Classifications

• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
  • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
  • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
  • G01N21/64—Fluorescence; Phosphorescence
  • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N1/00—Sampling; Preparing specimens for investigation
  • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
  • G01N1/38—Diluting, dispersing or mixing samples
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
  • G01N35/00584—Control arrangements for automatic analysers
  • G01N35/00594—Quality control, including calibration or testing of components of the analyser
  • G01N35/00613—Quality control
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
  • G01N35/0098—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor involving analyte bound to insoluble magnetic carrier, e.g. using magnetic separation
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
  • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
  • G01N35/1009—Characterised by arrangements for controlling the aspiration or dispense of liquids
  • G01N35/1016—Control of the volume dispensed or introduced
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N1/00—Sampling; Preparing specimens for investigation
  • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
  • G01N1/38—Diluting, dispersing or mixing samples
  • G01N2001/386—Other diluting or mixing processes
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
  • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
  • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
  • G01N21/64—Fluorescence; Phosphorescence
  • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
  • G01N2021/6439—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" with indicators, stains, dyes, tags, labels, marks
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
  • G01N35/00584—Control arrangements for automatic analysers
  • G01N35/00722—Communications; Identification
  • G01N2035/00891—Displaying information to the operator
  • G01N2035/009—Displaying information to the operator alarms, e.g. audible
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
  • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
  • G01N2035/1027—General features of the devices
  • G01N2035/1048—General features of the devices using the transfer device for another function
  • G01N2035/1062—General features of the devices using the transfer device for another function for testing the liquid while it is in the transfer device

Definitions

• the present disclosure relates to an inspection device.
• test devices that quantitatively or qualitatively detect a target substance in a sample are known. Many of such test devices utilize the principle of immunoassay, such as chemiluminescent enzyme immunoassay devices or fluorescence immunoassay devices (for example, Japanese Patent Laid-Open No. 2016-085093).
• immunoassay such as chemiluminescent enzyme immunoassay devices or fluorescence immunoassay devices (for example, Japanese Patent Laid-Open No. 2016-085093).
• the target substance in the sample is detected by detecting luminescence or fluorescence based on a label such as an enzyme label or a fluorescent label attached to the target substance in the sample using an immune reaction. Processing takes place. Furthermore, before such target substance detection processing, the sample is subjected to pretreatment such as adding a label to the target substance in the sample.
• the testing device is configured so that preprocessing and detection processing are automated, and when a sample collection container containing a collected specimen is loaded, preprocessing and detection processing are automatically performed, and detection results are output. There is something that has been done.
• the following process using, for example, magnetic particles is performed in order to label the target substance in the specimen.
• a first binding substance for example, a primary antibody
• a target substance for example, an antigen
• An immune complex is produced by combining the binding substances.
• the target substance is captured by the magnetic particles via the first binding substance.
• the immune complex is separated from the sample-derived components that do not form the immune complex (unreacted substances), so-called B/F (Bound/Free) separation.
• the mixed liquid is attracted while magnetic particles are temporarily adsorbed to the inner wall surface of the reaction cell by a magnet placed outside the reaction cell. Thereafter, a cleaning liquid is discharged into the reaction cell, and in a state where the cleaning liquid and the magnetic particles are mixed, the mixed liquid is sucked and discharged, thereby cleaning the magnetic particles.
• a labeling reagent containing a second binding substance for example, a secondary antibody
• the target substance captured by the magnetic particles and the second binding substance are combined via the first binding substance, so that the target substance is sandwiched between the first binding substance and the second binding substance. Generate immune complexes.
• the cleaning liquid and the magnetic particles are mixed and the magnetic particles are cleaned.
• the label is an enzyme label
• the magnetic particles and a reagent containing a luminescent substrate are further mixed and subjected to a test process.
• automated testing equipment internally processes particles such as mixing magnetic particles with a specimen, mixing magnetic particles with a cleaning solution, mixing magnetic particles with a labeling reagent, and mixing magnetic particles with a luminescent reagent.
• a mixing process is performed to mix the liquid and the liquid.
• the sample liquid is sucked from the sample collection container by the built-in sampling nozzle, and the sucked sample liquid is discharged into the reaction cell loaded in the testing device. Then, in the reaction cell, the particles and liquid are mixed as described above.
• the amount of specimen aspirated by the sampling nozzle is not sufficient, or if the aspirated specimen is contaminated with foreign matter, the amount of specimen used for subsequent pretreatment and detection processing will decrease.
• the detection accuracy in the detection process decreases, and as a result, the reliability of the test results decreases.
• Japanese Patent Application Publication No. 2005-345345 discloses a dispensing machine that takes an image of the dispensing liquid and dispenses a fixed amount with high precision, regarding a dispensing machine that sucks and discharges liquid. . If the technology disclosed in Japanese Unexamined Patent Application Publication No. 2005-345345 is adopted in a testing device, it is possible to maintain a constant amount of specimen used for detection processing and improve the reliability of test results. .
• the present disclosure has been made in view of the above circumstances, and aims to provide an inspection device with improved reliability of inspection results compared to conventional ones.
• the testing device of the present disclosure includes a detection unit that performs a detection process to detect a target substance in a sample; A mixing unit that performs a mixing process that mixes particles and liquid in a reaction cell, which is a process that is performed on a specimen for the detection process and is performed before the detection process; a first camera that photographs a mixture of particles and liquid in the reaction cell; a processor that determines the mixing state of the particles and the liquid based on the image of the liquid mixture taken by the first camera; When the processor determines that the mixing state is good, the processor causes the detection unit to detect the target substance.
• the inspection device of the present disclosure includes a first notification unit that notifies a user that the mixing state is bad, and when the processor determines that the mixing state is bad, the first notification unit causes the mixing state to be determined to be bad. It is also possible to notify that the product is defective and end the inspection.
• the processor may determine the mixing state based on the shading that occurs in the image of the mixed liquid as particles in the mixed liquid are dispersed.
• the processor may determine the mixing state based on the presence or absence of air bubbles in the liquid mixture in the image or the amount of bubbles in addition to the density that occurs in the image of the liquid mixture.
• the processor may determine the mixing state based on the presence or absence of bubbles in the liquid mixture in the image or the amount of bubbles.
• the particles may be magnetic particles.
• the testing device of the present disclosure includes a sample dispensing unit that includes a sampling nozzle that aspirates a sample and discharges the sample into a reaction cell, and a sample dispensing unit that includes a sampling nozzle that aspirates a sample and discharges the sample into a reaction cell. and a second camera that photographs the sampling nozzle in a held state, and the processor may determine the state of the specimen in the sampling nozzle based on the image of the sampling nozzle photographed by the second camera.
• the sampling nozzle may discharge the specimen into the reaction cell.
• the testing device of the present disclosure includes a second notification unit that notifies the user that the state of the specimen is bad, and when the processor determines that the state of the specimen is bad, the second notification unit It may also be possible to notify that the condition of the specimen is poor.
• the sample dispensing unit includes a moving mechanism that moves the sampling nozzle from a suction position where the sample is sucked to a discharge position where the sample is discharged into the reaction cell, and the second camera is moved by the moving mechanism.
• the sampling nozzle may be photographed while it is moving.
• the second camera may be a line scan camera.
• the detection unit detects the target substance by detecting luminescence or fluorescence from a label attached to the target substance using an antigen-antibody reaction.
• FIG. 1 is a configuration diagram of an inspection device 10 according to a first embodiment.
• FIG. 2A is a top view of the cartridge, and FIG. 2B is a front view.
• FIG. 3 is a diagram showing a step of adding a label to a target substance in a reaction cell. It is a figure for explaining a washing process.
• FIG. 3 is a diagram showing the arrangement of a first camera with respect to a reaction cell.
• FIG. 3 is a schematic diagram of an image taken by a first camera.
• 3 is a diagram showing an example of an inspection flow in the inspection device 10.
• FIG. It is a block diagram of the inspection device 110 of 2nd Embodiment.
• FIG. 7 is a diagram showing the arrangement of a second camera with respect to a sampling nozzle.
• FIG. 1 is a schematic diagram showing the configuration of an immunoassay device, which is an example of the testing device 10 according to the first embodiment of the present disclosure.
• the test device 10 After the test device 10 is loaded with a sample collection container containing a sample collected from a living body, it performs preprocessing to add a label to the target substance, which is the substance to be detected in the sample, and then transmits light from the label.
• This is an automatic immunoanalyzer that performs detection processing and outputs detection results.
• the testing device 10 includes a specimen transport section 12, a mixing section 13, a specimen dispensing section 14, a detection section 15, a processor 16, a memory 17, and a touch panel display 18.
• the detection unit 15 executes a detection process to detect the target substance A (see FIG. 3, etc.) in the specimen 22.
• the detection unit 15 includes a photodetector 50 such as a photomultiplier tube or a photodiode.
• the photodetector 50 is arranged to face the reaction cell R0, and detects the light L caused by the label S combined with the target substance A.
• an enzyme is used as the label S, and chemiluminescence generated by reaction with a luminescent substrate is detected.
• the processor 16 centrally controls each part of the inspection device 10.
• An example of the processor 16 is a CPU (Central Processing Unit) that performs various controls by executing programs.
• the CPU functions as a control unit that controls each unit by executing programs.
• the processor 16 acquires information on the amount of light L detected by the photodetector 50, and calculates the concentration of the target substance A based on the information on the amount of light.
• the memory 17 is an example of a memory connected to or built into the CPU as the processor 16.
• a control program is stored in the memory 17.
• the memory 17 stores setting information that is preset for the processor 16 to perform various controls.
• the memory 17 stores information indicating the correspondence between the amount of light L detected by the photodetector 50 and the amount of the target substance A.
• the correspondence relationship is stored, for example, as a calibration curve expressed as a function.
• the correspondence relationship may be in a table format.
• the processor 16 calculates the amount of the target substance A based on the amount of light L obtained from the photodetector 50 and the calibration curve stored in the memory 17, for example.
• the touch panel display 18 receives operation instructions such as an instruction to start an inspection (hereinafter referred to as an instruction to start an inspection) from the user. Further, the touch panel display 18 displays information such as test results.
• the specimen transport section 12 has a loading section (not shown) into which a specimen collection container 20 containing a specimen 22 is loaded, and the loaded specimen collection container 20 is transferred to a sampling nozzle 42 (described later) of the specimen dispensing section 14. transport it to a location where it can be accessed.
• the specimen 22 is, for example, a body fluid such as blood collected from a living body.
• the specimen 22 is blood, but the specimen is not limited to blood.
• the specimen collection container 20 is a blood collection tube.
• the whole blood is separated into blood cells and plasma, or blood clots and serum by centrifugation, and the plasma or serum is used for testing the target substance.
• Target substances to be tested that may be contained in the specimen 22 include antigens, antibodies, proteins, and low-molecular compounds.
• the mixing unit 13 executes a mixing process to mix particles and liquid in the reaction cell R0, which is a process performed on the specimen 22 for the detection process, which is performed before the detection process.
• the mixing process will be described later.
• the mixing section 13 includes a loading section (not shown) into which a cartridge RC having a plurality of cells including the reaction cell R0 is loaded, and a reagent dispensing section 13A.
• the cartridge RC is provided with cells R1 to R4 that contain various reagents, and the openings 30 to 34 of each cell R1 to R4 are sealed with a sealing film (not shown). has been done.
• the reagent dispensing section 13A is equipped with a perforation nozzle having a perforation function for piercing and making a hole in the sealing film provided on the cartridge RC.
• the mixing process is performed by repeating suction and discharge of the liquid mixed with particles in the reaction cell R0 by the perforated nozzle of the reagent dispensing section 13A.
• the mixing section 13 includes a conveying section 13B.
• the transport unit 13B transports the cartridge RC to a location in the mixing unit 13 where each processing step is performed. Further, the transport section 13B transports the cartridge RC from the mixing section 13 to the detection section 15.
• the sample dispensing unit 14 performs a sample dispensing process of aspirating the sample 22 from the sample collection container 20 and discharging it into the cartridge RC loaded in the mixing unit 13.
• the sample dispensing unit 14 includes a sampling nozzle 42 and a moving mechanism 46 that moves the sampling nozzle 42.
• the moving mechanism 46 moves the sampling nozzle 42 in the vertical and horizontal directions.
• the vertical and horizontal movements of the sampling nozzle 42 are, for example, performed by linear actuators, respectively.
• the sampling nozzle 42 includes, for example, a nozzle body and a tip 42A that is replaceably attached to the tip of the nozzle body. Tip 42A is replaced to prevent contamination of multiple liquids. Chip 42A is a one-time use type and is disposable. The tip 42A of the sampling nozzle 42 is replaced for each specimen 22.
• the moving mechanism 46 moves the sampling nozzle 42 in the horizontal direction between the sample suction position P1 of the sample transport section 12 and the sample discharge position P2 of the mixing section 13.
• the specimen suction position P1 is a position where the specimen 22 is aspirated from the specimen collection container 20.
• the sample discharge position P2 is a position where the sample 22 is discharged into the reaction cell R0 of the cartridge RC set in the mixing section 13.
• the moving mechanism 46 is configured to move the tip 42A from the entrance position where the chip 42A enters the specimen collection container 20 or the reaction cell R0 and from the inside of the specimen collection container 20 or the reaction cell R0 at each of the specimen suction position P1 and the specimen discharge position P2.
• the sampling nozzle 42 is moved in the vertical direction between the retracted position and the retracted position. At the entry position, the sampling nozzle 42 sucks and discharges the liquid.
• FIG. 2 is a schematic diagram of the cartridge RC, with FIG. 2A showing a top view of the cartridge RC, and FIG. 2B showing a front view of the cartridge RC.
• the cartridge RC includes a plate-shaped connecting portion 35 having five openings 30 to 34, and five cylindrical cells R0 to R4 extending downward, including the reaction cell R0, with each of the openings 30 to 34 serving as one end. Be prepared.
• the cartridge RC has a structure in which a plurality of cells R0 to R4 are integrated by a connecting portion 35. Among the plurality of cells R0 to R4, the reaction cell R0 and cell R1 arranged at both ends are longer than the other cells R2 to R4. The longest one is the reaction cell R0.
• the openings 30 to 34 of the cartridge RC are covered with a sealing film (not shown) before use.
• the cartridge RC is loaded in the testing device 10 in advance, and one cartridge RC is used for one specimen 22.
• the specimen 22 is dispensed into the reaction cell R0.
• the reaction cell R0 is a cell in which a process of labeling a target substance in the specimen 22 is performed.
• the reaction cell R0 accommodates a plurality of magnetic particles MB modified with a first binding substance B1 that specifically binds to the target substance.
• a mixing process is performed to mix the magnetic particles MB and the liquid.
• the mixing process of mixing the particles (magnetic particles MB in this case) and the liquid is a process performed to label the target substance in the specimen 22.
• the diameter is about 0.1 to 10 ⁇ m, preferably 0.1 to 5 ⁇ m, and more preferably about 1 to 3 ⁇ m.
• a buffer solution 36 is accommodated in the cell R1.
• the cell R2 accommodates a labeling reagent 37 containing a label S modified with a second binding substance B2 that specifically binds to the target substance.
• the first luminescent reagent 38 is housed in the cell R3, and the second luminescent reagent 39 is housed in the cell R4.
• the label S is an enzyme, and the label S emits light in the presence of the first luminescent reagent 38 and the second luminescent reagent 39.
• the first binding substance B1 and the second binding substance B2 that specifically bind to the target substance are, for example, when the target substance is an antigen, an antibody against the antigen, and when the target substance is an antibody, an antigen against the antibody.
• the target substance is a protein or a low-molecular compound, it is an aptamer for the protein or low-molecular compound.
• the first binding substance B1 and the second binding substance B2 may be the same or different.
• the specimen 22 held in the sampling nozzle 42 is dispensed into the reaction cell R0 containing the magnetic particles MB modified with the first binding substance B1 (step ST11).
• the buffer solution 36 contained in the cell R1 is dispensed into the reaction cell R0.
• the magnetic particles MB, the specimen 22, and the buffer solution 36 are mixed.
• the mixing process in which the magnetic particles MB, the specimen 22, and the buffer solution 36 are mixed is a mixing process in which the particles (here, the magnetic particles MB) and the liquid (here, the specimen 22 and the buffer solution 36) are mixed in the reaction cell R0. This is an example of this, and will be referred to as the first mixing process below.
• the first mixed solution containing the magnetic particles MB, the specimen 22, and the buffer solution 36
• a binding reaction occurs in which specifically binds (step ST12).
• the first binding substance B1 is an antibody, and the two bind through an antigen-antibody reaction.
• the target substance A in the specimen 22 binds to the first binding substance B1, so that the target substance A is captured by the magnetic particles MB via the first binding substance B1.
• step ST13 a first cleaning process (B/F separation) is performed to remove unreacted substances other than the target substance A captured by the magnetic particles MB (step ST13).
• step ST13 in FIG. 3 the double arrows in the up and down directions shown above the reaction cell R0 schematically show how the liquid in the reaction cell R0 is discharged and the liquid is supplied to the reaction cell R0. be.
• step ST13 Details of the first cleaning process (step ST13) will be explained with reference to FIG. 4.
• illustration of the target substance A and the first binding substance B1 is omitted.
• a magnet 48 is placed close to the outside of the reaction cell R0 in which the first reaction (step ST12) has been completed.
• the magnetic particles MB in the reaction cell R0 are attracted to the magnet 48 and collected on the inner wall surface of the side wall where the magnet 48 is disposed in close proximity, and magnetic separation is performed to separate the magnetic particles MB from the liquid ( Step ST1301).
• the liquid in the reaction cell R0 is discharged while the magnetic particles MB are attracted to the inner wall surface of the reaction cell R0 (step ST1302).
• the reaction cell R0 and the magnet 48 are separated. At this time, the reaction cell R0 and the magnet 48 are separated to such an extent that the magnetic force of the magnet 48 does not affect the magnetic particles MB in the reaction cell R0. Then, the cleaning liquid 40 is injected into the reaction cell R0 (step ST1303).
• a mixed liquid in which the cleaning liquid 40 and magnetic particles MB are mixed (hereinafter referred to as a second mixed liquid) is sucked and discharged, and the magnetic particles MB are contained in the cleaning liquid 40. It is redispersed (step ST1304).
• the mixing process in which the magnetic particles MB and the cleaning liquid 40 are mixed is a mixing process in which the particles (here, the magnetic particles MB) and the liquid (here, the cleaning liquid 40) are mixed in the reaction cell. This is an example of a process, and will be referred to as a second mixing process below.
• step ST1301 By repeating the steps from magnetic separation (step ST1301) to redispersion (step 1304) multiple times (for example, about three times), unreacted substances other than the target substance A captured by the magnetic particles MB are removed. B/F separation is performed through the above washing process, and the magnetic particles MB and the target substance A captured by the magnetic particles MB are left in the reaction cell R0.
• the labeled reagent 37 contained in the cell R2 is dispensed into the reaction cell R0 in which B/F separation has been performed as described above, and the magnetic particles MB and the labeled reagent 37 are mixed.
• the mixing process in which the magnetic particles MB and the labeled reagent 37 are mixed is an example of a mixing process in which the particles (here, the magnetic particles MB) and the liquid (here, the labeled reagent 37) are mixed in the reaction cell R0, Hereinafter, this will be referred to as the third mixing process.
• a mixed solution containing the labeled reagent 37 and magnetic particles MB (hereinafter referred to as a third mixed solution), as a second reaction, the target substance A captured by the magnetic particles MB and the second binding substance B2 are uniquely reacted.
• a binding reaction occurs (step ST14).
• the target substance A is sandwiched between the first binding substance B1 and the second binding substance B2, and the label S is given to the target substance A via the second binding substance B2.
• the target substance A is an antigen
• the second binding substance B2 is an antibody, and the two bind through an antigen-antibody reaction. That is, in this case, the label S is given to the target substance A using an antigen-antibody reaction.
• a second washing step (B/F separation) is performed to remove unreacted substances other than the second binding substance B2 bound to the target substance A captured by the magnetic particles MB in the labeling reagent 37 ( Step ST15).
• the double arrows in the up and down directions shown at the top of the reaction cell R0 indicate the discharge of the liquid in the reaction cell R0 and the supply of the liquid to the reaction cell R0, as in the case of step ST13. This figure schematically shows how the process is carried out.
• the second cleaning process (step ST15) is performed in the same manner as the cleaning process performed in the first cleaning process (step ST13). That is, the magnet 48 is placed close to the outside of the reaction cell R0 to perform magnetic separation, drain the liquid inside the reaction cell R0, inject the cleaning liquid 40, and redisperse the magnetic particles MB in the cleaning liquid 40. (See Figure 4).
• the mixing process in which the magnetic particles MB and the cleaning liquid 40 are mixed mixes the particles (here, the magnetic particles MB) and the liquid (here, the cleaning liquid 40) in the reaction cell R0. This is an example of a mixing process, and will be referred to as a fourth mixing process below.
• the mixed liquid in which the cleaning liquid 40 and the magnetic particles MB are mixed in the second cleaning process is hereinafter referred to as a fourth mixed liquid.
• the steps from magnetic separation to redispersion are repeated multiple times (for example, about three times).
• This second washing process performs B/F separation, and the magnetic particles MB, the target substance A captured by the magnetic particles MB, and the label S given to the target substance A are left in the reaction cell R0.
• the above steps are the processing for adding the label S to the target substance A in the specimen 22.
• the first luminescent reagent 38 housed in the cell R3 and the second luminescent reagent 39 housed in the cell R4 are added to the reaction cell R0 (step ST16).
• the magnetic particles MB, the first luminescent reagent 38, and the second luminescent reagent 39 are mixed.
• step ST16 of adding a luminescent reagent the mixing process in which the magnetic particles MB, the first luminescent reagent 38, and the second luminescent reagent 39 are mixed is a process in which particles (here, magnetic particles MB) and liquid (here, This is an example of a mixing process in which the first luminescent reagent 38 and the second luminescent reagent 39) are mixed, and is hereinafter referred to as a fifth mixing process. Further, the mixed liquid of the magnetic particles MB, the first luminescent reagent 38, and the second luminescent reagent 39 mixed in the fifth mixing process will be referred to as a fifth mixed liquid hereinafter.
• the above steps are pretreatment performed on the specimen 22 in the reaction cell R0 in the mixing section 13.
• the mixing unit 13 sucks and discharges various liquids using the reagent dispensing unit 13A in order to perform the above-mentioned pretreatment.
• the cleaning liquid 40 may be sucked from the cleaning liquid storage section containing the cleaning liquid 40 and the sucked cleaning liquid 40 may be discharged into the reaction cell R0, or each reagent may be sucked from each cell R1 to R4 and the suction The reagent is discharged into the reaction cell R0.
• the cartridge RC on which the above-mentioned pre-processing has been completed is transported to the detection section 15 by the transport section 13B, and subjected to detection processing in the detection section 15.
• the label S given to the target substance A reacts with the first luminescent reagent 38 and the second luminescent reagent 39, which are luminescent substrates added in the fifth mixing process, to generate chemiluminescence L.
• the photodetector 50 detects this chemiluminescence L.
• the inspection device 10 includes a camera 61 that photographs a liquid mixture in which particles (here, magnetic particles MB) and liquid are mixed in the reaction cell R0. As shown in FIG. 5, the camera 61 is arranged at a position where it can photograph the mixed liquid ML in the reaction cell R0. As shown in FIG. 5, the camera 61 photographs, for example, the first liquid mixture containing the magnetic particles MB, the specimen 22, and the buffer solution 36 as the liquid LQ in step ST12.
• the mixing unit 13 includes a first mixing process to a fifth mixing process as processes in which particles and liquid are mixed.
• the camera 61 photographs the liquid mixture mixed in at least one of these mixing processes.
• the camera 61 may photograph all of the first to fifth mixed liquids mixed in the first to fifth mixing processes, or may photograph some of the mixed liquids, such as one or two of them. It may also be for photographing.
• the number of cameras 61 is not limited to one, and a plurality of cameras may be provided.
• each camera is placed at a position where the reaction cell R0 of the cartridge RC transported to the position where each process is performed can be photographed.
• 61 may be arranged.
• the camera 61 corresponds to the first camera in the technology of the present disclosure.
• the camera 61 photographs at least one of the first to fifth mixed liquids in the reaction cell R0 in at least one of steps ST12 to ST16 shown in FIG.
• mixed liquid ML when there is no need to distinguish between the first to fifth mixed liquids, they are simply referred to as mixed liquid ML, and the liquids in the first to fifth mixed liquids are collectively referred to as liquid LQ.
• the processor 16 determines the mixing state of the particles (here, the magnetic particles MB) and the liquid LQ based on the image of the liquid mixture ML taken by the camera 61.
• FIG. 6 is a diagram schematically showing images P1A to P1C of the mixed liquid ML taken by the camera 61.
• the mixed liquid ML in the image P1A is in a state in which the magnetic particles MB in the mixed liquid ML are uniformly dispersed, and is in a good mixed state.
• the mixed liquid ML in the image P1B has air bubbles BB in the mixed liquid ML, the magnetic particles MB are not uniformly dispersed, and the mixing state is poor.
• the magnetic particles MB in the mixed liquid ML are partially aggregated, the magnetic particles MB are not uniformly dispersed, and the mixed state is poor.
• the magnetic particles MB are visibly shown, but in reality, the size of the magnetic particles MB is on the order of submicrons to microns, and it is difficult to distinguish between individual magnetic particles MB in the liquid mixture ML. It is. If the magnetic particles MB are uniformly dispersed in the mixed liquid ML, the mixed liquid ML will have a uniform concentration throughout, and if the dispersion is non-uniform, the mixed liquid will have shading. In the image of the mixed liquid ML, areas where the density of magnetic particles MB is low are light colored, and areas where the density of magnetic particles MB is high are dark colored. The processor 16 determines the mixing state of the mixed liquid ML based on the density that occurs in the image of the mixed liquid ML due to the dispersion of the magnetic particles MB in the mixed liquid.
• the processor 16 may determine the mixing state based on the presence or absence of the bubbles BB or the amount of bubbles when the bubbles BB are present in the liquid mixture ML. good.
• the image analysis method used by the processor 16 to determine the quality of the mixed state is not particularly limited.
• the density value of each pixel may be made into a histogram, the number of pixels having a density value exceeding a preset threshold value may be counted, and quality may be determined based on the number of counted pixels.
• information necessary for determining whether the mixed state of the liquid mixture is good or bad is recorded as setting information.
• the quality of the mixed state may be determined using a machine learning model that has been subjected to learning processing using teacher data that has already been determined to be good or bad.
• the detection unit 15 detects the target substance A after the processing in the mixing unit 13. On the other hand, if the processor 16 determines that the mixed state is defective, it causes the touch panel display 18 to display that the mixed condition is defective, and ends the inspection.
• the touch panel display 18 displays that the mixed state is poor. That is, the touch panel display 18 functions as a first notification section that notifies that the mixed state is poor.
• the first notification section for notifying that the mixing state is defective may include a speaker for notifying an error with audio, a light emitting section for notifying an error by emitting light, or the like.
• the sample collection container 20 is loaded into the testing device 10 by the user (step ST21).
• the processor 16 receives an instruction to start the test from the touch panel display 18, it starts processing for the test.
• the processor 16 transports the specimen collection container 20 to a position accessible to the sampling nozzle 42 in the specimen transport unit 12 (step ST22).
• the processor 16 controls the sample dispensing section 14 to perform the sample dispensing process (steps ST23 to ST25).
• the sampling nozzle 42 is inserted into the sample collection container 20 and the sample 22 is aspirated (step ST23).
• the moving mechanism 46 moves the sampling nozzle 42 from the sample suction position P1 to the sample discharge position P2 (step ST24).
• the specimen dispensing unit 14 moves the sampling nozzle 42 onto the reaction cell R0, which is the specimen discharge position P2, and then discharges the specimen 22 into the reaction cell R0 (step ST25).
• the processor 16 controls the mixing unit 13 and starts preprocessing including a mixing process of mixing particles and liquid (step ST26).
• the pretreatment performed in the mixing section 13 includes the steps of the first reaction (step ST12) to luminescent reagent addition (step ST16) shown in FIG.
• the first mixing process in the first reaction, the second mixing process in the first washing process, the third mixing process in the second reaction, the fourth mixing process in the second washing process, and the fifth mixing process in luminescent reagent addition This corresponds to the mixing process of magnetic particles and liquid in the following.
• a mixing process (step ST27) of the magnetic particles MB and the liquid LQ is performed. Note that during the mixing process, the mixing is promoted by repeatedly sucking and discharging the mixed liquid using the nozzle that injects the liquid LQ into the reaction cell R0.
• the processor 16 controls the camera 61 to photograph the mixed liquid ML (step ST28). Then, the processor 16 determines the state of the liquid mixture ML based on the image taken by the camera 61 (step ST29).
• step ST29: Yes If the processor 16 determines that the mixed liquid ML is in good condition (step ST29: Yes) and there is a next mixing process (step ST30: Yes), it repeats steps ST27-29.
• step ST29: No when the processor 16 determines that the state of the mixed liquid ML is poor (step ST29: No), the processor 16 outputs a message indicating that the mixed state is bad as an error output to the touch panel display 18 (step ST29: No). ST31), the inspection is ended.
• step ST30 If there is no next mixing process (step ST30: No), that is, if the fifth mixing process in addition of the luminescent reagent is completed, the processor 16 executes the detection process in the detection unit 15 (step ST32). In the detection unit 15, the light L caused by the label S generated from the reaction cell R0 is detected by the photodetector 50.
• the processor 16 calculates the concentration of the target substance A in the specimen 22 based on the information regarding the amount of light acquired from the photodetector 50.
• a message indicating the test result is displayed on the touch panel display 18 (step ST33), and the test ends.
• an inspection device such as the inspection device 10 described above, which includes a process of mixing particles and liquid as a process performed on a specimen before detection processing, when the mixing of particles and liquid is insufficient. , the reliability of test results may decrease.
• the first reaction described above if the mixing state of the first mixed liquid is poor, that is, if the magnetic particles MB and the specimen 22 are not sufficiently mixed, the first reaction There is a possibility that the binding between the binding substance B1 and the target substance A becomes insufficient, and less target substance A is captured by the magnetic particles MB. Therefore, the detected amount of the target substance A obtained as a test result may be lower than the amount of the target substance A originally contained in the specimen 22.
• the mixing state of the second mixed liquid is poor, that is, if the magnetic particles MB and the cleaning liquid 40 are not sufficiently mixed, unreacted particles non-specifically adsorbed to the magnetic particles MB It may not be possible to remove the substance sufficiently. If unreacted substances remain, the binding between the target substance A and the second binding substance B2 is inhibited in the second reaction of the next step, and the label that should be attached to the target substance A may not be attached. Therefore, the detected amount of the target substance A obtained as a test result may be lower than the amount of the target substance A originally contained in the specimen 22.
• the mixing state of the third mixed liquid is poor, that is, if the magnetic particles MB and the labeling reagent 37 are not sufficiently mixed, the bond between the second binding substance B2 and the target substance A becomes insufficient, and the amount of label S given to target substance A captured by magnetic particles MB decreases. Therefore, the detected amount of the target substance A obtained as a test result may be lower than the amount of the target substance A originally contained in the specimen 22.
• the mixing state of the fourth liquid mixture is poor, that is, if the magnetic particles MB and the washing liquid 40 are not sufficiently mixed, unreacted substances non-specifically adsorbed to the magnetic particles MB may be removed. It may not be possible to remove it sufficiently. If a label S other than the label S attached to the target substance A remains as an unreacted substance, the luminescence of the unreacted label S will be added to the luminescence of the label S originally attached to the target substance A, so the inspection The resulting detected amount of target substance A may be higher than the amount of target substance A originally contained in the specimen 22.
• the luminescent reagent when adding the luminescent reagent, if the mixing state of the fifth liquid mixture is poor, that is, if the magnetic particles MB, the first luminescent reagent 38, and the second luminescent reagent 39 are not sufficiently mixed, the label The reaction with the first luminescent reagent 38 and the second luminescent reagent 39 may be insufficient, a chemical reaction may not occur sufficiently, and the amount of luminescence may be lower than the original amount. Therefore, the detected amount of the target substance A obtained as a test result may be lower than the amount of the target substance A originally contained in the specimen 22.
• the mixing process that mixes particles and liquid which is a process that is performed on the sample 22 before the detection process that detects the target substance A in the sample 22, it is possible to ensure that the sample and the liquid are sufficiently mixed. If not, the concentration of the target substance A detected in the detection process may deviate from the actual concentration.
• the inspection device 10 of the present embodiment includes a first camera (here, the camera 61) that photographs the mixed liquid ML in which particles (here, magnetic particles MB) and liquid LQ are mixed in the reaction cell R0. Then, the processor 16 determines the mixed state of the particles and the liquid based on the image of the mixed liquid ML photographed by the first camera, and when it is determined that the mixed state is good, the detection unit 15 detects the target Execute the detection process for substance A. In this way, the inspection device 10 executes the detection process when it is determined that the mixing state is good, so that it is possible to obtain highly reliable inspection results.
• a first camera here, the camera 61
• the processor 16 determines the mixed state of the particles and the liquid based on the image of the mixed liquid ML photographed by the first camera, and when it is determined that the mixed state is good, the detection unit 15 detects the target Execute the detection process for substance A. In this way, the inspection device 10 executes the detection process when it is determined that the mixing state is good, so that it
• the inspection device 10 includes a first notification section (for example, the touch panel display 18) that notifies the user that the mixed state is defective.
• a first notification section for example, the touch panel display 18
• the processor 16 determines that the mixed state is defective
• the first notification section notifies that the mixed condition is defective, and the inspection ends. According to such a configuration, the user can be made aware that an error has occurred due to poor mixing, and a countermeasure such as re-inspection can be clarified.
• the processor 16 may perform the following processing without notifying an error and ending the inspection. For example, when the processor 16 determines that the mixed state of the liquid mixture in the reaction cell R0 is poor, the processor 16 restarts suction and discharge of the liquid mixture by the nozzle to promote mixing of the particles and the liquid. Then, the mixed liquid may be photographed again by the first camera 61, the mixed state may be determined by the processor 16, and the mixing and the mixed state determination may be repeated until the mixed liquid is in a good mixed state.
• the processor 16 is configured to determine the mixed state based on the shading that occurs in the image of the mixed liquid as particles in the mixed liquid are dispersed, the mixed state can be easily determined.
• the processor 16 may determine the mixing state based on the presence or absence of bubbles BB or the amount of bubbles BB in the mixed liquid ML in the image, in addition to the shading that occurs in the image of the mixed liquid ML.
• the mixed state can be determined more accurately than when the mixed state is determined based only on the density.
• the processor 16 can also adopt a mode in which the mixing state is determined based on the presence or absence of bubbles BB in the liquid mixture ML in the image or the amount of bubbles BB, without using the density that occurs in the image of the liquid mixture. .
• FIG. 8 is a diagram showing a schematic configuration of the inspection device 110 of the second embodiment.
• the same elements as those in the inspection device 10 of the first embodiment are given the same reference numerals, and detailed description thereof will be omitted.
• the inspection apparatus 110 of the second embodiment differs from the inspection apparatus 10 in that it includes a second camera 62 that photographs the sampling nozzle 42 holding the specimen 22.
• the second camera 62 is a camera provided separately from the camera 61 (hereinafter referred to as the first camera 61) that takes an image of the liquid mixture.
• the second camera 62 photographs the sampling nozzle 42 after the sample 22 is aspirated by the sampling nozzle 42 until it is discharged into the reaction cell R0.
• the second camera 62 detects the sampling nozzle 42 located at a position P3 between a sample suction position P1 where the sample 22 is aspirated by the sampling nozzle 42 and a sample discharge position P2 where the sample 22 is discharged. It is placed so that it can be photographed. In this embodiment, the second camera 62 photographs the sampling nozzle 42 while the sampling nozzle 42 is moving from the sample suction position P1 to the sample discharge position P2.
• the processor 16 determines the state of the specimen 22 within the sampling nozzle 42 based on the image of the sampling nozzle 42 taken by the second camera 62. For example, when the processor 16 determines that the state of the specimen 22 is normal, the processor 16 causes the specimen dispensing unit 14 to discharge the specimen 22 into the reaction cell R0. Thereafter, the sample 22 is subjected to a mixing process in the mixer 13 and subjected to a detection process in the detector 15.
• the state of the specimen 22 is determined by determining whether the specimen 22 is in a normal state that can be subjected to detection processing, or whether the specimen 22 is in an abnormal state.
• parameters for determining that the state of the specimen 22 is normal include the following (1) to (3).
• the processor 16 determines that the state of the specimen 22 is normal when all of (1) to (3) are satisfied, and if at least one of (1) to (3) is not satisfied, the state of the specimen 22 is determined to be normal. It is determined that the state of sample 22 is abnormal (specimen 22 has an abnormality).
• the parameters for determining normality can be set as appropriate depending on the inspection item or testing device, such as determining normality if (1) is satisfied, or normality if (1) and (2) are satisfied, etc. You can also. It is also possible to introduce parameters other than (1) to (3).
• FIG. 10 is a diagram schematically showing images P2A to P2D of the sampling nozzle 42 taken by the second camera 62.
• the specimen 22 in the image P2A has a suction amount that satisfies the specified value, and is in a normal state with no foreign matter or the like mixed in.
• the specimen 22 in the image P2B is in an abnormal state in which the amount of suction is less than the specified value.
• the specimen 22 in the image P2C contains a foreign object F and is in an abnormal state.
• the specimen 22 in the image P2D is in an abnormal state where hemolysis has occurred.
• the upper end position, the lower end position, and the distance between the upper and lower ends of the specimen 22 are determined from the image of the sampling nozzle 42 holding the specimen 22, and these are determined.
• An example of a method is to calculate the suction amount from the value of , and determine that if the calculated suction amount is equal to or greater than a specified value, it is normal, and if it is less than the specified value, it is determined that there is an abnormality.
• the upper end position and lower end position of the specimen 22 can be detected, for example, from fluctuations in the luminance value in the length direction (vertical direction) of the sampling nozzle 42.
• the specified value of the suction amount may be stored in advance in the memory as setting information. As the specified value, a required amount for use in the detection process, such as 25 ⁇ L, is set, for example.
• a variation in brightness value is detected in the length direction (vertical direction) of the sampling nozzle 42. If there is a location in the specimen 22 where the variation in brightness value is equal to or greater than a threshold value, it is determined that there is a foreign object, and if there is no location where the variation in brightness value is equal to or greater than the threshold value, it is determined that there is no foreign matter.
• a method for determining the presence or absence of hemolysis, jaundice, and chyle in the specimen 22 includes, for example, a method of determining based on the color of the specimen 22 in the image of the sampling nozzle 42 holding the specimen 22.
• the processor 16 determines that the state of the specimen 22 is abnormal (the specimen 22 has an abnormality), that is, if it determines that at least one of (1) to (3) is not satisfied, , information indicating that the state of the specimen 22 is abnormal is displayed on the touch panel display 18.
• the touch panel display 18 functions as a second notification unit that notifies the user that the state of the specimen 22 is abnormal.
• the second notification unit that notifies that the state of the specimen 22 is abnormal may include a speaker that notifies an error with audio, a light emitting unit that notifies an error with light emission, or the like.
• the processor 16 determines that the state of the specimen 22 is abnormal, it displays information to the effect that the state of the specimen 22 is abnormal on the touch panel display 18, and ends the test of the specimen 22.
• the specimen collection container 20 is loaded into the testing device 110 (step ST21), the specimen collection container 20 is transported by the specimen transport section 12 (step ST22), and the specimen 22 is aspirated by the specimen dispensing section 14 (step ST23).
• the process is the same as the inspection flow in the inspection device 10.
• the process of moving the sampling nozzle 42 and discharging the sample into the reaction cell R0 after the sample dispensing section 14 finishes aspirating the sample 22 is different from the testing apparatus 10.
• the movement of the sampling nozzle 42 that has sucked the specimen 22 is started (step ST241). While the sampling nozzle 42 is moving, the processor 16 controls the second camera 62 to photograph the sampling nozzle 42 (step ST242). The sampling nozzle 42 is moved to the sample discharge position P2 on the reaction cell R0, and nozzle movement is completed (step ST243). The processor 16 determines the state of the specimen 22 based on the image of the sampling nozzle 42 holding the specimen 22 acquired from the second camera 62, and when determining that the state of the specimen 22 is normal (step ST244: Yes), the sample 22 is discharged from the sampling nozzle 42 to the reaction cell R0 (step ST25). The subsequent steps are the same as the inspection flow in the inspection device 10.
• step ST244 determines that the state of the specimen 22 is abnormal (step ST244: No)
• it outputs a message indicating that the state of the specimen 22 is abnormal as an error output (step ST31), and performs the test. finish.
• a testing device that performs a detection process to detect a target substance in a specimen, such as the testing devices 10 and 110, if there is an abnormality in the specimen subjected to testing, the reliability of the test results may decrease.
• the amount of sample 22 sucked into the sampling nozzle 42 is less than the specified value, the amount of sample 22 discharged into the reaction cell R0 will be less than the specified value. If the sample amount is small, the target substance A in the sample will be relatively small, and when outputting the concentration for a specified amount of sample 22 as a test result, there is a possibility that a lower concentration than originally expected will be output as a detection result. There is.
• the binding between the target substance A and the first binding substance B1 in the first reaction is inhibited, and the target substance is captured by the magnetic particles MB.
• the amount of A will be less than the original amount. Therefore, the detected amount of the target substance A obtained as a test result may be lower than the amount of the target substance A originally contained in the specimen 22.
• the detection results may be affected. be.
• the concentration of the target substance A detected in the detection process may deviate from the actual concentration.
• the inspection device 110 of the second embodiment includes the second camera 62 that photographs the sampling nozzle 42 holding the specimen 22, and the processor 16 determines the state of the specimen 22 and determines the state of the specimen 22. 22 is determined to be normal. According to such a configuration, it is possible to exclude from the test a sample 22 that has an abnormality and for which an accurate test result cannot be obtained, and it is possible to improve the reliability of the test result.
• the test item (type of target substance A)
• the processor 16 may add an indication that the specimen 22 has an abnormality, specifically, hemolysis, jaundice, or chyle.
• the processor 16 is configured to eject the sample 22 from the sampling nozzle 42 to the reaction cell R0 when the state of the sample 22 is determined to be normal, as in the inspection device 110 of the above embodiment, an abnormality can be detected. Certain specimens 22 can be reliably excluded from the test.
• the second camera 62 photographs the sampling nozzle 42 being moved by the moving mechanism 46, but the second camera 62 may photograph the sampling nozzle 42 in a stationary state. .
• the throughput can be increased because there is no need to stop the sampling nozzle 42 for photographing.
• the second camera 62 may be placed at a position where it can photograph the sampling nozzle 42 when it is located at the suction position P1 or when it is located at the specimen discharge position P2.
• the second camera 62 may be an area scan camera or a line scan camera.
• costs can be reduced.
• a high-precision camera is required, so using a line scan camera is highly effective in reducing costs.
• an enzyme is used as the label S, and the detection section 15 is configured to detect luminescence generated by the reaction between the enzyme and the luminescent reagent.
• the label S is not limited to an enzyme, and may be a fluorescent label such as a fluorescent dye or a fluorescent bead.
• the detection unit 15 may include an excitation light source that irradiates the fluorescent label with excitation light and a photodetector that detects fluorescence generated from the fluorescent label.
• the inspection devices 10 and 110 of each of the above embodiments are configured to use magnetic particles MB as a solid phase for B/F separation, and determine the mixing state of the magnetic particles MB and liquid to determine whether the mixing state is good. Detection of the target substance is performed in certain cases.
• the technology of the present disclosure can be applied without limitation to an inspection apparatus including a mixing unit that performs a mixing process of mixing not only magnetic particles MB but also particles and liquid.
• processors can be used as the hardware structure of the processor 16 and a processing unit (Processing Unit) that executes various processes as its internal configuration.
• CPUs which are general-purpose processors that execute software and function as various processing units, as well as FPGAs (Field Programmable Gate Arrays), etc. whose circuit configurations can be changed after manufacture.
• FPGAs Field Programmable Gate Arrays
• a programmable logic device (PLD) which is a processor, or a dedicated electric circuit, which is a processor with a circuit configuration specifically designed to execute a specific process, such as an ASIC (Application Specific Integrated Circuit), etc. But included.
• One processing unit may be composed of one of these various processors, or a combination of two or more processors of the same type or different types (for example, a combination of multiple FPGAs and/or a CPU and (in combination with FPGA). Further, the plurality of processing units may be configured with one processor.
• one processor is configured with a combination of one or more CPUs and software, as typified by computers such as clients and servers.
• a processor functions as multiple processing units.
• SoC system-on-chip
• various processing units are configured using one or more of the various processors described above as a hardware structure.
• circuitry that is a combination of circuit elements such as semiconductor elements can be used.

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• 2023
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