized in the detection zone.
  • each magnetic particle will not cross-interference with each other, and there will be no mixing of different labeled ligand solutions, which has good stability and can
  • the accuracy of the detection result is greatly improved, and there is no requirement for the moving speed of the magnet, which is beneficial to realize the control of the device.
  • FIG. 1 is a schematic diagram of a magnetic particle light-emitting microfluidic chip provided with a plurality of labeled ligand storage parts, a reaction area, a cleaning area, and a light-emitting area according to an embodiment of the present invention
  • FIG. 2 is a schematic diagram of a magnetic particle light-emitting microfluidic chip provided with a plurality of sample application parts, a label ligand storage part, a reaction area, a cleaning area, and a light-emitting area provided by an embodiment of the present invention.
  • the present invention provides a magnetic particle luminescent microfluidic chip for multi-marker detection and a detection device.
  • the sample enters from the sample adding portion 11 of the top plate 1, and the sample and each labeling ligand are mixed with each other in the mixing zone 12, and then enters the diversion zone 21, and enter the different reaction zones 22 of the bottom plate 2 from the diversion zone 21, and enter different detection zones from the reaction zone 22.
  • the external magnet drives the magnetic particles of the magnetic particle ligand into different detection zones. Realizes luminescence detection. Since there are multiple reaction zones 22, the magnetic particles will not cross-interference with each other, and there will be no mixing of different labeled ligand solutions. The stability is good, and the accuracy of the detection results can be greatly improved. There is no requirement on the moving speed of the magnet, which is beneficial to realize the control of the device.
  • the first embodiment provides a magnetic particle luminescent microfluidic chip for multi-marker detection, including: a top plate 1, on which is provided at least one sample application portion 11, a mixing area 12 communicating with the sample application portion 11, and A plurality of labeling ligands arranged in the mixing zone 12, each labeling ligand is different from each other; the bottom plate 2, the bottom plate 2 includes a diversion zone 21 communicating with the mixing zone 12, and a plurality of reaction zones communicating with the diversion zone 21 22.
  • each reaction zone 22 is provided with a magnetic particle ligand, and each magnetic particle ligand The ligand is different;
  • the cleaning liquid storage part 24 is provided with cleaning liquid, and the luminescent liquid storage part 25 is stored with luminescent liquid;
  • the air pump 13 is arranged on the top plate 1 and used to drive the sample in the sample addition part 11 to flow through the mixing zone 12 , The air pump 13 can be selected as an air bag built in the top plate 1.
  • the sample to be tested can be put into the sample adding part 11, the air pump 13 is squeezed, the sample enters the mixing zone 12 through the sample adding part 11, and the multiple labeled ligands in the mixing zone 12 Mix with each other.
  • the sample enters the diversion zone 21 from the mixing zone 12, and the diversion zone 21 is provided with a blood filter membrane.
  • the plasma in the sample is separated from blood cells, and the plasma enters each reaction zone 22 from the diversion zone 21 and reacts with each The magnetic particle ligands in zone 22 are mixed, while blood cells remain in the diversion zone 21.
  • the sample After the sample is mixed with the magnetic particle ligand, the sample enters each detection zone from each reaction zone 22.
  • the external magnet drives the magnetic particles of the magnetic particle ligand from each reaction zone 22 into each detection zone, and each reaction zone 22 enters each detection zone.
  • the ligands of the magnetic particle ligands are different, but there are no requirements for the magnetic particles. They may be the same or different, depending on the specific test items.
  • the external magnet drives the magnetic particles in each reaction zone 22 to enter the detection zone, and the magnetic particle ligand also enters the detection zone.
  • the cleaning liquid storage portion 24 releases the cleaning liquid stored inside, and the cleaning liquid enters each detection area to clean the magnetic particles.
  • the luminescent fluid storage part 25 releases the luminescent fluid stored inside, and the luminescent fluid enters each detection area, thereby realizing the quantitative detection of the analyte in the sample. Since the magnetic particles are respectively distributed in different reaction zones 22, there will be no cross-interference phenomenon between each other, which can greatly improve the accuracy of the detection result. Moreover, since the magnetic particles are respectively distributed in different reaction zones 22, there is no need to control the magnetic particles to move into the detection zone one after another, and there is no requirement on the moving speed of the magnet, which is beneficial to realize the control of the device.
  • the blood filter membrane is pre-arranged in the diversion area 21, wherein the blood filter membrane can separate the liquid from the cells through physical apertures or biological/chemical reagents to achieve separation of plasma and red blood cells.
  • the plasma flows to the reaction zone 22, while the red blood cells stay in On the blood filter membrane, thereby reducing the interference of red blood cells on the test results.
  • the biological/chemical reagents include coagulants, etc., which can connect red blood cells to form clots and increase their size. After the increased size, the red blood cells are more easily blocked by the mesh structure of the blood filter membrane, thereby more effectively reducing the effect of red blood cells on the experiment. Disturbance of the result.
  • the cleaning solution is stored in the cleaning solution storage part 24 in advance, and the cleaning solution is used to clean the magnetic particles to remove non-specifically adsorbed analytes, luminescent agent markers, and other substances that affect the detection result.
  • the cleaning solution mainly contains buffer reagents, proteins and surfactants.
  • the buffer reagents include but are not limited to borate, phosphate, Tris-HCl and acetate, etc.
  • the pH range of the cleaning solution is 6.0 to 10.0.
  • the protein includes but is not limited to bovine serum albumin, casein and the like.
  • the surface activity includes, but is not limited to, Tween 20, Tween 80, Triton X-100, polyethylene glycol, and polyvinyl pyrrolidone.
  • the cleaning solution used is a pH 7.0 Tris-HCl buffer containing bovine serum albumin, Tween 20 and Proclin 300.
  • the luminescent liquid is stored in the luminescent liquid storage part 25 in advance, and the luminescent liquid is used to further clean the magnetic particles or enhance the luminescence signal.
  • the luminescence solution includes a substrate solution and a luminescence enhancement solution.
  • the substrate solution can be an acid solution containing luminol or an acid solution containing adamantane
  • the luminescence enhancement solution can be an alkaline solution containing a benzene derivative.
  • the luminescence liquid storage part 25 can be provided with a first luminescence liquid storage part 25 and a second luminescence liquid storage part 25, and the first luminescence liquid storage part
  • the substrate 25 is stored inside
  • the second luminescent fluid storage part 25 is stored with luminescence enhancing fluid
  • the bottom plate 2 is provided with a luminescent fluid mixing zone 12, which respectively communicates with the detection zone and the first luminescent fluid storage Section 25 and a second luminescent liquid storage section 25.
  • the cleaning liquid storage portion 24 and the luminescent liquid storage portion 25 are sealed cavities, and the sealing material used is an elastic material or a high-barrier film, specifically glass, plastic, rubber, aluminum foil or a high-barrier film, where the sealing material can be It is composed of the same material, or it can be a combination of multiple materials. Under physical squeezing, the cleaning liquid storage portion 24 and the luminescent liquid storage portion 25 may be partially ruptured, thereby releasing the stored materials.
  • the mixing zone 12 of the second embodiment is provided with a labeled ligand storage unit 14, and the labeled ligand storage unit 14 stores the labeled ligand inside. Since the labeled ligand is stored in the labeled ligand storage unit 14 in advance, it is beneficial to the long-term storage of the labeled ligand and avoids deterioration and damage of the labeled ligand. In addition, different labeled ligands can be stored in different labeled ligand storage parts 14, which can control the ratio of enzyme label required for different detection items, and can also prevent different labeled ligands from affecting each other during the storage process.
  • the enzyme can be selected from one or more of horseradish peroxide and alkaline phosphatase, and the ligand can be selected from antigen, antibody, hapten, and nucleic acid.
  • the magnetic particle ligand solution is pre-stored in the magnetic particle coating part 22.
  • the magnetic particle ligand solution includes magnetic particles, sugars, buffer reagents, proteins, surfactants, and preservatives.
  • the magnetic particles include but are not limited to iron trioxide. And iron tetroxide compounds.
  • the labeled ligand includes an enzyme-labeled ligand
  • the enzyme binds or competes with the analyte in the sample to form an enzyme-labeled ligand
  • the magnetic particle label binds or competes with the analyte in the sample to form a magnetic particle-labeled ligand
  • the two ligands can be the same or different; magnetically labeled ligands and enzyme-labeled ligands include nucleic acids, antigens, monoclonal antibodies, polyclonal antibodies, and hormone receptors.
  • the analytes in the sample include DNA, small molecules (drugs) Or drugs), antigens, antibodies, hormones, antibiotics, bacteria or viruses and other biochemical markers.
  • the labeled ligand can be combined with the magnetic particle ligand solution (such as the double antibody sandwich method), or the labeled ligand can compete with the labeled ligand (such as the competition method).
  • the enzyme-labeled ligand can be the same as or different from the magnetic particle ligand solution.
  • two different antibodies are selected as the labeled ligand and the magnetic particle ligand solution to detect the analyte by the double antibody sandwich method.
  • an antigen and an antibody are selected as the labeled ligand and the magnetic particle ligand solution to detect the analyte by the competition method.
  • the number of the sample application part 11 and the number of the labeled ligand storage part 14 of the third embodiment are consistent with each other, and each sample application part 11 is provided corresponding to each labeled ligand storage part 14 ,
  • the two are in one-to-one correspondence. In this way, it is possible to control the ratio of enzyme label required for different test items and also control the required samples.
  • the sample adding portion 11 of the fourth embodiment includes a sample adding port and a cover for opening or closing the sample adding port.
  • the sample can be added to the sample inlet from the outside. After the sample is added, the cover is closed to close the sample inlet.
  • the cover is provided with a first clamping member or a first clamping hole, and a second clamping hole or a second clamping member is provided at a position adjacent to the sample inlet, and the first clamping member and the second clamping hole cooperate with each other , Or through the mutual cooperation of the first card hole and the second card member, so that the cover can close the sample inlet.
  • the cover is also provided with a sealing member adapted to the sample inlet. When the cover is closed, the sealing member is inserted into the sample inlet at the same time to prevent the sample from leaking from the sample inlet.
  • the sample application part 11 also includes a rubber ring arranged on the sample injection port. Since the outside is often used to add samples through the pipette tip, the rubber ring has elasticity, which helps to seal with the pipette tip for more smooth Inject the sample from the injection port.
  • the top plate 1 of the fifth embodiment is provided with a first buckle or a first groove
  • the bottom plate 2 is provided with a second buckle or a second buckle.
  • the two slots are matched with each other, or the first slot and the second buckle are matched with each other, so that the top plate 1 and the bottom plate 2 are buckled with each other.
  • top plate 1 and the bottom plate 2 can also be combined with each other in other ways, which will not be repeated here.
  • the top plate 1 of the sixth embodiment is provided with a magnetic relief hole 15 on the corresponding communication track with the reaction zone 22 and the detection zone.
  • the top plate 1 is provided with a magnetic attraction relief hole 15 on the corresponding communication track with the reaction zone 22 and the detection zone.
  • the external magnet moves along the set direction of the magnetic attraction concession hole 15 and drives the magnetic particles to move along the reaction zone 22 and the detection zone in sequence.
  • a magnetic attraction hole 15 is provided, so that the magnet can be closer to the bottom plate 2 to avoid the top plate 1 between the bottom plate 2 and the magnet, and the reliability of the magnetic attraction is greatly improved.
  • the top plate 1 of the seventh embodiment is provided with cleaning liquid giving way holes and luminous liquid giving way holes on the bottom plate 2 at the corresponding positions of the cleaning liquid storage portion 24 and the luminous liquid storage portion 25.
  • the cleaning liquid storage portion 24 and the luminescent liquid storage portion 25 are often provided with a certain shape, such as a cylinder, etc., in order to adapt to the shape of the cleaning liquid storage portion 24 and the luminescent liquid storage portion 25 and avoid local protrusion of the chip, it is provided on the top plate 1
  • the cleaning fluid relief hole and the luminescent fluid relief hole are often provided with a certain shape, such as a cylinder, etc., in order to adapt to the shape of the cleaning liquid storage portion 24 and the luminescent liquid storage portion 25 and avoid local protrusion of the chip.
  • the cleaning fluid relief hole and the luminescent fluid relief hole jointly constitute the relief hole 16.
  • the diversion zone 21 of the eighth embodiment is provided with a groove whose height is lower than the bottom wall of the reaction zone 22, and a diversion portion arranged on the groove and connected to the reaction zone 22.
  • the diversion portion Optional hemofiltration membrane. Since the groove of the diversion zone 21 is lower than the bottom wall of the reaction zone 22, the height of the diversion part is also lower than the bottom wall of the reaction zone 22. After the sample enters the diversion zone 21, it will not automatically divert from the flow due to gravity. The part enters the reaction zone 22, but sucks the sample away from the guide part through capillary action. In this way, a smaller volume sample that can meet the detection requirements can be sucked away from a larger volume sample, avoiding the volume of the sample. Greatly affect the test results.
  • the detection area of the eighth embodiment includes a cleaning area 231 and a light-emitting area 232 that are connected to each other.
  • the diversion area 21, the reaction area 22, the cleaning area 231, and the light-emitting area 232 are connected and arranged in sequence.
  • the sample enters each reaction zone 22 from the diversion zone 21, mixes with the magnetic particle ligands in the reaction zone 22, and then enters the cleaning zone 231 from the reaction zone 22, and finally enters each detection zone from the cleaning zone 231, while the external magnet drives The magnetic particles of the magnetic particle ligand enter different cleaning areas 231 from different reaction zones 22.
  • the cleaning liquid storage part 24 releases the internally stored cleaning liquid, and the cleaning liquid flows into the cleaning area 231 to clean the magnetic particles, and then the different magnetic particles Then enter different detection areas from the cleaning area 231.
  • samples can be analyzed and tested again. If there is only one cleaning area 231, there is a risk of cross-interference when the magnetic particles are cleaned collectively. Therefore, there are multiple cleaning areas 231, and the cleaning areas 231 and the light-emitting areas 232 are arranged correspondingly, and the magnetic particles can enter after cleaning.
  • the corresponding light-emitting area 232 further improves the accuracy of the detection result.
  • the tenth embodiment provides a magnetic particle luminescence microfluidic detection device for multi-marker detection, including: the magnetic particle luminescence microfluidic chip as described in the first to the ninth embodiment; and a device for driving the magnetic particles to move Magnet unit; a squeezing unit for squeezing the cleaning liquid storage portion 24, the luminous liquid storage portion 25 and the air pump 13; a detection unit for detecting the luminescence signal in the detection area.
  • the magnet unit includes a magnet and a driving part for driving the magnet to move.
  • the driving part may be a linear motor, and the output shaft of the linear motor is fixedly connected to the magnet. After the linear motor is started, its output shaft extends to drive the magnet to move, and the magnet attracts the magnetic particles to drive the magnetic particles to move.
  • the squeezing unit may be a linear motor. After the linear motor is started, its output shaft extends to squeeze the cleaning liquid storage portion 24 and the luminous liquid storage portion 25, so that the cleaning liquid and the luminous liquid flow out respectively. And, after the linear motor is started, the reciprocating output shaft of the extended and retracted output shaft can repeatedly squeeze the air pump 13 to drive the liquid on the top plate 1 to flow.
  • an extrusion part can also be fixedly installed on the output shaft of the linear motor. The extrusion part matches the shape and size of each storage part.
  • the linear motor can be provided with one or more. The output shaft of the linear motor drives the extrusion part to move. , The squeezing part then squeezes the cleaning liquid storage part 24, the luminous liquid storage part 25 and the air pump 13.
  • the detection unit can be a photodiode, a photomultiplier tube or an avalanche photodiode.
  • the sample enters the detection area after mixing and reacting through the above process.
  • the mixed sample will have a luminescence signal.
  • the detection unit collects the luminescence signal, according to the intensity of the luminescence signal. In this way, the test results of the sample are obtained.
  • the squeezing unit can also be used to squeeze the labeling ligand storage part 14 to make the labeling ligand flow out.
  • the magnetic particle ligands can be coded, so as to accurately determine that the magnetic particles in different magnetic particle ligands enter different detection areas.

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Abstract

一种多标志物检测的磁微粒发光微流控芯片以及检测装置，属于微流控芯片发光免疫检测技术领域，包括：顶板（1），顶板（1）上设有加样部（11）、混合区（12）以及设在混合区（12）中的多个标记配体；底板（2），底板（2）包括导流区（21）、多个反应区（22）、多个与对应的反应区（22）相互连通的检测区、与检测区相互连通的清洗液存储部（24）和发光液存储部（25）；各个反应区（22）设有磁颗粒配体，各个磁颗粒配体的配体不同；清洗液存储部（24）内部设有清洗液，发光液存储部（25）内存储有发光液；设置在顶板（1）上并用于驱动加样部（11）中的样本流经混合区（12）的气泵（13）。由于反应区（22）设有多个，各个磁颗粒相互不会发生交叉干扰的现象，能够大大提高检测结果的准确性，并且对磁铁的移动速度也没有要求，有利于实现装置的控制。

Description

一种多标志物检测的磁微粒发光微流控芯片以及检测装置 技术领域
本发明属于微流控芯片发光免疫检测技术领域，尤其涉及一种多标志物检测的磁微粒发光微流控芯片以及检测装置。
 背景技术
目前，体外诊断(IVD)主要有两种发展趋势：一种是自动化、一体集成化，即利用大型医院配套的中心实验室的全自动化、高灵敏的大型仪器设备，实现高精度的疾病分析诊断；另一种小型化、床旁化，即通过掌上小型简易设备，实现现场快速分析诊断。但是，小型医院资金不足、样本量少，并不适合购买价格昂贵的大型设备。由此，现阶段大多医院采用的快速检测设备主要是试纸条及其配套设备，但试纸条只能实现定性或半定量检测，检测灵敏度低、特异性差、重复性差、受干扰明显。由于中国人口众多，老龄化加剧，发病率剧增，单纯依靠大型医院已不堪重负。因此研制操作简便、灵敏度高、重复性好和定量准确的快速检测方法和设备变得极为迫切。
化学发光是指化学反应过程中的反应中间体、反应产物或外加发光试剂将化学能转变为光能的现象。与荧光和吸收光相比，化学发光没有外来激发光源背景信号干扰，交叉干扰小，具有灵敏度高、线性范围宽等优点。由此建立的化学发光分析已广泛应用于临床诊断等领域。化学发光仪是主要的大型IVD分析检测设备。
微流控芯片技术是把生物、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。由于它在生物、化学、医学等领域的巨大潜力，已经发展成为一个生物、化学、医学、流体、材料、机械等多学科交叉的研究领域，被应用于生物医学研究、生化检测、司法鉴定等领域。
对于现有微流控芯片而言，在样本所需标记配体不同时，样本与标记配体混合之后进入与磁颗粒配体反应的反应区域，在反应之后样本再进入用于定量分析检测样本的检测区域。但是，均是将所有磁颗粒配体放置在同个反应区域，由于不同的磁颗粒配体的磁颗粒体积、重量和核质比不同，通过控制外部磁铁的移动速度，能够带动不同磁颗粒先后移动，从而进入检测区域。尽管磁颗粒的移动速度不同，但是，特别是在磁铁移动速度较快的情况下，磁颗粒的行程又较短，依然容易造成磁颗粒相互交叉干扰的现象，且不同标记配体溶液混合，不同磁颗粒配体混合存在稳定性较差的问题，大大降低了检测结果的准确性。
发明内容
本发明实施例提供一种多标志物检测的磁微粒发光微流控芯片以及检测装置，旨在解决现有磁微粒发光微流控芯片在检测时，磁颗粒容易相互交叉干扰，且稳定性较差，大大降低检测结果准确性的问题。
本发明实施例是这样实现的，提供一种多标志物检测的磁微粒发光微流控芯片，包括：顶板，顶板上设有至少一个加样部、与所述加样部相互连通的混合区、以及设在所述混合区中的多个标记配体，各个标记配体相互不同；底板，所述底板包括与所述混合区相互连通的导流区、多个与所述导流区相互连通的反应区、多个与对应的反应区相互连通的检测区、与所述检测区相互连通的清洗液存储部和发光液存储部；各个反应区设有磁颗粒配体，各个磁颗粒配体的配体不同；所述清洗液存储部内部设有清洗液，所述发光液存储部内存储有发光液；设置在所述顶板上并用于驱动所述加样部中的样本流经所述混合区的气泵。
更进一步地，所述混合区设有标记配体存储部，所述标记配体存储部的内部存储有所述标记配体。
更进一步地，所述加样部的数量与所述标记配体存储部的数量相互一致。
更进一步地，所述加样部包括加样口以及用于打开或封闭所述加样口的封盖，所述加样部还包括设在所述加样口上的橡胶圈。
更进一步地，所述顶板上设有第一卡扣或第一卡槽，所述底板上设有第二卡槽或第二卡扣，通过所述第一卡扣与所述第二卡槽的相互配合，或者通过所述第一卡槽与所述第二卡扣的相互配合，以使所述顶板与所述底板相互扣合。
更进一步地，所述顶板在与所述反应区和所述检测区的对应连通轨道上设有磁吸让位孔。
更进一步地，所述顶板在所述清洗液存储部和所述发光液存储部的对应位置设有清洗液让位孔和发光液让位孔。
更进一步地，所述导流区内部设有高度低于所述反应区底璧的凹槽以及设在所述凹槽上并连接所述反应区的导流部。
更进一步地，所述检测区包括相互连通的清洗区和发光区，所述清洗区和所述发光区均设有多个，并且所述反应区、所述清洗区与所述发光区一一对应设置。
本发明还提供一种多标志物检测的磁微粒发光微流控检测装置，包括：如上所述的磁微粒发光微流控芯片；用于带动所述磁颗粒移动的磁铁单元；用于挤压所述清洗液存储部、所述发光液存储部和所述气泵的挤压单元；用于检测所述检测区中的发光信号的检测单元。
本发明所达到的有益效果，与现有技术相比，本发明提供一种多标志物检测的磁微粒发光微流控芯片以及检测装置，样本从顶板的加样部进入，样本与各个标记配体在混合区相互混合，再进入导流区，并从导流区进入底板的不同反应区，并从反应区进入不同的检测区，此时，外部磁铁带动磁颗粒配体的磁颗粒进入不同的检测区，在检测区实现发光检测，由于反应区设有多个，各个磁颗粒相互不会发生交叉干扰的现象，并且不会发生不同标记配体溶液混合的情况，稳定性较好，能够大大提高检测结果的准确性，并且对磁铁的移动速度也没有要求，有利于实现装置的控制。
 附图说明
图1是本发明实施例提供的设有多个标记配体存储部、反应区、清洗区和发光区的磁微粒发光微流控芯片的示意图；
图2是本发明实施例提供的设有多个加样部、标记配体存储部、反应区、清洗区和发光区的磁微粒发光微流控芯片的示意图。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合附图及实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。
本发明提供一种多标志物检测的磁微粒发光微流控芯片以及检测装置，样本从顶板1的加样部11进入，样本与各个标记配体在混合区12相互混合，再进入导流区21，并从导流区21进入底板2的不同反应区22，并从反应区22进入不同的检测区，此时，外部磁铁带动磁颗粒配体的磁颗粒进入不同的检测区，在检测区实现发光检测，由于反应区22设有多个，各个磁颗粒相互不会发生交叉干扰的现象，并且不会发生不同标记配体溶液混合的情况，稳定性较好，能够大大提高检测结果的准确性，并且对磁铁的移动速度也没有要求，有利于实现装置的控制。
实施例一
本实施例一提供一种多标志物检测的磁微粒发光微流控芯片，包括：顶板1，顶板1上设有至少一个加样部11、与加样部11相互连通的混合区12、以及设在混合区12中的多个标记配体，各个标记配体相互不同；底板2，底板2包括与混合区12相互连通的导流区21、多个与导流区21相互连通的反应区22、多个与对应的反应区22相互连通的检测区、与检测区相互连通的清洗液存储部24和发光液存储部25；各个反应区22设有磁颗粒配体，各个磁颗粒配体的配体不同；清洗液存储部24内部设有清洗液，发光液存储部25内存储有发光液；设置在顶板1上并用于驱动加样部11中的样本流经混合区12的气泵13，气泵13可选为内置在顶板1上的气囊。
举样本为全血样本为例，可将待测试的样本放入加样部11中，挤压气泵13，样本通过加样部11进入混合区12，与混合区12中的多个标记配体相互混合。在混合之后，样本再从混合区12进入导流区21，导流区21上设有滤血膜，样本中的血浆与血细胞分离，血浆从导流区21进入各个反应区22，与各个反应区22中的磁颗粒配体混合，而血细胞留在了导流区21。
在样本与磁颗粒配体混合之后，样本从各个反应区22进入各个检测区，此时，外部的磁铁带动磁颗粒配体的磁颗粒从各个反应区22进入各个检测区，各个反应区22中的磁颗粒配体的配体不同，但是对磁颗粒没有要求，其可能相同也可能不相同，视具体检测项目而定。同时，外部的磁铁带动各个反应区22中的磁颗粒进入检测区，磁颗粒配体也进入检测区。随后，清洗液存储部24释放内部存储的清洗液，清洗液进入各个检测区，进行磁颗粒的清洗。然后，发光液存储部25释放内部存储的发光液，发光液进入各个检测区，进而实现对样本中的分析物的定量检测。由于磁颗粒分别分布在不同的反应区22中，相互之间不会发生交叉干扰的现象，能够大大提高检测结果的准确性。并且，由于磁颗粒分别分布在不同的反应区22中，无需控制磁颗粒先后移动进入检测区，对磁铁的移动速度并没有要求，有利于实现装置的控制。
其中，滤血膜预先设置在导流区21中，其中滤血膜可通过物理孔径或生物/化学试剂使液体与细胞分离，实现血浆与红细胞分离，血浆流到反应区22，而红细胞停留在滤血膜上，从而减少红细胞对试验结果的干扰。其中生物/化学试剂包含凝血剂等，可使红细胞间连接，形成凝块，增大尺寸，而增大尺寸之后的红细胞更容易被滤血膜的网状结构阻挡，从而更加有效减少红细胞对实验结果的干扰。
清洗液预先存储在清洗液存储部24中，清洗液用于清洗磁颗粒，去除非特异性吸附的分析物、发光剂标记物以及其他影响检测结果的物质。清洗液主要包含缓冲试剂、蛋白质和表面活性剂，其中缓冲试剂包含但不仅限于硼酸盐、磷酸盐、Tris-HCl和醋酸盐等，清洗液的pH范围为6.0～10 .0。其中蛋白质包含但不仅限于牛血清白蛋白、酪蛋白等。其中表面活性包含但不仅限于可包括吐温20、吐温80、曲拉通X-100、聚乙二醇和聚乙烯基吡咯烷酮等。作为优选，本实施例中，使用清洗液为包含牛血清白蛋白、吐温2 0 和Proclin300的pH7 .0 Tris-HCl缓冲液。
发光液预先存储在发光液存储部25中，发光液用于进一步清洗磁颗粒或增强发光信号。发光液包含底物液以及发光增强液，底物液可选为含鲁米诺的酸性溶液或者含金刚烷的酸性溶液，发光增强液可选为含苯衍生物的碱性溶液。
值得一提的是，考虑到底物液与发光增强液不宜长久混合保存，可将发光液存储部25设有第一发光液存储部25和第二发光液存储部25，第一发光液存储部25内部存储有底物液，第二发光液存储部25内部存储有发光增强液，并在底板2上设有发光液混合区12，发光液混合区12分别连通检测区、第一发光液存储部25和第二发光液存储部25。在第一发光液存储部25和第二发光液存储部25进行释放时，底物液和发光增强液进入发光液混合区12并相互混合，混合均匀之后再进入检测区。
在本实施例中，清洗液存储部24和发光液存储部25为密封腔，所用密封材料采用弹性材料或高阻隔薄膜，具体为玻璃、塑料、橡胶、铝箔或高阻隔薄膜，其中密封材料可为同种材料组成，也可为多种材料组合而成。在物理挤压下，清洗液存储部24和发光液存储部25可局部破裂，从而把储存的材料释放出来。
实施例二
参考图1和图2，在实施例一的基础上，本实施例二的混合区12设有标记配体存储部14，标记配体存储部14的内部存储有标记配体。由于标记配体预先存储在标记配体存储部14中，有利于标记配体的长久存放，避免标记配体的变质受损。另外，不同的标记配体可存储在不同的标记配体存储部14中，可控制针对不同检测项目所需的酶标比例，还可防止在存放过程中不同的标记配体相互影响。
在标记配体包括的是酶标记的配体时，酶可选为辣根过氧化物和碱性磷酸酶中的一种或多种，配体可选为抗原、抗体、半抗原和核酸中的一种或多种。磁颗粒配体溶液预先存储在磁颗粒包被部22中，磁颗粒配体溶液包括磁颗粒、糖类、缓冲试剂、蛋白质、表面活性剂以及防腐剂，磁颗粒包含但不仅限于三氧化二铁和四氧化三铁化合物。
在标记配体包括的是酶标记的配体时，酶与样本中的分析物结合或竞争，形成酶标记配体；磁颗粒标记与样本中的分析物结合或竞争，形成磁颗粒标记配体，这两种配体可相同或不同；磁标记配体、酶标记的配体包含核酸、抗原、单克隆抗体、多克隆抗体和激素受体，样本中的分析物包括DNA、小分子(药物或毒品)、抗原、抗体、激素、抗生素、细菌或病毒及其他生化标志物。
本实施例中，标记配体可与磁颗粒配体溶液结合(如双抗体夹心法)，或者标记配体可与标记配体竞争(如竞争法)。其中酶标记的配体可以与磁颗粒配体溶液相同，也可以不同。作为优选，在本发明的一个实施例中，选择两种不同抗体作为标记配体和磁颗粒配体溶液以双抗体夹心法检测分析物。本发明的另一个实施例中，选择一种抗原和一种抗体，分别作为标记配体和磁颗粒配体溶液以竞争法检测分析物。
实施例三
参考图2，在实施例二的基础上，本实施例三的加样部11的数量与标记配体存储部14的数量相互一致，各个加样部11与各个标记配体存储部14对应设置，两者是一一对应关系。如此一来，既能够控制针对不同检测项目所需的酶标比例，还能够控制所需的样本。
实施例四
在实施例一的基础上，本实施例四的加样部11包括加样口以及用于打开或封闭加样口的封盖。
在封盖打开时，外部可在加样口中加入样本，在加完样本之后，封盖关闭以使封闭加样口。
详细来说，封盖设有第一卡件或者第一卡孔，在邻近加样口的位置设有第二卡孔或者第二卡件，通过第一卡件与第二卡孔的相互配合，或者通过第一卡孔与第二卡件的相互配合，以使封盖封闭加样口。并且，封盖上还设有与加样口相适应的封合件，在封盖关闭时，封合件同时插入加样口，避免样本从加样口中漏出。
以及，加样部11还包括设在加样口上的橡胶圈，由于外部常通过移液器吸头加入样本，而橡胶圈具有弹性，有助于与移液器吸头密封，以更加顺利的将样本从加样口中注入。
实施例五
在实施例一的基础上，本实施例五的顶板1上设有第一卡扣或第一卡槽，底板2上设有第二卡槽或第二卡扣，通过第一卡扣与第二卡槽的相互配合，或者通过第一卡槽与第二卡扣的相互配合，以使顶板1与底板2相互扣合。通过上述的扣合方式，能够使得顶板1与底板2可拆卸设置，有利于操作人员进行检查或者更换。而在扣合之后，又能够保证顶板11与底板22牢牢相互固定。
当然，顶板1与底板2也可以通过其他方式相互结合，此处不一一赘述。
实施例六
参考图1和图2，在实施例一的基础上，本实施例六的顶板1在与反应区22和检测区的对应连通轨道上设有磁吸让位孔15。
顶板1在与反应区22和检测区的对应连通轨道上设有磁吸让位孔15。外部的磁铁沿着磁吸让位孔15的设定方向移动，带动磁颗粒依次沿着反应区22和检测区移动。并且，设有磁吸让位孔15，磁铁能够更加靠近底板2，避免底板2与磁铁之间间隔顶板1，大大提高磁吸的可靠性。
实施例七
在实施例一的基础上，本实施例七的顶板1在底板2上的清洗液存储部24和发光液存储部25的对应位置设有清洗液让位孔和发光液让位孔。
由于清洗液存储部24和发光液存储部25常设有一定形状，例如圆柱体等，为了适应清洗液存储部24和发光液存储部25的形状，避免芯片局部凸出，故在顶板1上设置清洗液让位孔和发光液让位孔。
在本实施例中，参考图1和图2，清洗液让位孔和发光液让位孔共同组成让位孔16。
实施例八
在实施例一的基础上，本实施例八的导流区21内部设有高度低于反应区22底璧的凹槽以及设在凹槽上并连接反应区22的导流部，导流部可选为滤血膜。由于导流区21的凹槽低于反应区22底壁，同样地，导流部的高度也是低于反应区22底壁，样本进入导流区21之后，不会因为重力作用自动从导流部进入反应区22，而是通过毛细作用从导流部上吸走样本，如此一来，能够在较大体积的样本中吸走能够满足检测需求的较小体积的样本，避免样本的体量较大影响检测结果。
实施例九
参考图1和图2，在实施例一至实施例八的基础上，本实施例八的检测区包括相互连通的清洗区231和发光区232，清洗区231设有多个，发光区232设有多个，反应区22、清洗区231和发光区232的数量均相同，相互一一对应设置。导流区21、反应区22、清洗区231与发光区232四者依次连通设置。样本从导流区21进入各个反应区22，与反应区22中的磁颗粒配体相互混合，再从反应区22进入清洗区231，最后从清洗区231进入各个检测区，同时外部的磁铁带动磁颗粒配体的磁颗粒从不同反应区22进入不同清洗区231，此时，清洗液存储部24释放内部存储的清洗液，清洗液流入清洗区231，对磁颗粒进行清洗，随后不同磁颗粒再从清洗区231进入不同检测区。在检测区，可再对样本进行分析检测。若是只设有一个清洗区231，对磁颗粒进行集中清洗时存在交叉干扰的风险，因此，设有多个清洗区231，并且清洗区231与发光区232对应设置，清洗完后磁颗粒可进入对应的发光区232，从而进一步地提高了检测结果的准确性。
实施例十
本实施例十提供一种多标志物检测的磁微粒发光微流控检测装置，包括：如实施例一至实施例九所述的磁微粒发光微流控芯片；用于带动所述磁颗粒移动的磁铁单元；用于挤压所述清洗液存储部24、所述发光液存储部25和所述气泵13的挤压单元；用于检测所述检测区中的发光信号的检测单元。
其中，磁铁单元包括磁铁以及用于驱动磁铁移动的驱动部，驱动部可选为直线电机，直线电机的输出轴固定连接磁铁。直线电机启动后，其输出轴伸出带动磁铁移动，磁铁吸附磁颗粒，带动磁颗粒移动。
其中，挤压单元可选为直线电机，直线电机启动后，其输出轴伸出，以挤破清洗液存储部24和发光液存储部25，分别使得清洗液和发光液流出。以及，直线电机启动后，其伸出及回缩往复运动的输出轴可以反复挤压气泵13，使得驱动顶板1上的液体流动。当然，也可在直线电机的输出轴上固定安装有挤压部，挤压部与各存储部形态大小匹配，直线电机可设有一个或多个，通过直线电机的输出轴带动挤压部移动，挤压部再挤压清洗液存储部24、发光液存储部25和气泵13。
其中，检测单元可选为光电二极管、光电倍增管或雪崩光电二极管，样本通过上述流程混合反应后进入检测区，混合后的样本会有发光信号，检测单元采集发光信号，根据发光信号的强弱以此得出对于样本的检测结果。
在磁微粒发光双层微流控芯片设有标记配体存储部14时，挤压单元也可用于挤破标记配体存储部14，以使标记配体流出。
其中，可对磁颗粒配体进行编码，以便后续准确判断不同磁颗粒配体中的磁颗粒进入不同的检测区。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种多标志物检测的磁微粒发光微流控芯片，其特征在于，包括：
    顶板，顶板上设有至少一个加样部、与所述加样部相互连通的混合区、以及设在所述混合区中的多个标记配体，各个标记配体相互不同；
    底板，所述底板包括与所述混合区相互连通的导流区、多个与所述导流区相互连通的反应区、多个与对应的反应区相互连通的检测区、与所述检测区相互连通的清洗液存储部和发光液存储部；
    各个反应区设有磁颗粒配体，各个磁颗粒配体的配体不同；
    所述清洗液存储部内部设有清洗液，所述发光液存储部内存储有发光液；
    设置在所述顶板上并用于驱动所述加样部中的样本流经所述混合区的气泵。
  2. 如权利要求1所述的磁微粒发光微流控芯片，其特征在于，所述混合区设有标记配体存储部，所述标记配体存储部的内部存储有所述标记配体。
  3. 如权利要求2所述的磁微粒发光微流控芯片，其特征在于，所述加样部的数量与所述标记配体存储部的数量相互一致。
  4. 如权利要求1所述的磁微粒发光微流控芯片，其特征在于，所述加样部包括加样口以及用于打开或封闭所述加样口的封盖，所述加样部还包括设在所述加样口上的橡胶圈。
  5. 如权利要求1所述的磁微粒发光微流控芯片，其特征在于，所述顶板上设有第一卡扣或第一卡槽，所述底板上设有第二卡槽或第二卡扣，通过所述第一卡扣与所述第二卡槽的相互配合，或者通过所述第一卡槽与所述第二卡扣的相互配合，以使所述顶板与所述底板相互扣合。
  6. 如权利要求1所述的磁微粒发光微流控芯片，其特征在于，所述顶板在与所述反应区和所述检测区的对应连通轨道上设有磁吸让位孔。
  7. 如权利要求1所述的磁微粒发光微流控芯片，其特征在于，所述顶板在所述清洗液存储部和所述发光液存储部的对应位置设有清洗液让位孔和发光液让位孔。
  8. 如权利要求1所述的磁微粒发光微流控芯片，其特征在于，所述导流区内部设有高度低于所述反应区底璧的凹槽以及设在所述凹槽上并连接所述反应区的导流部。
  9. 如权利要求1至8任一项所述的磁微粒发光微流控芯片，其特征在于，所述检测区包括相互连通的清洗区和发光区，所述清洗区和所述发光区均设有多个，并且所述反应区、所述清洗区与所述发光区一一对应设置。
  10. 一种多标志物检测的磁微粒发光微流控检测装置，其特征在于，包括：
    如权利要求1至9任一项所述的磁微粒发光微流控芯片；
    用于带动所述磁颗粒移动的磁铁单元；
    用于挤压所述清洗液存储部、所述发光液存储部和所述气泵的挤压单元；
    用于检测所述检测区中的发光信号的检测单元。
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CN211374779U (zh) * 2019-10-11 2020-08-28 深圳华迈兴微医疗科技有限公司 一种多标志物检测的磁微粒发光微流控芯片以及检测装置

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* Cited by examiner, † Cited by third party
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CN113281499A (zh) * 2021-05-18 2021-08-20 厦门先明生物技术有限公司 一种微流控免疫分析联检装置及其使用方法

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