Sample analyzer

Abstract

In order to improve the efficiency of capturing magnetic particles at a predetermined position and detect the magnetic particles with high sensitivity, the present disclosure proposes a sample analyzer (fig. 9) comprising: a flow path in which a capturing region is set and into which a sample liquid containing magnetic particles bound to a specific substance is introduced; a supply means for supplying the sample liquid to the flow path; a capture unit that generates a magnetic field and adsorbs the magnetic particles to a capture region by means of the magnetic field; a magnetic particle distribution adjustment means that, with respect to the distribution of magnetic particles in a cross-section perpendicular to the direction of flow of the sample liquid in the capture region of the flow path, makes the distribution of a near region closer to the capture region than the central axis of the flow path denser than the distribution of a far region farther than the central axis when viewed from the capture region; a measurement means for measuring the specific substance adsorbed in the capture region; and a discharge means for discharging the magnetic particles from the flow path after the measurement by the measurement means.

Description

Technical Field

[0001] The present disclosure relates to a sample analysis device. Background Art

[0002] First, we'll explain immunoassay as an example of sample analysis. Immunoassay involves the detection or measurement of antibodies and antigens in body fluids (such as plasma, serum, and urine) using the specific reaction between antigens and antibodies for the purpose of diagnosing diseases or conditions. A representative method is ELISA (Enzyme-Linked Immunosorbent Assay).

[0003] In a typical ELISA procedure, an antibody against the antigen to be measured (primary antibody) is immobilized in a container. A sample such as plasma, serum, or urine is added, allowing the antigen in the sample to bind to the primary antibody. A labeled antibody (secondary antibody) is then allowed to bind to the antigen bound to the primary antibody. The combination of primary antibody, antigen, secondary antibody, and label is captured, and the signal emitted from the label is detected to determine the presence and amount of the antigen in the sample.

[0004] As a label, for example, a fluorescent substance is used. In this case, the luminescence increases in proportion to the amount of the second antibody bound to the label, that is, the amount of antigen in the conjugate. By detecting the luminescence of the fluorescent substance with a photomultiplier tube or the like, the antigen in the sample can be quantified.

[0005] A specific example of an immunoassay device using the ELISA method is described below. In this example, magnetic particles are used as a solid phase, and the first antibody is fixed to the surface of the magnetic particles. A luminescent labeling substance containing a fluorescent dye as a label is bound to the second antibody. By mixing a detection substance (antigen) derived from a living organism with the magnetic particles fixed with the first antibody, an antigen-antibody reaction occurs, whereby the specific antigen contained in the sample binds to the magnetic particles via the first antibody. Furthermore, if the second antibody is reacted, the luminescent labeling substance binds to the magnetic particles via the second antibody, the antigen, and the first antibody. The amount of the luminescent labeling substance increases or decreases depending on the amount of the detection substance contained in the sample, that is, the amount of the antigen.

[0006] While a liquid sample containing magnetic particles bound to a test substance flows through a random flow path, the magnetic particles are captured (adsorbed) at a predetermined location along the flow path. By applying an external electric field, etc., to the captured magnetic particles, the luminescent labeling substance bound to the magnetic particles emits light. By measuring the intensity of this luminescence, the amount of test substance, i.e., antigen, in the sample can be determined, enabling quantitative measurement.

[0007] To perform highly sensitive immunoassays, magnetic particles bound to a test substance (antigen) are captured at specific locations using a magnet or other device, and the solution is replaced with a solution containing antibodies that are not bound to the antigen, so-called B / F separation (Bound / Free separation, separating antigen-antibody binding and unbound substances).

[0008] For example, Patent Document 1 discloses a method for capturing magnetic particles at a predetermined location in an analysis device using a magnet or the like. Specifically, Patent Document 1 describes a sample analysis device comprising at least one of a structure that increases the cross-sectional area of ​​the flow path downstream of the magnetic particle capture region relative to the cross-sectional area upstream of the magnetic particle capture region, and a structure that increases the magnitude of the magnetic field generated by a magnetic field generating unit relative to the upstream side of the magnetic particle capture region. This structure suppresses uneven adsorption.

[0009] Prior art literature

[0010] Patent Literature

[0011] Patent Document 1: International Publication No. 2011 / 155489 Summary of the Invention

[0012] Problems to be solved by the invention

[0013] However, in the sample analyzer disclosed in Patent Document 1, some of the introduced magnetic particles may not be captured and may flow out, which may result in a decrease in sensitivity.

[0014] In view of such circumstances, the present disclosure provides a sample analysis technology that improves the efficiency of capturing magnetic particles at predetermined positions and performs detection with high sensitivity.

[0015] Means for solving problems

[0016] In order to solve the above-mentioned problems, the present embodiment proposes a sample analysis device, which, as a representative sample analysis device, comprises: a flow path having a capture area set therein, for introducing a sample liquid containing magnetic particles bound to a specific substance into the capture area; a supply unit, for supplying the sample liquid to the flow path; a capture unit, for generating a magnetic field, for adsorbing the magnetic particles to the capture area by means of the magnetic field; a magnetic particle distribution adjustment unit, for adjusting the distribution of magnetic particles in a cross section perpendicular to the flow direction of the sample liquid at the capture area of ​​the flow path, so that the distribution of the magnetic particles in a proximal area closer to the capture area than the central axis of the flow path is denser than the distribution in a distal area farther from the central axis when viewed from the capture area; a measuring unit, for measuring the specific substance adsorbed on the capture area; and a discharge unit, for discharging the magnetic particles from the flow path after the measurement based on the measuring unit.

[0017] Further features related to the present disclosure will become apparent from the description of this specification and the accompanying drawings. In addition, the present disclosure is achieved through the elements and combinations of various elements, as well as the following detailed description and the accompanying technical solutions.

[0018] The descriptions in this specification are merely typical examples and do not limit the technical solutions or application examples of the present disclosure in any sense.

[0019] Effects of the Invention

[0020] According to the technology disclosed herein, in a sample analysis device, it is possible to improve the efficiency of capturing magnetic particles at predetermined positions and perform detection with high sensitivity. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 This is a diagram showing a schematic configuration example of the immunoassay device 100 according to this embodiment.

[0022] Figure 2 It is a diagram showing a flow cell and a magnetic field structure of a conventional configuration example using a permanent magnet.

[0023] Figure 3 A is a diagram showing the positional relationship between a shipper nozzle 30 and a suspension container 40 . Figure 3 B is a diagram showing a fluid region where calculation is performed by fluid analysis. Figure 3 C is a diagram showing a cross section of the nozzle tip portion 38 on a surface passing through the central axis of the nozzle 30 and parallel to the zx plane. Figure 3 D is a diagram showing a cross section on a plane passing through the central axis of the suction nozzle 30 and parallel to the yz plane. Figure 3 E is a diagram showing a cross section of the pipette nozzle 30 on a surface parallel to the xy plane.

[0024] Figure 4 A represents the existing immunoassay device Figure 2 Graph showing the distribution of magnetic particles in cross section 60. Figure 4 B means Figure 4 A diagram showing a state where the region A is divided into 12 parts in the circumferential direction. Figure 4 C is a graph showing the relationship between the distance from the center and the number of particles when the cross section 60 is centered on the axis of the suction nozzle 30 . Figure 4 D stands for Figure 4 B is a graph showing the relationship between the distance from the center of the pipette nozzle and the number of particles in each divided area.

[0025] Figure 5 Is based on Figure 4 A and Figure 4C is a diagram showing the distribution of magnetic particles 13 in the cross section 60 of the pipette nozzle 30 .

[0026] Figure 6 This figure shows that when a fluid-magnetic field analysis for capturing magnetic particles 13 is performed using a conventional immunoassay apparatus, only the magnetic particles in the black region are captured by the reaction field electrode 14 , while the magnetic particles in the gray region are not captured by the reaction field electrode 14 and flow out of the flow path 10 to the tube 33 .

[0027] Figure 7 A stands for Figures 2 to 6 FIG. 6 is a diagram schematically showing the distribution of magnetic particles in a cross section 60 of a conventional structural example. Figure 7 B is a schematic diagram of magnetic particle distribution example 1 in a cross section 60 implemented in an embodiment of the present disclosure. Figure 7 FIG. C is a schematic diagram of a second example of magnetic particle distribution in a cross section 60 implemented in an embodiment of the present disclosure.

[0028] Figure 8 A is an initial state of the analysis, and is a diagram showing a state in which the magnetic particles are distributed outside the flow path in the cross section 60 . Figure 8 B means from Figure 8 FIG. 6 is a diagram showing the distribution of magnetic particles in the cross section 63 after passing through the curved portion 80 in the initial state of FIG. Figure 8 C is a diagram showing a state in which magnetic particles are distributed inside the flow path in the cross section 60 . Figure 8 D means from Figure 8 FIG. 6 is a diagram showing the distribution of magnetic particles in the cross section 63 after passing through the curved portion 80 in the initial state of C.

[0029] Figure 9 A is a diagram showing the positional relationship between the pipette nozzle 30 and the suspension container 40 . Figure 9 B is a diagram showing a cross-sectional structure of the tip portion 38 of the suction nozzle 30 on a plane passing through the central axis of the suction nozzle 30 and parallel to the zx plane. Figure 9 C is a diagram showing a cross-sectional structure on a plane passing through the central axis of the suction nozzle 30 and parallel to the yz plane. Figure 9 D is a diagram showing a cross-sectional structure of the pipette nozzle 30 on a surface parallel to the xy plane.

[0030] Figure 10 A is a diagram showing the distribution of magnetic particles in the cross section 60 when the injection needle-shaped pipette nozzle 30 of Example 1 is used. Figure 10 B is a graph showing the relationship between the distance from the center and the number of particles when the cross section 60 is centered on the axis of the suction nozzle 30 . Figure 10 C is represented as Figure 4Graph showing the relationship between the distance from the center and the number of particles in each region divided in the circumferential direction as shown in D.

[0031] Figure 11 A is a diagram showing a region A (hatched region) in the distribution of magnetic particles in the cross section 60 of the pipette nozzle 30 . Figure 11 B represents a change in the angle α of the suction nozzle 30 (refer to Figure 9 B) A diagram showing the proportion of particles distributed within area A. Figure 11 FIG. C is a graph showing the particle distribution in the cross section 60 when the angle α=5°. Figure 11 D is a graph showing the particle distribution in the cross section 60 when the angle α=40°. Figure 11 FIG. E is a graph showing the particle distribution in the cross section 60 when the angle α=70°.

[0032] Figure 12 A is a diagram showing the positional relationship between the pipette nozzle 30 and the suspension container 40 in Modification 1 of Example 1. Figure 12 B is a diagram showing a cross section of the cross section 60 on a plane passing through the central axis of the suction nozzle 30 of the first modification and parallel to the zx plane. Figure 12 C is a diagram showing a cross section on a plane passing through the central axis of the suction nozzle 30 of Modification 1 and parallel to the yz plane. Figure 12 D is a diagram showing a cross section of the suction nozzle 30 according to Modification 1, taken along a surface parallel to the xy plane.

[0033] Figure 13 A is a diagram showing the positional relationship between the pipette nozzle 30 and the suspension container 40 in Modification 2 of Example 1. Figure 13 B is a diagram showing a cross section on a plane passing through the central axis of the suction nozzle 30 of Modification 2 and parallel to the zx plane in the cross section 60 . Figure 13 C is a diagram showing a cross section on a plane passing through the central axis of the suction nozzle 30 of Modification 2 and parallel to the yz plane. Figure 13 D is a diagram showing a cross section of the pipette nozzle 30 according to the second modification, taken along a surface parallel to the xy plane.

[0034] Figure 14 1 is a diagram showing the positional relationship between the pipette nozzle 30 and the suspension container 40 in Example 2.

[0035] Figure 15 A is a graph showing the distribution of magnetic particles in the cross section 60 in Example 2. Figure 15 B is a graph showing the relationship between the distance from the center and the number of particles when the center is the axis of the suction nozzle 30 in the cross section 60 in Example 2. Figure 15 C is represented in Example 2 with Figure 4FIG. 4 is a graph showing the relationship between the distance from the center of the suction nozzle 30 and the number of particles in each area divided similarly to D. FIG.

[0036] Figure 16 This is a structural example of the suction nozzle 30 of Example 3, and is a diagram showing a mode in which a contraction portion 82 is provided in the middle of the flow path so that the flow path becomes narrower with respect to the x-direction.

[0037] Figure 17 This is a structural example of the suction nozzle 30 of Example 3, and is a diagram showing a mode in which a hole 83 is formed along the x direction on the side surface in the middle of the flow path.

[0038] Figure 18 This is a structural example of the suction nozzle 30 of Example 3, and is a diagram showing a mode in which a branch flow path 84 is connected along the x direction to a side surface in the middle of the flow path.

[0039] Figure 19 This is a structural example of the suction nozzle 30 of Example 3, and is a diagram showing a form of the suction nozzle 30 formed so that the cross-sectional area on a surface parallel to the xy plane decreases from upstream to downstream, and the flow path center in each cross section moves from upstream to downstream in the +x direction.

[0040] Figure 20 This figure shows Example 4 and illustrates a state in which the central axis of the pipette nozzle 30 is arranged offset in the x-axis direction with respect to the central axis of the suspension container 40 .

[0041] Figure 21 A is a graph showing the distribution of magnetic particles in the cross section 60 in Example 4. Figure 21 B is a graph showing the relationship between the distance from the center and the number of particles when the center is the axis of the pipette nozzle 30 in the cross section 60 in Example 4. Figure 21 C is represented in Example 4 with Figure 4 FIG4 is a graph showing the relationship between the distance from the center and the number of particles in each region after similar division.

[0042] Figure 22 This is a modification of Example 4, and is a diagram showing a mode in which the central axis of the suspension container 40 is tilted in the x-axis direction (or the y-axis direction) relative to the central axis of the pipette nozzle 30 .

[0043] Figure 23 A is a structural example of Example 5, and is a diagram showing a cross-sectional structural example on a plane passing through the central axis of the suspension container 40 and parallel to the zx plane. Figure 23 B is a structural example of Example 5, and is a diagram showing a cross-sectional structural example on a plane passing through the central axis of the suspension container 40 and parallel to the yz plane. Figure 23 C is a diagram showing the cross-sectional structure of Example 5 on a surface parallel to the xy plane.

[0044] Figure 24 This is a modification of Example 5, and shows a method in which the axisymmetry of the fluid flow is destroyed (axisymmetry is achieved) by providing a protrusion in the x-axis direction in the suspension container 40 .

[0045] Figure 25 A is a flow path structure example of Example 6, and is a diagram showing an example in which a flow path 90 is connected horizontally to the upstream side of the flow path 10 and is connected to a pipe (flow path) 32 connected vertically downward (-z direction) through a confluence portion 85. Figure 25 B is a diagram showing a state where the suspension containing magnetic particles flowing from the tube (channel) 32 and the solvent flowing from the channel 90 merge at the merging portion 85 to form parallel flows in the channel 10 .

[0046] Figure 26 A is a graph showing the distribution of magnetic particles in the cross section 60 in Example 6. Figure 26 B is a diagram showing the distribution of magnetic particles in the cross section 63 in Example 6.

[0047] Figure 27 A is a diagram showing an example of the upper surface structure of the flow cell 200 of Example 7. Figure 27 B stands for Figure 27 A diagram showing an example of the structure of the AA cross section of A.

[0048] Figure 28 A is a diagram showing the distribution of magnetic particles in the cross section 64 on the upstream side of the contraction flow plate 86 in Example 7, and the magnetic particles are evenly distributed in the cross section 64 . Figure 28 B is a diagram showing the distribution of magnetic particles in the cross section 65 on the downstream side of the contraction flow plate 86 .

[0049] Figure 29 A is a diagram showing an example of the upper surface structure of the flow cell 300 of Example 8. Figure 29 B stands for Figure 29 A diagram showing an example of the structure of the AA cross section of A.

[0050] Figure 30 It is a diagram showing the state of the flow path when the suspension and the solvent are injected. DETAILED DESCRIPTION

[0051] Embodiments of the present disclosure relate to a sample analyzer that analyzes a sample, and more particularly, to a sample analyzer that utilizes a reaction between an antigen and an antibody.

[0052] Hereinafter, various embodiments of the present disclosure will be described with reference to the accompanying drawings. It should be noted that in the following multiple embodiments, common structures may be denoted by the same reference numerals and their descriptions may be omitted.

[0053] (1) Example 1

[0054] <Configuration Example of Sample Analyzer>

[0055] As an example of a sample analysis device according to this embodiment, an immunoassay device will be described. This embodiment is not limited to immunoassays; it is applicable to any sample analysis device that uses magnetic particles to capture them by switching the intensity of a magnetic field. It is also applicable to DNA and biochemical analysis devices. Furthermore, the embodiments described below are not limited to shape, size, or number, and can be modified without departing from the main purpose. Multiple embodiments may also be combined, including those described below.

[0056] Figure 1 This figure shows a schematic configuration example of an immunoassay device 100 according to this embodiment. In the immunoassay device 100, the portion consisting of the flow channel 10, the flow channel top wall 11, the flow channel bottom wall 12, the reaction field electrode 14, and the counter electrode 15 is referred to as the detection unit (or, as a single component, the flow cell). To enable the photodetector 23 to detect the wavelength of light emitted by the labeling substance bound to the magnetic particles 13 around the reaction field electrode 14, the flow channel top wall 11 of the flow cell is preferably made of a transparent material, such as glass or plastic.

[0057] A reaction field electrode 14 is provided around the lower portion of the flow channel 10, and a counter electrode 15 is provided around the opposite side of the flow channel 10. Furthermore, the reaction field electrode 14 and the counter electrode 15 are connected to a voltage application unit 16 via signal lines 55b and 55c. The voltage application unit 16 is connected to the controller 50 via a signal line 55a.

[0058] The materials of reaction field electrode 14 and counter electrode 15 are composed of, for example, gold, platinum, palladium, tungsten, iridium, nickel, alloys thereof, carbon materials, etc. Alternatively, reaction field electrode 14 and counter electrode 15 may be electrodes formed by forming a film of the above-mentioned materials on a base material such as titanium by plating, sputtering, etc.

[0059] For ease of luminescence measurement, the reaction field electrode 14 is typically a planar shape and is herein located on the bottom surface of the flow channel 10. However, it may be located on other surfaces within the flow channel 10, or on multiple surfaces arranged three-dimensionally. Furthermore, as long as it is suitable for capturing magnetic particles 13 or for electrochemiluminescence of labeled substances bound to magnetic particles 13, it does not necessarily need to be a planar shape; it may also be a linear shape, or a combination of a linear and planar shape. The counter electrode 15 may be any configuration or shape that generates a voltage within the flow channel 10 in combination with the reaction field electrode 14; it may be a linear shape, a planar shape, or a combination thereof.

[0060] In order to attract the magnetic particles, a magnet 20 (a permanent magnet or an electromagnet) is used as a magnetic field applying unit.

[0061] The voltage applying unit 16 is controlled by the controller 50. When a voltage is applied between the reaction field electrode 14 and the counter electrode 15 in the flow channel 10 according to the instruction of the controller 50 to the voltage applying unit 16, the labeling substance bound to the magnetic particles 13 adsorbed on the reaction field electrode 14 can be made to emit electrochemical luminescence.

[0062] The photodetector 23 can detect the wavelength of light emitted by the labeling substance bound to the magnetic particles 13 around the reaction field electrode 14 , and can be, for example, a camera or a photomultiplier tube. The photodetector 23 operates based on a signal from the controller 50 .

[0063] The flow channel 10 in the flow cell is connected to the pipette nozzle 30 and the pump 35 via tubes (flow channel) 32 and 33. The pipette nozzle 30 is movable by the arm 31, and the suspension container 40, the cleaning liquid container 42, and the buffer container 43 are arranged within its movable range.

[0064] A valve 36 is provided on the tube 33 between the flow path 10 and the pump 35. The pump 35 and the valve 36 are connected to the controller 50 via signal lines 52 and 53. Furthermore, the valve 37 and the tube 34 are connected to the waste liquid container 45.

[0065] The controller 50 is connected to the valves 36 and 37, the pump 35, the arm 31, the voltage applying units 16 and 17, and the photodetector 23 via independent signal lines 53, 51, 52, 54, 55a, 56a, and 57. Thus, the connected parts can be independently controlled.

[0066] The sample to be analyzed is a biological substance such as serum or urine. In the case of serum, the specific component to be analyzed may be, for example, a tumor marker, an antibody, an antigen-antibody complex, or a single protein. In the following description, the specific component is TSH (thyroid-stimulating hormone).

[0067] In the suspension container 40, as a pretreatment step, a sample to be analyzed is mixed with a bead solution and reagent, and then reacted at a certain temperature (e.g., 37°C) for a certain period of time. The bead solution is a solution in which magnetic particles 13, consisting of granular magnetic material embedded in a matrix material such as polystyrene, are dispersed in a buffer solution. Streptavidin, which can bind to biotin, is bound to the surface of the matrix material. The reagent contains a substance that binds the magnetic particles 13 to TSH, a specific component in the sample, and includes an anti-TSH (Thyroid Stimulating Hormone) antibody with biotin at its end. The reagent varies depending on the specific component being analyzed, and may include, for example, immunoglobulins, antigens, antibodies, or other biological substances.

[0068] The cleaning liquid container 42 contains a cleaning liquid for cleaning the flow path 10 and the interior of the tube (flow path) 32 .

[0069] Regarding the shape of the flow channel 10, while defining the length along the flow direction (path length), the thickness (vertical direction), and the width (horizontal direction) of the cross section perpendicular to the flow, it is preferable that the path length be 2 to 20 times the greater of the thickness or width. This is because ensuring a sufficient path length allows the magnetic particles 13 in the fluid to expand within the flow channel 10 and subsequently be more easily attracted to the reaction field electrodes 14 provided on the bottom surface of the flow channel 10.

[0070] The adsorption distribution of magnetic particles 13 within flow channel 10 is determined by the magnetic force received from a magnet (permanent magnet or electromagnet) positioned near flow channel 10 and the resistance caused by the fluid flow. The magnetic field within flow channel 10 preferably has a magnetic flux density of approximately 0.1 to 0.5 T. The fluid flow velocity at this time is preferably approximately 0.05 to 0.10 m / s.

[0071] The particles used as magnetic particles 13 are preferably the following. These particles are (i) particles exhibiting paramagnetism, superparamagnetism, ferromagnetism, or ferrimagnetism, or (ii) particles exhibiting paramagnetism, superparamagnetism, ferromagnetism, or ferrimagnetism encapsulated in materials such as synthetic polymers (polystyrene, nylon, etc.), natural polymers (cellulose, agarose, etc.), and inorganic compounds (silica, etc.). The particle size is preferably in the range of 0.01 to 200 μm, more preferably in the range of 1 to 10 μm. The specific gravity is preferably 1.3 to 1.5. These specifications make the magnetic particles 13 less likely to settle in liquid and more likely to float. The surface of the particles is bound to a substance that specifically binds to the substance being analyzed, such as an antibody that specifically binds to an antigen.

[0072] The labeling substance is preferably one shown below. Specifically, from the viewpoint of specifically binding the labeling substance to the analyte by appropriate means and causing it to emit light by appropriate means, the following examples can be cited.

[0073] (a) Labeling substances used in fluorescent immunoassays: for example, antibodies labeled with fluorescein isothiocyanate.

[0074] (b) Labeling substances used in chemiluminescent immunoassays: for example, antibodies labeled with acridinium esters.

[0075] (c) Labeling substances used in chemiluminescent enzyme immunoassays: for example, antibodies labeled with chemiluminescent enzymes that use luminol or adamantane derivatives as luminescent substrates.

[0076] The above is the immunoassay device 100 ( Figure 1 Next, an operation example of this embodiment will be described.

[0077] <Operation Example of Immunity Analyzer 100>

[0078] In the immunoassay analyzer 100 , one analysis is defined as one cycle, and a plurality of cycles are performed continuously as a basic operating state of the apparatus.

[0079] One analysis cycle consists of a suspension aspiration period, a magnetic particle capture period, a detection period, a washing period, a reset period, and a pre-aspiration period. One cycle begins when the suspension container 40 containing the suspension processed by the reaction unit 41 is placed at a predetermined position.

[0080] During suspension aspiration, valve 36 is set to open and valve 37 is closed. In response to a signal from controller 50, arm 31 operates to insert suction nozzle 30 into suspension container 40. Subsequently, pump 35, in response to a signal from controller 50, performs a predetermined amount of aspiration, allowing the suspension in suspension container 40 to enter tube (flow path) 32 via suction nozzle 30. In this state, pump 35 is stopped, and arm 31 is operated to insert suction nozzle 30 into cleaning mechanism 44. While passing through cleaning mechanism 44, suction nozzle 30 (tip portion) is cleaned.

[0081] During the magnetic particle adsorption period, a signal from controller 50 activates a sliding mechanism (not shown), moving magnet 20 toward the lower portion of flow channel 10. Pump 35 operates at a constant speed based on a signal from controller 50. During this period, the suspension within tube (flow channel) 32 flows through flow channel 10. Magnet 20 generates a magnetic field within flow channel walls 11 and 12, magnetic particles 13 contained in the suspension are magnetically attracted toward magnet 20 and captured (adsorbed) by reaction field electrode 14, which serves as the designated adsorption location. After a predetermined period of time, pump 35 ceases adsorption of the suspension.

[0082] During the detection period, the sliding mechanism (not shown) operates, and the magnet 20 moves away from the flow path 10. Then, based on the signal from the controller 50, the light detector 23 is operated, and the voltage is applied to the reaction field electrode 14 and the counter electrode 15. As a result, the light detector 23 can receive the luminescence from the labeling substance bound to the magnetic particles 13 while the magnetic particles 13 are held on the reaction field electrode 14, and the measurement can be performed. The intensity of the detected luminescence is recovered as a signal by the controller 50. After a certain period of time, the application of voltage to the reaction field electrode 14 and the counter electrode 15 and the light detector 23 are stopped. During the detection period, the arm 31 is operated, and the pipette nozzle 30 is inserted into the cleaning mechanism 44.

[0083] During cleaning, the controller 50 uses the pump 35 to draw cleaning liquid from the cleaning liquid container 42 and pass the drawn cleaning liquid through the flow path 10. At this time, since the magnet 20 is away from the flow path 10, the magnetic particles 13 are not retained on the reaction field electrode 14 but flow away with the cleaning liquid.

[0084] During the reset period, the controller 50 closes the valve 36 and opens the valve 37 to cause the pump 35 to perform a discharge operation. The liquid in the pump 35 is discharged to the waste liquid container 45.

[0085] During the pre-suction period, the controller 50 operates the pump 35 to suck the buffer solution from the buffer solution container 43, thereby filling the tube (channel) 32 and the channel 10 with the buffer solution. After the pre-suction period, the next cycle can be executed.

[0086] <Regarding the Relationship between the Distribution of Magnetic Particles in the Pipe Nozzle 30 and the Distribution of Captured Magnetic Particles>

[0087] (i) Existing structural examples

[0088] Reference Figures 2 to 6 , describing an example of calculating the relationship between the distribution of magnetic particles in the cross section 60 of the pipette nozzle 30 and the distribution of magnetic particles captured on the reaction field electrode 14 by fluid and magnetic field analysis in a sample analyzer (immunoassay analyzer) of a conventional configuration example.

[0089] Figure 2 It is a diagram showing a flow cell and a magnetic field structure of a conventional configuration example using a permanent magnet. Figure 2 The figure shows a cross section in the zx plane, where a coordinate system is set near the flow cell of a conventional immunoassay device, with the flow direction 61 in the flow channel 10 as the x-axis, the horizontal direction of the cross section perpendicular to the flow as the y-axis, and the vertical direction as the z-axis. The vicinity of the flow channel 10 comprises the flow channel 10, the flow channel top wall 11, the flow channel bottom wall 12, magnetic particles 13, a reaction field electrode 14, a counter electrode 15, and a magnet 20. The magnetic particles 13 flow within the flow channel 10 along the flow direction 61. A tube (flow channel) 32 is connected vertically downward to the curved portion 80.

[0090] Figure 3 This figure shows a state in which the pipette nozzle 30 is inserted into the suspension container 40 and the suspension is being sucked during the suspension suction period. Figure 3 A represents the positional relationship between the pipette nozzle 30 and the suspension container 40 . Figure 3 B represents the fluid region where calculations are performed by fluid analysis. Figure 3 C represents a cross section of the nozzle tip portion 38 on a plane that passes through the central axis of the nozzle 30 and is parallel to the zx plane. Figure 3 D represents a cross section on a plane that passes through the central axis of the suction nozzle 30 and is parallel to the yz plane. Figure 3 E represents a cross section of the pipette nozzle 30 parallel to the xy plane. In the conventional configuration example, the pipette nozzle 30 is arranged so as to include the central axis of the suspension container 40 and is arranged in a direction substantially perpendicular to the direction 61 of the flow in the flow path 10. The pipette nozzle 30 is cylindrical.

[0091] Figure 4 Shown in Figure 3 The calculation of the fluid region B is performed when the suspension is sucked from the state where the magnetic particles 13 are uniformly dispersed in the suspension container 40 through the pipette nozzle 30. Figure 2 The fluid analysis results of the magnetic particle distribution in the cross section 60 of FIG. It should be noted that the analytical model is symmetrical with respect to a plane that includes the central axis of the pipette nozzle 30 and is parallel to the zx plane. Figure 4 A represents Figure 2 Magnetic particle distribution in cross section 60. Figure 4 B means Figure 4 The region A is divided into 12 parts in the circumferential direction. Figure 4 C is a graph showing the relationship between the distance from the center and the number of particles when the cross section 60 is centered on the axis of the suction nozzle 30 . Figure 4 D stands for Figure 4 A graph showing the relationship between the distance from the center of the pipette nozzle and the number of particles in each area divided in B. Figure 4 A and Figure 4 As can be seen from C, the particle density increases near the center axis of the pipette nozzle 30 and slightly inside the outermost periphery in the cross section 60. Figure 4 As can be seen from D, there is almost no difference in the distribution of magnetic particles in the circumferential direction, and the distribution is axisymmetric.

[0092] Figure 5 Indicates based on Figure 4 A and Figure 4 The distribution of magnetic particles 13 in the cross section 60 of the pipette nozzle 30 is shown in FIG. Figure 6 As shown, it can be seen that only the magnetic particles in the region indicated by black are captured by the reaction field electrode 14 , while the magnetic particles in the region indicated by gray are not captured by the reaction field electrode 14 and flow out of the flow channel 10 to the tube 33 .

[0093] Figure 7 A represents Figures 2 to 6 Schematic diagram of the distribution of magnetic particles in the cross section 60 of the conventional structure example shown. Figure 7 As shown in A, in the conventional structure example, the particle distribution density becomes larger near the central axis and slightly inside the outermost periphery.

[0094] (ii) Case of this embodiment

[0095] Figure 7 B and Figure 7 C is a schematic diagram showing the distribution of magnetic particles in the cross section 60 implemented in this embodiment. Figure 7 In B, the magnetic particle distribution density is small on the inside of the cross section 60, and the magnetic particle distribution density is large on the outside of the cross section 60. Figure 7 In C, relative to the direction 61 of the flow in the flow path 10, the magnetic particle distribution density on the upstream side is small, and the magnetic particle distribution density on the downstream side is large. The results of the above fluid-magnetic field analysis are as follows: Figure 6 ,exist Figure 7 The number of particles captured by the reaction field electrode 14 can be increased in B. Figure 7 In C, the number of particles captured by the reaction field electrode 14 can be further increased. Since the flow velocity in the central area of ​​the suction nozzle 30 is high, when the flow direction changes at the bend 80, the magnetic particles 13 distributed in the central area move toward the upper surface side of the flow path 10 due to the centrifugal force. Therefore, in the upstream cross section 60, it is not the central area of ​​the suction nozzle 30 that is important, but the magnetic particles 13 distributed more on the peripheral side. In addition, when Figure 2When the curved portion 80 is bent in the +x direction, the particles on the +x side of the cross section 60 flow closer to the inner circumference than the particles on the -x side. As a result, they flow near the reaction field electrodes and are easily captured. Figure 7 As shown in C, it is more preferable that the magnetic particles 13 are mostly distributed on the outer periphery and the +x side. However, it is important to distribute the magnetic particles 13 on the outer periphery, assuming that the curved portion 80 is provided.

[0096] and then, Figure 8 It shows that Figure 2 Graph showing the results of fluid analysis of the relationship between the magnetic particle distribution in the upstream cross section 60 and the downstream cross section 63 of the curved portion 80 . Figure 8 A is the initial state of the analysis, indicating a state in which the magnetic particles are distributed outside the flow path in the cross section 60 . Figure 8 B means from Figure 8 The initial state of A is the distribution of magnetic particles in the cross section 63 after passing through the curved portion 80. On the other hand, Figure 8 C represents a state in which the magnetic particles are distributed inside the flow path in the cross section 60 . Figure 8 D means from Figure 8 The initial state of C is the distribution of magnetic particles in the cross section 63 after passing through the curved portion 80. Figure 8 The results of B show that when the density of magnetic particles on the outside of the cross section 60 on the upstream side of the bend 80 is high, the particles are biased toward the -z direction of the flow path in the cross section 63 on the downstream side of the bend 80. Figure 8 As a result of D, it can be seen that when the magnetic particle distribution density is high in the inner side (central region) of the cross section 60 on the upstream side of the curved portion 80 , the magnetic particles are biased toward the +z direction in the cross section 63 on the downstream side of the curved portion 80 .

[0097] Therefore, in order to increase the number of magnetic particles captured by the reaction field electrode 14, it is important to Figure 8 As shown in Figure B, the magnetic particles are distributed in the flow path cross section 63 on the downstream side of the bend 80 so that the magnetic particle distribution density is higher on the same side as the magnet 20. If such a magnetic particle distribution is achieved in the cross section 63, the flow path 10 is more easily affected by the magnetic field of the magnet 20, and the number of captured magnetic particles can be increased.

[0098] Moreover, in order to achieve Figure 8 The distribution of magnetic particles in the cross section 63 as shown in FIG. Figure 7 B and Figure 7 The magnetic particles are distributed as shown in C so that the magnetic particle distribution density becomes smaller on the inner side and larger on the outer side in the flow path cross section 60 on the upstream side of the curved portion 80 .

[0099] <Structural Example of the Suction Pipe Nozzle 30>

[0100] Figure 9 This is a diagram showing a configuration example (shape example) of the suction nozzle 30 according to Example 1. Figure 9 A is a diagram showing the positional relationship between the pipette nozzle 30 and the suspension container 40 . Figure 9 B is a diagram showing a cross-sectional structure of the tip portion 38 of the suction nozzle 30 on a plane passing through the central axis of the suction nozzle 30 and parallel to the zx plane. Figure 9 C is a diagram showing a cross-sectional structure on a plane passing through the central axis of the suction nozzle 30 and parallel to the yz plane. Figure 9 D is a diagram showing the cross-sectional structure of the suction nozzle 30 on a surface parallel to the xy plane. The suction nozzle 30 in Example 1 is in the shape of a syringe needle (the front end 38 is cut obliquely, and the shape of the opening is not a perfect circle but an ellipse), and is configured such that, for example, the upstream side is short and the downstream side is long relative to the direction 61 of the flow in the flow path 10. It should be noted that in Figure 9 In B, the angle formed by the cut surface at the front end of the suction pipe nozzle 30 and the horizontal plane is defined as α.

[0101] Figure 10 Shows the use of Figure 9 The injection needle-shaped pipette nozzle 30 of Example 1 shows the fluid analysis results of the magnetic particle distribution in the cross section 60 of the pipette nozzle 30 when the suspension is sucked through the pipette nozzle 30 from a state where the magnetic particles 13 are uniformly dispersed in the suspension container 40 . Figure 10 A represents the distribution of magnetic particles in the cross section 60 . Figure 10 B is a graph showing the relationship between the distance from the center and the number of particles when the cross section 60 is centered on the axis of the suction nozzle 30 . Figure 10 C is represented as Figure 4 A graph showing the relationship between the distance from the center and the number of particles in each area divided circumferentially as shown in D. Figure 10 A and Figure 10 As can be seen from B, when the pipette nozzle 30 of Example 1 is used, the particle distribution in the cross section 60 of the pipette nozzle 30 is different from Figure 4 A and Figure 4 Compared with the conventional structure example shown in C, the particle number density inside the cross section (near the central axis) is reduced, and the particle number density outside the cross section is increased. Figure 10 A and Figure 10 As can be seen from C, with respect to the direction 61 of the flow in the flow path 10, the particle number density on the downstream side is greater than that on the upstream side. Therefore, if the suction nozzle 30 of Example 1 is used, the particle number density on the downstream side is greater than that on the upstream side. Figure 7 The magnetic particle distribution shown in C can increase the number of magnetic particles captured by the reaction field electrode 14.

[0102] <Relationship between Angle α and Magnetic Particle Distribution>

[0103] Figure 11 : is a diagram showing the results of fluid analysis of the magnetic particle distribution in the cross section 60 when the angle α is changed. Figure 11 The hatched area of ​​A is defined as area A. Figure 11 FIG. B is a graph showing the ratio of particles distributed in region A when the angle α is changed. Figure 11 C to Figure 11 E represents the particle distribution in the cross section 60 .

[0104] Reference Figure 11 C to Figure 11 As can be seen from E, as the angle α increases, the number of particles on the inner side of the cross section 60 decreases, while the number of particles on the outer side increases. Figure 11 It can be seen from B that when the angle α is greater than 20°, the number of particles distributed in region A increases, and when the angle α is greater than 60°, the number of particles distributed in region A further increases, that is, the number of particles captured by the reaction field electrode 14 increases.

[0105] It should be noted that, in the first embodiment, the suction nozzle 30 is described as having a shorter length on the upstream side and a longer length on the downstream side relative to the direction 61 of the flow in the flow path 10. However, the same effect can be expected as long as the suction nozzle 30 has an asymmetrical shape relative to any surface (a surface forming an arbitrary angle with the direction 61 of the flow) passing through the center axis of the nozzle (the axis of the direction of the fluid flow). For example, the suction nozzle 30 may be formed so that the upstream side is longer and the downstream side is shorter at the front end portion of the suction nozzle 30. In this case, Figure 10 The particle distribution shown in A is reversed relative to the x-direction, with the particle number density being greater upstream than downstream relative to the direction 61 of the flow within the flow channel 10. However, the particle number density decreases on the inside of the cross section, while the particle number density increases on the outside of the cross section. This increases the number of magnetic particles captured by the reaction field electrode 14.

[0106] <Modification>

[0107] Figure 12 This is a diagram showing a configuration example of Modification 1 of Example 1. Figure 13 1 is a diagram showing a configuration example of a modified example 2 of the embodiment 1. Modified examples 1 and 2 are in which the tip of the suction pipe nozzle 30 is processed to be similar to the embodiment 1. Figure 9 Examples of different shapes. Figure 12 A and Figure 13 A and B are diagrams showing the positional relationship between the pipette nozzle 30 and the suspension container 40 . Figure 12 B and Figure 13B are diagrams showing a cross section on a plane passing through the central axis of the suction nozzle 30 and parallel to the zx plane in the cross section 60 . Figure 12 C and Figure 13 C are views showing cross sections on a plane passing through the central axis of the suction nozzle 30 and parallel to the yz plane. Figure 12 D and Figure 13 D are views showing a cross section of the pipette nozzle 30 on a surface parallel to the xy plane.

[0108] Figure 12 The tip of the suction nozzle 30 shown is formed into a stepped shape that is shorter on the upstream side and longer on the downstream side relative to the direction 61 of the flow in the flow path 10. Figure 13 The tip of the illustrated suction nozzle 30 is shaped so that it is shorter on the upstream side and longer on the downstream side with respect to the direction 61 of the flow in the flow path 10 .

[0109] As shown in this modified example, the flow path from the suspension container 40 to the flow path 10, that is, the flow path structure within the pipette nozzle 30 and the tube (flow path) 32, is made asymmetrical relative to the direction 61 of the flow in the flow path 10. As a result, as described above, it is possible to form a state in which the distribution density of magnetic particles in the cross section 60 is sparse on the inside of the cross section and dense on the outside of the cross section, and is sparse on the upstream side and dense on the downstream side relative to the direction 61 of the flow in the flow path 10. Therefore, the number of magnetic particles captured by the reaction field electrode 14 can be increased. It should be noted that Figure 12 and Figure 13 The variation of the suction nozzle 30 is also Figure 9 The structure shown similarly only needs to be asymmetric with respect to any plane passing through the central axis.

[0110] It should be noted that the structure described in Example 1 is merely an example, and as described above, a structure in which the positions are inverted relative to the x-direction is also possible. This structure also destroys the axisymmetry relative to the axial direction of the nozzle 30. With respect to the particle distribution in the cross section 60, the particle number density decreases on the inner side of the cross section, while the particle number density increases on the outer side of the cross section. This increases the number of magnetic particles captured by the reaction field electrode 14.

[0111] (2) Example 2

[0112] (i) Figure 14 : is a diagram showing the positional relationship between the pipette nozzle 30 and the suspension container 40 of Example 2. The pipette nozzle 30 of Example 2 is positioned at its front end. Figure 2 There are at least two bends in the flow path between the bends 80.

[0113] Figure 15 This is a diagram showing the results of fluid analysis in Example 2. Figure 15A represents the distribution of magnetic particles in the cross section 60. Figure 15 B is a graph showing the relationship between the distance from the center and the number of particles when the axis of the suction nozzle 30 is the center in the cross section 60. Figure 4 Similarly, Figure 15 C is a graph showing the relationship between the distance from the center of the suction nozzle 30 and the number of particles in each divided area.

[0114] Reference Figure 15 A and Figure 15 As can be seen from B, when the suspension is sucked using the pipette nozzle 30 of Example 2, the magnetic particles in the cross section 60 of the pipette nozzle 30 are distributed in the same manner as in the embodiment 2. Figure 4 A and Figure 4 Compared with the conventional structure example shown in C, the particle number density inside the cross section (near the central axis) is reduced, and the particle number density outside the cross section is increased. Figure 15 A and Figure 15 As can be seen from C, with respect to the direction 61 of the flow in the flow channel 10 , the particle number density on the downstream side is greater than that on the upstream side.

[0115] Therefore, the structure of the suction nozzle 30 of the second embodiment can increase the number of magnetic particles captured by the reaction field electrode 14. It should be noted that in the second embodiment, the suction nozzle 30 is connected to the front end of the suction nozzle 30. Figure 2 The case where the flow path between the bends 80 has two bends is described above, but the bends may not be two, but may be one or more than three. In addition, Example 2 shows an example of a 90-degree bend, but it may be other angles, and it may also be a smooth curved flow path shape. Furthermore, the bends provided in multiple locations in the suction nozzle 30 of Example 2 may not be configured to bend toward the direction 61 of the flow in the flow path 10, as long as they are consistent with the Figure 9 Similarly, in the structure shown in , the bent portion may be provided so as to be asymmetrical with respect to any plane passing through the central axis.

[0116] (ii) It should be noted that the structure described in Example 2 is merely an example; a structure in which the axes are inverted relative to the x-direction is also possible. This structure also destroys the axisymmetry relative to the axial direction of the nozzle 30 . With respect to the particle distribution in the cross section 60 , the particle number density decreases on the inner side of the cross section, while the particle number density increases on the outer side of the cross section. This increases the number of magnetic particles captured by the reaction field electrode 14 .

[0117] (3) Example 3

[0118] Example 3 proposes a structure in which an asymmetric flow path structure is formed with respect to the direction 61 of the flow in the flow path 10 by processing the flow path in the middle of the pipette nozzle 30. Figures 16 to 19, Example 3 is described.

[0119] (i) Figure 16 The illustrated suction nozzle 30 is provided with a contraction portion 82 in the middle of the flow path so that the flow path becomes narrower with respect to the x-direction.

[0120] in addition, Figure 17 The pipette nozzle 30 shown has a hole 83 formed on the side surface of the flow path in the x direction. In this case, the suspension is sucked from both the tip of the pipette nozzle 30 and the hole 83.

[0121] Figure 18 The illustrated pipette nozzle 30 is connected to a branch channel 84 on the side surface in the middle of the channel in the x direction. In this case as well, the suspension is sucked from both the tip of the pipette nozzle 30 and the branch channel 84.

[0122] Figure 19 The suction nozzle 30 shown is formed such that the cross-sectional area on a surface parallel to the xy plane decreases from upstream to downstream and the flow path center in each cross section moves in the +x direction from upstream to downstream.

[0123] Through these structures, an asymmetric flow path structure can be formed relative to the direction 61 of the flow in the flow path 10. Therefore, the magnetic particles in the pipette nozzle 30 can be distributed sparsely on the inner side of the tube cross section and densely on the outer side of the tube cross section, which can increase the number of magnetic particles captured by the reaction field electrode 14. It should be noted that the pipette nozzle 30 of Example 3 is also Figure 9 The structure shown in FIG. 1 is similar to that shown in FIG. 1 , as long as it has asymmetry with respect to any plane passing through the central axis. Therefore, hole 83 ( Figure 17 ) or branch flow path 84 ( Figure 18 ) can be set at any position of the suction nozzle 30. In addition, the direction of movement of the flow path center ( Figure 19 ) is also any direction in the suction nozzle 30 (for example, the y direction, the direction at 45 degrees to the x-axis, etc.).

[0124] (ii) It should be noted that the structure described in Example 3 is merely an example; a structure in which the axes are inverted relative to the x-direction is also possible. This structure also destroys the axisymmetry relative to the axial direction of the nozzle 30 . With respect to the particle distribution in the cross section 60 , the particle number density decreases on the inner side of the cross section, while the particle number density increases on the outer side of the cross section. This increases the number of magnetic particles captured by the reaction field electrode 14 .

[0125] (4) Example 4

[0126] Example 4 involves controlling the position of the pipette nozzle 30 and the suspension container 40 to achieve Figure 7 B. Figure 7 C. Figure 8 A and Figure 8 Specifically, Example 4 proposes that the insertion position of the pipette nozzle 30 into the suspension container 40 be offset relative to the central axis of the container, making the fluid region in the suspension container 40 asymmetric relative to the central axis of the pipette nozzle 30, thereby forming a deviation in the flow of the suspension.

[0127] (i) Basic structure example

[0128] Figure 20 This is a diagram showing a state in which the central axis of the pipette nozzle 30 is arranged so as to be offset in the x-axis direction with respect to the central axis of the suspension container 40 . Figure 21 Yes Figure 20 A diagram showing the results of fluid analysis in the illustrated configuration relationship. Figure 21 A represents the distribution of magnetic particles in the cross section 60 . Figure 21 B is a graph showing the relationship between the distance from the center and the number of particles when the cross section 60 is centered on the axis of the suction nozzle 30 . Figure 21 C is represented by Figure 4 FIG4 is a graph showing the relationship between the distance from the center and the number of particles in each region after similar division.

[0129] According to the fourth embodiment, for example, in response to an instruction from an operator or in response to a pre-set command, the controller 50 controls the movement of the pipette nozzle 30 and the positional relationship between the two so that the pipette nozzle 30 is inserted into the suspension container 40 at a position offset from the axis center (for example, an offset of 0.5 mm to 3 mm). Then, the controller 50 controls the movement of the pipette nozzle 30 and the positional relationship between the two so that the pipette nozzle 30 is inserted into the suspension container 40 at a position offset from the axis center (for example, an offset of 0.5 mm to 3 mm). Figure 20 ) and the pump 35 is activated to suck the suspension. Then, the magnetic particles in the cross section 60 of the pipette nozzle 30 are distributed in the same manner as Figure 4 A and Figure 4 Compared to the conventional structure example shown in B, the particle number density inside the cross section (near the central axis (center)) is reduced, and the particle number density outside the cross section is increased. Figure 21 A and Figure 21 As shown in FIG. 6B , the particle number density on the downstream side is greater than that on the upstream side relative to the flow direction 61 in the flow channel 10 . Therefore, by controlling the insertion position of the pipette nozzle 30 into the suspension container 40 in Example 4, the number of magnetic particles captured by the reaction field electrode 14 can be increased.

[0130] (ii) Modification

[0131] Figure 22 This is a modification of Example 4, and is a diagram showing a mode in which the central axis of the suspension container 40 is tilted in the x-axis direction (or the y-axis direction) relative to the central axis of the pipette nozzle 30 .

[0132] According to this modified example, similar to the basic configuration example described above, the fluid region formed by the suspension container 40 and the flow path within the pipette nozzle 30 can be asymmetrically formed relative to the flow direction 61 within the flow path 10. Consequently, the particle number density decreases on the inner side of the cross section (near the central axis), while the particle number density increases on the outer side of the cross section. Furthermore, with respect to the flow direction 61 within the flow path 10, the particle number density increases on the downstream side compared to the upstream side, thereby increasing the number of magnetic particles captured by the reaction field electrode 14.

[0133] It should be noted that the inclination of the suspension container 40 can be achieved, for example, by controlling the inclination of a carrier (not shown) on which the suspension container 40 is fixedly mounted via the controller 50 , or by configuring the suspension container 40 to be tilted from the beginning when mounted on the carrier.

[0134] (iii) It should be noted that the structure described in Example 4 is merely an example, and a structure in which the axes are inverted relative to the x-direction is also possible. This structure also destroys the axisymmetry relative to the axial direction of the nozzle 30 . With respect to the particle distribution in the cross section 60 , the particle number density decreases on the inner side of the cross section, while the particle number density increases on the outer side of the cross section. This increases the number of magnetic particles captured by the reaction field electrode 14 .

[0135] (5) Example 5

[0136] Example 5 involves designing the shape of the suspension container 40 to achieve Figure 7 B. Figure 7 C. Figure 8 A and Figure 8 The distribution pattern of magnetic particles of B.

[0137] (i) Basic structure example

[0138] Figure 23 1 is a diagram showing a structural example of a suspension container 40 according to a fifth embodiment. Figure 23 A is a diagram of a cross-sectional structure on a plane passing through the central axis of the suspension container 40 and parallel to the zx plane. Figure 23 B is a diagram of a cross-sectional structure on a plane passing through the central axis of the suspension container 40 and parallel to the yz plane. Figure 23 C is a diagram showing a cross-sectional structure on a surface parallel to the xy plane. Figure 23 As shown in C, the suspension container 40 shown in Example 5 has an elliptical shape with the x-axis direction as the short axis and the y-axis direction as the long axis in the cross section on the surface parallel to the xy plane.

[0139] With this structure, the flow of the fluid flowing from the suspension container 40 into the pipette nozzle 30 loses its axisymmetry. Consequently, in the cross-section 60 of the pipette nozzle 30, the particle number density decreases on the inside (near the central axis) and increases on the outside compared to the conventional structure described above. This increases the number of magnetic particles captured by the reaction field electrode 14.

[0140] (ii) Modification

[0141] Figure 24 This is a variation of Example 5, illustrating a method for disrupting the axial symmetry of the fluid flow (achieving axial asymmetry) by providing protrusions in the x-axis direction within the suspension container 40. With the structure shown in this variation, the protrusions disrupt the axial symmetry of the flow of the fluid flowing from the suspension container 40 into the pipette nozzle 30. Consequently, in a cross section 60 of the pipette nozzle 30, compared to the conventional structure described above, the particle number density is lower on the inside (near the central axis) and higher on the outside. This increases the number of magnetic particles captured by the reaction field electrode 14.

[0142] (iii) It should be noted that the structure described in Example 5 is merely an example, and a structure in which the axes are inverted with respect to the x-direction is also possible. This structure also destroys the axisymmetry with respect to the axial direction of the nozzle 30 . With respect to the particle distribution in the cross section 60 , the particle number density decreases on the inner side of the cross section, while the particle number density increases on the outer side of the cross section. This increases the number of magnetic particles captured by the reaction field electrode 14 .

[0143] (6) Example 6

[0144] Example 6 relates to the distribution of magnetic particles contained in the suspension sucked from the pipette nozzle 30 in the flow path 10 by flowing the solvent from a path different from the pipette nozzle 30. Figure 8 The method shown in B.

[0145] Figure 25 It is used to illustrate the flow path structure and formation of Example 6. Figure 8 B shows the distribution of magnetic particles. Figure 26 Indicates the results of fluid analysis. Figure 26 A is a graph showing the distribution of magnetic particles in the cross section 60. In this analysis, the uniformly dispersed Figure 26 The state shown in A is taken as the initial state. Figure 26 B is a diagram showing the distribution of magnetic particles in the cross section 63 .

[0146] like Figure 25As shown in FIG. 1A , a flow path 90 is connected horizontally upstream of the flow path 10. At the confluence portion 85, the flow path 90 is connected to a pipe (flow path) 32 extending vertically downward (in the −z direction). A mechanism (not shown) for flowing the solvent is connected to the flow path 90. In the flow path 90, the solvent, which does not contain the magnetic particles constituting the suspension, flows in a flow direction 91.

[0147] According to the structure of Example 6, Figure 25 As shown in FIG. 8B , at the confluence portion 85 , the suspension containing magnetic particles flowing from the tube (channel) 32 and the solvent flowing from the channel 90 merge to form parallel flows in the channel 10 . The suspension containing magnetic particles 13 flows primarily vertically downward in the channel 10 , while the solvent flowing from the channel 90 flows primarily vertically upward. Figure 26 As shown in FIG. 1B , the magnetic particles 13 flow downward relative to the vertical direction in the flow channel 10. Therefore, they are more susceptible to the magnetic force of the magnet 20 and are easily captured by the reaction field electrode 14. As a result, the number of captured magnetic particles can be increased.

[0148] (7) Example 7

[0149] Example 7 relates to the implementation of the flow cell 200 without the pipette nozzle 30. Figure 8 B shows the distribution of magnetic particles in mode 1.

[0150] Figure 27 This is a diagram showing a structural example of a flow cell in Example 7. Figure 27 A is a diagram showing an example of the upper surface structure of the flow cell 200 of Example 7. Figure 27 B stands for Figure 27 A diagram showing an example of the structure of the AA cross section of A. Figure 28 This is a diagram showing the results of fluid analysis in Example 7. Figure 28 A represents the distribution of magnetic particles in the cross section 64 on the upstream side of the contraction plate 86 , and is a diagram showing a state in which the magnetic particles are evenly distributed in the cross section 64 . Figure 28 B is a diagram showing the distribution of magnetic particles in the cross section 65 on the downstream side of the contraction flow plate 86 .

[0151] The flow cell 200 of Example 7 is constructed as a plate-shaped flow cell with a suspension inlet 87, a flow channel 90, and a flow channel 10 integrally formed. In the flow cell 200, the flow channel 90 is horizontally connected to the upstream side of the flow channel 10, and the suspension inlet 87 for supplying the suspension is connected to the upstream side thereof. A constricted flow plate 86 is provided midway along the flow channel 90, on the vertically upper side, i.e., on the flow channel top wall 11, to reduce the width of the flow channel 90.

[0152] The suspension containing magnetic particles prepared in advance is supplied to the suspension injection port 87 through a nozzle (not shown). Then, the controller 50 operates the pump 35, and the supplied suspension flows in the direction of the flow direction 61 and passes through the contraction plate 86. The magnetic particles 13 (see FIG. 1 ) are uniformly distributed on the upstream side of the contraction plate 86. Figure 28 A) When passing through the contraction plate 86, as Figure 28 As shown in B, the distribution of magnetic particles 13 is biased toward the vertically downward side. Therefore, magnetic particles 13 are easily affected by the magnetic force of magnet 20 in flow channel 10 and are easily captured by reaction field electrode 14. As a result, the number of captured magnetic particles 13 can be increased.

[0153] It should be noted that, while Example 7 shows a configuration in which the constricted flow plate 86 is provided in the flow channel 90, it may also be provided in the flow channel 10 upstream of the reaction field electrode 14 serving as the capture region. The closer the constricted flow plate 86 is to the capture region, the higher the capture effect.

[0154] (8) Example 8

[0155] Example 8 relates to the implementation of the flow cell 300 without the pipette nozzle 30. Figure 8 B shows the distribution of magnetic particles in mode 2.

[0156] Figure 29 This is a diagram showing a structural example of a flow cell in Example 8. Figure 29 A is a diagram showing an example of the upper surface structure of the flow cell 300 of Example 8. Figure 29 B stands for Figure 29 A diagram showing an example of the structure of the AA cross section of A. Figure 30 It is a diagram showing the flow path state when the suspension and the solvent are injected.

[0157] The flow cell 300 of Example 8 is constructed as a plate-shaped flow cell in which the suspension injection port 87, the solvent injection port 88, the flow path 90, and the flow path 10 are integrated. In the flow cell 300, the flow path 90 is horizontally connected to the upstream side of the flow path 10. In addition, the suspension injection port 87 and the solvent injection port 88 are provided on the upstream side of the flow path 90. It should be noted that the suspension injection port 87 is provided at a position upstream of the solvent injection port 88.

[0158] A suspension containing magnetic particles prepared in advance is supplied to the suspension injection port 87 through a nozzle (not shown), and a solvent containing no magnetic particles is supplied to the solvent injection port 88. Under the control of the controller 50, the suspension and solvent supplied by the pump 35 flow in the direction of the flow 61. When the suspension containing magnetic particles passes through the connection portion of the solvent injection port 88, it merges with the solvent to form a Figure 30At this time, magnetic particles 13 flow downward relative to the vertical direction within flow path 90 and flow path 10. Therefore, magnetic particles 13 are more susceptible to the magnetic force of magnet 20 and are therefore more easily captured by reaction field electrode 14. As a result, the number of magnetic particles captured can be increased.

[0159] Note that, in Example 8, a plate in which the suspension injection port 87 and the solvent injection port 88 are integrated is described. However, for example, the flow path, injection port, and confluence portion for performing pretreatment for preparing the suspension may be provided on a plate further upstream.

[0160] (9) Summary

[0161] (i) The embodiments of the present disclosure will be described in various embodiments. While all embodiments are presented here, the sample analyzer (immunoassay device 100) of the present disclosure is characterized by including a magnetic particle distribution adjustment unit (the structure of this magnetic particle distribution adjustment unit differs in Examples 1 to 8). This magnetic particle distribution adjustment unit distributes magnetic particles 13 in a cross section perpendicular to the flow direction 61 of the sample liquid (suspension) at the capture region (reaction field electrode 14) of the flow channel 10 so that the distribution in the proximal region, closer to the capture region (reaction field electrode 14) than the central axis of the flow channel 10, is denser than the distribution in the distal region, farther from the central axis when viewed from the capture region. The inclusion of the magnetic particle distribution adjustment unit improves the capture efficiency of magnetic particles at a predetermined location in the sample analyzer, enabling highly sensitive detection.

[0162] (ii) According to Example 1, the flow path 10 including the capture region (reaction field electrode 14) is placed horizontally. In this case, the magnetic particle distribution adjustment unit is composed of a sample liquid introduction tube (pipette nozzle 30) extending from the flow path 10 in the vertical direction. Moreover, the sample liquid introduction tube (pipette nozzle 30) is configured to be asymmetrical with respect to a predetermined plane including the central axis of the pipette nozzle 30. In this case, when the sample liquid (suspension) is introduced into the flow path 10 via the pipette nozzle 30, the distribution of the magnetic particles 13 in the cross section perpendicular to the flow direction of the sample liquid suspension at the pipette nozzle 30 or to the axis of the pipette nozzle 30 is greater on the outside of the cross section 60 than on the outside of the cross section 60 (refer to Figure 2 ) is denser on the inside (with respect to the direction 61 of the sample liquid flow, the downstream side is denser than the upstream side). Then, after the sample liquid (suspension) is transferred from the pipette nozzle 30 to the flow path 10, the distribution of the magnetic particles 13 in the cross section perpendicular to the direction 61 of the sample liquid (suspension) flow is denser in the proximal region than in the distal region. As a result, in the cross section 60 of the pipette nozzle 30, a Figure 8 The distribution of magnetic particles 13 as shown in A can be Figure 8The magnetic particles are distributed in the flow channel 10 as in B. Therefore, the capture rate of the magnetic particles in the capture region (reaction field electrode 14) can be improved.

[0163] The pipette nozzle 30 in Example 1 is shaped like a syringe needle. Specifically, the tip of the pipette nozzle 30, which extends vertically from the flow channel 10, is tilted at a predetermined angle to the horizontal, resulting in an elliptical opening. In this case, the predetermined angle is at least 20 degrees.

[0164] (iii) The nozzle 30 of Example 2 has a plurality of bends between its front end and the junction (bend 80) with the flow channel 10 (see Figure 14 By adopting the structure shown in Example 2, it is possible to form a Figure 8 The distribution of magnetic particles 13 as shown in A can be Figure 8 The magnetic particles are distributed in the flow channel 10 as in B. Therefore, the capture rate of the magnetic particles in the capture region (reaction field electrode 14) can be improved.

[0165] (iv) The nozzle 30 of Example 3 has a constricted flow portion 82 (see FIG. 8 ) that narrows the tube diameter between the tip and the junction with the flow path 10 (the bent portion 80 ). Figure 16 ). Alternatively, a hole may be provided on the side of the tube between the front end of the suction nozzle 30 and the joint (bend 80) (see Figure 17 Furthermore, the pipette nozzle 30 may be configured to have a branch tube on the side surface of the tube between the front end and the joint (bend 80) for introducing the sample liquid (suspension) from a direction different from that of the front end (see Figure 18 ). In addition, the suction nozzle 30 may be configured so that the tube diameter gradually changes from the front end portion to the joint portion (bend portion 80) (see Figure 19 By adopting the structure shown in Example 3, it is possible to form a Figure 8 The distribution of magnetic particles 13 as shown in A can be Figure 8 The magnetic particles are distributed in the flow channel 10 as in B. Therefore, the capture rate of the magnetic particles in the capture region (reaction field electrode 14) can be improved.

[0166] (v) According to Example 4, the flow channel 10 including the capture region (reaction field electrode 14) is placed horizontally. In this case, the magnetic particle distribution adjustment unit is configured to insert the pipette nozzle 30 extending vertically from the flow channel 10 into the sample container (suspension container 40) containing the sample liquid (suspension) at a predetermined offset from the central axis of the sample container, and to aspirate the sample liquid (refer to Figure 20 In addition, another embodiment of the present invention (according to Figure 22 ), the magnetic particle distribution adjustment unit is constructed so that a pipette nozzle 30 extending from the flow path 10 in the vertical direction is inserted into a sample container (suspension container) whose central axis is tilted relative to the horizontal direction, and the sample liquid (suspension) is sucked from the sample container. The tilt of the sample container can be achieved by controlling the carrier on which the sample container is placed to tilt the sample container, or the sample container itself can be tilted relative to the horizontal direction. With such a structure, the flow of the sample liquid (suspension) in the sample container (during suction) can be made asymmetrical around the pipette nozzle 30. Therefore, in the cross section 60 of the pipette nozzle 30, a Figure 8 The distribution of magnetic particles 13 as shown in A can be Figure 8 The magnetic particles are distributed in the flow channel 10 as in B. Therefore, the capture rate of the magnetic particles in the capture region (reaction field electrode 14) can be improved.

[0167] (vi) According to Example 5, in the sample analysis device (immunoassay device 100), the magnetic particle distribution adjustment unit is configured to insert a pipette nozzle 30 extending vertically from the flow path 10 into a sample container having an asymmetric shape (the sample container has an elliptical cross-section in the horizontal direction, or the sample container has a protrusion on its inner side surface) relative to a predetermined plane containing the central axis of the sample container (suspension container 40), and to aspirate the sample liquid (suspension) from the sample container. This structure can make the flow of the sample liquid (suspension) in the sample container (during aspiration) asymmetric around the pipette nozzle 30. Therefore, in the cross section 60 of the pipette nozzle 30, a Figure 8 The distribution of magnetic particles 13 as shown in A can be Figure 8 The magnetic particles are distributed in the flow channel 10 as in B. Therefore, the capture rate of the magnetic particles in the capture region (reaction field electrode 14) can be improved.

[0168] (vii) According to Example 6, in a sample analyzer (immunoassay device 100), a flow channel 10 including a capture region (reaction field electrode 14) is placed horizontally, and a magnetic particle distribution adjustment unit sucks a sample liquid (suspension) from a sample container (suspension container 40) using a pipette nozzle 30 extending vertically from the flow channel 10, and sucks a solvent through a solvent supply flow channel (flow channel 90) extending horizontally (in the opposite direction of the flow channel 10) from a connection portion (merging portion 85) between the flow channel 10 and the pipette nozzle 30, so that the sample liquid and the solvent merge at the junction portion (merging portion 85). Thus, it is possible to Figure 26 The magnetic particles are distributed in the flow channel 10 as in B. Therefore, the capture rate of the magnetic particles in the capture region (reaction field electrode 14) can be improved.

[0169] (viii) According to Example 7, in the sample analysis device (immunoassay device 100), the magnetic particle distribution adjustment unit is configured to have a sample liquid injection port (suspension injection port 87) provided on the upstream side of the flow path 10 for injecting the sample liquid (suspension), and to suck the sample liquid injected from the sample injection port of the sample liquid injection flow path (flow path 90) having a constriction plate 86 on the top surface of the flow path for limiting the flow path width, and to introduce the sample liquid into the capture area (reaction field electrode 14) of the flow path 10. Thus, it is possible to Figure 28 The magnetic particles are distributed in the flow channel 10 as in B. Therefore, the capture rate of the magnetic particles in the capture region (reaction field electrode 14) can be improved.

[0170] (ix) According to Example 8, in the sample analysis device (immunoassay device 100), the magnetic particle distribution adjustment unit is configured to include a sample liquid injection port (suspension injection port 87) provided on the upstream side of the flow path 10 for injecting the sample liquid (suspension) and a solvent injection port 88 for injecting the solvent, and the sample liquid injected from the sample injection port and the solvent injected into the solvent injection port are sucked and introduced into the capture area (reaction field electrode 14) of the flow path 10. Thus, it is possible to Figure 8 The magnetic particles are distributed in the flow channel 10 as in B. Therefore, the capture rate of the magnetic particles in the capture region (reaction field electrode 14) can be improved.

[0171] Description of reference numerals:

[0172] 10 flow path

[0173] 11 Flow path top wall

[0174] 12 Flow path bottom wall

[0175] 13 Magnetic particles

[0176] 14 Reaction Field Electrode

[0177] 15 Counter electrode

[0178] 16, 17 Voltage application unit

[0179] 20 magnets

[0180] 23 Photodetector

[0181] 30 straw nozzle

[0182] 31 Arm

[0183] 32, 33, 34 tubes (flow path)

[0184] 35 pumps

[0185] 36, 37 valves

[0186] 38 Tip of the pipette

[0187] 40 Suspension container

[0188] 41 reaction units

[0189] 42 Cleaning fluid container

[0190] 43 buffer container

[0191] 44 Cleaning mechanism

[0192] 45 Waste container

[0193] 50 Controller

[0194] 51, 52, 53 signal lines

[0195] 55a, 55b, 55c, 56a, b, 57 signal lines

[0196] 60 Cross section of the pipette nozzle 30

[0197] 61 Direction of flow in flow path 10

[0198] 63 downstream side section

[0199] 64 Cross section of upstream side of contraction plate 86

[0200] 65 Cross section of the downstream side of the contraction plate 86

[0201] 71 protrusion

[0202] 80 bend

[0203] 82 contraction

[0204] 83 holes

[0205] 84 branch flow path

[0206] 85 Convergence Department

[0207] 86 Constriction plate

[0208] 87 Suspension injection port

[0209] 88 Solvent injection port

[0210] 90 flow path

[0211] 91 Flow direction of flow path 90

[0212] 100 Immunoassay device (sample analysis device).

Claims

1. A sample analysis device, wherein: The sample analysis device comprises: a flow channel having a capture region defined therein, into which a sample solution containing magnetic particles bound to a specific substance is introduced; a supply unit that supplies the sample liquid to the flow path; a capture unit that generates a magnetic field, through which the magnetic particles are attracted to the capture area; a magnetic particle distribution adjusting unit configured to distribute the magnetic particles in a cross section perpendicular to the flow direction of the sample liquid at the capture region of the flow path so that the distribution of the magnetic particles in a proximal region closer to the capture region than the central axis of the flow path is denser than the distribution in a distal region farther from the central axis when viewed from the capture region; a measuring unit for measuring a specific substance adsorbed on the capture area; as well as A discharge unit discharges the magnetic particles from the flow path after the measurement by the measurement unit.

2. The sample analysis device according to claim 1, wherein The flow channel including the capture area is placed horizontally, The magnetic particle distribution adjustment unit is composed of a sample liquid introduction tube extending vertically from the flow path. The sample liquid introduction tube is configured to have an asymmetrical shape with respect to a predetermined plane including a central axis of the sample liquid introduction tube.

3. The sample analysis device according to claim 2, wherein: When the supply unit introduces the sample liquid into the flow path via the sample liquid introduction tube, the magnetic particles in a cross section perpendicular to the flow direction of the sample liquid at the sample liquid introduction tube or the axis of the sample liquid introduction tube are distributed more densely on the outside of the cross section than on the inside of the cross section. After the sample liquid is transferred from the sample liquid introduction tube to the flow channel, the magnetic particles are distributed more densely in the proximal region than in the distal region in a cross section perpendicular to the flow direction of the sample liquid.

4. The sample analysis device according to claim 3, wherein When the supply unit introduces the sample liquid into the flow path via the sample liquid inlet tube, the distribution of the magnetic particles in a cross section perpendicular to the flow direction of the sample liquid at the sample liquid inlet tube or the axis of the sample liquid inlet tube is denser on the downstream side than on the upstream side relative to the flow direction of the sample liquid in the flow path.

5. The sample analysis device according to claim 2, wherein: The distal end portion of the sample liquid introduction tube extending from the flow channel in the vertical direction is inclined to form a predetermined angle with the horizontal direction, and the opening of the distal end portion has an elliptical shape.

6. The sample analysis device according to claim 5, wherein: The predetermined angle is greater than or equal to 20 degrees.

7. The sample analysis device according to claim 6, wherein: The predetermined angle is greater than or equal to 60 degrees.

8. The sample analysis device according to claim 2, wherein: The sample liquid introduction tube has a plurality of bends between the distal end portion and the junction with the flow channel.

9. The sample analysis device according to claim 2, wherein: The sample liquid introduction tube has a constricted portion where the tube diameter is narrowed between the distal end portion and the junction with the flow path.

10. The sample analysis device according to claim 2, wherein The sample liquid introduction tube has a hole formed on a tube side surface between the distal end portion and the junction with the flow channel.

11. The sample analysis device according to claim 2, wherein: The sample liquid introduction tube has a branch tube on a tube side surface between a distal end portion and a junction with the flow channel for introducing the sample liquid from a direction different from that of the distal end portion.

12. The sample analysis device according to claim 2, wherein: The sample liquid introduction tube is configured such that a tube diameter gradually changes from a distal end portion to a junction with the flow channel.

13. The sample analysis device according to claim 1, wherein The flow channel including the capture area is placed horizontally, The magnetic particle distribution adjusting unit inserts a sample liquid introduction tube extending vertically from the flow path into a sample container containing the sample liquid at a predetermined offset from the central axis of the sample container, and aspirates the sample liquid.

14. The sample analysis device according to claim 1, wherein The flow channel including the capture area is placed horizontally, The magnetic particle distribution adjusting unit inserts a sample liquid introduction tube extending vertically from the flow path into a sample container whose central axis is inclined with respect to the horizontal direction, and aspirates the sample liquid from the sample container.

15. The sample analysis device according to claim 14, wherein The magnetic particle distribution adjusting unit controls a stage on which a sample container containing the sample liquid is placed to tilt the sample container.

16. The sample analysis device according to claim 14, wherein The sample container itself is configured to be inclined relative to the horizontal direction.

17. The sample analysis device according to claim 1, wherein The flow channel including the capture area is placed horizontally, The magnetic particle distribution adjustment unit inserts a sample liquid introduction tube extending vertically from the flow path into a sample container having an asymmetrical shape with respect to a predetermined plane including a central axis, and aspirates the sample liquid from the sample container.

18. The sample analysis device according to claim 17, wherein The cross section of the sample container in the horizontal direction has an elliptical shape.

19. The sample analysis device according to claim 17, wherein The sample container has a protrusion on an inner side surface of the sample container.

20. The sample analysis device according to claim 1, wherein The flow channel including the capture area is placed horizontally, The magnetic particle distribution adjustment unit uses a sample liquid introduction tube extending from the flow path in a vertical direction to draw the sample liquid from a sample container containing the sample liquid, and draws solvent through a solvent supply flow path extending from a connection portion between the flow path and the sample liquid introduction tube in a horizontal direction, so that the sample liquid and the solvent merge at the connection portion.

21. The sample analysis device according to claim 1, wherein The magnetic particle distribution adjustment unit is constructed to have a sample liquid injection port arranged on the upstream side of the flow path and used to inject the sample liquid, and to suck the sample liquid injected from the sample liquid injection port into the sample liquid injection path having a contraction portion on the top surface of the flow path that limits the flow path width, and introduce it into the capture area of ​​the flow path.

22. The sample analysis device according to claim 1, wherein The magnetic particle distribution adjustment unit is constructed to have a sample liquid injection port arranged on the upstream side of the flow path and used to inject the sample liquid, and a solvent injection port for injecting the solvent, and the sample liquid injected from the sample liquid injection port and the solvent injected into the solvent injection port are sucked and introduced into the capture area of ​​the flow path.

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