CN116539871B - Chemiluminescence measuring device based on microfluidics - Google Patents
Chemiluminescence measuring device based on microfluidics Download PDFInfo
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Classifications
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- G—PHYSICS
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- 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
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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
- B01L3/02—Burettes; Pipettes
- B01L3/021—Pipettes, i.e. with only one conduit for withdrawing and redistributing liquids
- B01L3/0217—Pipettes, i.e. with only one conduit for withdrawing and redistributing liquids of the plunger pump type
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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
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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
- B01L3/50273—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
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
- G01N21/76—Chemiluminescence; Bioluminescence
- G01N21/763—Bioluminescence
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- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- 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
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Abstract
The invention provides a chemiluminescent measuring device, which relates to the field of detecting instruments and comprises a device shell, a microfluidic chip module, a reagent module, an automatic pipetting module, an incubation bin module, a centrifugal motor driving module and a chemiluminescent signal detecting module which are arranged in the device shell, and a data interaction module and a power module which are arranged above the device shell, wherein the structure and the position of the device shell and the modules arranged are optimally configured, and particularly the microfluidic chip module with a plurality of parallel detecting units, the automatic pipetting module which is driven by 3 sets of motors to move in 3 directions, the centrifugal motor driving module with the centrifugal motor and an external magnet driving motor and the special structure of the closable incubation bin module are integrated.
Description
Technical Field
The invention relates to the field of detection instruments, in particular to a chemiluminescent measuring device, and especially relates to a portable, automatic, parallel and multi-index joint inspection and low-cost chemiluminescent measuring device for on-site rapid detection based on a microfluidic chip.
Background
Chemiluminescent immunoassay (chemiluminescence immunoassay, CLIA for short) is a detection and analysis technique combining a chemiluminescent assay technique with high sensitivity with a high-specificity immune reaction, wherein the magnetochemiluminescent immunoassay is an analysis method combining a magnetic separation technique, a chemiluminescent technique and an immunoassay technique, and has wide application in infectious disease detection, cardiovascular and cerebrovascular disease monitoring, tumor marker detection and hormone and drug detection.
The centrifugal microfluidic chip (centrifugal microfluidic chip) can integrate structures such as valves, fluid channels, heaters, separating devices, detectors and the like which are involved in the processes of sampling, liquid injection, incubation, adsorption and separation of magnetic beads, mixing and detection and the like in the process of chemiluminescent immunoassay of the magnet on the chip, and can realize detection analysis of various indexes of the same sample to be detected or the same index of the same sample to be detected by taking centrifugal force as fluid driving force.
At present, large and medium-sized chemiluminescent detectors on the market are large in size, complex in equipment, complex in operation, high in equipment cost and high in requirements on use environments, and often need to be arranged in a checking center of a large and medium-sized hospital, so that the detection environments and objective requirements of basic medical places are difficult to adapt. Point-of-care testing (POCT) has been widely accepted in clinical departments, rapid diagnosis of emergency treatment of critical patients, dynamic monitoring, treatment effect evaluation and other aspects due to the characteristics of convenient operation, low cost, short detection time and the like, but at the same time, the test precision is whether POCT equipment can become life and death proposition as a clinical diagnosis basis. The advantage of chemiluminescence is very high precision, and microfluidics provides a very favorable technical platform for the application of chemiluminescence technology in POCT. Therefore, how to provide a microfluidic-based chemiluminescent assay device, which can combine the advantages of inspection accuracy and small-volume flexible on-site detection, and can realize precise control, mixing, reaction and separation of liquid in a microfluidic chip, has become a problem to be solved.
Disclosure of Invention
The invention aims to at least partially overcome the technical defects of the traditional chemiluminescent assay device in POCT application and provides a microfluidic-based chemiluminescent assay device which can be centrifuged, is miniaturized, is simple to operate, has low cost and high detection accuracy.
In order to achieve the above object or one of the purposes, the present invention provides the following technical solutions:
a chemiluminescent assay device comprises a device shell, a microfluidic chip module, a reagent module, an automatic pipetting module, an incubation bin module and a centrifugal motor driving module, wherein the microfluidic chip module, the reagent module, the automatic pipetting module, the incubation bin module and the centrifugal motor driving module are arranged in the device shell; the micro-fluidic chip module comprises a micro-fluidic chip and a magnetic bead control layer, wherein the micro-fluidic chip and the magnetic bead control layer comprise three layers of structures of a cover plate, an intermediate layer and a bottom plate, the three layers of structures are arranged in an axisymmetric manner, and the micro-fluidic chip is provided with a plurality of groups of parallel detection units with the same structure; the magnetic bead control layer is tightly attached to the lower surface of the microfluidic chip and comprises an internal magnet arranged in a circular arc-shaped magnet channel; (2) the reagent module comprises gun tips, reagent test tubes and washing reagent test tubes, wherein the gun tips, the reagent test tubes and the washing reagent test tubes are respectively arranged in a plurality of rows which are arranged in parallel, and the number of the parallel rows is consistent with the number of parallel detection units on the microfluidic chip; (3) the automatic pipetting module is driven by 3 sets of motors respectively to control the pipetting motions of front and back, left and right, up and down in all directions and multiple angles, and comprises the left and right movements in the horizontal direction driven and controlled by an X-axis stepping motor; the Y-axis stepping motor drives and controls the horizontal direction to move back and forth; the Z-axis motor drives and controls the vertical direction to move up and down; the automatic pipetting module is fixed and supported above the reagent module through a support column; (4) the incubation bin module adopts an aluminum block heating mode, comprises a sliding table motor and a heating aluminum block, and constructs a closed and shading incubation reaction bin for the microfluidic chip by arranging a heating upper cover and a sealing lower cover; (5) the centrifugal motor driving module comprises a centrifugal motor, a centrifugal motor bracket, a flange base, an external magnet fixing piece and an external magnet driving motor, wherein the centrifugal motor, the centrifugal motor bracket and the flange base are positioned in the sealed lower cover; the external magnet driving motor is fixed on the support column and used for driving the external magnet to magnetically control the corresponding internal magnet.
Preferably, the number of support columns may be a multiple of 2, preferably 4.
Preferably, the external magnet drive motor may be fixed to the support column by pins and screws.
In the invention, three layers of the microfluidic chip are respectively a microfluidic chip cover plate, a microfluidic chip middle layer and a microfluidic chip bottom plate; the three-layer structure of the magnetic bead control layer is respectively a magnetic bead control layer cover plate, a magnetic bead control layer middle layer and a magnetic bead control layer bottom plate; and the three-layer structures of the microfluidic chip are respectively provided with a bonding positioning hole and/or a pin hole with corresponding positions, and the three-layer structures are fixed through the bonding positioning holes and/or the pin holes.
Preferably, the three layers are bonded and fixed in a hot pressing mode through bonding positioning holes and/or fixed by pins through pin holes.
In the invention, each group of parallel detection units of the middle layer of the microfluidic chip sequentially comprises a reaction cavity, a buffer cavity, a detection cavity and a waste liquid cavity; the reaction cavity is connected with the detection cavity through a first capillary valve, the buffer cavity is connected with the detection cavity through a buffer cavity liquid channel, and the detection cavity is connected with the waste liquid cavity through a second capillary valve with a circular blocking valve; the reaction cavity is provided with a reaction cavity air hole channel, the buffer cavity is provided with a buffer cavity air hole channel, and the detection cavity is provided with a detection cavity air hole channel; the reaction cavity is provided with a reaction cavity sample adding channel, and the buffer cavity is provided with a buffer cavity sample adding channel. The buffer cavity sample adding channel is used for adding excitation liquid into the buffer cavity, and the excitation liquid is thrown into the detection cavity through the buffer cavity liquid channel under the action of the centrifugal force of the centrifugal motor to perform luminescence reaction.
Preferably, the number of parallel detection units is set to 3 groups.
Further preferably, the microfluidic chip is disposable.
In the invention, the middle layer of the magnetic bead control layer is also provided with pin holes, light guide holes and spherical magnetic beads; the spherical magnetic beads are arranged at the left end and the right end of the circular arc-shaped magnet channel.
Preferably, one end of the circular arc-shaped magnet channel corresponds to the position of the reaction cavity up and down.
Further preferably, the number of spherical magnetic beads provided at each end is preferably 2.
In the invention, the distance from the circular arc-shaped magnet channel to the center of the middle layer of the magnetic bead control layer is consistent with the distance from the reaction cavity to the center of the middle layer of the microfluidic chip.
Preferably, under the drive of an external magnet driving motor, the magnetic bead control layer rotates anticlockwise, the internal magnet moves to the near end right below the reaction cavity in the circular arc-shaped magnet channel, and the magnetic beads in the reaction cavity are fixed; under the drive of an external magnet driving motor, the magnetic bead control layer rotates clockwise, the internal magnet moves to the far end far away from the reaction cavity in the circular arc-shaped magnet channel, and the magnetic attraction fixation of the magnetic beads in the reaction cavity is released, so that the magnetic beads can move freely in the reaction cavity.
In the present invention, an internal magnet is provided on an intermediate layer of a magnetic bead control layer.
According to a preferred embodiment of the invention, the microfluidic chip module is fixed on a flange base above the centrifugal motor, the flange base is nested on a central shaft of the centrifugal motor above the centrifugal motor bracket, and the component fixed on the flange base is driven by the centrifugal motor to rotate and centrifuge around the central shaft of the centrifugal motor.
Preferably, the microfluidic chip module is fixed on a flange base above the centrifugal motor through a butterfly screw and a chip pressing piece.
According to a preferred embodiment of the invention, the external magnet, in the non-centrifuged state, extends under the internal magnet inside the sealed lower housing through an external magnet channel provided in the side of the sealed lower housing, and the magnetic force controls the movement of the internal magnet inside the circular arc-shaped magnet channel.
According to the invention, the heating upper cover is controlled by the sliding table motor to move up and down in the Z-axis direction, and the height of the heating upper cover is adjusted.
Preferably, the slipway motor can heat the height of the upper housing in the range of 50 mm.
In the invention, the device shell is made of metal material with heat conducting property, the rear side plate of the device shell is provided with the radiating fin, and the middle of the radiating fin is fixedly provided with the radiating fin fan.
According to a preferred embodiment of the invention, a data interaction module and a power module are further arranged above the device shell, and the data interaction module provides a man-machine interaction interface through a touch screen; the power module is matched with the power adapter to provide stable output power.
Preferably, the power module in combination with the power adapter provides a stable output power of up to 220 watts.
Preferably, on the device shell, the data interaction module displays the numerical value or the numerical curve of the detected chemiluminescent signal in real time through the touch screen; the data interaction module is also provided with data processing software, the chemiluminescent signals detected by the photomultiplier are calculated through a four-parameter model algorithm or other algorithms, the concentration of the sample to be detected added by the microfluidic chip is calculated, and the concentration data are displayed in real time through the touch screen, so that quantitative detection of the chemiluminescent signals is realized.
In the incubation bin module, a sliding table motor is fixed on a device bottom plate of a device shell through a sliding table motor support frame, a heating aluminum block is fixed on the inner side of a heating upper cover, a heating film is tightly attached to the upper surface of the heating aluminum block, and the heating film corresponds to the center position of the heating aluminum block; the heating aluminum block moves to the upper part of the microfluidic chip along with the heating upper cover, heats the microfluidic chip and controls the temperature of the incubation bin module.
Preferably, the heating aluminum block may be fixed to the inner side of the heating upper cover by screws.
Preferably, the heated aluminum block can provide temperature control to the incubation chamber module via PID algorithm.
In the invention, the chemiluminescent measuring device is also provided with a chemiluminescent signal detection module which comprises a photomultiplier and a light pipe, wherein one end of the light pipe is fastened with a window of the photomultiplier and is fixed on a device bottom plate of a device shell; the other end of the light pipe extends into the lower part of the microfluidic chip module through a light pipe channel arranged on the surface of the sealing lower cover, is aligned with a detection cavity of the microfluidic chip and is used for detecting a chemiluminescent signal generated by the microfluidic chip.
In the invention, the light pipe is cylindrical and can be formed by wrapping optical fibers (polymethyl methacrylate, polymethyl Methacrylate and PMMA) by a jacket (PVC).
According to a preferred embodiment of the invention, a grating sheet is arranged at the upper part of the centrifugal motor, a slit is arranged on the grating sheet, and the grating sheet is fixed on the side surface of the flange base; the bottom of the sealed lower cover is provided with a positioning optical coupler, and the positioning optical coupler is provided with an optical channel.
Preferably, the grating sheet can be fixed on the side surface of the flange base by a screw.
Preferably, the slit corresponds to an optical channel for positioning the microfluidic chip.
Preferably, the slits on the grating sheet are 1, and the slit width is 0.1 mm-0.5 mm, for example, 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm or 0.5 mm, etc.
In the present invention, in the centrifugal motor driving module, the centrifugal motor may be a servo motor, a stepping motor, a direct current brushless motor, or other motors, and may provide a rotational speed in the range of 1000 rpm to 12000 rpm, and the rotational speed may be 1000 rpm, 2000 rpm, 3000 rpm, 4000 rpm, 5000 rpm, 6000 rpm, 7000 rpm, 8000 rpm, 9000 rpm, 10000 rpm, 11000 rpm, 12000 rpm, or the like, for example.
In the automatic pipetting module, 3 sets of motors control the number of steps of motor movement by converting electric pulse signals into corresponding linear displacement; the movement in the X-axis and Y-axis directions is achieved by an X-axis guide rail and a Y-axis guide rail, respectively, and the movement in the Z-axis direction is achieved by a Z-axis motor.
Preferably, the Z-axis motor is a lead screw motor.
Further preferably, 3 corresponding touch switches are respectively arranged on 3 sets of motors in the X-axis, Y-axis and Z-axis directions, namely an X-axis touch switch, a Y-axis touch switch and a Z-axis touch switch.
Still preferably, in the Z-axis direction, a pipette is fixed at one end of the pipette body, a hose connector is fixed at the other end of the pipette body, the hose connector is connected with a plunger pump through a gas path hose, and the gas pressure in the gas path hose is controlled through the movement of the plunger pump, so that the pipetting action of the pipette body is controlled through the gas pressure.
Further preferably, the air path hose is a flexible, transparent tube.
In the invention, the chemiluminescent measuring device is also provided with an auxiliary module, the auxiliary module comprises a main control board and a main control board bracket, the main control board is fixed on the main control board bracket, the main control board bracket is fixed on a device bottom plate of the device shell, and the main control board is arranged in parallel with a rear side plate of the device shell; the operation of other modules is controlled through the main control board, and data interaction with the data interaction module is provided.
In the invention, the reagent module also comprises a reagent box, a reagent box supporting plate and a reagent box supporting frame, wherein the reagent box is fixed on the reagent box supporting plate through a convex clamping structure of the reagent box supporting plate, and the reagent box supporting frame is fixed with a device bottom plate of the device shell through a screw; the kit is provided with a hole site for placing a gun tip, a reagent test tube and a washing reagent test tube.
Preferably, the kit is further provided with a gun tip disposal bin.
Further preferably, the number of the 3 groups of parallel detection units at the middle layer of the microfluidic chip corresponds to that of the gun tips, the reagent test tubes and the washing reagent test tubes which are arranged in 3 rows in parallel, and the 3 groups of parallel detection units are respectively applied to the microfluidic chip.
The invention also claims the application of the chemiluminescence measuring device in chemiluminescence immunoassay.
The invention has the beneficial effects that:
the chemiluminescent measuring device comprises a device shell, a microfluidic chip module, a reagent module, an automatic pipetting module, an incubation bin module and a centrifugal motor driving module which are arranged in the device shell, and is also provided with a chemiluminescent signal detection module adopting a high-sensitivity photomultiplier and an auxiliary device adopting a main control board to control the operation of other modules. The device shell is made of a metal material with good heat conduction performance, and heat on the centrifugal motor driver abutted against the inner side of the rear side plate can be rapidly and effectively conducted away. And the rear side plate is also provided with a radiating fin, and a radiating fin fan is nested in the middle of the radiating fin, so that the speed of absorbing and guiding away redundant heat is further increased. Meanwhile, the separator is arranged in the centrifugal motor driver and the incubation bin module in the device, so that the influence of heat generated by the centrifugal motor driver on the reaction temperature in the reaction process is effectively prevented, and the accuracy of temperature control is realized.
And a data interaction module and a power module are further arranged above the device shell. The power module is matched with the power adapter, can provide output power of up to 220 watts, provides stable high-power output for the device, and ensures that the device can normally and stably operate. The data interaction module provides a man-machine interaction interface through the touch screen, and after the man-machine interaction interface receives related instructions, the functions of automatic control, information acquisition, storage, display, analysis, feedback and the like of the chemiluminescent detection device are realized through the main control board of the auxiliary module. In addition, the data interaction module displays the numerical value or the numerical curve of the detected chemiluminescent signal in real time through the touch screen; the data processing software configured by the data interaction module can calculate the chemiluminescent signal detected by the photomultiplier through a four-parameter model algorithm or other algorithms, calculate the concentration of the sample to be detected added by the microfluidic chip, and display the detection result of the concentration data in real time through the touch screen, thereby realizing the real-time quantitative detection of the chemiluminescent signal.
The microfluidic chip module consists of the three-layer-structured microfluidic chip and the magnetic bead control layer, wherein the three-layer-structured microfluidic chip is axially symmetrically arranged, a plurality of groups of parallel detection units with the same structure can be arranged on the microfluidic chip, joint detection of multiple markers of the same sample to be detected can be realized, or joint detection of the same markers of multiple samples to be detected can be realized, and rapid parallel detection can be realized.
For example, when the parallel detection units are preferably 3 groups, a microfluidic chip for 3 myocardial necrosis markers related to myocardial infarction may be provided, and the 3 myocardial necrosis markers may include: troponin (cTnI), creatine kinase isozyme (CK-MB) and myoglobin (Myo), realizing rapid joint inspection and minimizing detection time, thereby realizing instant diagnosis and timely treatment of myocardial infarction, and having important clinical application value and significance for rapid detection and timely diagnosis of critical diseases like myocardial infarction.
In addition, each group of parallel detection units in the middle layer of the microfluidic chip sequentially comprises a reaction cavity, a buffer cavity, a detection cavity and a waste liquid cavity, wherein the reaction cavity is connected with the detection cavity through a first capillary valve, the buffer cavity is connected with the detection cavity through a buffer cavity liquid channel, and the detection cavity is connected with the waste liquid cavity through a second capillary valve with a circular blocking valve; the first capillary valve, the second capillary valve and the circular blocking valve prevent the sample or reagent in the chamber from being thrown into the next chamber before the reaction is completed. The first capillary valve is connected with the reaction cavity and the detection cavity, so that magnetic beads, samples or reagents are prevented from being thrown into the detection cavity when the reaction cavity is mixed, and uneven mixing of partial magnetic beads is avoided; the second capillary valve is connected with the detection cavity and the waste liquid cavity, so that the magnetic beads and the pre-excitation liquid are prevented from being directly thrown into the waste liquid cavity when being transferred to the detection cavity, and the loss of the magnetic beads is avoided; the circular blocking valve is arranged at the middle position of the second capillary valve, so that the breakthrough rotation speed of the second capillary valve is further increased, and the loss of the magnetic beads is further avoided.
The microfluidic chip can also generate Europe pulling force or centrifugal force under the drive of a centrifugal motor, and the magnetic beads, the samples or the reagents sequentially complete each step of chemiluminescent reaction in each chamber under the action of Europe pulling force or centrifugal force: firstly, adding a magnetic bead solution and a sample into a reaction cavity, mixing the magnetic bead solution and the sample under the action of Euler force, adsorbing the magnetic beads after the mixing is finished, enabling the solution and the sample to quickly pass through a detection cavity under the action of centrifugal force, and finally throwing the solution and the sample into a waste liquid cavity; secondly, introducing washing liquid for 3 times to wash the magnetic beads, and throwing the waste liquid after washing into a waste liquid cavity after passing through a detection cavity under the action of centrifugal force; then adding a luminous marker into the reaction cavity, mixing with the magnetic beads again, and introducing washing liquid for 3 times to wash the magnetic beads, wherein waste liquid generated in the process is thrown into the waste liquid cavity; and adding pre-excitation liquid into the reaction cavity, transferring the pre-excitation liquid and the magnetic beads into the detection cavity, finally adding excitation liquid into the buffer cavity, throwing the excitation liquid into the detection cavity under the action of centrifugal force, and reacting and emitting the magnetic beads, the pre-excitation liquid and the excitation liquid in the detection cavity to complete a chemiluminescent reaction experiment.
In the chemiluminescent measuring device, the internal magnet is arranged on the middle layer of the magnetic bead control layer, and the optimization strategy of rapid switching of the working state is realized through the movement of the internal magnet, namely, the real-time control and rapid switching of the position of the internal magnet are realized, so that different reaction operations such as magnetic bead adsorption, aggregation or mixing are realized. Specifically, the magnetic bead control layer is placed close to the lower surface of the microfluidic chip, wherein a circular arc-shaped magnet channel is designed, the distance from the circular arc-shaped magnet channel to the center of the middle layer of the magnetic bead control layer is consistent with the distance from the reaction cavity to the center of the middle layer of the microfluidic chip, one end of the circular arc-shaped magnet channel corresponds to the reaction cavity of the microfluidic chip up and down, and an internal magnet is arranged in the circular arc-shaped magnet channel. The inner magnet is located at the end of the circular arc-shaped magnet channel far from the reaction chamber of the microfluidic chip, which is called the distal end, and correspondingly, when the inner magnet is located at the end right below the reaction chamber of the microfluidic chip, which is called the proximal end. In the reaction process, when the reagent is required to be transferred through the high-speed rotation of the microfluidic chip or waste liquid is finally thrown into the waste liquid cavity through the detection cavity, in order to prevent the magnetic beads from being thrown into the next cavity, the internal magnet is required to adsorb and fix the magnetic beads, at this time, the external magnet firstly stretches into the lower part of the magnetic bead control layer along the horizontal direction under the driving of the external magnet driving motor, the magnetic bead control layer rotates anticlockwise, the internal magnet in the circular arc-shaped magnet channel can automatically move to the near end (namely, directly under the reaction cavity) along the circular arc-shaped magnet channel under the magnetic force of the external magnet, and the magnetic beads are efficiently adsorbed and fixed. In the reaction process, when the magnetic beads and the sample or the reagent need to be mixed, the external magnet stretches into the lower part of the magnetic bead control layer along the horizontal direction under the drive of the external magnet driving motor, the magnetic bead control layer rotates clockwise, the internal magnet can automatically move to the far end (namely away from the reaction cavity) along the circular arc-shaped magnet channel under the magnetic force action of the external magnet, the magnetic beads are not adsorbed, and the free movement and the mixing of the magnetic beads are realized.
The reagent module of the invention corresponds to the number of parallel detection units in the middle layer of the microfluidic chip, gun tips, reagent test tubes and washing reagent test tubes are arranged in parallel to form the same number of rows, and the same number of rows of the reagent test tubes corresponds to each detection unit on the microfluidic chip. For example, when the parallel detection units of the middle layer of the microfluidic chip are 3 groups, the gun tips, the reagent test tubes and the washing reagent test tubes are arranged in 3 rows in parallel, and can be correspondingly applied to the 3 detection units on the microfluidic chip. In addition, the kit is also provided with a gun tip discarding bin for storing the discarded gun tips after each sample addition is finished, so that pollution is avoided.
According to the automatic pipetting module, 3 sets of motors in 3 directions are arranged, the 3 sets of motors control the number of steps of motor movement by converting electric pulse signals into corresponding linear displacement, so that accurate movement of a pipetting device in the directions of an X axis, a Y axis and a Z axis is realized, wherein the movement in the directions of the X axis and the Y axis is realized through a guide rail, the movement of the pipetting device in the direction of the Z axis is realized through a Z axis motor, and the Z axis motor is preferably a screw motor. In addition, the X, Y, Z shaft directions are all provided with touch switches for determining the moving zero positions, so that the operations of loading and falling of gun tips, sampling and injecting samples and the like are flexibly and conveniently realized. A pipette is fixed at one end of the pipette body, so that loading and falling-off of a gun tip are realized; the other end of the liquid transfer device main body is fixed with a hose joint, the hose joint is connected with a plunger pump through an air path hose, and the air pressure in the air path hose is increased or decreased through the movement of the plunger pump, so that the operations such as sampling, sample injection and the like of a sample or a reagent are controlled through the air pressure, namely the liquid transfer action is controlled through the air pressure; wherein, the air path hose is a flexible transparent hose. Because 3 sets of motors in 3 directions are arranged, the sample adding position of the automatic pipetting module can be fixed, and the accuracy of pipetting is improved.
The centrifugal motor driving module can be a servo motor, a stepping motor, a direct current brushless motor or other motors, can provide a rotating speed in the range of 1000 rpm-12000 rpm, and can meet the rotating speed required by each reaction step required by chemiluminescent reaction; by means of centrifugal force generated by high-speed rotation and combining with the functional design of the reaction cavity and the channel on the microfluidic chip, the sample or the reaction reagent to be tested gradually completes various reaction steps required by the chemiluminescent reaction on the microfluidic chip, such as the steps of mixing the sample and the magnetic beads, cleaning the magnetic beads, transferring the reagent, discharging waste and the like. The centrifugal motor is fixedly provided with a grating sheet, the grating sheet is provided with 1 slit, the positioning optocoupler is fixed at the bottom of the sealed lower cover, the positioning optocoupler is provided with an optical channel, the slit corresponds to the optical channel of the positioning optocoupler, and the slit can continuously pass through the positioning optocoupler in the rotating process of the microfluidic chip and is used for positioning the microfluidic chip.
The incubation bin module is particularly provided with the heating upper cover and the sealing lower cover, and the incubation bin with dual functions can be constructed together with the sealing lower cover by the up-and-down movement of the heating upper cover, so that a closed temperature control environment can be provided, the accurate temperature control of the microfluidic chip module is realized, and the interference and influence of environmental temperature fluctuation are overcome; on the other hand, a shading environment can be provided, the interference and influence of environment stray light on the collection of high-sensitivity chemiluminescence signals based on the photomultiplier can be overcome, and the accurate collection and analysis of the chemiluminescence signals can be realized. Further, the sliding table motor controls the heating upper cover to move in the vertical direction through the heating upper cover connecting piece, the height of the heating upper cover can be adjusted within the range of 50 mm, and the heating upper cover is in a lifting state before placing a chip, so that the placement of a microfluidic chip module is not affected. After the microfluidic chip is placed, the upper heating cover falls down and is fastened on the lower sealing cover, so that an incubation bin is formed.
The external magnet driving motor is further arranged below the incubation bin module and is fixed on the support column and used for driving the external magnet, the external magnet can extend below the internal magnet through the external magnet channel on the right side of the sealing lower cover, the internal magnet can move from the near end to the far end or from the far end to the near end, the structure is simple and convenient, meanwhile, the switching of the working state of the internal magnet is flexibly realized, the continuity and the flexibility of the reaction are greatly improved, meanwhile, the external magnet driving motor is directly fixed on the support column, the structure of an instrument is optimized, and the layout of internal parts of the instrument is more compact.
The incubation bin module is integrated in the chemiluminescent measuring device, so that the comprehensive performance of the measuring device is effectively improved, the temperature of the whole incubation bin module is controlled through a PID algorithm, and the temperature in the incubation bin is dynamically regulated in time according to a temperature set value required by chemiluminescent reaction, so that the temperature in the whole incubation bin is always kept within the temperature required by the reaction, and the accuracy of detecting a final chemiluminescent signal is ensured. Meanwhile, a capsule-shaped through structure is designed at the same position of the heating upper cover, the heating film and the heating aluminum block, so that the light leakage area of the microfluidic chip can be reduced to the greatest extent. The heating aluminum block is fixed on the inner side of the heating upper cover, the heating film is clung to the upper surface of the heating aluminum block, and stable temperature is further provided for the corresponding heating aluminum block.
In the luminous signal detection module, a light pipe is particularly arranged, one end of the light pipe is tightly aligned on a window of a photomultiplier, and the other end of the light pipe extends into the lower surface of the microfluidic chip module through a light pipe channel of a sealed lower cover and is aligned with a microfluidic chip detection cavity. The light pipe not only solves the problem that the photomultiplier cannot be directly arranged below the microfluidic chip module to detect the chemiluminescent signal, but also can rapidly collect and transmit the weak chemiluminescent signal generated by the reaction, thereby avoiding the loss of the weak chemiluminescent signal in the internal space of the instrument and improving the detection accuracy; the diameter of the light guide hole is basically consistent with that of the light guide pipe, so that the interference and influence of ambient stray light on the acquisition of high-sensitivity chemiluminescence signals based on the photomultiplier are effectively overcome, and meanwhile, the luminescence signals can be acquired rapidly and accurately. The auxiliary device controls the operation of other modules through the main control board, wherein the main control board not only controls the operation of other modules, but also provides data interaction with the data interaction module. When the magnetic beads, the pre-excitation liquid and the excitation liquid enter the detection cavity to react and emit light, the generated weak light signals are transmitted to the photomultiplier through the light pipe, and the photomultiplier can amplify and convert the weak light signals into electric signals, so that the collection of chemiluminescent signals and the reaction and emission of the magnetic beads, the pre-excitation liquid and the excitation liquid in the detection cavity are realized, the weak light signals possibly lost in the detection process are amplified, and the detection accuracy is further improved.
Compared with the prior large and medium-sized chemiluminescent detector in the market, the chemiluminescent detection device integrates the advantages of chemiluminescence, microfluidics and POCT, has the characteristics of capability of centrifugation, small volume, convenience in movement, simplicity in operation, high automation degree, low equipment cost, short detection time, flexibility in use, high detection precision and the like, is an instant chemiluminescent detection system more suitable for site rapid detection (POCT) application scenes, and is more suitable for rapid multi-index or multi-item joint detection of POCT in basic medical units, such as multi-index joint and rapid detection of critical diseases such as myocardial infarction by means of the mutual cooperation of the disposable microfluidic chip and detection equipment.
Drawings
FIG. 1 is a perspective view of the right front side of a chemiluminescent assay device of the present invention;
FIG. 2 is a perspective view of the left rear side of the chemiluminescent assay device of the present invention;
FIG. 3 is a perspective view of the structure of a microfluidic chip and a magnetic bead control layer of the chemiluminescent assay device of the present invention;
FIG. 4 is a top view of a microfluidic chip cover plate of a chemiluminescent assay device of the present invention;
FIG. 5 is a top view of a microfluidic chip backplane of a chemiluminescent assay device of the present invention;
FIG. 6 is a top view of an intermediate layer of a microfluidic chip of a chemiluminescent assay device of the present invention;
FIG. 7 is a top view of the magnetic bead control layer cover plate and the magnetic bead control layer bottom plate of the chemiluminescent assay device of the present invention;
FIG. 8 is a top view of an intermediate layer of a magnetic bead control layer of a chemiluminescent assay device of the present invention;
FIG. 9 is an enlarged view showing a partial structure of an intermediate layer of a magnetic bead control layer of the chemiluminescent assay device of the present invention;
FIG. 10 is a perspective view of the left front side of the internal structure of the device housing of the chemiluminescent assay device of the present invention;
FIG. 11 is a perspective view of the right rear side of the internal structure of the device housing of the chemiluminescent assay device of the present invention;
FIG. 12 is a perspective view of the front left side of the reagent module of the chemiluminescent assay device of the present invention;
FIG. 13 is a perspective view of the left rear side of the X-axis portion of the automatic pipetting module of the chemiluminescent assay of the present invention;
FIG. 14 is a perspective view of the front right side of the X-axis portion of the automatic pipetting module of the chemiluminescent assay of the present invention;
FIG. 15 is a side perspective view of the Y-axis portion of the automatic pipetting module of the chemiluminescent assay apparatus of the present invention;
FIG. 16 is a side perspective view of the Z-axis portion of the automatic pipetting module of the chemiluminescent assay apparatus of the present invention;
FIG. 17 is a side perspective view of an incubation chamber module of the chemiluminescent assay device of the present invention;
FIG. 18 is a bottom view and perspective view of a heating top cover of an incubation chamber module of the chemiluminescent assay device of the present invention;
FIG. 19 is a perspective and bottom view of a sealed lower housing of an incubation chamber module of the chemiluminescent assay device of the present invention;
FIG. 20 is a front view of a chemiluminescent signal detection module of the chemiluminescent assay device of the present invention;
FIG. 21 is a perspective view of a centrifugal motor drive module of the chemiluminescent assay device of the present invention;
FIG. 22 is a perspective view of an external magnet drive motor of the chemiluminescent assay device of the present invention.
In the figure: 1-a reaction cavity sample adding hole; 2-buffer cavity air holes; 3-a buffer cavity sample adding hole; 4-reaction cavity air holes; 5-detecting air holes of the cavity; 6-bonding the positioning holes; 7-pin holes; 8-a reaction chamber; 9-a reaction cavity sample adding channel; 10-a buffer cavity air hole channel; 11-a buffer cavity sample addition channel; 12-a buffer chamber; 13-buffer chamber liquid channel; 14-a detection chamber; 15-a circular blocking valve; 16-a second capillary valve; 17-a waste liquid chamber; 18-reaction chamber air hole channel; 19-a first capillary valve; 20-detecting a cavity air hole channel; 21-a light guide hole; 22-an internal magnet; 23-spherical magnetic beads; 24-a microfluidic chip cover plate; 25-an intermediate layer of a microfluidic chip; 26-a microfluidic chip base plate; 27-a magnetic bead control layer cover plate; 28-a bead control layer interlayer; 29-a magnetic bead control layer bottom plate; 30-a touch screen; 31-upper side plate; 32-a front panel; 33-hatch door handle; 34-cabin door; 35-rubber foot pads; 36-hinge; 37-right side plate; 38-right side panel handle; 39-a rear side plate; 40-cooling fins; 41-a fin fan; 42-left side plate; 43-left side panel handle; 44-an automatic pipetting module; 45-reagent module; 46-a stepper motor driver; 47-device backplane; 48-a chemiluminescent signal detection module; 49-a centrifugal motor drive module; 50-incubating the cartridge module; 51-microfluidic chip module; 52-a main control board; 53-a main control board bracket; 54-centrifugal motor drive; 55-a plunger pump mount; 56-a plunger pump solenoid valve fixing piece; 57-plunger pump solenoid valve; 58-plunger pump; 59-a centrifugal motor driver diaphragm; 60-drive shaft bearings; 61-kit; 62-a kit support plate; 63-a kit support; 64-clamping structure; 65-gun tip discard bin; 66-reagent test tube; 67-washing reagent tube; 68-gun tip; 69-X axis left driving wheel; 70-X axis touch switch fixing frame; 71-X axis touch switch; 72-X axis left toothed plate fixing piece; 73-X axis stepping motor; 74-X axis left toothed plate; 75-X axis drag chain; 76-X axis left support plate; 77-X axis left driven wheel fixing piece; 78-X axis left driven wheel; 79-support columns; 80-X axis right cantilever pin; 81-X axis guide rail; 82-X axis guide rail slide block; 83-Y-axis support plate; an 84-X axis left cantilever pin; 85-X axis right driven wheel fixing piece; 86-X axis right driven wheel; 87-X axis right support plate; 88-X axis belt; 89-X axis right toothed plate fixing piece; 90-X axis right toothed plate; 91-X axis right driving wheel; 92-X axis right bearing mount; 93-a drive shaft; 94-X axis stepping motor synchronous wheel; 95-X axis stepper motor fixing frame; 96-drive shaft belt; 97-drive shaft synchronizing wheel; 98-X axis left bearing fixing piece; a 99-Y axis stepper motor; a 100-Y axis stepping motor bracket; 101-Y axis driving wheels; 102-Y axis belt; 103-pipettor bottom plate; 104-Y axis toothed plate; 105-Y axis guide rail frame; 106-Y axis driven wheels; 107-Y axis driven wheel fixing piece; 108-Y axis cantilever pin; 109-Y axis touch switch; 110-Y axis touch switch fixing frame; a 111-Y axis drag chain bottom plate; 112-Y axis guide rail slide block; 113-a pipette floor pad; 114-Y axis drag chain bracket; 115-Y axis drag chain; 116-Y axis guide rail; 117-Z axis motor; 118-Z axis touch switch; 119-Z axis guide axis; 120-a support block at the top of a sliding block of the pipettor; 121-a pipettor slide; 122-hose connector; 123-a pipette body; 124-pipette; 125-a stopper at the tail of the bottom plate of the pipettor; 126-a bottom support block of a slide block of the pipettor; 127-Z axis guide shaft bearings; 128-pipettor slide side connector; 129-spring; 130-Z axis motor fixing piece; 131-heating the upper housing connection; 132-a slipway motor support frame; 133-a slipway motor; 134-heating the upper housing; 135-sealing the lower housing; 136-heating the aluminum block; 137-heating the film; 138-light pipe channels; 139-external magnet channel; 140-positioning an optocoupler; 141-positioning an optical coupler wiring hole; 142-light pipe; 143-photomultiplier tubes; 144-butterfly screw; 145—chip hold-down; 146-microfluidic chip; 147-magnetic bead control layer; 148-grating sheets; 149-a flange base; 150-a centrifugal motor; 151-a centrifugal motor support; 152-an external magnet drive motor; 153-external magnet fixture; 154-an external magnet; 155-a direct current motor touch switch fixing piece; 156-a direct current motor touch switch; 157-a rail mount; 158-rail bearings; 159-a DC motor slider; 160-a guide rail; 161-dc motor; 162-dc motor mount; 163-capsule-shaped through structure; 164-air path hose.
Detailed Description
Exemplary embodiments of the present invention are described in detail below with reference to the attached drawing figures, wherein the same or similar reference numerals denote the same or similar elements. Furthermore, in the following detailed description, for purposes of explanation, numerous specific details are set forth in order to provide a thorough understanding of the embodiments of the present disclosure. It may be evident, however, that one or more embodiments may be practiced without these specific details. In other instances, well-known structures and devices are shown in the drawings in order to simplify the drawings.
According to the general inventive concept, there is provided a novel chemiluminescent assay device for detecting a microfluidic chip, the chemiluminescent assay device including a device housing, and a microfluidic chip module, a reagent module, an automatic pipetting module, an incubation chamber module, a centrifugal motor driving module and a chemiluminescent signal detection module disposed inside the device housing, and a data interaction module and a power module disposed above the device housing. The chemiluminescence measuring device integrates a microfluidic chip module with a plurality of parallel detection units, an automatic pipetting module which is driven by 3 sets of motors to move in 3 directions respectively, a centrifugal motor driving module with a centrifugal motor and an external magnet driving motor and a special structure of a closable incubation bin module, the structure of a reagent module is matched with the number of the parallel detection units of the microfluidic chip module, and the magnetic force action between the internal magnet of the microfluidic chip module and the external magnet of the centrifugal motor driving module realizes real-time control and rapid switching of different reaction states of magnetic beads. The chemiluminescent measuring device has the characteristics of small volume, convenient movement, simple operation, low equipment cost, short detection time, flexible use, high detection precision and the like, can realize automatic control, and is particularly suitable for popularization and application in the POCT field.
The invention is described in further detail below with reference to fig. 1-22.
Fig. 1 and 2 show perspective views of the right front side and the left rear side of the chemiluminescent measuring device according to the present invention, respectively, and as can be seen in combination with fig. 10, the chemiluminescent measuring device according to the present invention comprises a device housing, and components disposed inside the device housing, and a data interaction module and a power module are disposed above the device housing. The device housing includes an upper side plate 31, a device bottom plate 47, a front panel 32, a rear side plate 39, a left side plate 42, and a right side plate 37; the upper side plate 31 and the device bottom plate 47 are respectively connected with the left side plate 42, the right side plate 37, the front panel 32 and the rear side plate 39 by screws, so that the fastening of the shell is ensured; the device shell is made of metal materials with good heat conduction performance, and heat can be quickly and effectively conducted away.
The data interaction module is arranged on the upper side plate 31 of the device housing. The rubber foot pad 35 is arranged at the bottom of the device bottom plate 47, so that the device is in soft contact with the placement plane, and collision is avoided. The cabin door 34 is arranged on the front panel 32 through a hinge 36, so that a user can conveniently place and take out the microfluidic chip module 51; the protruding structure on the inner side of the cabin door 34 corresponds to the recessed structure on the front panel 32, so that the sealing performance is ensured; the cabin door 34 is also provided with a cabin door handle 33, and the cabin door handle 33 is fixed on the cabin door 34 through screws, so that a user can conveniently open and close the cabin door 34; the rear side plate 39 is provided with a radiating fin 40, and a radiating fin fan 41 is fixedly arranged in the middle of the radiating fin 40, so that the device is further prevented from being disturbed and influenced by heat generated by the operation of each component in the operation process, and a stable temperature environment is provided; the left side plate 42 and the right side plate 37 are respectively provided with a right side plate handle 38 and a left side plate handle 43, and the left side plate handle 43 and the right side plate handle 38 are fixed on the left side plate 42 and the right side plate 37 through screws, so that a user can conveniently carry the mobile device.
As can be seen from fig. 1, the data interaction module includes a touch screen 30, the touch screen 30 is fixed above the outer surface of the upper side plate 31 of the device housing, the data interaction module provides a friendly man-machine interaction interface for a user, transmits corresponding instructions to the auxiliary module to execute corresponding actions, receives and processes corresponding data collected by the auxiliary module, and can realize automatic real-time drawing of a luminous value curve and display a detection result. Specifically, the data interaction module displays the numerical value or numerical curve of the detected chemiluminescent signal in real time through the touch screen 30; the data interaction module is further configured with data processing software, calculates the concentration of the sample to be detected added by the microfluidic chip 146 through a four-parameter model algorithm or other algorithms, and displays the concentration data in real time through the touch screen 30, thereby realizing quantitative detection of the chemiluminescent signal.
Fig. 3 is a perspective view of the structure of a microfluidic chip and a magnetic bead control layer of the chemiluminescent assay device of the present invention, and as can be seen from fig. 3, the microfluidic chip module 51 of the chemiluminescent assay device of the present invention comprises a microfluidic chip 146 and a magnetic bead control layer 147 (see fig. 21 for positions), and the magnetic bead control layer 147 is placed closely to the lower surface of the microfluidic chip 146. The three-layer structure of the microfluidic chip 146 comprises a microfluidic chip cover plate 24, a microfluidic chip intermediate layer 25 and a microfluidic chip bottom plate 26; the magnetic bead control layer 147 includes a magnetic bead control layer cover plate 27, a magnetic bead control layer intermediate layer 28, and a magnetic bead control layer bottom plate 29.
Fig. 4, 5 and 6 show three layers of the microfluidic chip cover plate 24, the microfluidic chip bottom plate 26 and the microfluidic chip intermediate layer 25 of the microfluidic chip module 51 according to the present invention, respectively. The three layers are all axisymmetrically arranged, and are all provided with a bonding positioning hole 6 and a pin hole 7, and the three layers are bonded in a hot pressing mode, so that the accuracy of sample adding of the microfluidic chip 146 is ensured.
The microfluidic chip 146 is provided with a plurality of parallel detection units having the same structure, and the number of parallel detection units which are arranged axisymmetrically in the figure is preferably 3, and 1 group is taken as an example for illustration. Regarding the parallel detection unit: by arranging a plurality of groups of parallel detection units, on one hand, multi-index joint inspection aiming at the same sample to be detected can be realized, for example, 3 parallel detection units with the same structure are constructed, and 3 myocardial necrosis markers related to myocardial infarction are included: troponin (cTnI), creatine kinase isozyme (CK-MB) and myoglobin (Myo), and realizing rapid parallel detection; on the other hand, the method can realize the rapid parallel detection of the same index on a plurality of different samples to be detected.
Fig. 6 shows: each group of parallel detection units of the micro-fluidic chip interlayer 25 sequentially comprises a reaction cavity 8, a buffer cavity 12, a detection cavity 14 and a waste liquid cavity 17; the reaction chamber 8 is connected with the detection chamber 14 through a first capillary valve 19, the buffer chamber 12 is connected with the detection chamber 14 through a buffer chamber liquid channel 13, and the detection chamber 14 is connected with the waste liquid chamber 17 through a second capillary valve 16 with a circular blocking valve 15; the reaction chamber 8 is provided with a reaction chamber air hole channel 18, the buffer chamber 12 is provided with a buffer chamber air hole channel 10, and the detection chamber 14 is provided with a detection chamber air hole channel 20; the reaction chamber 8 is provided with a reaction chamber sample adding channel 9, the buffer chamber 12 is provided with a buffer chamber sample adding channel 11, the buffer chamber sample adding channel 11 is used for adding excitation liquid into the buffer chamber 12, and the excitation liquid is thrown into the detection chamber 14 through the buffer chamber liquid channel 13 under the centrifugal force of the centrifugal motor 150 to perform luminescence reaction.
The first capillary valve 19 can prevent the magnetic beads, the sample or the reagent from being thrown into the detection cavity 14 when the reaction cavity 8 is mixed, so that partial magnetic beads are prevented from being mixed unevenly; the second capillary valve 16 can prevent the magnetic beads and the pre-excitation liquid from being directly thrown into the waste liquid cavity 17 when the magnetic beads and the pre-excitation liquid are transferred to the detection cavity 14, so that the loss of the magnetic beads is avoided; the circular blocking valve 15 and the second capillary valve 16 avoid reagent from entering the waste liquid cavity at a lower rotation speed and avoid the condition of reagent loss. Wherein the circular blocking valve 15 may further prevent a breakthrough rotational speed of the second capillary valve 16, thereby avoiding further losses of magnetic beads or reagents. In addition, the first capillary valve 19, the second capillary valve 16 and the circular blocking valve 15 also prevent the sample or reagent in the 2 chambers of the reaction chamber 8 and the detection chamber 14, respectively, from being thrown into the waste chamber 17 before the reaction is completed.
Specifically, the magnetic bead solution and the sample are injected into the reaction chamber 8 through the reaction chamber sample-adding channel 9 to carry out a mixing reaction, after the mixing reaction is finished, the chip is centrifuged under the action of centrifugal force (or Euler force) generated by the centrifugal motor 150, the solution except the magnetic beads is thrown into the waste liquid chamber 17 through the first capillary valve 19 and the second capillary valve 16, then washing liquid is added from the reaction chamber sample-adding channel 9, the magnetic beads are mixed and washed for 3 times, after washing is finished, the washing liquid is thrown into the waste liquid chamber 17 under the action of centrifugal force generated by the centrifugal motor 150, then the luminescent marker is added from the reaction chamber sample-adding channel 9 to carry out a mixing reaction, after the mixing reaction is finished for 3 times, the luminescent marker waste liquid except the magnetic beads is thrown into the waste liquid chamber 17 through the first capillary valve 19 and the second capillary valve 16 under the high rotation speed generated by the centrifugal motor, the magnetic beads are thrown into the reaction chamber 17 again, the magnetic beads are mixed and washed for 3 times through the magnetic beads are excited and washed through the first capillary valve 19 and the second capillary valve 16, the luminescent marker is thrown into the reaction chamber 14 through the first capillary valve 19 and the second capillary valve 16, the luminescent marker is excited into the reaction chamber 14 after the centrifugal motor is excited into the reaction chamber, and the luminescent marker is excited into the reaction chamber 14 after the reaction chamber is excited into the reaction chamber through the centrifugal motor for detecting.
With respect to centrifugation in the above reaction: the microfluidic chip 146 is driven by the centrifugal motor 150 to generate a euro-pull force or a centrifugal force, and the magnetic beads, the samples or the reagents sequentially complete each step of chemiluminescent reaction in each chamber under the action of the euro-pull force or the centrifugal force: firstly, adding a magnetic bead solution and a sample into a reaction cavity 8, mixing the magnetic bead solution and the sample under the action of Euler force, adsorbing the magnetic beads after the mixing is finished, and finally throwing the solution and the sample into a waste liquid cavity 17 under the action of centrifugal force; secondly, introducing washing liquid for 3 times to wash the magnetic beads, and finally throwing the waste liquid after washing into a waste liquid cavity 17 under the action of centrifugal force; then adding a luminous marker into the reaction cavity 8, mixing with the magnetic beads again, and introducing washing liquid for 3 times to wash the magnetic beads, wherein the waste liquid generated in the process is finally thrown into the waste liquid cavity 17; then, adding a pre-excitation liquid into the reaction cavity 8, and transferring the pre-excitation liquid and the magnetic beads to the detection cavity 14; finally, excitation liquid is added into the buffer cavity 12 and is thrown into the detection cavity 14 under the action of centrifugal force, and the magnetic beads, the pre-excitation liquid and the excitation liquid perform luminescent reaction in the detection cavity 14 together, so that a chemiluminescent reaction experiment is completed.
In fig. 6, since the microfluidic chip cover plate 24 and the microfluidic chip bottom plate 26 are provided with air holes at positions corresponding to the air hole channels, the reaction chamber 8 on the microfluidic chip intermediate layer 25 is provided with the reaction chamber air hole channel 18, the buffer chamber 12 is provided with the buffer chamber air hole channel 10, and the detection chamber 14 is provided with the detection chamber air hole channel 20, and the reaction chamber air hole 5, the buffer chamber air hole 2 and the detection chamber air hole 4 are respectively communicated with the microfluidic chip 146 and the external atmospheric pressure, so that sample addition is smooth.
Fig. 7, 8 and 9 show a top view of the magnetic bead control layer cover plate 27 and the magnetic bead control layer bottom plate 29, a top view of the magnetic bead control layer intermediate layer 28, and an enlarged view of a partial structure of the position of the spherical magnetic bead 23 in the magnetic bead control layer intermediate layer 28, respectively, in the microfluidic chip module 51 according to the present invention. As can be seen from fig. 7, the magnetic bead control layer cover plate 27 and the magnetic bead control layer bottom plate 29 have the same structure, and each of the magnetic bead control layer cover plate and the magnetic bead control layer bottom plate includes a light guide hole 21 and a pin hole 7, wherein the positions of the 3 light guide holes 21 respectively correspond to the positions of the detection cavities 14 of the microfluidic chip 146, so as to facilitate the detection of the luminescence signals. Fig. 8 and 9 both relate to the bead control layer interlayer 28, and fig. 8 can be seen: corresponding to the number of parallel detection units in the microfluidic chip 146, the number of specific structural components of the intermediate layer 28 of the magnetic bead control layer is also that a plurality of groups of circular arc-shaped magnet channels are axially symmetrically arranged, and the number of the groups of circular arc-shaped magnet channels with the same structure is preferably 3. The internal magnet 22 is disposed within a circular arc shaped magnet path that can limit movement of the internal magnet 22 within the circular arc shaped magnet path. In each group of parallel detection units, the distance from the circular arc-shaped magnet channel to the center of the magnetic bead control layer middle layer 28 is consistent with the distance from the reaction cavity 8 to the center of the micro-fluidic chip middle layer 25, and one end of the circular arc-shaped magnet channel corresponds to the position of the reaction cavity 8 up and down. Fig. 9 shows in particular an optimization strategy for the rapid switching of the reaction states by means of an enlarged view of the location of the spherical magnetic beads 23. Spherical magnetic beads 23 are provided at both right and left ends of the circular arc-shaped magnet passage where the internal magnet 22 is located, and the number of spherical magnetic beads 23 provided at each end of the internal magnet 22 is preferably 2.
Strategy for fast switching of reaction states: by moving the internal magnet 22, the magnetic beads in the reaction chamber 8 are switched in adsorption state, so that different magnetic reactions such as adsorption fixation or free mixing are completed, and real-time control and rapid switching of different reaction states of the magnetic beads are realized. Specifically, the magnetic bead control layer interlayer 28 realizes real-time control and reaction state switching of the position of the internal magnet 22 by driving the external magnet driving motor 152. Specifically, the magnetic bead control layer 147 is placed against the lower surface of the microfluidic chip 146, wherein the magnetic bead control layer intermediate layer 28 includes the pin holes 7, the light guide holes 21, the internal magnet 22, and the spherical magnetic beads 23; the internal magnet 22 is arranged in a circular arc-shaped magnet channel, the distance from the circular arc-shaped magnet channel to the center of the magnetic bead control layer middle layer 28 is consistent with the distance from the reaction cavity 8 to the center of the micro-fluidic chip middle layer 25, and one end of the circular arc-shaped magnet channel corresponds to the reaction cavity 8 of the micro-fluidic chip 146 up and down. The inner magnet 22 is located at the end of the circular arc-shaped magnet channel away from the reaction chamber 8 of the microfluidic chip 146, referred to as the distal end (as shown in the left-hand view of fig. 8), and correspondingly, when the inner magnet 22 is located at the end of the circular arc-shaped magnet channel directly below the reaction chamber 8 of the microfluidic chip 146, referred to as the proximal end (as shown in the right-hand view of fig. 8). As can be seen in connection with fig. 9, a partial enlarged view of the location of the spherical magnetic beads 23: when the internal magnet 22 is at the proximal end or the distal end, the spherical magnetic beads 23 can generate magnetic attraction to the internal magnet 22, so that the influence on the state of the magnetic beads caused by the movement of the internal magnet during the rotation process of the microfluidic chip 146 is avoided.
In the reaction process, the reagent is required to be transferred or the waste liquid is required to be thrown into the waste liquid cavity 17 through high-speed rotation, in order to prevent the magnetic beads from being thrown into the next cavity in advance, the internal magnet 22 is required to adsorb and fix the magnetic beads, firstly, the external magnet 154 stretches into the lower part of the magnetic bead control layer 147 along the horizontal direction through the driving of the external magnet driving motor 152, so that the magnetic bead control layer 147 rotates anticlockwise, the internal magnet 22 positioned in the circular arc-shaped magnet channel automatically moves to the near end along the circular arc-shaped magnet channel (namely, under the action of the magnetic force of the external magnet 154, and high-efficiency adsorption is implemented on the magnetic beads, thereby fixing the magnetic beads in the reagent. Secondly, in the reaction process, when the magnetic beads in the reagent and the sample need to be mixed, the external magnet 154 stretches into the lower part of the magnetic bead control layer 147 along the horizontal direction under the driving of the external magnet driving motor 152, so that the magnetic bead control layer 147 rotates clockwise, and the internal magnet 22 automatically moves to the far end (namely away from the reaction cavity 8) along the circular arc-shaped magnet channel under the magnetic force of the external magnet 154, so that the magnetic beads are not adsorbed, and the free movement and mixing of the magnetic beads are realized.
Fig. 10 and 11 are perspective views showing the left front side and the right rear side of the internal structure of the device case of the chemiluminescent measuring device of the present invention, respectively, mainly showing the positional arrangement relationship of the respective modules of the internal structure of the device case. As can be seen in fig. 10 and 11, the internal structure of the device housing of the chemiluminescent assay device according to the present invention comprises a reagent module 45, an automatic pipetting module 44, an incubation chamber module 50, a chemiluminescent signal detection module 48, a centrifugal motor driving module 49 and an auxiliary module, which are mainly fixed on a device bottom plate 47 of the device housing. The stepper motor driver 46 and the plunger pump 58, the plunger pump fixing member 55, the plunger pump solenoid valve 57 and the plunger pump solenoid valve fixing member 56 in the automatic pipetting module 44 are all fixed on the device bottom plate 47. In fig. 10, an external magnet driving motor 152 is further disposed below the incubation chamber module 50, and the external magnet driving motor 152 is fixed on the support column 79, so as to drive an external magnet 154 (as can be seen in fig. 21) to extend into the incubation chamber module 50 along the horizontal direction and below the magnetic bead control layer 147, and drive the internal magnet 22 to rotate in the circular arc-shaped magnet channel under the action of magnetic force, so as to realize the real-time control of the position of the internal magnet 22 and the switching of the reaction state of the magnetic bead control layer 147.
The chemiluminescent measuring device is also provided with an auxiliary module, the auxiliary module comprises a main control board 52 and a main control board bracket 53, the main control board 52 is fixed on the main control board bracket 53, the main control board bracket 53 is fixed on a device bottom plate 47 of a device shell, and the main control board 52 is arranged in parallel with a rear side plate 39 of the device shell; the operation of other modules is controlled by the main control board 52 and data interaction with the data interaction module is provided.
Fig. 10 and 11 also show the centrifugal motor drive module 49 and its centrifugal motor drive 54, respectively, wherein a centrifugal motor drive partition 59 is provided on the front side of the centrifugal motor drive 54, wherein the centrifugal motor drive 54 and the centrifugal motor drive partition 59 are also fixed on the device base plate 47, and the provision of the centrifugal motor drive partition 59 can avoid a potential influence of heat generation of the centrifugal motor drive 54 on the reaction temperature. The centrifugal motor driver 54 is closely adjacent to the rear side plate 39, and generated heat is timely taken away by the cooling fins 40 and the cooling fin fans 41 arranged on the rear side plate 39, so that the accuracy of temperature control is further ensured on the premise of reducing the interference of temperature on the device.
Fig. 10 and 11 can be seen: the microfluidic chip module 51 is disposed in the middle of the incubation chamber module 50. The drive shaft bearing 60 is a component of the automatic pipetting module 44 in the X-axis direction and reduces friction generated during operation of the X-axis portion of the automatic pipetting module 44.
Fig. 12 shows a perspective view of the left front side of the reagent module 45 of the present invention, mainly showing the reagent cartridge 61, the reagent cartridge supporting plate 62 and the reagent cartridge supporting frame 63 in the reagent module 45. As can be seen, the gun tip 68, the reagent test tube 66 and the wash reagent test tube 67 are all located in corresponding holes on the kit 61, and the gun tip 68, the reagent test tube 66 and the wash reagent test tube 67 on the kit 61 are respectively arranged in a plurality of parallel rows, and the number of parallel rows is consistent with the number of parallel detection units on the microfluidic chip 146; 1 gun tip discarding bin 65 is also arranged on the kit 61 and is used for recycling gun tips after each sample addition; the cartridge 61 is fixed by a raised detent structure 64 on a cartridge support plate 62, and the cartridge support 63 is fixed to the device bottom plate 47 by screws.
The automatic pipetting module 44 includes automatic control of the left and right, front and back, and up and down 3 directions by 3 stepper motors: the horizontal left-right movement (i.e., X-axis) is controlled by the X-axis stepper motor 73; the back and forth movement in the horizontal direction (i.e., the Y-axis) is controlled by a Y-axis stepper motor 99; vertical up-and-down motion (Z-axis) is controlled by a Z-axis motor 117; namely, 3 sets of motors drive the automatic pipetting module 44 to realize front-back, left-right and up-down all-dimensional multi-angle pipetting movements.
Fig. 13 and 14 show perspective views of the left rear side and the right front side, respectively, of the automatic pipetting module 44 of the invention, mainly showing the core components of the X-axis portion of the automatic pipetting module 44. As can be seen, 4 support columns 79 are vertically "concave" in shape and are fixed to the device floor 47, with the automatic pipetting module 44 being fixed and supported above the reagent module 45 by the 4 support columns 79; the automatic pipetting module 44 has 2X-axis support plates, i.e., an X-axis left support plate 76 and an X-axis right support plate 87, symmetrically disposed at left and right positions, and the 2X-axis support plates are respectively fixed to the support columns 79 symmetrically right and left. Specifically, the X-axis left support plate 76 and the X-axis right support plate 87 are L-shaped, are screwed to the X-axis guide rails 81 at the left and right ends, and are connected by a drive shaft 93.
In the X-axis portion, the X-axis drag chain 75 is also fixed above the X-axis left support plate 76, and the X-axis stepper motor 73 is fixed below one end of the X-axis left support plate 76 near the drive shaft 93 by the X-axis stepper motor fixing frame 95. Further, the shaft of the X-axis stepper motor 73 and the driving shaft 93 are respectively fixed on an X-axis stepper motor synchronizing wheel 94 and a driving shaft synchronizing wheel 97, the 2 synchronizing wheels are connected through a driving shaft belt 96, and the driving shaft 93 is driven to rotate through the X-axis stepper motor 73, so that movement in the X-axis direction is realized; the two ends of the driving shaft 93 are respectively linearly matched with 1 driving shaft bearing 60 (see fig. 11), the driving shaft bearing 60 is embedded and arranged in the 2X-axis bearing fixing pieces (the X-axis right bearing fixing piece 92 and the X-axis left bearing fixing piece 98), and the friction force of the movement between the 2X-axis bearing fixing pieces and the driving shaft 93 can be reduced through the driving shaft bearing 60, so that the purpose of rapid and stable movement is achieved.
In the X-axis portion, 2 driven wheels (an X-axis left driven wheel 78 and an X-axis right driven wheel 86) and 2 driving wheels (an X-axis left driving wheel 69 and an X-axis right driving wheel 91) are symmetrically arranged at left and right positions, and corresponding accessories; wherein the 2 driven wheels are fastened by 2 cantilever pins (an X-axis left cantilever pin 84 and an X-axis right cantilever pin 80) and 2 driven wheel fixing pieces (an X-axis left driven wheel fixing piece 77 and an X-axis right driven wheel fixing piece 85) respectively; the 2 driven wheel fixtures are fixed to the heads of the X-axis left support plate 76 and the X-axis right support plate 87, respectively; the 2 driving wheels (the X-axis left driving wheel 69 and the X-axis right driving wheel 91) are respectively fixed at two ends of a driving shaft 93 through screws, and the driving shaft 93 is fixed through 2 bearing fixing pieces (an X-axis right bearing fixing piece 92 and an X-axis left bearing fixing piece 98); the 2 driven wheels are respectively connected with the corresponding 2 driving wheels by using 2X-axis belts 88, the 2X-axis belts 88 are respectively pressed between 2X-axis toothed plates (an X-axis left toothed plate 74 and an X-axis right toothed plate 90) symmetrically arranged at left and right positions and the corresponding 2 toothed plate fixing pieces (an X-axis left toothed plate fixing piece 72 and an X-axis right toothed plate fixing piece 89), and the 2X-axis toothed plates are connected with the corresponding 2 toothed plate fixing pieces by screws; specifically, the X-axis left driven wheel mount 77 and the X-axis right driven wheel mount 85, the X-axis right bearing mount 92, and the X-axis left bearing mount 98 are all "L" shaped; further preferably, the 2 rack fixing members (the X-axis left rack fixing member 72 and the X-axis right rack fixing member 89) are vertically "concave" shaped, one ends of which are respectively connected to the 2X-axis rack plates (the X-axis left rack plate 74 and the X-axis right rack plate 90), and the other ends of which are fixed to the Y-axis support plate 83 by screws, thereby achieving the fastening of the Y-axis support plate 83.
An X-axis touch switch 71 is further disposed at one end, close to the driving shaft 93, above the X-axis left support plate 76, and the X-axis touch switch 71 is fixed on the X-axis touch switch fixing frame 70, and the X-axis touch switch fixing frame 70 is further fixed on the X-axis left support plate 76, and is used for determining and controlling the initial position of the X-axis part through the X-axis touch switch 71, so as to achieve the purpose of limiting.
Fig. 15 shows a side perspective view of the Y-axis portion of the automatic pipetting module 44 of the invention, primarily showing the core components of the Y-axis portion. Referring to fig. 13 and 14, first, the Y-axis support plate 83 is screwed to the X-axis guide rail slider 82; next, the stepper motors include an X-axis stepper motor 73 and a Y-axis stepper motor 99, the X-axis stepper motor 73 is fixed on the X-axis left support plate 76 by an X-axis stepper motor fixing frame 95 (see fig. 14), and the Y-axis stepper motor 99 is fixed on the upper portion of the Y-axis stepper motor bracket 100 by screws; the Y-axis driving wheel 101 is positioned on the central shaft of the Y-axis stepping motor 99 and is fixed at the lower part of the Y-axis stepping motor bracket 100; further, the Y-axis stepper motor bracket 100 and the Y-axis driven wheel fixing member 107 are respectively fixed on the left side and the right side of the Y-axis supporting plate 83 through screws, the Y-axis driven wheel 106 is fastened through the Y-axis cantilever pin 108 and the Y-axis driven wheel fixing member 107, and the Y-axis driven wheel 106 is connected with the Y-axis driving wheel 101 through a Y-axis belt 102.
The Y-axis guide rail 116 is fixed on the Y-axis guide rail frame 105, the Y-axis guide rail 116 is also provided with a Y-axis guide rail sliding block 112, and the Y-axis guide rail frame 105 is also fixed on the Y-axis support plate 83 through screws; the Y-axis drag chain 115 is U-shaped, one end of the U-shaped opening of the Y-axis drag chain 115 is also provided with a Y-axis drag chain bracket 114, the Y-axis drag chain 115 is fixed on the Y-axis drag chain bottom plate 111 through screws, and the Y-axis drag chain bottom plate 111 is fixed on the rear side of the Y-axis support plate 83 through screws. The Y-axis belt 102 is pressed between the Y-axis toothed plate 104 and the protruding structure behind the bottom plate 103 of the pipettor, a cushion block 113 of the bottom plate of the pipettor is further arranged on the upper part of the protruding structure behind the bottom plate 103 of the pipettor, and the Y-axis toothed plate 104 and the bottom plate 103 of the pipettor are connected through screws, so that the automatic pipetting module 44 is fastened at the Z-axis part.
In the Y-axis part, a Y-axis touch switch 109 is further arranged, the Y-axis touch switch 109 is mounted on a Y-axis touch switch fixing frame 110, the Y-axis touch switch fixing frame 110 is fixed on the upper end of one side of the Y-axis support plate 83, which is close to the Y-axis driven wheel 106, and the initial position of the Y-axis part is determined and controlled through the Y-axis touch switch 109, so that the limiting purpose is achieved.
Fig. 16 shows a side perspective view of the Z-axis portion of the automatic pipetting module 44 of the invention, primarily showing the core components of the Z-axis portion. As can be seen in fig. 16 in combination with fig. 10 and 15, in the Z-axis section, the Z-axis motor 117 is fixed to the top of the pipette bottom plate 103 by the Z-axis motor fixing member 130, and the pipette bottom plate tail stopper 125 is fixed to the tail of the pipette bottom plate 103 by screws; the Z-axis motor fixing piece 130 is connected with the rear stop block 125 of the bottom plate of the liquid-transfering device through 2Z-axis guide shafts 119 which are symmetrically arranged, and the Z-axis guide shafts 119 are respectively fixed with the Z-axis motor fixing piece 130 and the rear stop block 125 of the bottom plate of the liquid-transfering device through screws to play a role in bearing and guiding in the Z-axis direction; further, the 2Z-axis guide shafts 119 are respectively matched with 1Z-axis guide shaft bearing 127, and the Z-axis guide shaft bearings 127 are symmetrically embedded in the pipette slide 121, so that friction force generated during movement between the pipette slide 121 and the Z-axis guide shafts 119 can be reduced, and the purpose of rapid and stable movement is achieved. In the Z-axis portion, pipetting is achieved by up-and-down movement of the pipette slide 121.
The top support block 120 of the liquid-transfering device slide block, the liquid-transfering device slide block 121 and the bottom support block 126 of the liquid-transfering device slide block are orderly and slidably arranged on the Z-axis guiding shaft 119 from top to bottom and are arranged between the Z-axis motor fixing piece 130 and the tail stop block 125 of the liquid-transfering device bottom plate; a spring 129 is arranged between the pipette slide 121 and the support block 120 at the top of the pipette slide, so that the elastic movement of the pipette slide 121 is realized; the top support block 120 of the liquid transfer device slide block and the bottom support block 126 of the liquid transfer device slide block are fixed on the side connecting piece 128 of the liquid transfer device slide block through screws; the U-shaped structure protruding from the front side of the pipette slide block 121 is fastened with the pipette main body 123 through pins, the hose connector 122 and the pipette 124 are respectively fixed at the upper end and the lower end of the pipette main body 123 through screws, namely, one end of the pipette main body 123 is fixed with the pipette 124, so that loading and falling-off of gun tips are realized; the hose connector 122 is fixed to the other end of the pipette body 123, the hose connector 122 is connected with the plunger pump 58 through the air path hose 164, and the air pressure in the air path hose 164 is increased or decreased through the movement of the plunger pump 58, so that the operations such as sampling and sample injection of samples or reagents are controlled through the air pressure, namely, the pipetting action is controlled through the air pressure.
In the Z-axis part, a Z-axis touch switch 118 is further arranged, the Z-axis touch switch 118 is fixed on a Z-axis motor fixing piece 130 through a screw, and the Z-axis touch switch 118 is used for determining and controlling the initial position of the Z-axis part so as to achieve the purpose of limiting.
As can be seen from a comprehensive examination of fig. 13 to 16: in the automatic pipetting module 44, 3 sets of motors in the X-axis, Y-axis and Z-axis directions are respectively: the X-axis stepping motor 73, the Y-axis stepping motor 99 and the Z-axis motor 117,3 are used for controlling the number of steps of motor movement by converting electric pulse signals into corresponding linear displacement, so that the accurate movement of the pipette in the X-axis, Y-axis and Z-axis directions is realized; the movement in the X-axis and Y-axis directions is realized by an X-axis guide rail 81 and a Y-axis guide rail 116 respectively, the movement in the Z-axis direction is realized by a Z-axis motor 117, and the Z-axis motor 117 is a screw motor; 3 corresponding touch switches are further arranged on the 3 sets of motors in the X axis, Y axis and Z axis directions, namely an X axis touch switch 71, a Y axis touch switch 109 and a Z axis touch switch 118, and are used for determining the moving zero point position, and loading and falling of gun tips, sampling and sample injection operations of samples and the like are flexibly and conveniently achieved.
Fig. 17, 18 and 19 show a side perspective view of the incubation chamber module 50 of the present invention and a partial block diagram of the heating upper and sealing lower hoods, respectively. The incubation chamber module 50 (see fig. 10) adopts an aluminum block heating mode for controlling the reaction temperature, and fig. 17 shows that the incubation chamber module 50 comprises a sliding table motor 133, a heating upper cover 134 and a sealing lower cover 135; wherein, the slipway motor 133 is fixed on the device bottom plate 47 (see fig. 10) through the slipway motor support 132, the heating upper cover 134 and the slipway motor 133 are connected through the heating upper cover connecting piece 131, the slipway motor 133 controls the heating upper cover 134 to vertically move in the Y-axis direction through the heating upper cover connecting piece 131, the height of the heating upper cover 134 can be adjusted within the range of 50 mm, thus before the microfluidic chip module 51 is placed, the heating upper cover 134 is in a lifting state, the placing action of the microfluidic chip module 51 is not affected, after the microfluidic chip module 51 is placed, the heating upper cover 134 falls down and is fastened on the sealing lower cover 135, and an incubation bin is formed.
In fig. 18, a heating film 137 is tightly attached to the heating aluminum block 136, and the heating film 137 corresponds to the heating aluminum block 136; the heating aluminum block 136 is fixed to the inner side of the heating upper housing 134 by screws. At the same time, the upper heated hood 134 moves downward to be wrapped by the lower sealed hood 135, thereby forming a sealed, dual-function incubation chamber. On one hand, the incubation bin can provide a closed temperature control environment, so that accurate temperature control of the microfluidic chip module 51 is realized, and interference and influence caused by environmental temperature fluctuation can be avoided to the greatest extent; on the other hand, the incubation bin can also provide a shading environment, so that interference and influence of stray light in the environment on chemiluminescent signal acquisition are avoided to the greatest extent, the sensitivity of light signal acquisition is improved, and therefore accurate signal acquisition and analysis are realized. In addition, in the incubation chamber module 50, circular through holes are provided in the middle of the heating upper cover 134, the heating film 137, the heating aluminum block 136 and the sealing lower cover 135, and the heating upper cover 134, the heating film 137 and the heating aluminum block 136 are fixed by screws, and the sealing lower cover 135 is fixed on the centrifugal motor bracket 151 (see fig. 21) by screws; the capsule-shaped penetration structure 163 is provided at the corresponding positions of the heating upper cover 134, the heating film 137 and the heating aluminum block 136, so that the light leakage area of the microfluidic chip can be minimized. The heating upper cover 134, the heating film 137 and the heating aluminum block 136 are all circular, the heating film is customized, and double-sided adhesive tape can be tightly adhered to the upper surface of the heating aluminum block 136.
Fig. 19 shows that the surface of the sealing lower cover 135 is provided with a light pipe channel 138, the side surface of the sealing lower cover 135 is provided with an external magnet channel 139, the bottom of the sealing lower cover 135 is fixedly provided with a positioning optocoupler 140, the positioning optocoupler 140 is provided with an optical channel, and the side surface of the sealing lower cover 135 far away from the external magnet channel 139 is also provided with a positioning optocoupler wiring hole 141.
FIG. 20 shows a front view of the chemiluminescent signal detection module 48 of the present invention, the chemiluminescent signal detection module 48 collecting chemiluminescent signals through the photomultiplier tube 143 with relatively high sensitivity; in the chemiluminescent signal detection module 48, a light pipe 142 is further provided, and the light pipe 142 is cylindrical and is formed by wrapping an optical fiber (PMMA) with a jacket (PVC). The chemiluminescent signal detection module 48 solves the problem that the photomultiplier 143 cannot be directly arranged below the microfluidic chip module 51 to detect chemiluminescent signals by arranging the light pipe 142, and meanwhile, weak chemiluminescent signals generated by the reaction can be quickly collected and transmitted, so that the loss of the weak luminescent signals in the inner space of the instrument is avoided, and the detection accuracy is improved. One end of the light pipe 142 is fastened on the photomultiplier 143 through threads, the chemiluminescent signal detection module 48 is fixedly arranged on the device bottom plate 47 through the photomultiplier 143 and is located below the sealed lower cover 135 in the incubation chamber module 50, and the other end of the light pipe 142 extends into the lower side of the aligned microfluidic chip module 51 through the light pipe channel 138 (see fig. 19) of the sealed lower cover 135 and is aligned with the detection cavity 14 of the microfluidic chip 146 to detect chemiluminescent signals generated by the microfluidic chip 146. In the detection process, when the magnetic beads, the pre-excitation liquid and the excitation liquid enter the detection cavity 14 together to react and emit light, the generated weak light signals are transmitted to the photomultiplier 143 through the light pipe 142, and the photomultiplier 143 amplifies and converts the weak light signals into electric signals, so that the collection and detection of chemiluminescent signals are realized, and the sensitivity of chemiluminescent signal collection is improved.
Fig. 21 is a perspective view showing the internal structure of the centrifugal motor driving module 49 of the present invention with the sealing lower cover 135 removed, and is located inside the sealing lower cover 135, and the structure of the centrifugal motor driving module 49 (see fig. 10) is visible from fig. 21: the centrifugal motor bracket 151 is fixed on the device bottom plate 47, the centrifugal motor 150 is fixed on the centrifugal motor bracket 151 through screws, the flange base 149 is nested on the central shaft of the centrifugal motor 150 above the centrifugal motor bracket 151, and the components fixed on the flange base 149 are driven by the centrifugal motor 150 to rotate and centrifuge around the central shaft of the centrifugal motor 150; specifically, the microfluidic chip module 51 (including the microfluidic chip 146 and the magnetic bead control layer 147) is fixed on the flange base 149 above the centrifugal motor 150 by the butterfly screw 144 and the chip pressing member 145, and the butterfly screw 144, the chip pressing member 145, the microfluidic chip 146, the magnetic bead control layer 147 and the flange base 149 are sequentially located above the central axis of the centrifugal motor 150 from top to bottom, with the central axis of the centrifugal motor 150 as the center, and the centrifugal motor 150 is used for driving the microfluidic chip module 51 and other components to perform rotary centrifugation.
Further, a positioning optocoupler 140 is fixed at the bottom of the sealing lower cover 135, and the positioning optocoupler 140 is provided with an optical channel. The upper part of the centrifugal motor 150 is further provided with a grating piece 148, the grating piece 148 is fixed on the side surface of the flange base 149 through a screw, and the grating piece 148 is provided with 1 slit with the width of 0.1-mm-0.5 mm, and the slit corresponds to an optical channel of the positioning optical coupler 140 (see fig. 19) and is used for positioning the microfluidic chip 146.
Outside the sealed lower housing 135, the structure of the centrifugal motor drive module 49 (see fig. 10) is visible in fig. 21: the external magnet 154 is fixed at one end of the external magnet fixing member 153, the external magnet fixing member 153 is connected with the external magnet driving motor 152, the external magnet driving motor 152 is fixed on the supporting column 79 through a pin and a screw, and the external magnet controlling motor 152 is used for driving the external magnet 154 and controlling the moving state of the internal magnet 22 in the reaction process. In addition, when the centrifugal motor 150 is in a non-centrifugal state, the external magnet 154 may extend into the sealed lower cover 135 through the external magnet channel 139 provided on the side surface of the sealed lower cover 135, and is located below the internal magnet 22 in the microfluidic chip module 51, the external magnet 154 corresponds to the position of the internal magnet 22 up and down, and the external magnet 154 magnetically controls the corresponding internal magnet 22 under the driving of the external magnet driving motor 152, so as to control the switching of the reaction state of the magnetic bead control layer 147.
Fig. 22 shows a perspective view of the core components of the external magnet driving motor 152 of the present invention, which mainly includes a dc motor touch switch fixing member 155, a dc motor touch switch 156, a rail frame 157, a rail bearing 158, a dc motor slider 159, a rail 160, a dc motor 161 and a dc motor bracket 162, and the external magnet driving motor 152 is fixed at a proper height of the support column 79 through a connecting member, so that the layout of the internal parts of the apparatus is more compact. The guide rail bearings 158 are symmetrically embedded in the direct current motor sliding block 159, so that friction force between the direct current motor sliding block 159 and the guide rail 160 can be reduced, the purpose of rapid and stable movement is achieved, the direct current motor sliding block 159 is fixed with the external magnet 154 through a connecting piece, the external magnet driving motor 152 is further provided with a direct current motor touch switch 156, and the direct current motor touch switch 156 is fixed on the direct current motor touch switch fixing piece 155 and used for determining and controlling starting and stopping of the external magnet driving motor 152.
The chemiluminescent measuring device creatively integrates special structures such as a microfluidic chip module with a plurality of parallel detection units, an automatic pipetting module with 3 sets of motors for respectively driving 3 directions to move, a centrifugal motor driving module with a centrifugal motor and an external magnet driving motor, and the like. In addition, the incubation bin and the vertical movement of the incubation bin driven by the sliding table motor provide a controllable closed and shading environment for the microfluidic chip module, so that the temperature control and heat preservation of the device can be effectively realized, and the interference and influence of all stray light on chemiluminescent signal acquisition can be effectively avoided. The finally innovative and optimized chemiluminescence measuring device has the advantages of small volume, low cost, high flux, simple structure, convenient operation, high sensitivity, accurate result and the like, and can automatically and flexibly detect samples to be detected which are put into the microfluidic chip module in a multi-item combined mode.
Claims (9)
1. A chemiluminescent assay device comprising a device housing and a device disposed within the device housing:
the micro-fluidic chip module (51) comprises a micro-fluidic chip (146) and a magnetic bead control layer (147), wherein the micro-fluidic chip is of a three-layer structure, multiple groups of parallel detection units with the same structure are arranged in an axisymmetric manner, the three-layer structure of the micro-fluidic chip (146) is respectively a micro-fluidic chip cover plate (24), a micro-fluidic chip middle layer (25) and a micro-fluidic chip bottom plate (26), the three-layer structure of the magnetic bead control layer (147) is respectively a magnetic bead control layer cover plate (27), a magnetic bead control layer middle layer (28) and a magnetic bead control layer bottom plate (29), and each group of parallel detection units of the micro-fluidic chip middle layer (25) sequentially comprises a reaction cavity (8), a buffer cavity (12), a detection cavity (14) and a waste liquid cavity (17); the magnetic bead control layer (147) is tightly attached to the lower surface of the microfluidic chip (146), and a circular arc-shaped magnet channel, an internal magnet (22) in the circular arc-shaped magnet channel and spherical magnetic beads (23) at the left end and the right end of the circular arc-shaped magnet channel are arranged on the middle layer (28) of the magnetic bead control layer;
The reagent module (45) comprises gun tips (68), reagent test tubes (66) and washing liquid test tubes (67), and the reagent module is arranged in a plurality of rows which are arranged in parallel, and the number of the parallel rows is consistent with the number of parallel detection units on the microfluidic chip (146);
the automatic pipetting module (44) is driven by 3 sets of motors respectively to control the pipetting movement of front and back, left and right, up and down in all directions and the movement in the X-axis and Y-axis directions is realized by an X-axis guide rail (81) and a Y-axis guide rail (116) respectively: the X-axis direction is provided with 2X-axis guide rails (81) and 2 corresponding X-axis guide rail sliding blocks (82), 2X-axis support plates are symmetrically arranged and connected with the X-axis guide rails (81) at the left end and the right end, the 2X-axis support plates are connected through driving shafts (93), shafts of X-axis stepping motors (73) and the driving shafts (93) are respectively fixed on X-axis stepping motor synchronous wheels (94) and driving shaft synchronous wheels (97), the X-axis stepping motor synchronous wheels (94) are connected with the driving shaft synchronous wheels (97) through driving shaft belts (96), and the X-axis stepping motors (73) drive the driving shafts (93) to rotate, so that left-right movement of the X-axis stepping motors (73) in the horizontal direction is realized; the Y-axis guide rail (116) is fixed on a Y-axis guide rail frame (105), a Y-axis guide rail sliding block (112) is further arranged on the Y-axis guide rail (116), the Y-axis guide rail frame (105) is fixed on a Y-axis supporting plate (83), the Y-axis supporting plate (83) is fixed on an X-axis guide rail sliding block (82), 2X-axis belts (88) are respectively pressed between 2X-axis toothed plates which are symmetrically arranged and 2 toothed plate fixing pieces which are vertical concave, one end of each of the 2 toothed plate fixing pieces is respectively connected with the 2X-axis toothed plates, and the other end of each of the 2 toothed plate fixing pieces is fixed on the Y-axis supporting plate (83), so that the Y-axis connection is realized and the horizontal direction front-back movement which is driven and controlled by a Y-axis stepping motor (99) is realized; the vertical direction of the Z-axis motor (117) is controlled to move up and down, the Z-axis motor (117) is a screw motor, a pipette (124) is fixed at one end of a pipette body (123) in the Z-axis direction, a hose connector (122) is fixed at the other end of the pipette body (123), the hose connector (122) is connected with a plunger pump (58) through a gas path hose (164), the gas pressure in the gas path hose (164) is controlled through the movement of the plunger pump (58), and then the pipetting action of the pipette body (123) is controlled through the gas pressure; the automatic pipetting module (44) is fixed and supported above the reagent module (45) by a support column (79);
The incubation bin module (50) adopts an aluminum block heating mode, comprises a sliding table motor (133) and a heating aluminum block (136), and constructs a closed and shading incubation reaction bin for the microfluidic chip (146) by arranging a heating upper cover (134) and a sealing lower cover (135); the heating aluminum block (136) is fixed on the inner side of the heating upper cover (134), a heating film (137) is adhered to the upper surface of the heating aluminum block (136), the heating film (137) corresponds to the center position of the heating aluminum block (136), and a capsule-shaped through structure (163) is arranged at the corresponding positions of the heating upper cover (134), the heating film (137) and the heating aluminum block (136);
a centrifugal motor driving module (49) comprising a centrifugal motor (150) positioned inside the sealed lower cover (135), a centrifugal motor bracket (151), a flange base (149), and an external magnet (154), an external magnet fixing member (153) and an external magnet driving motor (152) positioned outside the sealed lower cover (135); the external magnet driving motor (152) is fixed on the supporting column (79) and is used for driving the external magnet (154) to magnetically control the corresponding internal magnet (22); the centrifugal motor (150) is one of a servo motor, a stepping motor, a DC brushless motor or other motors to provide a rotational speed in the range of 1000 rpm-12000 rpm;
One end of the circular arc-shaped magnet channel corresponds to the position of the reaction cavity (8) up and down, the inner magnet (22) moves to one end of the micro-fluidic chip (146) right below the reaction cavity (8) in the circular arc-shaped magnet channel, which is called a near end, the inner magnet (22) moves to one end of the reaction cavity (8) far away from the micro-fluidic chip (146) in the circular arc-shaped magnet channel, which is called a far end, in a non-centrifugal state, the outer magnet (154) stretches into the lower part of the inner magnet (22) in the sealing lower cover (135) through an outer magnet channel (139) arranged on the side surface of the sealing lower cover (135), and the magnetic force controls the inner magnet (22) to move in the circular arc-shaped magnet channel, so that the switching of the reaction state of the magnetic bead control layer (147) is controlled.
2. The chemiluminescent assay of claim 1 wherein: the three-layer structures of the microfluidic chip (146) are respectively provided with a bonding positioning hole (6) and/or a pin hole (7) with corresponding positions, and the three-layer structures are fixed through the bonding positioning holes (6) and/or the pin holes (7);
The reaction cavity (8) is connected with the detection cavity (14) through a first capillary valve (19), the buffer cavity (12) is connected with the detection cavity (14) through a buffer cavity liquid channel (13), the detection cavity (14) is connected with the waste liquid cavity (17) through a second capillary valve (16) with a circular blocking valve (15), and magnetic beads, samples or reagents sequentially complete all steps of chemiluminescent reaction in all the cavities;
the reaction cavity (8) is provided with a reaction cavity air hole channel (18), the buffer cavity (12) is provided with a buffer cavity air hole channel (10), and the detection cavity (14) is provided with a detection cavity air hole channel (20);
the reaction chamber (8) is provided with a reaction chamber sample adding channel (9), the buffer chamber (12) is provided with a buffer chamber sample adding channel (11), the buffer chamber sample adding channel (11) is used for adding excitation liquid into the buffer chamber (12), and the excitation liquid is thrown into the detection chamber (14) through a buffer chamber liquid channel (13) under the centrifugal force action of the centrifugal motor (150) to perform luminous reaction.
3. The chemiluminescent assay of claim 1 wherein: the microfluidic chip module (51) is fixed on the flange base (149) above the centrifugal motor (150), the flange base (149) is nested on the central shaft of the centrifugal motor (150) above the centrifugal motor bracket (151), and under the driving of the centrifugal motor (150), the component fixed on the flange base (149) is driven to rotate and centrifuge around the central shaft of the centrifugal motor (150).
4. The chemiluminescent assay of claim 1 wherein: the sliding table motor (133) controls the heating upper cover (134) to move up and down in the Z-axis direction, and the height of the heating upper cover (134) is adjusted.
5. The chemiluminescent assay of claim 1 wherein: the middle layer (28) of the magnetic bead control layer is also provided with a pin hole (7) and a light guide hole (21); under the drive of an external magnet driving motor (152), the magnetic bead control layer (147) rotates anticlockwise, the internal magnet (22) moves to the near end right below the reaction cavity (8) in the circular arc-shaped magnet channel, and the magnetic beads in the reaction cavity (8) are fixed; under the drive of an external magnet driving motor (152), the magnetic bead control layer (147) rotates clockwise, the internal magnet (22) moves to the far end far away from the reaction cavity (8) in the circular arc-shaped magnet channel, and the magnetic attraction fixation of the magnetic beads in the reaction cavity (8) is released, so that the magnetic beads move freely in the reaction cavity (8); the spherical magnetic beads (23) generate magnetic attraction to the internal magnets (22), and the number of the spherical magnetic beads is 2.
6. The chemiluminescent assay according to any one of claims 1-5 wherein: the device shell is made of a metal material with heat conducting performance, a radiating fin (40) is arranged on a rear side plate (39) of the device shell, and a radiating fin fan (41) is fixedly arranged in the middle of the radiating fin (40);
A data interaction module and a power module are further arranged above the device shell, and the data interaction module provides a man-machine interaction interface through a touch screen (30); the power module is matched with the power adapter to provide stable output power.
7. The chemiluminescent assay according to any one of claims 1-5 wherein: in the incubation bin module (50), the sliding table motor (133) is fixed on a device bottom plate (47) of the device shell through a sliding table motor support frame (132), and the heating aluminum block controls the temperature of the incubation bin module through a PID algorithm;
the heating aluminum block (136) moves to the upper side of the micro-fluidic chip (146) along with the heating upper cover (134), heats the micro-fluidic chip (146), and controls the temperature of the incubation bin module (50).
8. The chemiluminescent assay according to any one of claims 1-5 wherein: the device is also provided with a chemiluminescent signal detection module (48) which comprises a photomultiplier (143) and a light pipe (142), wherein one end of the light pipe (142) is fastened with a window of the photomultiplier (143) and is fixed on a device bottom plate (47) of the device shell; the other end of the light pipe (142) extends below the microfluidic chip module (51) through a light pipe channel (138) arranged on the surface of the sealing lower cover (135), is aligned to the detection cavity (14) of the microfluidic chip (146) and is used for detecting a chemiluminescent signal generated by the microfluidic chip (146);
A grating sheet (148) is arranged at the upper part of the centrifugal motor (150), a slit is arranged on the grating sheet (148), and the grating sheet (148) is fixed on the side surface of the flange base (149); a positioning optocoupler (140) is arranged at the bottom of the sealing lower cover (135), and the positioning optocoupler (140) is provided with an optical channel; the slit corresponds to the optical channel for positioning the microfluidic chip (146).
9. Use of a chemiluminescent assay device according to any one of claims 1-8 in chemiluminescent immunoassay.
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