Sample analysis device

Abstract

To provide a sample analyzer that realizes an increase in capture rate of magnetic particles.SOLUTION: A sample analyzer comprises: a flow channel for introducing a sample liquid that contains magnetic particles bound to a specific substance into a capture region; supply means for supplying the sample liquid to the flow channel; capture means which has a magnetic field structure to generate a magnetic field, and causes the magnetic field to adsorb the magnetic particles in the capture region; measurement means for measuring the specific substance adsorbed in the capture region; and ejection means for ejecting the magnetic particles from the flow channel after measurement performed by the measurement means. The magnetic field structure is located outside of the flow channel and includes a plurality of magnets differing in the direction of magnetization from each other, the plurality of magnets being arranged so that the flux density on the flow channel side is larger than the flux density on the side opposite the flow channel.SELECTED DRAWING: Figure 4

Description

Technical Field

[0001] The present invention relates to a sample analyzer, for example, one that utilizes the reaction between an antigen and an antibody.

Background Art

[0002] First, as an example of sample analysis, immunoassay will be described.

[0003] Immunoassay is to detect or measure antibodies or antigens in body fluids (such as plasma, serum, urine, etc.) by utilizing the specific reaction between an antigen and an antibody for the purpose of diagnosing diseases or pathological conditions. As a typical method, there is the ELISA method (Enzyme-Linked Immunosorbent Assay).

[0004] As a typical implementation process of the ELISA method, an antibody (primary antibody) against the antigen to be measured is immobilized in a container, and then samples such as plasma, serum, and urine are put therein to bind the antigen in the sample to the primary antibody. Further, an antibody (secondary antibody) with a label bound thereto is bound to the antigen bound to the primary antibody. The conjugate of the primary antibody, antigen, secondary antibody, and label is collected, and by detecting the signal emitted from the label, the presence or amount of the antigen in the sample is measured.

[0005] As the label, for example, a fluorescent substance or the like is used. In this case, the luminescence becomes stronger in proportion to the number of secondary antibodies bound with the label, that is, the amount of antigen in the conjugate, and by detecting the luminescence of the fluorescent substance with a photomultiplier tube or the like, the antigen in the sample can be quantified.

[0006] In a specific example of an immunoassay device using the ELISA method, magnetic particles are used as the solid phase, and the primary antibody is immobilized on the surface of the magnetic particles. A substance (luminescent labeling substance) with a fluorescent dye bound as a label is bound to the secondary antibody. By mixing a biological-derived detection substance (antigen) and the magnetic particles with the primary antibody immobilized thereon to cause an antigen-antibody reaction, a specific antigen contained in the sample binds to the magnetic particles via the primary antibody. Further, when the secondary antibody is reacted, the luminescent labeling substance binds to the magnetic particles via the secondary antibody, antigen, and primary 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.

[0007] While flowing a sample containing magnetic particles to which a detection substance is bound through an arbitrary flow path, the magnetic particles are adsorbed at a predetermined position in the middle of the flow path. By applying a laser or the like to the adsorbed magnetic particles, the luminescent labeling substance bound to the magnetic particles is caused to emit light. By detecting the luminescence intensity at this time, the amount of the detection substance in the sample, that is, the amount of the antigen, can be measured, and quantitative measurement is performed.

[0008] In order to perform highly sensitive immunoassay, so-called B / F separation (Bound / Free separation, separation of antigen-antibody conjugates and unconjugates) is performed in which magnetic particles to which a detection substance (antigen) is bound are adsorbed and captured at a specific location using a magnet or the like, and the solution containing the antibody not bound to the antigen is replaced.

[0009] In the analyzer, there is Patent Document 1 as a method of adsorbing magnetic particles at a predetermined position using a magnet or the like.

[0010] Further, Non-Patent Document 1 describes the action of a magnetic field on a substance and the like.

Prior Art Documents

Patent Documents

[0011]

Patent Document 1

Non-Patent Documents

[0012]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0013] When adsorbing magnetic particles using a magnet or the like, in order to efficiently detect luminescence and luminescence intensity, it is necessary to perform adsorption to a predetermined range (predetermined position) on the flow path wall surface. However, there are the following problems in adsorbing magnetic particles to a predetermined position.

[0014] To adsorb magnetic particles to a predetermined position, a magnetic field is generated using a magnet or the like to apply a magnetic force to the magnetic particles. However, if there is a weak magnetic field area within the range of the predetermined position, the magnetic particles cannot be sufficiently adsorbed. That is, the capture rate of the magnetic particles becomes low. This is particularly remarkable when the flow rate of the sample liquid in the flow path is large, or when the cross-sectional area of the flow path is large and the magnetic field of the magnet hardly affects the entire cross-section of the flow path. Here, the capture rate is the ratio of the magnetic particles that could be captured at a predetermined position among the magnetic particles contained in the sample.

[0015] Even when the magnetic field is sufficiently strengthened within the range of the predetermined position, in the process of adsorbing magnetic particles from the fluid, the behavior of the magnetic particles becomes asymmetric between the upstream side and the downstream side depending on the direction of the flow. Also, near the wall surface and near the center in the flow path, the behavior of the magnetic particles is different because the fluid behavior is different. From these, the adsorption distribution of the magnetic particles can become non-uniform.

[0016] Regarding the non-uniform adsorption distribution of magnetic particles, for example, magnetic particles adsorbed at a location outside the predetermined position do not contribute to luminescence, thus degrading the measurement performance. Also, inside the predetermined position, variations in the density of the adsorbed magnetic particles may occur, and the sparse areas reduce the luminescence sensitivity, so the measurement performance is also degraded in this case.

[0017] In addition, if adsorption that protrudes beyond the predetermined position of the magnetic particles or variations in density during adsorption occur, when replacing the solution during B / F separation, the solution remains in the aggregated portion of the magnetic particles due to the interfacial tension of the solution, and sufficient B / F separation cannot be achieved.

[0018] In Patent Document 1, as a method for preventing non-uniform adsorption caused by the asymmetry between the upstream and downstream flows, a structure in which magnets are arranged at an inclination and a structure in which the ends of the magnets are cut off are shown. Methods such as increasing the distance between the flow path and the magnet on the upstream side to weaken the magnetic field, while achieving uniform collection of magnetic particles, partially impair the original material function of the magnet and the advantages of the magnet arrangement. Therefore, increasing the collection rate of magnetic particles has been a problem. Here, the material function is, for example, the residual magnetic flux density of the material, and the advantage of the magnet arrangement is, for example, that the magnet is located close to the object for which a magnetic field is to be generated.

[0019] In view of the above problems, an object of the present invention is to provide a sample analysis apparatus that realizes an increase in the collection rate of magnetic particles.

Means for Solving the Problems

[0020] An example of the sample analysis apparatus according to the present invention is a flow path for introducing a sample liquid containing magnetic particles bound to a specific substance into a capture region, supply means for supplying the sample liquid to the flow path, capture means having a magnetic field structure that generates a magnetic field and adsorbs the magnetic particles to the capture region by the magnetic field, measurement means for measuring the specific substance adsorbed in the capture region, discharge means for discharging the magnetic particles from the flow path after measurement by the measurement means, in a sample analysis apparatus comprising the magnetic field structure is arranged outside the flow path and includes a plurality of magnets having different magnetization directions, and the plurality of magnets are arranged such that the magnetic flux density on the flow path side is larger than the magnetic flux density on the side opposite to the flow path. characterized in that 。

Advantages of the Invention

[0021] The sample analyzer according to the present invention can increase the capture rate of magnetic particles.

Brief Description of the Drawings

[0022]

Figure 1

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Figure 15

Modes for Carrying Out the Invention

[0023] Hereinafter, embodiments of the present invention will be described with reference to the drawings.

Embodiment

[0024] As an example of a sample analyzer which is one of the embodiments, an immunoassay analyzer will be described. The present invention is applicable not only to immunoassay, but also to a sample analyzer that captures magnetic particles using magnetic particles, and can be similarly used for analyzers for DNA, biochemistry, etc. In addition, in the following description, unless otherwise specified, the terms "direction" and "orientation" follow general physical expressions, where "direction" simply means a straight line state, and "orientation" means the progress from a certain starting point in one direction.

[0025] Fig. 1 shows a schematic configuration diagram of the immunoassay analyzer. In Fig. 1, the flow path 10 is connected to the sipper nozzle 30 and the pump 35 through the tubes 32 and 33. The sipper nozzle 30 is movably attached by the arm 31, and the suspension container 40, the cleaning liquid container 42, and the buffer solution container 43 are installed within its moving range.

[0026] The valve 36 is provided in the tube 33 between the flow path 10 and the pump 35. The pump 35 is controlled from the controller 50 through the signal line 52, and is capable of accurately sucking and discharging a liquid volume. The pump 35 further continues to the waste liquid container 45 through the tube 34.

[0027] The part composed of the flow path 10, the flow path walls 11 and 12, and the adsorption predetermined position 14 is called a detection unit (or a flow cell as an integral member). The flow path wall 11 of the flow cell is formed of a transparent material, and the flow path 10 through which a solution flows is formed inside. The flow path walls 11 and 12 can be configured using, for example, planar plates respectively, but are not limited thereto. Since the flow path wall 11 is formed of a transparent material, it transmits light and the internal flow state can be observed. It is not necessarily required that the entire flow path wall 11 be transparent, and it is sufficient that only the portion through which light transmits is transparent as a window.

[0028] The flow path wall 11 is preferably made of a material that is substantially transparent to the wavelength of the light emitted by the labeling substance of the magnetic particle composite adsorbed on the adsorption portion in the flow cell. For example, it is preferably made of glass, plastic, or the like.

[0029] At the adsorption predetermined position 14 installed in the flow path 10, a reaction field electrode 16 is installed. Further, from the reaction field electrode 16 (adsorption predetermined position 14), a counter electrode 17 is installed around the facing surface in the flow path 10. Furthermore, the reaction field electrode 16 and the counter electrode 17 are connected to a voltage application means 18 via lead wires 19a and 19b. The voltage application means 18 is connected to a controller 50 via a signal line 58.

[0030] Furthermore, a magnet 15 is used as a magnetic field application means for adsorbing magnetic particles. The magnet 15 is a permanent magnet or an electromagnet. When adsorbing magnetic particles, for example, the magnet 15 is moved directly below the flow path 10. For example, the magnet 15 is installed in a slide mechanism 20 that can be freely moved in the horizontal direction, and the magnet 15 is moved directly below the flow path 10 when adsorbing magnetic particles.

[0031] The magnetic particles 13 are adsorbed to the adsorption predetermined position 14 in the flow path 10 by the magnetic force received from the magnetic field of the magnet 15. The adsorption predetermined position 14 is a surface having a predetermined area, which is easy to perform luminescence measurement. In this embodiment, the adsorption predetermined position 14 is provided on the bottom surface of the flow path 10, but it may be on other surfaces in the flow path 10 or a plurality of three-dimensionally arranged surfaces.

[0032] When cleaning the inside of the flow path 10, for example, by moving the magnet 15 to a position where the influence of the magnet 15 in the flow path 10 can be sufficiently reduced, it can be sufficiently cleaned.

[0033] The slide mechanism 20 does not necessarily need to move horizontally. As long as it can reduce the influence of the magnetic field during cleaning, it may move vertically, or move in both horizontal and vertical directions. Further, the magnet 15 may be an electromagnet. In that case, instead of moving the position, the magnetic field in the flow path 10 can be controlled by the applied current.

[0034] The controller 50 is connected to the valves 36 and 37, the pump 35, the arm 31, the voltage application means 18, the photodetector 23, and the slide mechanism 20 by signal lines 51, 52, 53, 54, 56, 57, 58, and can be independently controlled.

[0035] In the measurement, the voltage application means 18 is controlled by the controller 50. Accordingly, when a voltage is applied between the reaction field electrode 16 and the counter electrode 17 in the flow path 10, the labeling substance combined with the magnetic particles 13 adsorbed on the reaction field electrode 16 (adsorption predetermined position 14) can be electrochemically luminesced. The flow path wall 11 does not need to be a transparent material in other parts as long as the periphery of the counter electrode 17 is made of a transparent material so that measurement by the photodetector 23 is possible.

[0036] The materials of the reaction field electrode 16 and the counter electrode 17 can be composed of, for example, gold, platinum, palladium, tungsten, iridium, nickel, their alloys, carbon materials, etc. Further, for the reaction field electrode 16 and the counter electrode 17, those formed by plating or sputtering the above materials on a base material such as titanium can also be used.

[0037] By adopting the light emission method using the counter electrode 17, the reaction field electrode 16 and the counter electrode 17 can be fixed to the flow cell. Compared with the immunoassay apparatus using the laser light described in FIG. 2 hereinafter, the immunoassay apparatus of FIG. 1 does not require the condenser lens 21 and the laser light source 22. Therefore, the positioning of the laser light, the selection and installation of the transparent material at the adsorption predetermined position 14 are omitted, and simplification of the apparatus and suppression of the variation in light emission can be expected.

[0038] For the photodetector 23, for example, a camera or a photomultiplier tube can be used.

[0039] The sample to be analyzed is a substance derived from a living body such as serum or urine. When the sample is serum, the specific components to be analyzed are, for example, tumor markers, antibodies, or antigen-antibody complexes, single proteins. In the following description, it is assumed that the specific component is TSH (thyroid-stimulating hormone).

[0040] In the suspension container 40, as a pretreatment process, the sample to be analyzed is mixed with a bead solution and a reagent, and then reacted at a constant temperature (for example, 37 degrees) for a certain period of time (suspension). The bead solution is a solution in which magnetic particles 13 in which particulate magnetic substances are embedded in a matrix material such as polystyrene are dispersed in a buffer solution, and streptavidin capable of binding to biotin is bound to the surface of the matrix material. The reagent contains a substance that binds the magnetic particles 13 to the specific component TSH in the sample, and this includes an anti-TSH (Thyroid Stimulating Hormone) antibody with a biotinylated end. The reagent varies depending on the type of specific component to be analyzed, and for example, immunoglobulins, antigens, antibodies, or other biological substances are used.

[0041] The cleaning liquid container 42 contains a cleaning liquid for cleaning the inside of the flow path 10 and the tube 32.

[0042] When the shape of the flow path 10 is defined by the length in the direction along the flow (path length), the thickness (vertical dimension) of the cross section perpendicular to the flow, and the width (horizontal dimension), it is desirable that the path length is formed to be 2 to 20 times the length of the larger one of the thickness and the width. This is to ensure a sufficient path so that the magnetic particles 13 in the fluid spread in the flow path 10 and then easily adsorb to the adsorption predetermined position 14 provided on the bottom surface of the flow path 10.

[0043] The adsorption distribution of the magnetic particles 13 in the flow path 10 is determined by the magnetic force received from the magnet 15 installed near the flow path 10 and the resistance force due to the flow of the fluid (suspension). The magnetic field in the flow path 10 preferably has a magnetic flux density magnitude of 0.1 to 0.5 T. The flow velocity of the fluid at that time is preferably 0.05 to 0.10 m / s.

[0044] The particles used as the magnetic particles 13 are preferably particles as shown below. (1) Particles showing paramagnetism, superparamagnetism, ferromagnetism, or ferrimagnetism, (2) Particles encapsulating particles showing paramagnetism, superparamagnetism, ferromagnetism, or ferrimagnetism in materials such as synthetic polymer compounds (polystyrene, nylon, etc.), natural polymers (cellulose, agarose, etc.), inorganic compounds (silica, etc.).

[0045] Also, 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. With this specification, the magnetic particles 13 are difficult to sediment in the liquid and easy to suspend. A substance having a property of specifically binding to the analyte substance, for example, an antibody having a property of specifically binding to an antigen, is bound to the surface of the particle.

[0046] The labeling substance is preferably a substance as shown below. Specifically, from the viewpoint of specifically binding the labeling substance to the analyte substance by appropriate means and emitting light by appropriate means, the following examples can be given. (1) A labeling substance used in fluorescence immunoassay. For example, an antibody labeled with fluorescein isothiocyanate. (2) A labeling substance used in chemiluminescence immunoassay. For example, an antibody labeled with acridinium ester. (3) A labeling substance used in chemiluminescent enzyme immunoassay. For example, an antibody labeled with a chemiluminescent enzyme using luminol or an adamantyl derivative as a luminescent substrate.

[0047] The above is an example of the immunoassay device (Figure 1) according to this embodiment. As an example of a device according to a modified example with a different mechanism, Figure 2 shows a schematic configuration diagram of an immunoassay device using laser light.

[0048] In FIG. 2, a laser light source 22 and a condenser lens 21 are installed around the lower part of the flow path 10, and the flow path walls 11 and 12 of the flow cell are made of a transparent material. At the adsorption predetermined position 14 installed in the flow path walls 11 and 12 of the detection unit, the laser light irradiated from the lower part of the flow path 10 through the laser light source 22 and the condenser lens 21 is condensed. At this time, in order to be able to irradiate the adsorption predetermined position 14 with laser light, the adsorption predetermined position 14 is preferably made of a material that is substantially transparent to the wavelength of the light emitted by the labeling substance of the magnetic particle composite adsorbed on the adsorption part in the flow cell. For example, it is preferably made of glass, plastic, or the like.

[0049] Further, for example, when the laser light source 22 and the condenser lens 21 are configured so that the laser light does not need to pass through the adsorption predetermined position 14 by means of arrangement or the like, the adsorption predetermined position 14 is preferably made of a material excellent in mechanical strength, corrosion resistance, processing efficiency, etc., such as gold, platinum, carbon, etc., in consideration of adsorbing the magnetic particle composite on its upper surface. Further, when the laser light does not need to pass through the adsorption predetermined position 14, the flow path wall 12 does not need to be a transparent material, and materials such as ceramics, metal, and plastic can be used.

[0050] When measuring the light emission, first stop the fluid in the flow path 10, and further release the magnetic force in the flow path 10 by removing the magnet 15 from the position directly below the flow path 10 by the slide mechanism 20. Thereby, the light emission by laser light irradiation can be generated while the magnetic particles 13 are held at the adsorption predetermined position 14. The measurement can be carried out by receiving the light emission from the labeling substance bound to the magnetic particles 13 with the photodetector 23.

[0051] The controller 50 is connected to the valves 36 and 37, the pump 35, the arm 31, the laser light source 22, the photodetector 23, the slide mechanism 20 by signal lines 51, 52, 53, 54, 55, 56, 57, and can be independently controlled.

[0052] Note that, in this modified example (Figure 2), a labeling substance different from that in Example 1 (Figure 1) may be used. Specific examples of the labeling substance can be appropriately designed by those skilled in the art based on known techniques and the like.

[0053] In the immunoassay apparatus of Figure 2, the controller 50, the arm 31, the slide mechanism 20, the pump 35, the valves 36 and 37, the suspension container 40, the cleaning liquid container 42, the buffer solution container 43, the flow path 10, the magnetic particles 13, the labeling substance, etc. are the same as those in the immunoassay apparatus of Figure 1.

[0054] Next, the operation of the sample analyzer in this example will be described by taking the immunoassay apparatus of Figure 1 as an example.

[0055] One cycle of the analysis consists of a suspension suction period, a magnetic particle capture period, a detection period, a cleaning period, a reset period, and a preliminary suction period. One cycle starts from when the suspension container 40 containing the suspension processed in the reaction unit 41 is set at a predetermined position.

[0056] During the suspension suction period, the valve 36 is opened and the valve 37 is set to the closed state. According to the signal from the controller 50, the arm 31 operates to insert the sipper nozzle 30 into the suspension container 40. Subsequently, according to the signal from the controller 50, the pump 35 performs a suction operation of a certain amount. The suspension in the suspension container 40 is sucked into the fluid in the tube 32 and enters the tube 32 via the sipper nozzle 30. In this state, the pump 35 is stopped, and the arm 31 is operated to insert the sipper nozzle 30 into the cleaning mechanism 44. When passing through the cleaning mechanism 44, the sipper nozzle 30 is cleaned.

[0057] During the magnetic particle adsorption period, the slide mechanism 20 operates according to the signal from the controller 50, and the magnet 15 moves to the lower part of the flow path 10. The pump 35 sucks at a constant speed according to the signal from the controller 50. During that time, the suspension present in the tube 32 passes through the flow path 10. Since a magnetic field from the magnet 15 is generated in the flow path walls 11 and 12, the magnetic particles 13 contained in the suspension are attracted toward the magnet 15 by the magnetic force and captured (adsorbed) at the adsorption predetermined position 14. After a certain period of time, the suction of the suspension by the pump 3 is stopped.

[0058] During the detection period, the slide mechanism 20 operates and the magnet 15 is moved away from the flow path 10. The voltage application means 18 is controlled by the controller 50, and a voltage is applied between the reaction field electrode 16 and the counter electrode 17 in the flow path 10. Thereby, the labeling substance bound to the magnetic particles 13 adsorbed on the reaction field electrode 16 (adsorption predetermined position 14) can be electrochemically luminesced. The luminescence is, in some cases, wavelength - selected by a filter and detected by a photodetector 23 such as a camera or a photomultiplier tube. The intensity of the detected luminescence is recovered as a signal by the controller 50. After a certain period of time, the voltage application is stopped. During the detection period, the arm 31 is operated and the sipper nozzle 30 is inserted into the cleaning mechanism 44.

[0059] During the cleaning period, by sucking using the pump 35, the cleaning liquid sucked from the cleaning liquid container 42 is passed through the flow path 10. At this time, since the magnet 15 is moved away from the flow path 10, the magnetic particles 13 are not held at the adsorption predetermined position 14 and are washed away together with the cleaning liquid.

[0060] During the reset period, the valve 36 is closed, the valve 37 is opened, and the pump 35 performs a discharging operation. The liquid in the pump 35 is discharged to the waste liquid container 45.

[0061] During the preliminary suction period, the buffer liquid is sucked from the buffer liquid container 43, and the tube 32 and the flow path 10 are filled with the buffer liquid. After the preliminary suction period, the next cycle becomes executable.

[0062] As described above, the sample analysis apparatus according to this embodiment - a flow path for introducing a sample liquid containing magnetic particles 13 bound to a specific substance (substance to be analyzed) into a capture region (adsorption predetermined position 14); - supply means (pump 35) for supplying the sample liquid to the flow path; - capture means (magnet 15) having a magnetic field structure for generating a magnetic field and adsorbing the magnetic particles 13 to the capture region by the magnetic field; - measurement means (photodetector 23) for measuring the specific substance adsorbed in the capture region; - discharge means (pump 35) for discharging the magnetic particles from the flow path after measurement by the measurement means; and is provided with. In this embodiment, the pump 35 is used for both the supply means and the discharge means, but individual components may be used for these. Here, the sample liquid is a liquid containing the substance to be analyzed, for example, a suspension.

[0063] Further, instead of the configuration described above in relation to FIGS. 1 and 2, a part of a known sample analysis apparatus may be used.

[0064] Regarding the above sample analysis apparatus, the structure around the adsorption predetermined position 14 and the magnet 15 will be described with reference to FIGS. 3, 4, 5, and 6. The structure described below is applicable to both the above-described Example 1 (FIG. 1) and the modified example (FIG. 2).

[0065] FIG. 3 is an enlarged view of the configuration near the flow path of the immunoassay apparatus. When a coordinate system is set with the x-axis as the direction of flow progress at the center of the flow cell, the y-axis as the horizontal direction of the cross section perpendicular to the flow, and the z-axis as the vertical direction, the cross section of the xy plane (FIG. 3(a)) and the cross section of the zx plane (FIG. 3(b)) are shown.

[0066] The suspension containing the magnetic particles 13 travels in the +z direction through the path formed by the flow channel walls 11a and 12 in Fig. 3(b) and enters the flow cell. The suspension then travels in the +x direction along the direction 60 of the flow in the flow channel. When it reaches the end of the flow channel 10, it travels in the -z direction through the path formed by the flow channel walls 11b and 12 and is discharged from the flow cell. During this time, the suspension is subjected to the magnetic field of the magnet 15, and the magnetic particles 13 are captured (adsorbed) onto the surface of the adsorption predetermined position 14 by the magnetic force (the adsorbed magnetic particles 13a).

[0067] Fig. 4 is an enlarged view of the vicinity of the flow channel when the magnet structure of this embodiment is used. In this embodiment, the magnet 15 is arranged outside the flow channel and includes a plurality of magnets 15a with different magnetization directions. A magnetic field structure is formed by these plurality of magnets 15a. That is, the magnetic field structure is arranged outside the flow channel and includes a plurality of magnets 15a with different magnetization directions respectively.

[0068] In Fig. 4, permanent magnets are used as the magnets 15a. Three magnets 15a of the same size are arranged in a row along the x direction without gaps, and the magnetization directions of each magnet 15a are -z, +x, and +z respectively starting from the one arranged on the upstream side of the flow channel 10. In the flow channel 10, the suspension flows from upstream to downstream. That is, when a single magnetic particle 13 flowing together with the suspension is at the first position at the first time and at the second position at the second time after the first time, the first position is upstream of the second position, and the second position is downstream of the first position. It is an arrangement in which magnetic fluxes in opposite directions are generated by the magnets on the upstream and downstream sides of the flow channel 10 sandwiching the middle magnet.

[0069] Here, the magnetization direction 61 of the magnet is shown using an arrow so that it is S pole → N pole inside the magnet material (N pole → S pole outside the magnet such as air) in accordance with the general magnetic flux notation.

[0070] General magnet materials can be used for the magnets 15a, and materials such as ferrite magnets, neodymium magnets, samarium cobalt magnets, alnico magnets, or combinations thereof may be used.

[0071] In addition, the plurality of magnets 15a juxtaposed in the above-described form may be adhered to each other by an adhesive such as a curable resin, or may be fixed by a jig made of a non-magnetic material such as plastic or ceramics.

[0072] FIG. 5 shows the magnet structure and the generated magnetic flux of this embodiment. One of the effects of this embodiment will be described with reference to this figure. FIG. 5(a) is a magnet structure showing the form of FIG. 4 three-dimensionally. In this form, FIG. 5(b) is a view showing the magnetic flux lines 62 generated along the magnetization direction 61 in the magnet cross section of the zx plane. The magnetic flux lines 62 are loop-shaped. For example, inside each of the three magnets 15a, similar to the magnetization direction 61, the arrow directions of -z, +x, and +z are shown from the element arranged on the upstream side of the flow path 10.

[0073] In this embodiment, the three magnets 15a each have the same shape of a rectangular parallelepiped and are arranged such that each face is orthogonal to the x-axis, y-axis, or z-axis. Note that the specific configuration is not limited to that shown in FIG. 5, and for example, a known Halbach array may be used.

[0074] By arranging the magnets 15a with different magnetization directions 61, in a part of the region outside the magnets, the magnetic flux lines 62 of different magnets overlap so as to reinforce each other. In particular, directly above the magnet, the directions of the magnetic flux lines 62 formed by the central magnet among the three arranged magnets 15a and the other two magnets at the ends are aligned, so that the magnetic flux vectors are synthesized and the generated magnetic fluxes reinforce each other. As shown by the direction 62a of the reinforced magnetic flux, in this embodiment, the magnetic fluxes in the -z and +z directions are reinforced directly above the magnet.

[0075] In this way, the plurality of magnets 15a are arranged such that the magnetic fluxes generated by each of the two adjacent magnets reinforce each other at at least a part of the adsorption predetermined position 14. "The magnetic fluxes reinforce each other" means, for example, that the magnetic flux vectors reinforce each other. Or, it means that the signs of the components in the z direction among the magnetic flux vectors match.

[0076] Thus, in the arrangements of FIGS. 4 and 5, the plurality of magnets 15a are arranged such that the magnitude of the magnetic flux density on the flow path side (for example, the magnetic flux density on the magnet surface on the flow path side) is greater than the magnitude of the magnetic flux density on the side opposite to the flow path (for example, the magnetic flux density on the magnet surface on the side opposite to the flow path).

[0077] As a result of this, as an effect of this embodiment, the magnetic field applied to the flow path 10 can be strengthened, and the collection rate of the magnetic particles 13 can be increased. Here, the collection rate is a value obtained by taking the ratio of the number of magnetic particles 13a adsorbed at the adsorption predetermined position 14 to the number of magnetic particles 13 contained in the sample.

[0078] According to Non-Patent Document 1, the force that a substance in a magnetic field receives from the magnetic field is generally known by the following formula. F = -grad(E)=(1 / μ 0 )χB(dB / dl) However, F is the force vector, E is the energy vector, grad() is the operator representing the spatial gradient, μ 0 is the magnetic permeability of vacuum, χ is the magnetic susceptibility, B is the magnetic flux density vector, and l is the position.

[0079] In a strengthened magnetic field, the magnetic flux density vector B increases, and the force acting on the magnetic particles 13 also increases. In particular, in the configuration of FIG. 5, since the magnetic flux density of the -z and +z components is strengthened and functions with respect to the vertical component of the force, when it is desired to capture the magnetic particles 13 on the bottom surface of the flow path 10, there is an effect of improving the collection rate of the magnetic particles 13.

[0080] To confirm the increase in the magnetic flux density, the magnitude |B| of the magnetic flux density was calculated by magnetic field analysis (FIG. 6) (hereinafter, unless otherwise specified, |B| shall indicate the magnitude of the magnetic flux density). The magnetic field analysis was performed by a general-purpose magnetic field analysis method based on Maxwell's equations and Ampere's law.

[0081] FIG. 6(a0) is a magnet model of a single body magnetized in the +x direction prepared for comparison, and the outside of the magnet is filled with air. The analysis results are shown in FIG. 6(a1). Here, the surface 70a where the magnetic field analysis was performed was taken as the internal cross-section of the magnet parallel to the zx plane, and the position in the y direction of the surface 70a was taken as the central position of the magnet. According to the analysis results, in the air region near the position 71a of the magnet, the magnetic flux density is large, and as the distance from the magnet increases, a distribution in which the magnetic flux density decreases isotropically was obtained.

[0082] FIG. 6(b0) is a model according to Embodiment 1 of the present invention. The magnet has the same material and outer dimensions as FIG. 6(a0), and is arranged as shown in FIG. 5. Three magnets 15a of the same size are arranged in a row along the x direction without gaps. The surface 70b where the magnetic field analysis was performed was taken as the internal cross-section of the magnet in the zx plane.

[0083] The results of the magnetic field analysis are shown in FIG. 6(b1). From the analysis results, similar to the single-body magnet model of FIG. 6(a1), in the air region near the position 71b of the magnet, the magnetic flux density is large, and as the distance from the magnet increases, the magnetic flux density decreases. Also, in FIG. 6(b1), it was obtained that the magnetic flux density on the vertical upper surface of the magnet is larger than that on the vertical lower surface.

[0084] From the sharp change in the magnetic flux density, it was also shown that the gradient (dB / dl) of the magnetic flux density in FIG. 6(b1) is larger than that in FIG. 6(a1). Although the flow path 10 is shown in FIGS. 6(a1) and (b1) as the case where the flow path 10 is installed at a position vertically above the magnet surface, it can be seen that in the case of this embodiment of FIG. 6(b1), a larger magnetic flux density is generated in the flow path than in the case of FIG. 6(a1) (single magnet). According to this embodiment, it was confirmed that the magnetic flux density and its gradient increase.

[0085] The effect of increasing the magnetic flux density and its gradient is extremely pronounced, for example, at positions from 0 to 1 mm in the +z direction from the upper surface of the magnet when the outer dimension of the magnet is 1 to 10 mm, and is also well observed at positions from 1 mm to 20 mm in the +z direction from the magnet surface. However, there are no restrictions on the material and dimensions of the magnet, or the position and shape of the flow path. By appropriately designing the position where the magnetic flux density is to be enhanced according to the configuration of the sample analyzer, a higher effect can be obtained.

[0086] According to this embodiment, it is possible to reduce the magnetic flux density on the side opposite to the flow path 10 on the magnet surface and increase the magnetic flux density on the flow path 10 side, concentrating on the target flow path 10 side to obtain the effect of extracting a performance exceeding the performance originally possessed by the magnet material (a single magnet model in Fig. 6(a1)). Also, reducing the magnetic flux density on a specific side surface, like the vertical lower surface of the magnet in Fig. 6(b1), can reduce magnetic noise for the sample analyzer or another device arranged adjacent thereto.

[0087] Next, focusing on the flow path 10, the collection rate of magnetic particles and other associated effects in this form will be described with reference to Figs. 7, 8, 9, and 10.

[0088] Fig. 7 shows a magnet model and analysis results when magnetic field analysis is performed under the same model and conditions as in Fig. 6, focusing on the flow path 10. Fig. 7(a0) is a single magnet model magnetized in the +x direction, and Fig. 7(b0) is a magnet model in which three magnets 15a of this embodiment are arranged without gaps.

[0089] Assuming that there is a flow path 10 vertically above each magnet, planes 70c and 70d for performing magnetic field analysis are defined within the air region vertically above the upper surfaces 71c and 71d of the magnet. Planes 70c and 70d are parallel to the xy plane.

[0090] With this arrangement, in the case of Fig. 7(b0), the magnetic particles 13 pass over the upper surfaces of the magnets of a plurality of individuals by flowing through the flow path 10. In the present embodiment using three magnets 15a, for the most upstream magnet 15a (first magnet), the next magnet 15a (second magnet), and the next (i.e., the most downstream) magnet 15a (third magnet), the sample liquid passes through all of the region closer to the first magnet than the second and third magnets, the region closer to the second magnet than the first and third magnets, and the region closer to the third magnet than the first and second magnets. Thus, the three magnets 15a are arranged in parallel in the direction in which the sample liquid flows in the flow path 10, and the sample liquid passes above all of the magnets 15a. The same arrangement is possible when two or four or more magnets 15a are used.

[0091] Figs. 7(a1) and (b1) are the analysis results of the magnetic flux density of each model. However, when comparing the magnitudes of the magnetic flux density, Fig. 7(b1) according to the present embodiment showed a larger value. Also, it was confirmed that the change in the magnetic flux density near the magnet was abrupt and the gradient was large. Therefore, by using the present embodiment, the magnetic flux density and its gradient can be increased.

[0092] This tendency was also observed in the vertical component of the magnetic flux density shown in Figs. 7(a2) and (b2), and it was confirmed that by using the form of the present embodiment, the vertical force acting on the magnetic particles can be increased. When the adsorption predetermined position 14 is provided on the bottom surface of the flow path 10, the magnetic particles 13 in the flow path 10 are adsorbed to the adsorption predetermined position 14 by the vertically downward magnetic force, so that the adsorption of the magnetic particles 13 can be promoted.

[0093] Here, in FIGS. 7(a2) and 7(b2), paying attention to the change in the magnetic flux density near the magnet, for a region where the vertical component of the magnetic flux density is relatively large (i.e., a region that is whiter or blacker than the surroundings), for example, when comparing the width 72 of the same blackness range, the width of FIG. 7(b2) according to this embodiment is narrower. In this embodiment, from the region where the magnetic flux density on the upper surface of the magnet is large, as the distance increases, the magnetic flux density rapidly decreases, and the regions where the magnetic force acting on the magnetic particles is strong and weak are clearly distinguished. As a result, the magnetic particles 13 can be adsorbed at a high density at the adsorption predetermined position 14, and at the same time, adsorption to places other than the adsorption predetermined position 14 can be prevented. The controllability of the adsorption distribution can be enhanced, and non-uniform adsorption can be prevented.

[0094] To confirm the effects of this embodiment, the adsorption process was analyzed using a numerical simulator capable of accurately analyzing the behavior of magnetic particles. FIG. 8 shows a flowchart of the analysis of the behavior of magnetic particles in a flow field and a magnetic field.

[0095] When the calculation starts (S1), fluid analysis in the flow path 10 is performed using general-purpose fluid analysis software to obtain the velocity field and the pressure field. At the same time, separately, the magnetic field around the magnet is obtained using general-purpose magnetic field analysis software. Next, the particle behavior analysis program reads the data of the flow field and the magnetic field (S2), and the force acting on the particles can be calculated using the values of the flow field and the magnetic field at each particle position (S3). Here, as the force acting on the particles, the force received from the flow, gravity, and the force received from the magnet are evaluated. For each particle, the behavior of the magnetic particles is analyzed while updating the position of the magnetic particles by sequentially solving Newton's equation of motion (S4). The calculation is repeated until the specified elapsed time is reached (S5), and when it is reached, the calculation is terminated (S6).

[0096] Figures 9(a) and (b) respectively show the results of analyzing the adsorption distribution of magnetic particles when the magnets in Figs. 7(a0) and (b0) in the flow path 10 are used. Fig. 10 shows the position distribution of the adsorbed magnetic particles along the x-axis and y-axis in the form of a histogram based on the normalized length unit σ. Figs. 9(a), 10(a1), and (a2) show the adsorption distribution of magnetic particles in a single magnet model, and Figs. 9(b), 10(b1), and (b2) show the adsorption distribution of magnetic particles in this embodiment.

[0097] By comparing the number of adsorbed magnetic particles in Figs. 9(a) and (b), 10(a1) and (b1), and 10(a2) and (b2), it was found that the collection rate of magnetic particles is higher in this embodiment. Here, in Fig. 9, the ratio of the magnetic particles 13 in the fluid adsorbed at the adsorption predetermined position 14 is shown as the collection rate, and the value in the case of this embodiment in Fig. 9(b) is higher than that in the case of a single magnet in Fig. 9(a).

[0098] In Fig. 9, when comparing the adsorption positions of magnetic particles with respect to the position 71 of the magnet indicated by the dotted line, in the case of a single magnet model (Fig. 9(a)), magnetic particles are adsorbed in an x-axis region wider than the position 71 of the magnet, and its increase and decrease also change gently depending on the position. On the other hand, in the case of this embodiment (Fig. 9(b)), the position 71 of the magnet and the position where many magnetic particles are adsorbed are almost in the same region.

[0099] These can be confirmed from the histograms of the x-axis shown in Figs. 10(a1) and (b1). In the case of a single magnet model (Fig. 10(a1)), a certain number of adsorptions are also seen at positions outside the adsorption predetermined position 14, but in the case of this embodiment (Fig. 10(b1)), the adsorptions at positions outside the adsorption predetermined position 14 are few. Thus, the controllability of the adsorption position is enhanced by this embodiment.

[0100] Furthermore, for example, by appropriately designing the shape and dimensions of the adsorption predetermined position 14, such as making the dimension of the adsorption predetermined position 14 in the x-direction match the position 71 of the magnet, further improvement in measurement accuracy is possible.

[0101] According to the above-described present embodiment, it is possible to provide a sample analyzer that realizes an increase in the capture rate of magnetic particles, suppression of non-uniform adsorption by improving the controllability of the adsorption distribution of magnetic particles, or both of them.

Example

[0102] As another example of the present invention, an example using a magnet different from that in Example 1 is shown. In Example 2 and subsequent examples, for sample analyzers other than magnets such as flow cells, it is the same as in Example 1, and detailed description thereof will be omitted. The forms described in each example are not limited to the shape, dimensions, number, etc., and can be changed without departing from the gist thereof, and a plurality of examples including the foregoing or following examples may be combined.

[0103] The plurality of magnets used in this example may be a combination of magnets having a magnetization direction different from that in FIG. 5 as long as they can achieve an effect of increasing the capture rate of magnetic particles or both an effect of increasing the capture rate of magnetic particles and suppressing non-uniform adsorption by improving the controllability of the adsorption distribution of magnetic particles.

[0104] FIG. 11(a) is an example in which a structure in which three magnets 15a of the same size are arranged in a row without gaps is constituted by a combination of magnets with different magnetization directions. As shown in FIG. 11(a), even when arranged in the magnetization directions of +x, +z, and -x from the upstream side of the flow path, the magnetic flux density on the upper surface of the magnet increases due to the strengthening of the magnetic flux vectors. Thereby, an effect of increasing the capture rate of the magnetic particles 13 is obtained.

[0105] In this embodiment, it is based on the fact that the magnetization directions of adjacent magnets are relatively different by 90 degrees. However, the reinforcement of the magnetic flux vectors can be obtained with any relative difference except when the magnetization directions of adjacent magnets are the same (the relative difference in angle is 0 degrees). When the relative difference in angle is defined in the range of -90 degrees to +90 degrees, the absolute value of the relative difference in angle only needs to be a value greater than 0 degrees, preferably 45 degrees or more, more preferably 75 degrees or more, and even more preferably 85 degrees or more. When the absolute value of the relative difference is 90 degrees, it is easy to obtain the effect that the magnetic flux density on one side (the upper surface of the magnet) is greater than that on the opposite side (the lower surface of the magnet). However, depending on the shape of the adsorption predetermined position 14, the target collection rate, and the capture distribution, the absolute value of the relative difference may be set to less than 90 degrees.

[0106] Also, when there are three or more magnets, the relative differences in the angles of the magnetization directions of adjacent magnets do not all have to be the same, and different relative differences in angles may be used in combination at multiple adjacent locations. Thereby, the degree of reinforcement of the magnetic flux generated in the flow path 10 and the degree of weakening of the magnetic flux in the space on the side opposite to the flow path 10 can be controlled.

[0107] In particular, in an embodiment where three or more magnets are arranged in a row, as exemplified in FIGS. 5(a) and 11(a), by a structure in which another magnet is arranged between two magnets that generate magnetic fluxes in opposite directions, the locations and regions where the magnetic fluxes are reinforced can be increased.

[0108] Note that the modification example of the relative difference in the magnetization direction is not limited to this embodiment and is also applicable to other embodiments.

[0109] The plurality of magnets may be arranged adjacent to each other across the flow path 10. For example, as shown in FIG. 11(b), a structure in which three magnets 15a of the same size are arranged in a row along the y direction without gaps may be used. The plurality of magnets 15a are arranged in parallel in a direction perpendicular to the direction in which the sample liquid flows in the flow path 10, and the sample liquid passes above each different magnet.

[0110] That is, in this case, the flow path (for example, the adsorption predetermined position 14 and the space above it) can be said to have a right-side region, a central region, and a left-side region in the direction crossing the flow path, and the plurality of magnets 15a can be arranged such that the sample liquid passes above different magnets 15a in the right-side region, the central region, and the left-side region, respectively.

[0111] Also in this form, the effects of increasing the magnetic flux density on the upper surface of the magnet and increasing the capture rate of the magnetic particles 13 are obtained. In particular, the generated magnetic field distribution in the y direction can be controlled by the configuration of FIG. 11(b). Therefore, it is effective when optimizing the distribution of the adsorbed magnetic particles 13a in the y direction according to the arrangement form of the mechanism for causing the luminescent labeling substance to emit light after capturing the magnetic particles 13. For example, in a mechanism using the reaction field electrode 16 and the counter electrode 17, when the counter electrode 17 is arranged along the y direction, the magnetic particles 13 can be controlled to be sufficiently distributed and adsorbed near the center of the flow path or the side surface of the flow path (the vertical wall surface parallel to the flow path in the flow cell).

[0112] The adjacent arrangement of the plurality of magnets is based on a direction parallel or perpendicular to the flow path 10, but depending on the adsorption predetermined position 14, the shape and arrangement of the mechanism, it may be arranged along other directions. For example, in the arrangement and shape of the adsorption predetermined position 14 shown in FIG. 9, when using an arrangement in which the adsorption predetermined position 14 is rotated 45 degrees in the xy plane around the center point of the flow path, the arrangement of the plurality of magnets 15a may be rotated in the same manner.

[0113] The number of magnets may be other than three. For example, FIG. 12 shows examples of structures in which two (a), four (b), or five (c) magnets 15a are arranged in a row along the x direction without gaps. Some of the effects of this embodiment can be obtained regardless of the number of magnets, and six or more magnets may be used. By increasing the number of magnets, the distribution of the generated magnetic field can be controlled densely. On the other hand, if the number of magnets is small, the effects of this embodiment can be obtained by a simple manufacturing method by omitting the adhesion and fixing between the magnets.

[0114] In particular, if three or more magnets are included as a plurality of magnets, it becomes possible to flexibly control the formation of the magnetic field. When three or more magnets are used, it is not essential to arrange them in a line. For example, a plurality of magnets may be arranged two-dimensionally in the xy plane. When juxtaposition in the x and y directions is performed by a plurality of magnets respectively, the magnetic field in the flow path 10 can be precisely controlled. Similarly, a plurality of magnets may be arranged three-dimensionally. When a plurality of magnets (for example, three from the first to the third) are arranged three-dimensionally, when the sample liquid is in the flow path 10, the magnets are arranged so that the sample liquid passes through all of a region closer to the first magnet than the second and third magnets, a region closer to the second magnet than the first and third magnets, and a region closer to the third magnet than the first and second magnets, whereby it is easy to obtain the effect of increasing the magnetic flux density on the upper surface of the magnet. However, it is not necessarily required to be arranged to pass through the above three regions, and any arrangement that can obtain the effect of increasing the magnetic flux density on the upper surface of the magnet is acceptable.

[0115] Also, when only two magnets are used, the magnetization directions of the two magnets are not limited to the pattern shown in Fig. 12(a), and a pattern obtained by extracting any two adjacent ones from the five in Fig. 12(c) may be used. Further, even when three or more magnets are used, as the magnetization directions of two adjacent magnets, a pattern obtained by extracting any two adjacent ones from the five in Fig. 12(c) can be used.

[0116] As described above, a sample analyzer can be provided that uses a magnet arrangement different from that of Example 1 to achieve an increase in the capture rate of magnetic particles, suppression of non-uniform adsorption by improving the controllability of the adsorption distribution of magnetic particles, and the coexistence of both.

Example

[0117] The plurality of magnets used in this embodiment may be magnets with different dimensions. For example, two or more magnets with different dimensions along the x, y, or z axes may be arranged in a row along the x direction without gaps. Fig. 13 shows a structure in which the magnet arranged on the upstream side of the flow path is smaller than the magnet arranged on the downstream side of the flow path (Fig. 13(a)(b)), and a structure in which a magnet that generates a magnetic field in the vertical direction is arranged only on the downstream side of the flow path (Fig. 13(c)).

[0118] In the sample analyzer shown in Example 1, in the process of adsorbing the magnetic particles 13 from the fluid, the magnetic particles will approach the upstream side of the flow path of the magnet first, and the number of particles adsorbed on the upstream side of the flow path, that is, the density of the adsorbed magnetic particles will increase. As a result, for example, when using a single magnet (Fig. 6(a), Fig. 7(a)), the number of particles adsorbed on the downstream side of the flow path will be relatively small, so the uniformity of the magnetic particle distribution at the predetermined adsorption position 14 will decrease.

[0119] Figs. 13(a)(b) show a structure in which the magnet arranged on the upstream side of the flow path is smaller than the magnet arranged on the downstream side of the flow path, and the magnetic field generated on the downstream side of the flow path is larger than the magnetic field generated on the upstream side of the flow path. Thereby, it is possible to suppress the decrease in uniformity between the upstream and downstream of the flow path that is likely to occur when using a single magnet, and improve the uniformity of the magnetic particle distribution at the predetermined adsorption position 14.

[0120] At this time, the magnet on the upstream side of the flow path may have a smaller dimension in the direction parallel to the direction of the flow 60 in the flow path (the x direction in Fig. 13(a)) as shown in Fig. 13(a), or may have a smaller dimension in the direction perpendicular to the direction of the flow 60 in the flow path (the y direction or the z direction) as shown in Fig. 13(b), or a combination thereof.

[0121] By arranging the vertically upper surface of the magnet on the upstream side of the flow path and the vertically upper surface of the other magnet on the same plane, without weakening the magnetic field generated on the upstream side of the flow path (without impairing the superiority of the magnet material and arrangement), the magnetic field generated on the downstream side of the flow path can be made larger than the magnetic field generated on the upstream side of the flow path. Thereby, for example, measurement in an environment where it is more difficult to adsorb magnetic particles, such as a high-speed fluid or a flow path 10 having a large cross-sectional area, can be realized.

[0122] However, it is not always necessary to arrange the vertically upper surface of the magnet on the upstream side of the flow path and the vertically upper surface of the other magnet on the same plane. For example, when it is desired to make the magnetic field generated on the downstream side of the flow path larger than that on the upstream side in order to improve the uniformity of the magnetic particle distribution, it can be realized by separating the vertically upper surface of the magnet on the upstream side of the flow path to a position farther from the flow path than the vertically upper surface of the other magnet.

[0123] FIG. 13(c) shows a structure using a plurality (two) of magnets 15a having different areas of the opposing surface to the flow path. In particular, a magnet with a large dimension in the x direction is used as the magnet on the upstream side of the flow path, and a magnet that generates a magnetic field only in the vertical direction is arranged only on the downstream side of the flow path. The plurality of magnets 15a includes a first magnet and a second magnet having a different area of the opposing surface to the flow path from the first magnet. In this structure, since the magnetic flux enhancement occurs only on the downstream side of the flow path, the magnetic flux density on the downstream side can be made larger than that on the upstream side of the flow path. Due to the large size of the magnet on the upstream side of the flow path, magnetic particles can be adsorbed with the same distribution and collection rate as in the case of using a single magnet on the upstream side. On the other hand, on the downstream side of the flow path, magnetic particles that cannot be collected and flow out when using a single magnet can be adsorbed inside the adsorption predetermined position 14 by a strong magnetic field, and an improvement in the collection rate and uniformity can be realized.

[0124] In the above-described Example 3, the regions of "upstream" and "downstream" may be defined with respect to the space of the flow path or may be defined with respect to the bottom surface of the flow path (the same applies to other embodiments). When defined with respect to the space, the plurality of magnets 15a can be arranged such that the magnetic flux density on the downstream side is greater than that on the upstream side in the space within the flow path above the adsorption predetermined position 14. On the other hand, when defined with respect to the bottom surface, the plurality of magnets 15a can be arranged such that the magnetic flux density on the downstream side is greater than that on the upstream side on the bottom surface of the flow path (for example, the portion constituting the adsorption predetermined position 14).

Example

[0125] Regarding the plurality of magnets used in this example, there may be a gap between each magnet. FIG. 14 shows a structure in which three magnets 15a are arranged in a row along the x direction with a gap provided in part. At this time, the gap may be composed of air, a resin material, ceramics, metal, etc. The gap can be used, for example, for fixing arbitrary magnets to each other with an adhesive or a jig made of ceramics or metal.

[0126] The gap between two adjacent magnets can be set to a dimension that enhances the magnetic field by the synthesis of magnetic flux vectors. Assuming that two adjacent magnets are arranged along the x-axis, in order to increase the magnetic flux density and gradient, the minimum distance (interval) between the magnets is preferably smaller than the larger one of the x-axis dimensions of both magnets (denoted as Lx). That is, the plurality of magnets 15a are preferably arranged such that the interval between two adjacent magnets is smaller than the width (dimension in the arrangement direction) of any of the two adjacent magnets.

[0127] From the same perspective, the minimum distance (interval) between the magnets is more preferably smaller than Lx / 2. In particular, it is even more preferable to bring the magnets into contact with each other, such as the two upstream magnets shown in FIG. 14, in order to increase the magnetic flux density and gradient.

Example

[0128] Among the plurality of magnets used in this embodiment, the shape of each magnet is not limited to a rectangular parallelepiped, and for example, it may have a shape including peculiar parts such as grooves, concavities, and convexities. FIG. 15 shows a structure in which at least one magnet 15a having a shape similar to a groove or concavities and convexities is used, and three magnets 15a are arranged in a row along the x direction.

[0129] FIG. 15(a) shows a form in which a groove is formed in the central portion in the y direction for the magnet located on the upstream side of the flow path in a structure (FIG. 5(a)) in which three magnets 15a of the same size are arranged in a row without a gap. By reducing the magnet on the upstream side of the flow path by a volume corresponding to the groove, the magnetic field generated on the downstream side of the flow path can be made larger than the magnetic field generated on the upstream side of the flow path, and the uniformity of the magnetic particle distribution can be improved. Further, by forming a groove extending in the z direction in the central portion in the y direction, the magnetic field on the side wall side (both sides in the y direction) can be strengthened more than that in the central portion of the flow path. With such a structure, the controllability of the magnetic particle distribution in the y direction can be improved.

[0130] In the example of FIG. 15(a), the flow path (for example, the adsorption predetermined position 14 and the space above it) can be said to have a right-side region, a central region, and a left-side region in a direction crossing the flow path (particularly a direction horizontally crossing), and at least one of the plurality of magnets (the upstream magnet) can be said to have a shape in which the magnetic flux density generated in the right-side region and the left-side region by the magnet is larger than the magnetic flux density generated in the central region by the magnet.

[0131] By forming the groove or concavities and convexities in a sharp shape (for example, including 90-degree concavities and convexities), the magnetic flux density gradient from the magnet to the air region can be increased, which is useful for the design of a flow cell in which the collection rate is desired to be improved. In particular, from the viewpoint of improving the collection rate, it is desirable to use the configuration of this embodiment, for example, near the interface between the adsorption predetermined position 14 and other regions.

[0132] Fig. 15(b) shows a structure in which three magnets 15a of the same size are arranged in a row without gaps (Fig. 5(a)). For the magnets located at the center and on the downstream side of the flow path, concavo-convex portions that fit together are formed. Two adjacent magnets face each other through surfaces with complementary shapes. In the example of Fig. 15(b), they are in contact facing each other, but they may be arranged at a distance as shown in Fig. 14 in a facing arrangement.

[0133] The central magnet has a shape in which both sides in the y direction of the +x side surface of a rectangular parallelepiped are removed to form a convex shape in the +x direction, and its volume is smaller than that of the original rectangular parallelepiped. The downstream magnet has a shape in which both sides in the y direction of the -x side surface of a rectangular parallelepiped protrude toward the -x side to form a concave facing the -x direction, and its volume is larger than that of the original rectangular parallelepiped. In this way, by making the magnet on the downstream side of the flow path larger, the magnetic field generated on the downstream side of the flow path can be made larger than the magnetic field generated on the upstream side of the flow path, and the uniformity of the magnetic particle distribution can be improved with respect to the x-axis direction.

[0134] By forming grooves or concavo-convex portions in a gentle shape (for example, including concavo-convex portions of 45 degrees or less), compared with the case of forming them in a sharp shape, a sudden change in the magnetic field in the region where the magnets are adjacent can be suppressed, which is useful for designing a flow cell with improved uniformity. This is particularly relevant to the distribution at the location where magnetic particles are adsorbed, so it is desirable to use this form inside the adsorption predetermined position 14.

[0135] In the above-described embodiments and modifications, the plurality of magnets may include permanent magnets or may include electromagnets. When using a permanent magnet, heat generation can be suppressed. When using an electromagnet, the magnetic field can be eliminated when the magnetic field is not required, and the influence of the magnetic field on the surrounding components can be suppressed.

[0136] Also, the plurality of magnets may include permanent magnets and electromagnets. Alternatively, the plurality of magnets may include a permanent magnet made of a first material and a permanent magnet made of a second material different from the first material. The material is, for example, neodymium, ferrite, samarium cobalt, alnico, etc., and can be appropriately selected based on known technologies and the like. By using magnets with different configurations in this way, more flexible control of the magnetic field at each position becomes possible.

[0137] Through the above embodiments, the embodiments and variations of the present invention have been specifically described. However, the present invention is not limited to the above-described embodiments and variations, and can be changed without departing from the gist thereof. Through the embodiments and variations of the present invention, a sample analysis apparatus can be provided that realizes an increase in the collection rate of magnetic particles, suppression of non-uniform adsorption by improving the controllability of the adsorption distribution of magnetic particles, and the compatibility of both.

Explanation of Reference Numerals

[0138] 10…Flow path 11, 12…Flow path walls 11a, 11b…Flow path walls 13…Magnetic particles 13a…Adsorbed magnetic particles 14…Adsorption predetermined position (supplementary region) 15, 15a…Magnets 16…Reaction field electrode 17…Counter electrode 18…Voltage application means 19a, 19b…Lead wires 20…Slide mechanism 21…Condensing lens 22…Laser light source 23…Photodetector 30…Sipper nozzle 31…Arm 32, 33, 34…Tubes 35…Pump 36, 37…Valves 40…Suspension container 41…Reaction unit 42…Washing liquid container 43…Buffer solution container 44…Washing mechanism 45… Waste liquid container 50… Controller 51, 52, 53, 54, 55, 56, 57, 58… Signal lines 60… Flow direction in the flow path 61… Magnetization direction 62… Magnetic flux lines 62a… Direction of enhanced magnetic flux 70a, 70b, 70c, 70d… Surfaces on which magnetic field analysis was performed 71, 71a, 71b… Positions of magnets 71c, 71d… Upper surfaces of magnets 72… Width of the region where the vertical component of magnetic flux density is relatively large

Claims

1. A flow path for introducing a sample liquid containing magnetic particles bound to a specific substance into a capture region, Supply means for supplying the sample liquid to the flow path, Capture means having a magnetic field structure that generates a magnetic field and adsorbs the magnetic particles to the capture region by the magnetic field, Measurement means for measuring the specific substance adsorbed to the capture region, Discharge means for discharging the magnetic particles from the flow path after measurement by the measurement means, In a sample analyzer comprising: The magnetic field structure is disposed outside the flow path and includes a plurality of magnets having different magnetization directions, and the plurality of magnets are arranged such that the magnetic flux density on the flow path side is greater than the magnetic flux density on the side opposite to the flow path, The plurality of magnets are arranged such that in the space in the flow path above the capture region, the magnetic flux density on the downstream side of the flow path is greater than the magnetic flux density on the upstream side of the flow path. A sample analyzer characterized by this.

2. In the sample analyzer according to claim 1, The plurality of magnets are arranged such that the magnetic fluxes generated by each of two adjacent magnets reinforce each other at at least a part of the capture region, A sample analyzer characterized by this.

3. In the sample analyzer according to claim 1, The plurality of magnets are arranged in parallel in the direction in which the sample liquid flows in the flow path, and the sample liquid passes above all of the plurality of magnets. A sample analyzer characterized by this.

4. In the sample analyzer according to claim 1, The plurality of magnets are arranged in parallel in a direction perpendicular to the direction in which the sample liquid flows in the flow path, and the sample liquid passes above different magnets. A sample analyzer characterized by this.

5. In the sample analyzer according to claim 1, the plurality of magnets include three or more magnets. A sample analyzer characterized by this.

6. In the sample analyzer according to claim 1, The plurality of magnets are arranged such that the distance between two adjacent magnets is smaller than the width of any of the two adjacent magnets, A sample analyzer characterized by this.

7. In the sample analyzer according to claim 1, The plurality of magnets are arranged such that two adjacent magnets face each other through surfaces having a shape that fits together A sample analyzer characterized by this.

8. In the sample analyzer according to claim 1, The flow path has a right-side region, a central region, and a left-side region in a direction crossing the flow path. At least one of the plurality of magnets has a shape such that the magnetic flux density generated in the right-side region and the left-side region by the magnet is greater than the magnetic flux density generated in the central region by the magnet. A sample analyzer characterized by this.

9. In the sample analyzer according to claim 1, the plurality of magnets include permanent magnets. A sample analyzer characterized by this.

10. In the sample analyzer according to claim 1, the plurality of magnets include electromagnets. A sample analyzer characterized by this.

11. In the sample analyzer according to claim 1, the plurality of magnets - include permanent magnets and electromagnets, or - include a permanent magnet made of a first material and a permanent magnet made of a second material. A sample analyzer characterized by this.

12. In the sample analyzer according to claim 1, the plurality of magnets include a first magnet and a second magnet having a different area of the facing surface with the flow path from that of the first magnet. A sample analyzer characterized by this.

13. A flow path for introducing a sample liquid containing magnetic particles bound to a specific substance into a capture region, feeding means for feeding the sample liquid into the flow path, capturing means having a magnetic field structure for generating a magnetic field and adsorbing the magnetic particles to the capture region by the magnetic field, measuring means for measuring the specific substance adsorbed to the capture region, discharging means for discharging the magnetic particles from the flow path after measurement by the measuring means, In a sample analyzer provided with the magnetic field structure is disposed outside the flow path and includes a plurality of magnets having different magnetization directions, and the plurality of magnets are arranged such that the magnetic flux density on the flow path side is greater than the magnetic flux density on the side opposite to the flow path. The plurality of magnets are arranged such that the magnetic flux density on the downstream side of the flow path is greater than the magnetic flux density on the upstream side of the flow path at the bottom surface of the flow path constituting the capture region. A sample analyzer characterized by this.

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