WO2020009023A1 - Substrat d'analyse d'échantillon et procédé d'analyse d'échantillon - Google Patents

Substrat d'analyse d'échantillon et procédé d'analyse d'échantillon Download PDF

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Publication number
WO2020009023A1
WO2020009023A1 PCT/JP2019/025833 JP2019025833W WO2020009023A1 WO 2020009023 A1 WO2020009023 A1 WO 2020009023A1 JP 2019025833 W JP2019025833 W JP 2019025833W WO 2020009023 A1 WO2020009023 A1 WO 2020009023A1
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WIPO (PCT)
Prior art keywords
chamber
substrate
sample analysis
flow path
main chamber
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PCT/JP2019/025833
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English (en)
Japanese (ja)
Inventor
由枝 小松
房俊 岡本
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Ｐｈｃホールディングス株式会社
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Priority to JP2020528837A priority Critical patent/JP6994113B2/ja
Publication of WO2020009023A1 publication Critical patent/WO2020009023A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/536—Immunoassay; Biospecific binding assay; Materials therefor with immune complex formed in liquid phase
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N37/00—Details not covered by any other group of this subclass

Definitions

  • the present disclosure relates to a sample analysis substrate and a sample analysis method.
  • a technique using a sample analysis substrate is known.
  • a liquid containing a sample such as blood is introduced into a sample analysis substrate provided with a chamber, a flow path, and the like, and the sample analysis substrate is rotated to transfer, distribute, mix, and mix the liquid with the reagent.
  • a reaction or the like is performed to analyze components in the sample (for example, see Patent Document 1).
  • the components in the liquid are combined with the antibody containing the magnetic beads and the labeled antibody in the reaction chamber, and then a washing step is performed in the measurement chamber where the washing is performed while being suctioned by the magnet.
  • a technique in which the concentration of a component to be detected is increased and then optically detected for example, see Patent Document 2.
  • a non-limiting exemplary embodiment of the present application provides a sample analysis substrate and a sample analysis method capable of improving measurement accuracy.
  • the substrate for sample analysis is a substrate for sample analysis for transferring a liquid containing a sample and analyzing a specific substance in the sample.
  • a main chamber having a space for holding a complex in which a specific component, a labeling substance, and a magnetic particle are bound, a magnet disposed in close proximity to the main chamber,
  • a collection chamber having a space for holding a liquid transferred from the chamber, wherein at least a part of the space is located on an outer peripheral side in a radial direction with respect to a space of the main chamber, and a collection chamber;
  • a flow path located in the substrate and having a first opening and a second opening, wherein the first opening and the second opening are respectively the main chamber and the second opening; Wherein provided is connected to the collection chamber was a channel, it is held in the collection chamber, and an active inhibitor which reduces the activity of the labeled substance.
  • the reaction in the reaction chamber is performed more uniformly, and highly accurate measurement can be performed.
  • FIG. 1 is an example of a schematic diagram illustrating a sandwich immunoassay method using magnetic particles.
  • FIG. 2A is a schematic diagram illustrating an example of the configuration of the sample analysis system according to the embodiment.
  • FIG. 2B is a schematic diagram illustrating an example of a configuration for detecting the origin of the sample analysis substrate in the sample analysis system.
  • FIG. 3A is an exploded perspective view illustrating an example of a sample analysis substrate.
  • FIG. 3B is a plan view showing an example of the sample analysis substrate.
  • FIG. 3C is a plan view showing a configuration related to the transfer of a reaction solution among the sample analysis substrates shown in FIG. 3A.
  • FIG. 3D is a plan view showing a configuration related to the transfer of the cleaning liquid among the sample analysis substrates shown in FIG. 3A.
  • FIG. 3E is a plan view showing a configuration related to transfer of a substrate solution among the sample analysis substrates shown in FIG. 3A.
  • FIG. 3F is a perspective view showing another example of the method of holding the magnet on the sample analysis substrate.
  • FIG. 4 is an enlarged plan view showing a part of the structure of the sixth flow path of the sample analysis substrate. It is a perspective view which shows another example of the holding method of a magnet.
  • FIG. 5 is a flowchart illustrating an example of the operation of the sample analysis system.
  • FIG. 6 is a diagram schematically illustrating an example of the stop angle of the sample analysis substrate and the position of the liquid during the operation of the sample analysis system.
  • FIG. 7 is a diagram schematically illustrating an example of the stop angle of the sample analysis substrate and the position of the liquid during the operation of the sample analysis system.
  • FIG. 8 is a diagram schematically illustrating an example of the stop angle of the sample analysis substrate and the position of the liquid during the operation of the sample analysis system.
  • FIG. 9 is a diagram schematically illustrating an example of the stop angle of the sample analysis substrate and the position of the liquid during the operation of the sample analysis system.
  • FIG. 10 is a diagram schematically illustrating an example of the stop angle of the sample analysis substrate and the position of the liquid during the operation of the sample analysis system.
  • FIG. 11 is a diagram schematically illustrating an example of the stop angle of the sample analysis substrate and the position of the liquid during the operation of the sample analysis system.
  • FIG. 12 is a diagram schematically illustrating an example of the stop angle of the sample analysis substrate and the position of the liquid during the operation of the sample analysis system.
  • FIG. 13 is a diagram schematically illustrating an example of the stop angle of the sample analysis substrate and the position of the liquid during the operation of the sample analysis system.
  • FIG. 14 is a diagram schematically illustrating an example of the stop angle of the sample analysis substrate and the position of the liquid during the operation of the sample analysis system.
  • FIG. 15 is a diagram schematically illustrating an example of the stop angle of the sample analysis substrate and the position of the liquid during the operation of the sample analysis system.
  • FIG. 16 is a diagram schematically illustrating an example of the stop angle of the sample analysis substrate and the position of the liquid during the operation of the sample analysis system.
  • FIG. 17 is a diagram schematically illustrating an example of the stop angle of the sample analysis substrate and the position of the liquid during the operation of the sample analysis system.
  • FIG. 18 is a diagram schematically illustrating an example of the stop angle of the sample analysis substrate and the position of the liquid during the operation of the sample analysis system.
  • FIG. 19 is a diagram schematically illustrating an example of the stop angle of the sample analysis substrate and the position of the liquid during the operation of the sample analysis system.
  • FIG. 20 is a plan view showing another example of the sample analysis substrate.
  • FIG. 21 is a plan view showing another example of the sample analysis substrate.
  • FIG. 22 is a plan view showing another example of the sample analysis substrate.
  • FIG. 23 is a plan view showing another example of the sample analysis substrate.
  • FIG. 24A is a cross-sectional view of the collection chamber taken along line A-A ′ shown in FIG.
  • FIG. 24B is a cross-sectional view of the collection chamber taken along line B-B ′ shown in FIG.
  • FIG. 24C is a circumferential cross-sectional view of the collection chamber.
  • FIG. 24D is a cross-sectional view illustrating another example of the circumferential direction of the collection chamber.
  • FIG. 25 is a flowchart showing a procedure for performing sample analysis using the sample analysis substrate shown in FIG.
  • the present inventor has studied in detail the cause of the decrease in measurement accuracy in the analysis using the conventional sample analysis substrate, and found a problem in the recovery chamber.
  • the liquid containing the sample is weighed in the reaction chamber, and the magnetic particle-immobilized antibody and the labeled antibody are combined with the antigen which is the component to be detected in the sample.
  • the antigen bound to the magnetic particle-immobilized antibody and the labeled antibody is washed with a washing solution while being suctioned by a magnet.
  • the used cleaning solution is transferred to the collection chamber.
  • the substrate solution is introduced into the measurement chamber, and the substrate is reacted with the labeled antibody to detect luminescence or the like. At this time, the excess substrate solution is transferred to the collection chamber.
  • the used washing solution transferred to the collection chamber contains labeled antibodies that did not react with the antigen. Therefore, when the substrate solution is also transferred to the collection chamber, the labeled antibody reacts with the substrate in the collection chamber to generate luminescence, which may affect the detection of luminescence in the measurement chamber.
  • a sample analysis substrate and a sample analysis method according to one embodiment of the present application are as follows.
  • a flow path located in the substrate and having a first opening and a second opening, wherein the first opening and the second opening are connected to the main chamber and the collection chamber, respectively.
  • a substrate for sample analysis comprising:
  • the collection chamber has a first end and a second end, and extends circumferentially; 10.
  • the sample analysis substrate according to any one of items 1 to 9, wherein the second opening of the flow path is connected to a first end side of the recovery chamber between a first end and a second end thereof.
  • the collection chamber has a first height and a second height along a thickness direction of the substrate, The first height is located closer to the first end than the middle, the second height is located closer to the second end than the middle, and the first height is greater than the second height. 13.
  • the collection chamber has a side wall located on the outer peripheral side of the space, The first distance from the center of the substrate to the side wall at a first position located between the first end and the middle is the substrate at a second position located between the second end and the middle 12.
  • a sample analysis method for analyzing a specific substance in a sample using the sample analysis substrate according to item 1 A step of introducing a reaction solution containing a complex in which the specific component, the labeling substance, and the magnetic particles in the sample are bound to the main chamber, By rotating the sample analysis substrate while holding the complex in the main chamber by the magnetic force of the magnet, the reaction solution is transferred to the collection chamber, and the reaction solution is stored in the collection chamber. Reacting the labeling substance not forming the complex therein with the activity inhibitor.
  • a sample analysis method comprising:
  • a binding reaction between an analyte to be analyzed and a ligand that specifically binds to the analyte may be used.
  • an analysis method include an immunoassay method and a genetic diagnosis method.
  • Examples of the immunoassay include a competitive method and a non-competitive method (sandwich immunoassay).
  • An example of a genetic diagnosis method is a gene detection method by hybridization.
  • magnetic particles sometimes referred to as “magnetic beads”, “magnetic particles”, or “magnetic beads”.
  • a sandwich immunoassay method using magnetic particles will be specifically described.
  • an antigen-antibody reaction is performed between a primary antibody 304 (hereinafter, referred to as “magnetic particle-immobilized antibody 305”) immobilized on the surface of a magnetic particle 302 and an antigen 306 to be measured.
  • a primary antibody 304 hereinafter, referred to as “magnetic particle-immobilized antibody 305”
  • an antigen 306 to be measured.
  • the secondary antibody hereinafter, referred to as “labeled antibody 308”
  • labeling substance 307 is bound and the antigen 306 are bound by an antigen-antibody reaction.
  • the labeling substance 307 includes, for example, enzymes (for example, peroxidase, alkaline phosphatase, luciferase, etc.), chemiluminescent substances, electrochemical luminescent substances, fluorescent substances, and the like. Signals such as luminescence and fluorescence are detected.
  • the sandwich immunoassay method using magnetic particles has been described as an example.
  • B / F separation is performed by an immunoassay method using a competitive method or a non-competitive method, or by hybridization, regardless of the use of magnetic particles. It is required when performing a gene detection method.
  • a ligand immobilized by physical adsorption on a solid phase composed of a material such as polystyrene or polycarbonate, a ligand immobilized on a solid phase by chemical bonding, or a metal composed of gold or the like For example, immobilization using a self-assembled monolayer (SAM: Self-Assembled @ Monolayer) is used.
  • SAM Self-Assembled @ Monolayer
  • the magnetic particles including the complex 310 In order to sufficiently perform the B / F separation, it is preferable to wash the magnetic particles including the complex 310 a plurality of times with a washing solution. Specifically, first, in a reaction solution containing the complex 310, the unreacted antigen 306, the labeled antibody 308, and the like, only the reaction solution is removed while the complex 310 containing the magnetic particles is captured by the magnet. . After that, the complex 310 is washed by adding a washing solution, and the washing solution is removed. By repeating this washing a plurality of times, B / F separation from which unreacted substances and non-specifically adsorbed substances have been sufficiently removed can be achieved. After washing the complex 310 several times, the complex 310 is reacted with a substrate solution to generate a signal based on the labeling substance 307.
  • FIG. 2A is a schematic diagram showing the entire configuration of the sample analysis system 501.
  • the sample analysis system 501 includes the sample analysis substrate 100 and the sample analyzer 200.
  • the sample analyzer 200 includes a motor 201, an origin detector 203, a rotation angle detection circuit 204, a control circuit 205, a drive circuit 206, and an optical measurement unit 207.
  • the motor 201 has a rotation axis 201A inclined from the gravity (vertical) direction G at an angle ⁇ greater than 0 ° and 90 ° or less with respect to the direction of gravity of the turntable 201a and the direction of gravity, and a sample analysis mounted on the turntable 201a.
  • Substrate 100 is rotated around rotation axis 201A. Since the rotation axis 201A is tilted, the transfer of the liquid in the sample analysis substrate 100 can be performed not only by centrifugal force due to rotation but also by movement due to gravity.
  • the inclination angle of the rotating shaft 201A with respect to the direction of gravity G is preferably 5 ° or more, more preferably 10 ° or more and 45 ° or less, and even more preferably 20 ° or more and 30 ° or less.
  • the motor 201 may be, for example, a DC motor, a brushless motor, an ultrasonic motor, or the like.
  • the origin detector 203 detects the origin of the sample analysis substrate 100 attached to the motor 201.
  • the origin detector 203 includes a light source 203a, a light receiving element 203b, and an origin detecting circuit 203c, and is arranged such that the sample analysis substrate 100 is located between the light source 203a and the light receiving element 203b. Is done.
  • the light source 203a is a light emitting diode
  • the light receiving element 203b is a photodiode.
  • the sample analysis substrate 100 has a marker 210 provided at a specific position.
  • the marker 210 has, for example, a light blocking property of blocking at least a part of light emitted from the light source 203a.
  • the area of the marker 210 has a low transmittance (for example, 10% or less), and the area other than the marker 210 has a high transmittance (for example, 60% or more).
  • the light receiving element 203b When the substrate for sample analysis 100 is rotated by the motor 201, the light receiving element 203b outputs a detection signal corresponding to the amount of incident light to the origin detection circuit 203c.
  • the detection signal increases or decreases at the edges 210a and 210b of the marker 210 according to the rotation direction.
  • the origin detection circuit 203c detects a decrease in the amount of detected light and outputs it as an origin signal.
  • the position of the edge 210a of the marker 210 is treated as the origin position of the sample analysis substrate 100 (the reference angular position of the sample analysis substrate 100).
  • a position at a specific angle arbitrarily determined from the position of the edge 210a of the marker 210 may be determined as the origin.
  • the marker 210 has a sector shape and its central angle is smaller than the angle detection accuracy required for sample analysis, the marker 210 itself may be determined as the origin position.
  • the origin position is used by the sample analyzer 200 to acquire information on the rotation angle of the substrate 100 for sample analysis.
  • the origin detector 203 may have another configuration.
  • the sample analysis substrate 100 may include a magnet for detecting the origin, and the origin detector 203 may be a magnetic detection element that detects the magnetism of the magnet. Further, a magnet for capturing magnetic particles, which will be described later, may be used for origin detection.
  • the origin detector 203 may not be provided.
  • the rotation angle detection circuit 204 detects the angle of the rotation shaft 201A of the motor 201.
  • the rotation angle detection circuit 204 may be a rotary encoder attached to the rotation shaft 201A.
  • the rotation angle detection circuit 204 includes a Hall element provided in the brushless motor and a detection circuit that receives an output signal of the Hall element and outputs an angle of the rotation shaft 201A. Is also good.
  • the drive circuit 206 rotates the motor 201. Specifically, based on a command from the control circuit 205, the sample analysis substrate 100 is rotated clockwise or counterclockwise. In addition, based on the detection result of the rotation angle detection circuit 204 and the origin detector 203 and the command from the control circuit 205, the sample analysis substrate 100 is rocked and stopped.
  • the optical measurement unit 207 detects a signal (for example, a dye, luminescence, or fluorescence) corresponding to the labeling substance 307 of the labeled antibody 308 bound to the complex 310 (FIG. 1) held on the sample analysis substrate 100.
  • a signal for example, a dye, luminescence, or fluorescence
  • the control circuit 205 includes, for example, a CPU provided in the sample analyzer 200.
  • the control circuit 205 executes a computer program read into a RAM (Random Access Memory) (not shown) to send instructions to other circuits according to the procedure of the computer program.
  • Each circuit that has received the instruction operates as described herein to realize the function of each circuit.
  • the command from the control circuit 205 is sent to a drive circuit 206, a rotation angle detection circuit 204, an optical measurement unit 207, and the like, for example, as shown in FIG. 2A.
  • the procedure of the computer program is illustrated by the flowchart in the accompanying drawings.
  • the RAM loaded with the computer program in other words, the RAM storing the computer program may be volatile or non-volatile.
  • a volatile RAM is a RAM that cannot hold stored information unless power is supplied.
  • dynamic random access memory DRAM
  • a non-volatile RAM is a RAM that can hold information without supplying power.
  • a magnetoresistive RAM MRAM
  • ReRAM resistance change type memory
  • FeRAM ferroelectric memory
  • Both volatile RAM and non-volatile RAM are examples of non-transitory, computer-readable storage media.
  • a magnetic recording medium such as a hard disk
  • an optical recording medium such as an optical disk are examples of non-temporary, computer-readable recording media. That is, the computer program according to the present disclosure can be recorded on various non-transitory computer-readable media other than the medium (temporary medium) such as the atmosphere that propagates the computer program as a radio signal.
  • control circuit 205 is described as a component separate from the rotation angle detection circuit 204 and the origin detection circuit 203c of the origin detector 203.
  • these may be realized by common hardware.
  • a CPU computer
  • a computer program functioning as a control circuit 205
  • a computer program functioning as a rotation angle detection circuit 204 and a computer program functioning as an origin detection circuit 203c of the origin detector 203. May be performed serially or in parallel. Thereby, the CPU can be apparently operated as a different component.
  • FIG. 3A is an exploded perspective view of the sample analysis substrate 100.
  • the sample analysis substrate 100 includes a rotation axis 110 and a plate-shaped substrate 100 ′ having a predetermined thickness in a direction parallel to the rotation axis 110.
  • the substrate 100 ′ of the sample analysis substrate 100 includes a base substrate 100a and a cover substrate 100b.
  • the substrate 100 ′ of the sample analysis substrate 100 has a circular shape, but may have, for example, a polygonal shape, an elliptical shape, a fan shape, or the like.
  • the substrate 100 ' has two main surfaces 100c and 100d.
  • the main surface 100c and the main surface 100d are parallel to each other, and the thickness of the substrate 100 ′ (the distance between the two main surfaces) defined by the distance between the main surface 100c and the main surface 100d is The same is true at any position of 100 '.
  • the main surfaces 100c and 100d need not be parallel.
  • a part of the two main surfaces may be non-parallel or parallel, or may be entirely non-parallel.
  • at least one of the main surfaces 100c and 100d of the substrate 100 ' may have a configuration having a concave portion or a convex portion.
  • FIG. 3B is a plan view of the base substrate 100a.
  • the sample analysis substrate 100 includes a first holding chamber 101, a second holding chamber 102, a third holding chamber 103, a first storage chamber 104, and a second storage chamber, which are respectively located inside the substrate 100 '. 105, a reaction chamber 106, a main chamber 107 and a collection chamber 108.
  • the shape of each chamber is not limited, and may have any shape, unless otherwise specified below.
  • Each chamber generally has a space defined by upper and lower surfaces parallel to the two main surfaces 100c, 100d (FIG. 3A) of the substrate 100 'and three or more side surfaces located therebetween. Two adjacent surfaces of the upper surface, the lower surface, and the side surfaces may not be separated by a clear ridge.
  • the shape of each chamber may be a flat sphere or a spheroid.
  • the sample analysis substrate 100 further includes a first flow path 111, a second flow path 112, a third flow path 113, a fourth flow path 114, a fifth flow path 115, a sixth flow path And a seventh channel 117.
  • the first flow path 111 connects the first holding chamber 101 and the second holding chamber 102.
  • the second flow path 112 connects the second holding chamber 102 and the main chamber 107.
  • the third flow path 113 connects the main chamber 107 and the collection chamber 108.
  • the fourth flow path 114 connects the first storage chamber 104 and the first holding chamber 101.
  • the fifth flow path 115 connects the second storage chamber 105 and the third holding chamber 103.
  • the sixth flow path 116 connects the third holding chamber 103 and the main chamber 107.
  • the seventh flow path 117 connects the reaction chamber 106 and the main chamber 107.
  • Transfer of liquid between chambers through the flow path can be realized by various methods. For example, transfer by gravity and transfer by capillary force and centrifugal force by rotation can be used. Hereinafter, these two transfer methods will be generally described.
  • the liquid can move in the flow path by gravity.
  • the sample analysis substrate 100 is supported with the rotation shaft 110 inclined at an angle of more than 0 degrees and 90 degrees or less with respect to the direction of gravity G.
  • the transfer source chamber in which the liquid exists is located at a higher position than the transfer destination chamber. "High” refers to being higher in the direction of gravity G.
  • the flow path that can be transferred by gravity is not a capillary path described below.
  • the flow path that can be transferred by gravity has, for example, a thickness of 1 mm or more.
  • the channel may be a capillary channel.
  • “Capillary channel” refers to a channel having a narrow cross section that allows at least a portion of the interior to be filled with liquid by capillary forces due to capillary action.
  • the transfer of liquid by a capillary channel will be described by taking as an example a configuration having chambers A and B that are not capillary spaces and a capillary channel connecting chambers A and B.
  • the liquid in the flow path is stationary due to the balance between the capillary force, the atmospheric pressure, and the gravity, and the liquid is not transferred from the chamber A to the chamber B. Also, by rotating the sample analysis substrate, liquid transfer does not occur even when a centrifugal force equal to or less than the capillary force acts on the liquid in the channel.
  • the chamber B is arranged at a position farther than the chamber A with respect to the rotation axis, and the sample analysis substrate is rotated so that a centrifugal force larger than the capillary force acts on the liquid in the flow path of the capillary channel. Then, the liquid in the chamber A can be transferred to the chamber B by the centrifugal force.
  • the flow path has a thickness of, for example, 50 ⁇ m to 300 ⁇ m.
  • different thicknesses can be realized by changing the depth of a space provided in the base substrate 100a.
  • the depth of the space provided in the base substrate 100a is made constant, and a convex portion having a different height is provided at a position corresponding to each chamber or flow channel of the cover substrate 100b, so that the thickness of each flow channel and chamber is different. You may let it.
  • a part or all of the flow path may form a capillary space so that a part or all of the chamber is surely filled with the retained liquid.
  • the thickness of the region serving as the capillary space is 50 ⁇ m to 300 ⁇ m as described above.
  • the sample analysis substrate 100 having a diameter of 60 mm can be rotated in a range of 100 rpm to 8000 rpm.
  • the rotation speed is determined according to the shape of each chamber and flow path, the physical properties of the liquid, the timing of liquid transfer and processing, and the like.
  • Hydrophilic treatment may be applied to the inner surface of the channel or chamber where the capillary force acts and the inner surface near the connection part of the chamber to which the channel is connected. Capillary force works greatly by the hydrophilic treatment.
  • the hydrophilic treatment is performed by, for example, applying a nonionic, cationic, anionic or zwitterionic surfactant to the above-described inner surface, performing corona discharge treatment, or providing physical fine irregularities. (See, for example, JP-A-2007-3361).
  • the third flow path 113, the fourth flow path 114, the fifth flow path 115, and the sixth flow path 116 are spaces in which the internal liquid can be filled by capillary action, these flow paths May also be subjected to a hydrophilic treatment.
  • Each of the first holding chamber 101, the second holding chamber 102, the third holding chamber 103, the first storage chamber 104, the second storage chamber 105, the reaction chamber 106, the main chamber 107, and the collection chamber 108 has at least one air hole. 122 are provided. Thereby, the inside of each chamber is kept at the atmospheric pressure under the environment, and each flow path can be moved by the principle of capillary action and siphon. Further, the first storage chamber 104, the second storage chamber 105, and the reaction chamber 106 may be provided with an opening 123 for injecting a liquid such as a substrate solution, a sample washing solution, a reaction solution, or the like. The air holes 122 may also serve as the openings 123.
  • Each space of the first holding chamber 101, the second holding chamber 102, the third holding chamber 103, the first storage chamber 104, the second storage chamber 105, the reaction chamber 106, the main chamber 107, and the collection chamber 108 is a base substrate 100a
  • the upper and lower portions of each space are formed by covering the base substrate 100a with the cover substrate 100b. That is, these spaces are defined by the inner surface of the substrate 100 '.
  • the first flow path 111, the second flow path 112, the third flow path 113, the fourth flow path 114, the fifth flow path 115, the sixth flow path 116, and the seventh flow path 117 are also formed on the base substrate 100a.
  • the base substrate 100a and the cover substrate 100b define an upper surface and a lower surface, respectively.
  • the substrate 100 ' can be made of, for example, a resin such as acrylic, polycarbonate, or polystyrene.
  • Table 1 shows that, in the sample analysis substrate 100 of the present embodiment, the substance or liquid to be introduced at the start of the sample analysis, the chamber to be introduced first, and the order in which the introduced substance or liquid is introduced to the main chamber.
  • the combination is shown.
  • the combinations shown in Table 1 are only one combination illustrated, and the materials and liquids to be introduced into the chamber and the order of introduction into the main chamber 107 are not limited to those shown in Table 1.
  • the magnetic particle-immobilized antibody 305, the specimen containing the antigen 306, and the labeled antibody 308 are introduced into the reaction chamber 106, and the complex 310 is generated in the reaction chamber 106. Further, a substrate solution is introduced into the first storage chamber 104. The cleaning liquid is introduced into the second storage chamber 105.
  • FIGS. 3C to 3E the chambers and flow paths for the complex 310, the washing solution, and the substrate solution will be described in accordance with the order of introduction into the main chamber 107 shown in the above table. 3C to 3E, for the sake of simplicity, structures that are not related or not mentioned of the sample analysis substrate 100 are not shown.
  • reaction chamber 106 As shown in FIG. 3C, a reaction chamber 106 is provided on the substrate 100 for sample analysis. As described with reference to FIG. 1, the reaction chamber 106 is a reaction field for reacting the magnetic particle-immobilized antibody 305, the specimen containing the antigen 306, and the labeled antibody 308 to form a complex 310. .
  • the shape of the reaction chamber 106 is not particularly limited.
  • the reaction chamber 106 is provided as a reaction field for forming the complex 310.
  • the transfer of the sample containing the magnetic particle-immobilized antibody 305, the antigen 306, and the labeled antibody 308 to the reaction chamber 106 can be performed by various means.
  • a mixed solution in which a sample containing the magnetic particle-immobilized antibody 305 and the antigen 306 and the labeled antibody 308 are mixed in advance is weighed, the mixed solution is injected into the sample analysis substrate 100, and the complex is formed in the reaction chamber 106. It may be formed.
  • the sample analysis substrate 100 includes, for example, a chamber for holding each of the specimen including the magnetic particle-immobilized antibody 305 and the antigen 306 and the labeled antibody 308, and a flow path (for example, a capillary tube) connecting the respective chambers to the reaction chamber 106. Road).
  • a flow path for example, a capillary tube connecting the respective chambers to the reaction chamber 106. Road.
  • the sample containing the magnetic particle-immobilized antibody 305 and the antigen 306 and the labeled antibody 308 are weighed into each chamber, and the sample containing the magnetic particle-immobilized antibody 305 and the antigen 306 injected into each chamber and the labeled antibody 308 are collected.
  • the complex 310 may be formed by transferring to the reaction chamber 106 and mixing in the reaction chamber 106.
  • the magnetic particle-immobilized antibody 305 and the labeled antibody 308 may be dried (hereinafter, referred to as “drying reagent”).
  • drying reagent may be formed by holding the dry reagent in the reaction chamber 106 and dissolving the dry reagent in a liquid containing a sample solution containing the antigen 306.
  • the complex 310 may be formed by dissolving the dry reagent held in a certain chamber at the time of measurement with a predetermined solution, and mixing the sample solution containing the antigen 306 in the reaction chamber 106.
  • the solution containing the complex 310 in the reaction chamber 106 is transferred to the main chamber 107 via the seventh channel 117.
  • the seventh channel 117 has an opening 117g and an opening 117h.
  • the opening 117g of the seventh flow path 117 is the outermost peripheral side surface 106a located on the side farthest from the rotation shaft 110 or the adjacent side surface adjacent to the outermost peripheral side surface 106a among the side surfaces of the reaction chamber 106, It is preferable to be provided at a position including a connection portion with the side surface 106a. This is because, when the liquid in the reaction chamber 106 is transferred to the main chamber 107, it is possible to suppress the occurrence of liquid residue in the reaction chamber 106.
  • FIG. 3C shows an example in which the opening 117g is provided in a part of the outermost peripheral side surface 106a.
  • the opening 117h of the seventh flow path 117 is located farther from the rotation shaft 110 than the opening 117g.
  • the opening 117h is connected to the side surface of the main chamber 107 as described below.
  • the solution including the complex 310 in the reaction chamber 106 is centrifuged. It is transferred to the main chamber 107 via the seventh channel 117.
  • the seventh flow path 117 may be a capillary path or a flow path that can be transferred by gravity.
  • the main chamber 107 is a place where B / F separation of the solution containing the complex 310 is performed.
  • the sample analysis substrate 100 includes a magnet 121 disposed in the substrate 100 ′.
  • the magnet 121 is located in the sample analysis substrate 100 close to the space of the main chamber 107. More specifically, the magnet 121 is arranged close to the outermost peripheral side surface 107a farthest from the rotation shaft 110 among the plurality of side surfaces of the main chamber 107. However, the magnet 121 in the sample analysis substrate 100 may be arranged at a position close to the upper surface or lower surface other than the outermost peripheral side surface 107a of the main chamber 107. That is, as long as the magnetic particles can be captured on the wall surface of the main chamber 107 by the magnet 121, the position is not particularly limited.
  • the magnet 121 may be configured to be detachable according to B / F separation, may be irremovably attached to the substrate 100 ′, or may be configured to be provided on the sample analyzer 200 side. Is also good.
  • the substrate 100 ′ includes a storage chamber that can store the magnet 121.
  • the substrate 100 ' may include a concave storage chamber 120 having an opening 120a in the main surface 100c.
  • the storage room 120 has a space in which the magnet 121 can be stored.
  • the opening 120a of the storage chamber 120 may be provided on the main surface 100d, or may be provided on a side surface located between the two main surfaces 100c and 100d.
  • the turntable 201a of the sample analyzer 200 may include a magnet unit having the magnet 121.
  • the magnet 121 is arranged at a position where the magnetic particles can be captured on the wall surface of the main chamber 107.
  • the sample analyzer 200 may include a magnet 121 and a drive mechanism for moving the magnet 121.
  • the sample analysis substrate 100 has a storage chamber for holding the magnet 121, and the driving mechanism inserts the magnet 121 into the storage chamber of the sample analysis substrate 100 in accordance with the B / F separation, and May be taken out.
  • the complex 310 and the unreacted magnetic particle-immobilized antibody 305 in the reaction solution (hereinafter, when both of them are indicated, simply The magnetic particles 311) are collected and captured on the outermost peripheral side 107a side by the magnetic force of the magnet 121 arranged close to the outermost peripheral side 107a.
  • the space of the main chamber 107 may include a first region 107f and a second region 107e adjacent to and connected to the first region 107f.
  • the first region 107f is a space in which the liquid can move by gravity
  • the second region 107e is a capillary space where a capillary force acts.
  • the thickness of the first region 107f is larger than the thickness of the second region 107e
  • the first region 107f has a larger space than the second region 107e.
  • the thicknesses of the first region 107f and the second region 107e are values within the above-described range specifically described as the thickness of the flow path.
  • the second region 107e is in contact with the outermost peripheral side surface 107a, and it is preferable that at least a part of the first region 107f is closer to the rotation shaft 110 than the second region 107e.
  • the opening 117h of the seventh channel 117 is provided on one of the side surfaces that are in contact with the first region 107f.
  • the liquid in the main chamber 107 is transferred to the collection chamber 108 via the third channel 113.
  • the opening 113g of the third channel 113 is provided on a side surface that is in contact with the second region 102e so as to be connected to the space of the second region 102e.
  • the first region 107f is a space in which the liquid can move by gravity, so that a space having a size as needed can be secured. Since the second region 107e is a capillary space, the second region 107e is always filled with a part of the liquid held in the main chamber 107. Therefore, when the third channel 113 contacts the second region 107e, the liquid in the main chamber 107 can be transferred to the collection chamber 108 via the third channel 113 without any excess. In addition to the reaction solution, the washing solution and the substrate solution are introduced into the main chamber 107. Therefore, the main chamber 107 must have a sufficient space for holding these liquids, and if necessary, the holding chamber may collect the liquids. The ability to reliably transfer to 108 is an important feature.
  • the third channel 113 has an opening 113g and an opening 113h, the opening 113g is connected to the main chamber 107, and the opening 113h is connected to the collection chamber 108.
  • the opening 113g of the third flow path 113 is the outermost peripheral side 107a located on the side farthest from the rotation shaft 110 or the adjacent side adjacent to the outermost peripheral side 107a among the side surfaces of the main chamber 107. It is preferably provided at a position including a connection portion with the side surface 107a.
  • FIG. 3B shows an example in which the opening 113g is provided on the adjacent side surface adjacent to the outermost peripheral side surface 107a. As described above, the opening 113g is connected to the second region 107e of the main chamber 107.
  • the opening 113h of the third flow path 113 is located farther from the rotation shaft 110 than the opening 113g.
  • the opening 113h is the innermost peripheral side surface 108b located on the side closest to the rotation shaft 110 or the side surface adjacent to the innermost peripheral side surface 108b among the side surfaces of the collection chamber 108, and is the innermost peripheral side surface 108b. It is preferable to be provided at a position close to.
  • FIG. 3B shows an example in which the opening 113h is provided in a part of the innermost peripheral side surface 103b.
  • the third channel 113 can also suck the liquid held in the main chamber 107 by capillary action.
  • the thickness of the third channel 113 is smaller than the thickness of the second region 107e of the main chamber 107. This makes it possible to exert a stronger capillary force on the third flow path 113 than in the second area 107 e of the main chamber 107, and a part of the liquid in the second area 107 e of the main chamber 107 flows to the third flow path 113. It is sucked.
  • the third channel 113 can further control the movement of the liquid by the siphon principle. Therefore, as a siphon structure, the third channel 113 has a first bent portion 113n and a second bent portion 113m.
  • the first bent portion 113n has a convex shape on the opposite side to the rotating shaft 110
  • the second bent portion 113m has a convex shape on the rotating shaft 110 side.
  • the first bent portion 113n is located between the second bent portion 113m and the main chamber 107 located closer to the rotating shaft 110, of the main chamber 107 and the collection chamber 108 to which the third flow path 113 is connected. ing.
  • the siphon principle here refers to liquid supply control based on the balance between the centrifugal force applied to the liquid by the rotation of the sample analysis substrate 100 and the capillary force of the flow path.
  • the third channel 113 is a capillary channel having no siphon structure
  • the third channel 113 is transferred from the reaction chamber 106 to the main chamber 107 via the seventh channel 117 by centrifugal force generated by rotation of the sample analysis substrate 100.
  • the liquid transferred to the main chamber 107 is filled in the third flow channel 113 by the capillary force of the third flow channel 113.
  • the sample analysis substrate 100 is rotating at a rotation speed at which a centrifugal force stronger than the capillary force of the third flow path 113 can be applied.
  • the third flow path 113 has a siphon structure
  • the liquid transferred from the reaction chamber 106 to the main chamber 107 will cause the liquid to flow into the third flow path 113 due to the capillary force of the third flow path 113. Be drawn in.
  • the centrifugal force is higher than the capillary force applied to the liquid. Is stronger, the entire inside of the third flow path 113 is not filled with the liquid. That is, the third flow path 113 is filled with the liquid only up to the same height as the distance of the liquid level of the liquid existing in the main chamber 107 with respect to the rotation shaft 110.
  • the sample analysis substrate 100 is rotating at a rotational speed that applies a centrifugal force weaker than the capillary force of the third flow channel 113, the third flow channel 113 is filled with liquid by the capillary force, No further movement of the liquid is caused by the force.
  • the sample analysis substrate 100 When it is desired to transfer the liquid in the main chamber 107 to the collection chamber 108, the sample analysis substrate 100 is rotated at a rotation speed (including rotation stop) at which a centrifugal force equal to or less than the capillary force of the third flow path 113 can be applied. By rotating, the entire third flow path 113 is filled with the liquid by the capillary force. Thereafter, when the sample analysis substrate 100 is rotated at a rotation speed at which a centrifugal force stronger than the capillary force of the third flow path 113 can be applied, the liquid in the main chamber 107 can be transferred to the collection chamber 108. .
  • the reaction solution, the washing solution, and the substrate solution can be once held in the main chamber 107, and B / F separation, cleaning of magnetic particles and The reaction with the substrate solution can be appropriately performed.
  • the distance between the rotating shaft 110 and the innermost peripheral side surface 108b closest to the rotating shaft 110 of the collection chamber 108 located farthest from the rotating shaft 110 is R1
  • the rotating shaft is Assuming that the distance from 110 to a point located farthest from the rotation axis 110 of the first bent portion 113n is R2, it is preferable that R1> R2 (condition 1) is satisfied.
  • the sample analysis substrate 100 is transferred to the liquid in the third flow path 113 by a capillary. If the reaction solution or the washing solution transferred to the main chamber 107 is rotated at a rotation speed at which a centrifugal force stronger than the force is applied, the reaction solution or the washing solution transferred to the recovery chamber 108 can be prevented.
  • the recovery chamber 108 stores a reaction liquid other than the magnetic particles 311 transferred from the main chamber 107 via the third flow path 113 and a used cleaning liquid.
  • the recovery chamber 108 has a space with a larger volume than the total amount of the above-described reaction solution and the total used washing solution according to the number of times of washing. It is preferable that the main part of the collection chamber 108 that holds the liquid is located farther from the rotation axis 110 than the main chamber 107.
  • the second storage chamber 105 stores a cleaning liquid used for cleaning at the time of B / F separation.
  • the complex 310 can be washed a plurality of times during B / F separation.
  • the second storage chamber 105 has a space capable of holding a total volume of the cleaning liquid according to the number of times of cleaning.
  • the cleaning liquid in the second storage chamber 105 is transferred to the third holding chamber 103 via the fifth flow path 115.
  • the fifth channel 115 has an opening 115g and an opening 115h.
  • the opening 115g of the fifth flow path 115 is the outermost peripheral side surface 105a located on the side farthest from the rotation shaft 110 among the side surfaces of the second storage chamber 105, or the adjacent lateral side adjacent to the outermost peripheral side surface 105a, It is preferable to be provided at a position including a connection portion with the outermost peripheral side surface 105a.
  • FIG. 3D shows an example in which the opening 115g is provided at a connection portion between the outermost peripheral side surface 105a and the adjacent side surface.
  • the opening 115h of the fifth flow passage 115 is located farther from the rotation shaft 110 than the opening 115g.
  • the opening 115h is connected to the side surface of the third holding chamber 103, as described below.
  • the cleaning liquid in the second storage chamber 105 is subjected to the fifth flow by centrifugal force. It is transferred to the third holding chamber 103 via the path 115.
  • the fifth flow path 115 may be a capillary path or a flow path that can be transferred by gravity.
  • the third holding chamber 103 holds all the cleaning liquid stored in the second storage chamber 105. Thereafter, in order to clean the complex 310 in the main chamber 107, a part of the cleaning liquid is transferred to the main chamber 107, and the rest is retained. The amount of the cleaning liquid used for one cleaning is measured by the sixth flow path 116 as described below. For this reason, the third holding chamber 103 has a volume equal to or larger than the sixth flow path 116, and has a volume equal to or larger than the total amount of the cleaning liquid for the number of times of cleaning (for example, if the cleaning is performed twice, the sixth flow path 116 is used). Twice or more times, and three times of washing, three times or more the volume of the sixth flow path 116).
  • the opening 115h of the fifth flow path 115 is provided on one inner peripheral side opposed to the outermost peripheral side 103a of the third holding chamber 103 with a space for holding the liquid therebetween.
  • the sixth flow passage 116 includes a first portion 116q and a second portion 116r connected to the first portion 116q.
  • the first portion 116q includes an opening 116g and is connected to the third holding chamber 103.
  • the second portion 116r has a second opening 116h and is connected to the main chamber 107.
  • the two parts 116r are capillary channels.
  • a part of the third holding chamber 103 and a part of the sixth flow path 116 are located substantially in the radial direction about the rotation shaft 110 with the opening 116g interposed therebetween.
  • the first portion 116q of the sixth channel 116 includes a first region 116qe and a second region 116qf.
  • the first portion 116q has a shape extending in a direction oblique to the radial direction of the sample analysis substrate 100.
  • the second region 116qf is located closer to the rotation shaft 110 than the first region 116qe in the first portion 116q.
  • the first region 116qe is a capillary space, and the second region 116qf is not a capillary space capable of filling a liquid by capillary action.
  • the thickness of the second region 116qf is larger than the thickness of the first region 116qe, and the second region 116qf is not filled with liquid when the first region 116qe is filled with liquid due to capillary action.
  • An air hole 122 is provided in the second region 116qf.
  • the second region 116qf is an airway for ensuring air movement.
  • the rotation angle of the sample analysis substrate 100 is changed to a position where the cleaning liquid comes into contact with the opening 116g while the cleaning liquid is held in the third holding chamber 103, the third area excluding the second region 116qf is removed.
  • the six channels 116 are filled with the cleaning liquid by capillary action.
  • the sample analysis substrate 100 is rotated at a rotation speed at which a centrifugal force stronger than the capillary force applied to the cleaning liquid in the sixth flow path 116 is applied. In this case, as shown in FIG.
  • the cleaning liquid transferred to the third holding chamber 103 and the sixth flow are set with reference to a straight line db connecting the rotation axis 110 and the position z.
  • the cleaning liquid returns to the path 116.
  • the reference position z is, as shown in FIG. 4, two side surfaces s1 and s2 located farther from the rotation axis 110 than the space of the third holding chamber 103 or the space of the sixth flow passage 116. Is defined by the boundary position between the side surface s1 inclined toward the third holding chamber 103 and the side surface s2 inclined toward the second holding chamber with respect to the tangential direction dt of the arc ar about the rotation axis 110. .
  • the cleaning liquid for one time is weighed, and the cleaning liquid is transferred to the main chamber 107.
  • the cleaning liquid transferred to the main chamber 107 is transferred to the collection chamber 108 via the third channel 113 as described above.
  • the first storage chamber 104 stores the substrate solution at the start of the analysis using the sample analysis system.
  • the shape of the first storage chamber 104 is not particularly limited, and may have an arbitrary shape.
  • the fourth flow path 114 connects the first storage chamber 104 and the first holding chamber 101.
  • the fourth flow path 114 extends, for example, in the radial direction around the rotation shaft 110 and is configured by a capillary path.
  • the fourth flow path 114 has an opening 114g and an opening 114h.
  • the opening 114g is provided at a position closest to the outermost peripheral side surface 104a, which is the outermost peripheral side surface 104a farthest from the rotation shaft 110 or a side surface adjacent to the outermost peripheral side surface 104a among the side surfaces of the first storage chamber 104.
  • an opening 114g is provided in the outermost peripheral side surface 104a.
  • the opening 114h is connected to the first holding chamber 101.
  • the first holding chamber 101 holds the substrate solution transferred from the first storage chamber 104 during the B / F separation including washing after the start of the analysis using the sample analysis system.
  • the first holding chamber 101 is located farther from the rotation shaft 110 than the first storage chamber 104 is.
  • the first holding chamber 101 has a first outer peripheral side surface 101a1 and a second outer peripheral side surface 101a2, and a first inner peripheral side surface 101b1 and a second inner peripheral side surface 101b2 sandwiching a space for holding the substrate solution.
  • the first outer peripheral side 101a1 and the second outer peripheral side 101a2 do not overlap in the radial direction, and the first outer peripheral side 101a1 is located farther from the rotating shaft 110 than the second outer peripheral side 101a2.
  • the first inner peripheral side surface 101b1 and the second inner peripheral side surface 101b2 do not overlap in the radial direction, and the first inner peripheral side surface 101b1 is located farther from the rotation shaft 110 than the second inner peripheral side surface 101b2.
  • the first holding chamber 101 further has an adjacent side surface 101c adjacent to the first outer peripheral side surface 101a1 and the first inner peripheral side surface 101b1, and an adjacent side surface 101d adjacent to the second outer peripheral side surface 101a2 and the second inner peripheral side surface 101b2.
  • the space of the first holding chamber 101 is sandwiched between the adjacent side surfaces 101c and 101d and has a shape extending in the circumferential direction.
  • the opening 111g of the first flow path 111 is provided on the first inner peripheral side surface 101b1.
  • the opening 111g of the first flow path 111 which will be described in detail below, is located adjacent to a connection position of the adjacent side surface 101d with the second inner peripheral side surface 101b2. That is, the first flow path 111 is provided on the side closer to the rotation shaft 110 of the adjacent side surface 101d.
  • most of the space of the first holding chamber 101 is located farther from the rotation shaft 110 than the opening 111h of the first flow path 111. Therefore, even when the sample analysis substrate 100 is held at various rotation angles, the substrate solution held in the first holding chamber 101 is transferred to the second holding chamber 102 via the first flow path 111. Can be suppressed.
  • the first outer peripheral side surface 101a1 is located far from the rotation shaft 110, and the space of the first holding chamber 101 includes a convex portion 101r that is in contact with the first outer peripheral side surface 101a1 and protrudes to the outer peripheral side. Therefore, by holding the substrate solution in the convex portion 101r of the space of the first holding chamber 101, the liquid surface of the substrate solution held in the first holding chamber 101 is separated from the opening 111g of the first flow path 111. Therefore, the transfer to the second holding chamber 102 via the first flow path 111 can be suppressed more reliably.
  • the first flow path 111 connects the first holding chamber 101 and the second holding chamber 102.
  • the first flow path 111 has an opening 111g and an opening 111h, and the opening 111g is provided on the adjacent side surface 101d of the first holding chamber 101.
  • the opening 111h is provided on one of the side surfaces of the second holding chamber 102.
  • the first flow path 111 is a flow path in which the liquid can move by gravity.
  • the second holding chamber 102 holds the substrate solution transferred from the first holding chamber 101 via the first flow path 111.
  • the second holding chamber 102 includes a first portion 102q circumferentially adjacent to the first holding chamber 101 and a second portion 102r circumferentially adjacent to the second flow path 112. The first portion 102q and the second portion 102r are arranged in the radial direction.
  • the second holding chamber 102 is close to the adjacent side face 101d of the first holding chamber 101.
  • the main chamber 107 is located on the side 101c adjacent to the first holding chamber 101.
  • the second holding chamber 102 has an outermost peripheral side surface 102a farthest from the rotation shaft 110 and a second adjacent side surface 102c2 adjacent to the outermost peripheral side surface 102a. Further, it has an innermost peripheral side surface 102b closest to the rotating shaft 110 and a first adjacent side surface 102c1 adjacent to the innermost peripheral side surface 102b. With respect to the space of the second holding chamber 102, the first adjacent side face 102c1 and the second adjacent side face 102c2 are arranged on the same side, that is, the side facing the first holding chamber 101 and the second flow path 112. A concave portion 102s is formed between the first adjacent side surface 102c1 and the second adjacent side surface 102c2, and the first adjacent side surface 102c1 and the second adjacent side surface 102c2 are separated by the concave portion 102s.
  • the first portion 102q of the second holding chamber 102 includes an innermost peripheral side surface 102b and a first adjacent side surface 102c1, and the second portion 102r includes an outermost peripheral side surface 102a and a second adjacent side surface 102c2.
  • an opening 111h of the first flow path 111 is provided at a position of the first adjacent side surface 102c1 near the innermost peripheral side surface 102b.
  • an opening 112g of the second flow path 112 is provided at a position of the second adjacent side surface 102c2 that is separated from the outermost peripheral side surface 102a, more specifically, at a position closest to the rotating shaft 110.
  • the second channel 112 is a capillary channel
  • the second portion 102r is a capillary space that connects the outermost peripheral side surface 102a and the portion where the opening 112g of the second channel 112 is located.
  • 102re may be provided. In this case, it is preferable that the capillary space 102re is located along the second adjacent side surface 102c2.
  • the second flow path 112 has a first portion 112q and a second portion 112r, and an opening 112g and an opening 112h. One end of the first portion 112q and one end of the second portion 112r are connected to each other.
  • the opening 112g is located at the other end of the first portion 112q, and is connected to the second adjacent side surface 102c2 of the second holding chamber 102 as described above.
  • An opening 112h is located at the other end of the second portion 112r, and is connected to the main chamber 107.
  • the second portion 112r is a capillary channel.
  • the first portion 112q includes a first region 112qe and a second region 112qf.
  • the first portion 112q has a shape extending in the circumferential direction.
  • the second region 112qf is located closer to the rotation shaft 110 than the first region 112qe.
  • the first region 112qe is a capillary space, and the second region 112qf is not a capillary space that can be filled with liquid by capillary action.
  • the thickness of the second region 112qf is larger than the thickness of the first region 112qe.
  • An air hole 122 is provided in the second region 112qf. Further, the thickness of the first region 112qe is preferably smaller than the thickness of the capillary space 102re of the second holding chamber 102. Thereby, the substrate solution held in the capillary space 102re of the second holding chamber 102 can be drawn into the second channel 112.
  • each part of the second flow path 112 is positioned at the same position as the opening 112 g from the rotating shaft 110 or is opened from the rotating shaft 110. Preferably, it is located farther than 112 g. With this, when a centrifugal force stronger than the capillary force applied to the substrate solution in the second flow path 112 acts on the substrate solution in a state where the second flow path 112 is filled with the substrate solution, all of the liquid in the second flow path 112 Is transferred to the main chamber 107.
  • the total volume of the first region 112qe and the second portion 112r of the first portion 112q corresponds to the amount of the substrate solution used for the analysis, and by filling these portions with the substrate solution by the capillary force, the weighing of the substrate solution is reduced. Done.
  • the second region 112qf of the first portion 112q functions as an airway. For some reason, when bubbles are generated in the substrate solution held in the first region 112qe of the first portion 112q, the bubbles move to the second region 112qf, and the bubbles in the substrate solution are easily removed. Become. Accordingly, when the sample analysis substrate 100 is rotated, it is possible to particularly suppress the air bubbles from entering the second portion 112r and hindering the movement of the substrate solution.
  • the first region 112qe and the second portion 112r of the first portion 112q have been described as being the capillary space and the capillary channel. However, these spaces are the space where the liquid moves by gravity and the flow channel. It may be.
  • FIG. 5 is a flowchart showing the operation of the sample analysis system 501.
  • a program that defines a procedure for controlling each unit of the sample analysis system 501 for operating the sample analysis system 501 is stored in, for example, the memory of the control circuit 205.
  • the execution of the program by the arithmetic unit causes the following operations to be performed. Realize. Prior to the following steps, the sample analysis substrate 100 is loaded into the sample analyzer 200, and the origin of the sample analysis substrate 100 is detected.
  • a substrate solution and a washing solution are introduced into the first storage chamber 104 and the second storage chamber 105, respectively.
  • the substrate solution contains a substrate that emits light, changes fluorescence, or changes in absorption wavelength by reaction with the labeling substance 307 or catalysis by the labeling substance 307.
  • a sample containing the magnetic particle-immobilized antibody 305, the antigen 306, and the labeled antibody 308 is introduced into the reaction chamber 106.
  • a liquid containing the magnetic particle-immobilized antibody 305 is held in the reaction chamber 106, and a chamber (not shown) provided on the sample analysis substrate 100 holds a liquid containing the antigen 306 and the labeled antibody 308.
  • the magnetic particle-immobilized antibody 305, the antigen 306 in the sample, and the labeled antibody 308 are combined by an antigen-antibody reaction to form a complex 310.
  • the fourth flow path 114, the fifth flow path 115, and the seventh flow path 117 are filled with the reaction solution containing the substrate solution, the washing solution, and the complex 310, respectively, by capillary action.
  • Step S12 After the complex 310 is generated, the sample analysis substrate 100 is rotated, and the reaction solution containing the complex 310 is moved to the main chamber 107. As described above, the seventh channel 117 is filled with the reaction solution by the capillary phenomenon. For this reason, when a centrifugal force stronger than the capillary force applied to the reaction solution in the seventh flow path 117 by the rotation of the sample analysis substrate 100 acts on the reaction solution containing the complex 310 in the reaction chamber 106, the reaction solution becomes main. It is transferred to the chamber 107. The reaction solution transferred to the main chamber 107 is not subsequently transferred to the collection chamber 108 while the sample analysis substrate 100 is rotating.
  • the rotation speed of the sample analysis substrate 100 is set such that a liquid such as a reaction solution does not move due to gravity due to the centrifugal force generated by the rotation, and a centrifugal force stronger than the capillary force of each capillary path can be applied. Is done.
  • this rotation speed is set for rotation using centrifugal force.
  • the rotation direction of the sample analysis substrate 100 may be clockwise or counterclockwise.
  • the washing solution is transferred from the second storage chamber 105 to the third holding chamber 103 through the fifth flow path 115. Further, the substrate solution is transferred from the first storage chamber 104 to the first holding chamber 101 through the fourth flow path 114.
  • the sample analysis substrate 100 is stopped at a predetermined first angle.
  • the predetermined first angle means that the cleaning liquid transferred to the third holding chamber 103 in the sample analysis substrate 100 passes through the opening 116 g of the sixth flow path 116 and the first portion. 116q, the substrate solution in the first holding chamber 101 does not come into contact with the opening 111g of the first flow path 111, and the reaction solution in the main chamber 107 comes into contact with the opening 113g of the third flow path 113. It is the angle that can be touched.
  • This angle depends on the shapes of the first holding chamber 101, the main chamber 107, and the third holding chamber 103, the positions in the substrate 100 ', the amounts of the washing solution, the substrate solution and the reaction solution, the inclination angle ⁇ of the sample analysis substrate 100, and the like.
  • Dependent In the example shown in FIG. 7, the direction of gravity (indicated by an arrow) in the sample analysis system 501 projected on a plane parallel to the sample analysis substrate 100 only needs to be within the angle range of the sample analysis substrate 100 indicated by ⁇ 1. .
  • reaction liquid in the main chamber 107 is in contact with the opening 113g of the third channel 113, and fills the third channel 113 by capillary force.
  • Step S13 The sample analysis substrate 100 is rotated. A centrifugal force is generated with the rotation, and acts on the reaction liquid and the magnetic particles 311 (composite 310 and unreacted magnetic particles) in the main chamber 107. This centrifugal force acts to move the liquid and the complex 310 toward the outermost peripheral side surface 107a of the main chamber 107. Therefore, the magnetic particles 311 are pressed against the outermost peripheral side surface 107a.
  • the reaction solution subjected to the centrifugal force is discharged from the third channel 113 and transferred to the collection chamber 108. Due to the sum of the centrifugal force and the attractive force of the magnet 121, the magnetic particles 311 are strongly pressed against the outermost peripheral side surface 107a and are captured.
  • the cleaning liquid in the third holding chamber 103 receives centrifugal force due to rotation, but stays in the third holding chamber 103 because it is pressed against the outermost peripheral side surface 103a of the third holding chamber 103.
  • the substrate solution in the first holding chamber 101 also receives centrifugal force due to rotation, but stays in the first holding chamber 101 because it is pressed against the first outer peripheral side surface 101a1.
  • the reaction liquid and the magnetic particles 311 are separated. Specifically, the reaction solution moves to the recovery chamber 108, and the magnetic particles 311 stay in the main chamber 107. Even when the rotation of the sample analysis substrate 100 stops, the magnetic particles 311 can maintain the state of being collected on the outermost peripheral side surface 107a by the attraction force received from the magnet 121.
  • the stop angle at this time may be the first angle, the second angle in the next step, or another angle.
  • Step S14 As shown in FIG. 9, when the sample analysis substrate 100 is not stopped at the second angle in the previous step, the sample analysis substrate 100 is slightly rotated counterclockwise to stop at the predetermined second angle.
  • the second angle is an angle at which the cleaning liquid transferred to the third holding chamber 103 comes into contact with the opening 116g of the sixth flow path 116.
  • the gravitational direction is located at an angle within the angle range indicated by ⁇ 2 of the sample analysis substrate 100.
  • the cleaning liquid comes into contact with the first portion 116q of the sixth channel 116 through the opening 116g, it is sucked into the entire first region 116qe of the first portion 116q by the capillary force, and the first portion 116q of the sixth channel 116 is formed. And the second portion 116b is filled with the cleaning liquid. As a result, one cleaning liquid is weighed.
  • the sixth flow path 116 may be rotated clockwise and counterclockwise alternately about several degrees around the second angle, that is, rocked, so as to ensure that the sixth flow path 116 is filled with the cleaning liquid. At this time, the cleaning liquid does not move from the second portion 116b of the sixth flow path 116 to the main chamber 107 because the capillary force acts on the sixth flow path 116.
  • Step S15 Subsequently, the sample analysis substrate 100 is rotated. The centrifugal force due to the rotation acts on the cleaning liquid in the sixth flow path 116 and the third holding chamber 103. As described with reference to FIG. 4, the cleaning liquid located on the sixth flow path 116 side with respect to the straight line db moves to the main chamber 107 via the sixth flow path 116. Further, the cleaning liquid located on the third holding chamber 103 side with respect to the straight line db is returned to the third holding chamber 103 by centrifugal force. Therefore, as shown in FIG. 10, only the cleaning liquid weighed by the sixth flow path 116 is transferred to the main chamber 107.
  • the cleaning liquid Since a centrifugal force also acts on the cleaning liquid transferred to the main chamber 107, the cleaning liquid does not move in the direction of the rotation axis 110 in the third flow path 113, and the cleaning liquid substantially stays in the main chamber 107. As a result, the magnetic particles 311 in the main chamber 107 come into contact with the cleaning liquid, and the first cleaning is performed.
  • the substrate solution is pressed against the first outer peripheral side surface 101a1 in the first holding chamber 101 by centrifugal force. Thus, the substrate solution remains in the first holding chamber 101.
  • the sample analysis substrate 100 is stopped at a predetermined third angle.
  • the third angle is an angle at which the cleaning liquid in the third holding chamber 103 does not come into contact with the opening 116 g and the cleaning liquid transferred to the main chamber 107 can come into contact with the opening 113 g of the third flow path 113.
  • the gravity direction of the sample analysis system 501 projected on a plane parallel to the sample analysis substrate 100 only needs to be within the angle range indicated by ⁇ 3 on the sample analysis substrate 100.
  • Step S16 The sample analysis substrate 100 is rotated. A centrifugal force is generated with the rotation, and acts on the cleaning liquid and the magnetic particles 311 in the main chamber 107. The centrifugal force acts so that the cleaning liquid and the magnetic particles 311 move to the outermost peripheral side surface 107a of the main chamber 107, and the magnetic particles 311 are captured on the outermost peripheral side surface 107a by the centrifugal force and the attraction force of the magnet 121.
  • the cleaning liquid subjected to the centrifugal force is discharged from the third flow path 113 and transferred to the collection chamber 108. Therefore, only the cleaning liquid is discharged from the third channel 113, and the magnetic particles 311 stay in the main chamber 107.
  • the cleaning solution in the third holding chamber 103 and the substrate solution in the first holding chamber 101 are pressed against the outermost peripheral side surface 103a and the first outer peripheral side surface 101a1, respectively, and remain in the third holding chamber 103 and the first holding chamber 101.
  • the rotation of the sample analysis substrate 100 is stopped. Thereby, the cleaning liquid and the magnetic particles 311 are separated. Specifically, the cleaning liquid moves to the recovery chamber 108, and the magnetic particles 311 stay in the main chamber 107. Even when the rotation of the sample analysis substrate 100 stops, the magnetic particles 311 can maintain the state of being collected on the outermost peripheral side surface 107a by the attraction force received from the magnet 121.
  • the stop angle at this time may be a third angle or a fourth angle in the next step.
  • Step S17 As shown in FIG. 13, when the sample analysis substrate 100 is not stopped at the fourth angle in the previous step, the sample analysis substrate 100 is slightly rotated counterclockwise to stop at the predetermined fourth angle.
  • the fourth angle is an angle at which the cleaning liquid transferred to the third holding chamber 103 comes into contact with the opening 116g of the sixth flow path 116.
  • the angle is such that the direction of gravity is located within the angle range indicated by ⁇ 4 of the substrate for sample analysis 100. Since the amount of the cleaning liquid remaining in the third holding chamber 103 in step S4 is different, the angle range ⁇ 4 may be different from the angle range ⁇ 2.
  • the cleaning liquid is sucked into the sixth flow path 116 from the third holding chamber 103 by the capillary force in the first part 116q of the sixth flow path 116, and the first part 116q and the second part 116r of the sixth flow path 116 are cleaned with the cleaning liquid. It is filled. Thereby, the washing liquid for one time is weighed again.
  • the sample analysis substrate 100 may be swung about the fourth angle so that the sixth flow path 116 is reliably filled with the cleaning liquid. At this time, the cleaning liquid does not move from the sixth flow path 116 to the main chamber 107 because the capillary force acts on the sixth flow path 116.
  • Step S18 Subsequently, the sample analysis substrate 100 is rotated. The centrifugal force due to the rotation acts on the cleaning liquid in the sixth flow path 116 and the third holding chamber 103. As in the first cleaning, the cleaning liquid located on the sixth flow path 116 side moves to the main chamber 107 via the sixth flow path 116 with reference to the straight line db shown in FIG. Further, the cleaning liquid located on the third holding chamber 103 side with respect to the straight line db is returned to the third holding chamber 103 by centrifugal force. Only the cleaning liquid weighed by the sixth flow path 116 is transferred to the main chamber 107.
  • the cleaning liquid Since a centrifugal force also acts on the cleaning liquid transferred to the main chamber 107, the cleaning liquid does not move in the direction of the rotation axis 110 in the third flow path 113, and the cleaning liquid substantially stays in the main chamber 107. Thereby, the magnetic particles 311 in the main chamber 107 come into contact with the cleaning liquid, and the second cleaning is performed.
  • the substrate solution is pressed against the side surface of the main chamber 107 farthest from the rotation shaft 110 by centrifugal force. Thus, the substrate solution remains in the first holding chamber 101.
  • the sample analysis substrate 100 is stopped at a predetermined fifth angle.
  • the fifth angle is an angle at which the cleaning liquid in the third holding chamber 103 does not come into contact with the opening 116 g and the cleaning liquid transferred to the main chamber 107 can come into contact with the opening 113 g of the third flow path 113.
  • the direction of gravity of the sample analysis system 501 projected on a plane parallel to the sample analysis substrate 100 only needs to be within the angle range indicated by ⁇ 5 on the sample analysis substrate 100.
  • Step S19 The sample analysis substrate 100 is rotated. A centrifugal force is generated with the rotation, and acts on the cleaning liquid and the magnetic particles 311 in the main chamber 107. The centrifugal force acts so that the cleaning liquid and the magnetic particles 311 move to the outermost peripheral side surface 107a of the main chamber 107, and the magnetic particles 311 are captured on the outermost peripheral side surface 107a by the centrifugal force and the attraction force of the magnet 121.
  • the washing liquid subjected to the centrifugal force is discharged from the third flow path 113 and transferred to the collection chamber 108. Therefore, only the cleaning liquid is discharged from the third channel 113, and the magnetic particles 311 stay in the main chamber 107.
  • the cleaning liquid in the third holding chamber 103 is pressed against the outermost peripheral side surface 103a and stays in the third holding chamber 103.
  • the substrate solution is also pressed against the first outer peripheral side surface 101a1 and stays in the first holding chamber 101.
  • the rotation of the sample analysis substrate 100 is stopped.
  • the cleaning liquid and the magnetic particles 311 are separated. Specifically, the cleaning liquid moves to the recovery chamber 108, and the magnetic particles 311 stay in the main chamber 107. Even when the rotation of the sample analysis substrate 100 stops, the magnetic particles 311 can maintain the state of being collected on the outermost peripheral side surface 107a by the attraction force received from the magnet 121.
  • the stop angle at this time may be the fifth angle or the sixth angle in the next step.
  • Step S20 Process (a, b))
  • the substrate solution is moved from the first holding chamber 101 to the second holding chamber 102.
  • the sample analysis substrate 100 is rotated counterclockwise to stop at the predetermined sixth angle.
  • the sample analysis substrate 100 is rotated clockwise.
  • the sixth angle is an angle at which the substrate solution in the first holding chamber 101 comes into contact with the opening 111g of the first flow path 111, and the entire amount of the substrate solution can move to the second holding chamber 102 by gravity. This is an angle at which the first flow path 111 is arranged along the direction of gravity. As a result, the substrate solution in the first holding chamber 101 is transferred to the second holding chamber 102.
  • the sample analysis substrate 100 is rotated clockwise, and at a predetermined seventh angle at which the substrate solution contacts the capillary space 102re of the second portion 102r in the second holding chamber 102. Stop.
  • the substrate solution is sucked into the capillary space 102re by the contact between the capillary space 102re and the substrate solution.
  • the substrate solution filling the capillary space 102re is sucked into the second channel 112 from the opening 112g by the capillary force, and the first region 112qe and the second region 112qe of the first portion 112q of the second channel.
  • Portion 112r is filled with a substrate solution. Thereby, the substrate solution is weighed.
  • the second flow path 112 may be alternately rotated clockwise and counterclockwise about the seventh angle by several degrees, that is, rocked. At this time, the cleaning liquid does not move from the second portion 112r of the second flow path 112 to the main chamber 107 because the capillary force acts on the second flow path 112.
  • Step S21 (Step (c))
  • the sample analysis substrate 100 is rotated. Centrifugal force due to the rotation acts on the cleaning liquid in the second flow path 112 and the third holding chamber 103.
  • the substrate solution in the second flow path 112 moves to the main chamber 107 by centrifugal force.
  • the substrate solution located closer to the second holding chamber 102 than the opening 112g is pressed against the outermost peripheral side surface 102a of the second holding chamber 102 by centrifugal force, and stays in the second holding chamber 102.
  • the substrate solution moved to the main chamber 107 contains a substrate.
  • This substrate reacts with the labeling substance 307 contained in the labeled antibody 308 in the magnetic particles 311 held in the main chamber 107, or changes in light emission, fluorescence or absorption wavelength by a catalytic reaction of the labeling substance 307. .
  • the rotation of the sample analysis substrate 100 is stopped at the eighth angle as shown in FIG.
  • the eighth angle is set so that the light-receiving element of the optical measurement unit 207 is close to the main chamber 107 so that the change in the emission, fluorescence or absorption wavelength of the substrate in the main chamber 107 can be detected. This is an angle arranged in a predetermined positional relationship with respect to the unit 207.
  • the optical measurement unit 207 performs an optical measurement of the liquid held in the main chamber 107. Specifically, the optical measurement unit 207 detects a signal such as a dye, luminescence, or fluorescence of a substrate corresponding to the labeling substance 307 of the labeled antibody 308 bound to the complex 310 included in the magnetic particle 311. Thus, detection of the antigen 306, quantification of the concentration of the antigen 306, and the like can be performed.
  • a signal such as a dye, luminescence, or fluorescence of a substrate corresponding to the labeling substance 307 of the labeled antibody 308 bound to the complex 310 included in the magnetic particle 311.
  • the optical measurement by the optical measurement unit 207 may be performed while the sample analysis substrate 100 is rotated.
  • signals such as the dye, luminescence, and fluorescence of the substrate may be detected while the sample analysis substrate 100 is rotated.
  • the reaction solution, the substrate solution, and the washing solution are introduced into the reaction chamber 106, the first storage chamber 104, and the second storage chamber 105, respectively, and are sequentially transferred to the main chamber 107. It is preferable that the substrate solution to be transferred last is securely held so as not to be transferred to the main chamber 107 until the reaction solution and the washing solution are transferred to the main chamber 107.
  • the first holding chamber 101 holding the substrate solution has a space 101 extending in the circumferential direction, and the two holding chambers adjacent to the outermost peripheral side face.
  • the adjacent side surface is located adjacent to the reaction chamber 106, the third holding chamber 103 holding the cleaning solution, and the adjacent side surface that is close to the main chamber 107, and is located further away from the adjacent side surface, and is close to the rotation shaft 110.
  • the opening of the first flow path 111 is provided on the side. For this reason, even when the sample analysis substrate 100 is rotated at various angles, it is difficult for the substrate solution to come into contact with the opening 111g of the first flow path 111, and the transfer of the substrate solution to the second holding chamber 102 is suppressed. Can be.
  • Sample Analysis Substrate 100 (Other Examples of Sample Analysis Substrate 100) Various modifications can be made to the sample analysis substrate 100 of the above embodiment.
  • the first region 116qe of the first portion 112q of the second flow path 112 is a capillary space
  • the second portion 112r is a capillary passage
  • the second flow path may be a space in which liquid due to gravity can be transferred.
  • the entire amount of the substrate solution held in the second holding chamber 102 may be transferred to the main chamber 107 via the second channel 112.
  • the sample analysis substrate is stopped at the sixth angle, and the substrate solution in the first holding chamber 101 is moved to the second holding chamber 102 via the first channel 111.
  • the sample analysis substrate 100 is rotated clockwise and stopped at a predetermined seventh angle.
  • the second adjacent side surface 102c2 is inclined with respect to the horizontal direction such that the opening 112g is located below in the direction of gravity. Accordingly, all of the substrate solution in the second holding chamber 102 moves from the opening 112g to the second flow path 112 by weight. The substrate solution that has moved to the second flow path 112 further moves to the main chamber 107 by gravity.
  • the second holding chamber 102 may be divided into two. 20, in the sample analysis substrate 161, the second holding chamber 102 includes a first sub-chamber 102A, a second sub-chamber 102B, and an eighth flow path 118.
  • the first sub-chamber 102A is arranged in a substantially circumferential direction with respect to the first holding chamber 101, and is connected by a first flow path 111.
  • the second sub-chamber 102B is arranged substantially in the circumferential direction with respect to the third flow path 113.
  • the first sub-chamber 102A and the second sub-chamber 102B are arranged substantially in the radial direction, and are connected to each other by an eighth flow path 118.
  • a capillary space 102Be is provided along the outermost peripheral side surface 102Ba farthest from the rotation shaft 110 among the side surfaces of the second sub-chamber 102B. Further, a capillary space 102Be is provided along the adjacent side surface adjacent to the outermost peripheral side surface 102Ba, and connects the opening 112g of the second flow path 112 and the capillary space 102be.
  • the entire amount of the substrate solution held in the first holding chamber 101 is transferred to the first sub-chamber 102A through the first flow path 111. Furthermore, it is transferred from the first sub-chamber 102A to the second sub-chamber 102B through the eighth flow path 118.
  • the substrate solution transferred to the second sub-chamber 102B comes into contact with the capillary space 102Be and the capillary space 102Be in the second sub-chamber 102B, whereby a capillary force acts to be sucked into the second flow path 112.
  • the substrate solution can be transferred stepwise using a narrower space, so that the controllability of the transfer of the substrate solution can be improved. Therefore, it is possible to more reliably suppress the substrate solution from being erroneously transferred to the main chamber 107 during the B / F separation and washing steps.
  • the sample analysis substrate 162 illustrated in FIG. 21 includes a third holding chamber 133 including a first portion 133q, a second portion 133r, and a connection portion 133p that connects the second portion 133r and the first portion 133q.
  • the second portion 133r and a part of the first portion 133q are generally arranged in a circumferential direction around the rotation shaft 110.
  • the wall portion 100f formed by the inner surface of the substrate 100 ' is located between the second portion 133r and the first portion 133q.
  • the wall portion 100f separates the second portion 133r and the first portion 133q.
  • the connection portion 133p is located on the same radial direction as the wall portion 100f of the substrate 100 ', and is located closer to the rotation shaft 110 than the wall portion 100f.
  • the connecting portion 133p is not filled with the liquid by the capillary action, and moves the liquid between the first portion 133q and the second portion 133r by gravity.
  • the second portion 133r is located outside the circular arc ca whose center is the rotation shaft 110 and whose radius is a line segment connecting the rotation shaft 110 and the point 100e closest to the rotation axis of the wall portion 100f (the rotation shaft 110). (Located at a distance from the rear). With this part 133re, a predetermined amount of cleaning liquid used for one cleaning can be measured.
  • the distance from the rotation shaft 110 to the opening 116g of the sixth flow path 116 in the second portion 133r is longer than the distance from the rotation shaft 110 to a point 100e closest to the rotation axis of the wall portion 100f. Therefore, the washing liquid measured by the portion 133re can be transferred from the sixth flow passage 116 to the main chamber 107 by centrifugal force due to rotation.
  • the first portion 133q of the third holding chamber 133 includes a side 133qt and a bottom 133qs.
  • the side portion 133qt is located on the side of the second storage chamber 105 in the circumferential direction around the rotation shaft 110.
  • the bottom 133qs is located farther from the rotation axis 110 than the second storage chamber 105 is. Further, a part of the side portion 133qt and the entire bottom portion 133qs of the first portion 133q are located farther from the rotation shaft 110 than the second portion 133r.
  • the side portion 133qt preferably includes a portion 133qt ′ located on the rotation shaft 110 side and a portion 133qt ′′ located outside the arc ca. As described above, the portion 133qt 'is circumferentially adjacent to the first portion 133q and is connected to the connection portion 133p.
  • a portion located outside the arc ca (far from the rotation axis 110), that is, the total volume of the portion 133qt ′′ and the bottom 133qs is the second storage chamber. It is preferable that the cleaning liquid is larger than the total amount of the cleaning liquid held in 105.
  • the space of the third holding chamber 133 includes the bottom portion 133qs, in a state where the sample analysis substrate 162 is stopped at a predetermined angle, a part of the cleaning liquid stored in the second storage chamber 105 is caused by capillary action.
  • the fifth flow path 115 is filled. Then, by rotating the sample analysis substrate 162 in a state where the fifth flow path 115 is filled with the cleaning liquid, the cleaning liquid in the second storage chamber 105 flows to the bottom 133qs via the fifth flow path 115 by the centrifugal force. Be transported.
  • the volume of the portion of the second portion 133r located outside the circular arc ca whose radius is a line segment connecting the rotation axis 110 and the point 100e closest to the rotation axis 110 of the wall portion 100f has a capacity of the third holding chamber 133. It is 1/2 or less of the volume.
  • FIG. 21 shows a configuration including a part of the side portion 133qt and the bottom portion 133qs as the first portion 133q.
  • the first portion 133q has the rotation shaft 110 as the center, and the rotation shaft 110 and the rotation shaft 110 of the wall portion 100f. It is sufficient to include a portion located outside a circular arc whose radius is a line segment connecting the point closest to.
  • the cleaning liquid measured in a predetermined amount fills the sixth flow passage 116 by a capillary phenomenon, and then moves the sample analysis substrate 162 to a smaller force than the capillary force applied to the liquid inside the sixth flow passage 116.
  • the liquid is transferred to the main chamber 107 through the sixth flow passage 116 by the centrifugal force.
  • the third holding chamber 103 holds a plurality of cleaning liquids.
  • a plurality of chambers holding one cleaning liquid may be provided.
  • the sample analysis substrate 163 shown in FIG. 22 includes a second storage chamber 105A, a third storage chamber 105B, a fifth flow path 115A, a ninth flow path 115B, a third holding chamber 103A, a fourth holding chamber 103B, and a sixth flow chamber.
  • a passage 116A and a tenth passage 116B are provided.
  • the fifth flow path 115A and the ninth flow path 115B connect the second storage chamber 105A and the third storage chamber 105B to the third holding chamber 103A and the fourth holding chamber 103B, respectively.
  • the channel 116B connects the third holding chamber 103A and the fourth holding chamber 103B with the main chamber 107.
  • the fifth channel 115A and the ninth channel 115B are capillary channels and have a siphon structure.
  • the sixth flow path 116A and the tenth flow path 116B have a structure that can transfer liquid by gravity.
  • the third holding chamber 103A and the sixth flow path 116A are located farther from the rotation shaft 110 than the second storage chamber 105A and the third storage chamber 105B, respectively.
  • the sixth flow path 116A and the tenth flow path 116B can transfer liquid by gravity.
  • the third holding chamber 103A has an outermost peripheral side surface 103Aa and an adjacent side surface 103Ac adjacent to the outermost peripheral side surface.
  • a tapered surface, a curved surface, or the like for smoothing a corner (ridge) may be provided between the outermost peripheral side surface 103Aa and the adjacent side surface 103Ac.
  • the opening 116Ag of the sixth flow passage 116A is disposed at the end of the adjacent side surface 103Ac where the outermost peripheral side surface 103Aa is not located.
  • a concave portion having an opening on the rotating shaft 110 side is formed by the outermost peripheral side surface 103Aa and the adjacent side surface 103Ac, and one cleaning liquid is held.
  • the fourth holding chamber 103B has an outermost peripheral side surface 103Ba and an adjacent side surface 103Bc adjacent to the outermost peripheral side surface.
  • a tapered surface, a curved surface, or the like for smoothing a corner (ridge) may be provided between the outermost peripheral side surface 103Ba and the adjacent side surface 103Bc.
  • An opening 116Bg of the tenth flow path 116B is arranged at an end of the both ends of the adjacent side surface 103Bc where the outermost peripheral side surface 103Ba is not located.
  • a concave portion having an opening on the rotating shaft 110 side is formed by the outermost peripheral side surface 103Ba and the adjacent side surface 103Bc, and one cleaning liquid is held.
  • the third holding chamber 103A and the fourth holding chamber 103B are located on the same one of two regions divided by a straight line connecting the center of the main chamber 107 and the rotation axis 110.
  • the rotation axis 110 of the sample analysis substrate 163 is inclined at an angle greater than 0 ° and 90 ° or less with respect to the direction of gravity so that the concave portion of the third holding chamber 103A and the concave portion of the fourth holding chamber 103B can hold the liquid. Support to be.
  • the sample analysis substrate 163 is held at a predetermined rotation angle such that the main chamber 107 is located below the third holding chamber 103A and the fourth holding chamber 103B in the direction of gravity. In this case, since the adjacent side surface 103Ac of the third holding chamber 103A and the adjacent side surface 103Bc of the fourth holding chamber 103B are non-parallel when viewed from a direction parallel to the rotation shaft 110, they are held by one of the chambers.
  • the other chamber may hold at least a part of the cleaning liquid. Therefore, by appropriately selecting the rotation angle of the sample analysis substrate 163, the cleaning liquid can be selectively transferred from the third holding chamber 103A and the fourth holding chamber 103B to the main chamber 107 at different timings.
  • an angle ⁇ formed by the adjacent side face 103Ac with a straight line connecting the center of the main chamber 107 and the rotation axis 110 is an angle ⁇ formed by the adjacent side face 103Bc. Greater than. Therefore, the rotation angle of the sample analysis substrate 163 such that the third holding chamber 103A and the fourth holding chamber 103B are located below the main chamber 107 in the direction of gravity (P1 shown in FIG.
  • the adjacent side surface 103Ac first becomes parallel (horizontal direction) to the direction orthogonal to the direction of gravity, so that the inside of the third holding chamber 103A is The entire amount of the cleaning liquid can be selectively transferred to the main chamber 107, and thereafter, the cleaning liquid held in the fourth holding chamber 103B can be selectively transferred to the main chamber 107.
  • FIG. 23 shows a plan view of the sample analysis substrate 164 of the present embodiment.
  • the sample analysis substrate 164 includes a main chamber 107 and a collection chamber 148 located in the substrate 100, a magnet 121 disposed close to the main chamber 107, a third channel 113, and an activity inhibitor 151.
  • the sample analysis substrate 164 further includes a first storage chamber 104, a second storage chamber 105, a first path, and a second path located in the substrate.
  • the main chamber 107 has a space for holding the complex 310 (shown in FIG. 1) in which the antigen 306, which is a specific component in the sample, and the labeling substance 307 and the magnetic particles 302 are bound.
  • the third flow path 113 has an opening 113g and an opening 113h, and the opening 113g and the opening 113h are connected to the main chamber 107 and the collection chamber 148.
  • the recovery chamber 148 has a space at least partially located on the outer peripheral side of the space of the main chamber 107 in the radial direction of the sample analysis substrate 164. Therefore, when the sample analysis substrate 164 is rotated while the liquid containing the complex 310 is held in the main chamber 107, the complex 310 is captured by the magnet 121 and held in the main chamber 107 as described above. In this state, the reaction solution containing the unreacted title substance and the like is transferred to the collection chamber 148 through the third channel 113.
  • the first storage chamber 104 holds the substrate solution containing the substrate substance.
  • the second storage chamber 105 holds a cleaning liquid.
  • the first storage chamber and the main chamber 107 are connected by a first path. Specifically, the first storage chamber 104 is connected to the main chamber 107 by the fourth flow path 114, the first holding chamber 101, the second holding chamber 102, and the second flow path 112, and the substrate solution is Transferred to 107.
  • the second storage chamber 105 and the main chamber 107 are connected by a second path. Specifically, the second storage chamber 105 is connected to the main chamber 107 by the fifth flow path 115, the third holding chamber 103, and the sixth flow path 116, and the cleaning liquid is transferred to the main chamber 107.
  • the activity inhibitor 151 is disposed in the collection chamber 148.
  • the activity inhibitor 151 reduces the activity of the labeling substance 307.
  • Table 2 shows examples of the activity inhibitor.
  • the labeling substance is an enzyme, and the activity inhibitor uses the following mechanism in order to suppress the activity of the labeling substance, specifically, the luminescence due to the reaction of the labeling substance with the substrate.
  • the pH of the solution in which the labeling substance is dissolved is changed to suppress the reaction between the labeling substance and the substrate, to denature and inactivate the labeling substance, or to cause the reaction between the labeling substance and the substrate. Suppresses light emission.
  • the activity inhibitor using this mechanism is a pH adjuster and includes, for example, at least one selected from the group consisting of sodium orthovanadate, arsenic acid, phenylalanine, homoarginine, and inorganic phosphoric acid.
  • (B) Desorption / inactivation of the central metal ion of the labeling substance By desorbing or inactivating the central metal ion contained in the labeling substance, it is possible to suppress the reaction between the labeling substance and the substrate, Suppresses luminescence due to the reaction between the labeling substance and the substrate.
  • An activity inhibitor utilizing this mechanism is a chelating agent.
  • the activity inhibitor when the activity inhibitor is an aminocarboxylic acid-based chelating agent, the activity inhibitor is EDTA (ethylenediaminetetraacetic acid), NTA, DTPA, HEDTA, TTHA, PDTA, DPTA-OH, HIDA, DHEG, GEDTA, It is at least one kind obtained from the group consisting of CMGA, EDDS, and the like.
  • the activity inhibitor is a phosphinic acid-based chelating agent
  • the activity inhibitor is at least one obtained from the group consisting of HEDP, NTMP, PBTC, EDTMP, and the like.
  • (C) Denaturation of protein By denaturing a protein which is a labeling substance, the reaction between the labeling substance and the substrate is suppressed, and the luminescence due to the reaction between the labeling substance and the substrate is suppressed.
  • An activity inhibitor that utilizes this mechanism is a protein denaturant, and for example, the activity inhibitor is at least one selected from the group consisting of guanidine hydrochloride, guanidine thiocyanate, thiourea, and urea.
  • (D) Ionic surfactant By covering the labeling substance with the ionic surfactant, the reaction between the labeling substance and the substrate is suppressed, the labeling substance is denatured and inactivated, or the reaction between the labeling substance and the substrate is performed. To suppress light emission.
  • the activity inhibitor using this mechanism is an ionic surfactant, and is at least one selected from the group consisting of SDS, CTAB, and the like.
  • the activity inhibitor is a salt containing a polyvalent ion, for example, a salt containing a sulfate ion, a phosphate ion, and a citrate ion. More specifically, the activity inhibitor is at least one selected from the group consisting of magnesium sulfate, ammonium sulfate, sodium sulfate, potassium phosphate, sodium citrate and the like.
  • the activity inhibitor 151 When the activity inhibitor 151 is a solid, the activity inhibitor 151 may be placed in the space of the recovery chamber 148 as it is, or a binder or the like dissolvable in a reaction solution or a washing solution and the activity inhibitor 151 may be used. May be mixed and applied to a wall surface that defines a space in the collection chamber 148, or the like, for example.
  • the activity inhibitor 151 When the activity inhibitor 151 is a liquid, the activity inhibitor 151 is absorbed by a porous body such as sponge, filter paper, or the like, and the porous body, filter paper, or the like is disposed in the space of the collection chamber 148. Is also good.
  • a porous body such as sponge, filter paper, or the like
  • the activity inhibitory substance 151 is disposed in the collection chamber 148, when the reaction solution containing the unreacted labeling substance is transferred to the collection chamber 148, the labeling substance is Are inactivated. For this reason, even if the substrate solution is subsequently transferred into the collection chamber 148 for any reason, emission of the labeling substance in the collection chamber 148 is suppressed. Therefore, stray light affecting the emission field measurement in the main chamber 107 can be suppressed, and highly accurate emission measurement can be performed.
  • the recovery chamber 148 may have a structure in which the transferred reaction solution is more easily moved.
  • the collection chamber 148 has a shape extending along the circumferential direction, and has a first end 148E1 and a second end 148E2.
  • the third flow path 113 is connected to the first end 148E1 side of the middle 148C between the first end 148E1 and the second end 148E2 of the collection chamber 148.
  • FIGS. 24A and 24B show cross sections (A-A 'and B-B' cross sections) of the space of the collection chamber 148 at the first position 148P1 and the second position 148P2.
  • the height of the collection chamber 148 along the thickness direction of the sample analysis substrate 164 at the first position 148P1 and the second position 148P2 is set to a first height h1 and a second height h2, respectively. Assuming the height h2, the first height h1 is larger than the second height h2. That is, h1> h2 is satisfied. More preferably, the height of the collection chamber 148 decreases continuously or stepwise from the first end 148E1 to the second end 148E2.
  • FIGS. 24C and 24D show a circumferential section (C-C ′ section) of the collection chamber 148.
  • the upper surface 100u of the space formed in the base substrate 100a in the case where the main surface 100d is arranged so as to be lower.
  • the position of the bottom or the bottom may be different along the circumferential direction.
  • the thickness of the layer 151 'containing the activity inhibitor 151 disposed on the upper surface 100u may be varied in the circumferential direction.
  • the bottom of the recovery chamber 148 when the main surface 100d of the substrate for sample analysis 164 faces down becomes shallower toward the second end 148E2.
  • the sample analysis substrate 164 is rotated with the main surface 100d downward so that the second end 148E2 of the collection chamber 148 is directed toward the first end 148E1, a reaction flowing into the collection chamber 148 from the third flow path 113.
  • the liquid moves to the second end 148E2 side of the collection chamber 148 by the inertial force.
  • the bottom of the recovery chamber 148 becomes shallower with the movement of the reaction solution, so that the liquid surface of the moving reaction solution becomes higher and the reaction solution is stirred. Therefore, the reaction solution and the activity inhibitor 151 easily come into contact with each other in the collection chamber 148, and the labeling substance in the reaction solution can be more uniformly deactivated.
  • first distance r1 and a second distance r2 the distance from the center 110 of the sample analysis substrate 164 to the side surface 148a located on the outer peripheral side of the collection chamber 148 is referred to as a first distance r1 and a second distance r2, respectively.
  • the first distance R1 is shorter than the second distance R2 (r1 ⁇ r2). That is, the side surface 148a of the second position 148P2 is located closer to the outer periphery than the first position 148P1.
  • the outer peripheral side surface of the collection chamber 148 becomes farther from the center toward the second end 148E2. For this reason, when the sample analysis substrate 164 is rotated so that the second end 148E2 of the collection chamber 148 is directed toward the first end 148E1 with the main surface 100d facing down, the sample analysis substrate 164 enters the collection chamber 148 from the third channel 113. Since the side surface extends in the direction in which the component of the resultant force of the inertial force and the centrifugal force received by the flowing reaction solution is generated, the reaction solution can smoothly move to the second end 148E2 while accelerating. For this reason, the reaction solution and the activity inhibitor 151 easily come into contact with each other in the collection chamber 148, and the labeling substance in the reaction solution can be more uniformly deactivated.
  • a sample analysis method for analyzing a specific substance in a sample using the sample analysis substrate 164 can be performed in the same manner as the analysis method described in (operation of the sample analysis system 501) with reference to the flowchart shown in FIG. .
  • the flowchart shown in FIG. 25 corresponds to the flowchart shown in FIG. 5, and the detailed procedure of each step shown in FIG. 25 has been described in (Operation of Sample Analysis System 501) described above with reference to FIG.
  • step S111 a substrate for sample analysis in which a substrate solution containing a substrate substance and a washing solution are held in the first storage chamber 104 and the second storage chamber 105 is prepared.
  • the reaction chamber 106 a complex in which the labeling substance and the magnetic particles are bound is formed.
  • step S112 the reaction solution containing the complex is introduced into the main chamber.
  • step S113 corresponding to step S13 in FIG. 5
  • the sample analysis substrate 146 is rotated while the complex is held in the main chamber 107 by the magnetic force of the magnet 121, whereby the reaction solution Is transferred to the collection chamber 148.
  • the labeling substance in the reaction solution that does not form a complex reacts with the activity inhibitor 151, and the labeling substance in the collection chamber 148 is deactivated.
  • step S114 corresponding to steps S14 to S19 in FIG. 5
  • the cleaning liquid is transferred from the second storage chamber 105 to the main chamber 107, and the held complex is cleaned with the cleaning liquid.
  • the cleaning liquid is transferred to the collection chamber 148.
  • step S115 As shown in step S115 (corresponding to steps S20 and S21 in FIG. 5), the substrate solution is transferred from the first storage chamber 104 to the main chamber 107. Finally, as shown in step S116 (corresponding to step S21 in FIG. 5), a signal obtained from the labeling substance of the complex held in the main chamber 107 is measured.
  • the labeling substance held in the collection chamber 148 is deactivated. Therefore, even when the substrate solution is transferred to the collection chamber 148, emission of light in the collection chamber 148 is suppressed. Therefore, it is possible to measure light emission with high accuracy.
  • the sample analysis substrate, the sample analyzer, the sample analysis system, and the sample analysis system program according to one embodiment of the present application include the magnetic particles. It is not limited to the measurement system used.
  • the target on which the primary antibody is immobilized may be a wall surface in the chamber instead of the magnetic particles.
  • the chamber is made of a material such as polystyrene or polycarbonate, the primary antibody can be immobilized on the wall surface of the chamber by physical adsorption, and sandwich-type binding with an antigen or a labeled antibody in the chamber can be achieved. Allow the reaction to occur.
  • a functional group for example, an amino group or a carboxyl group capable of binding to the primary antibody is provided on a wall surface in the chamber, and the primary antibody can be immobilized by chemical bonding. Can be caused to undergo a sandwich-type binding reaction.
  • the configuration is such that a metal substrate is provided on the wall surface in the chamber, for example, the primary antibody can be bound to the metal substrate using SAM and immobilized. Can be reacted.
  • the primary antibody is immobilized on the wall of the chamber by physical adsorption or chemical bonding, it is mainly used for a system for detecting a dye, chemiluminescent or fluorescent signal.
  • the primary antibody when it is immobilized on a metal substrate, it is mainly used in a system for detecting an electrochemical signal (for example, an electric current) and an electrochemiluminescent signal. In this case, the magnet 121 shown in FIG. 3B is unnecessary.
  • the reaction field for forming the complex 310 is not the reaction chamber 106 but the main chamber 107. Therefore, the primary antibody needs to be immobilized on the wall surface of the main chamber 107.
  • the substrate for sample analysis, the sample analyzer, the sample analysis system, and the program for the sample analysis system of the present disclosure can be applied not only to the non-competitive method (sandwich immunoassay method) but also to a competitive method and a gene detection method by hybridization. It is.
  • the sample analysis substrate, the sample analyzer, and the sample analysis system according to the present embodiment divide a solution other than the cleaning solution into a plurality of times as described above. And can be applied to various sample analysis methods that are introduced into the same chamber. Further, in the above embodiment, the introduction of the liquid into the chamber is continuously performed. However, the rotation and the stop of the sample analysis substrate and the control of the angle at the time of the stop are appropriately performed so that other liquids are interposed therebetween. Steps can also be included.
  • the cleaning is performed twice, but may be performed three or more times as needed.
  • sample analysis substrate the sample analyzer, the sample analysis system, and the program for the sample analysis system disclosed in the present application can be applied to the analysis of a specific component in a sample using various reactions.
  • Reference Signs List 100 Sample analysis substrate 100 'Substrate 100a Base substrate 100b Cover substrate 100c, 100d Main surface 100f Wall portion 101 First holding chamber 101a1 First outer peripheral side surface 101a2 Second outer peripheral side surface 101b1 First inner peripheral side surface 101b2 Second inner peripheral side surface 101c , 101d adjacent side surface 101r convex portion 102 second holding chamber 102A first sub-chamber 102B second sub-chamber 102Ba outermost peripheral surface 102Be outermost peripheral surface 102b innermost peripheral surface 102be innermost peripheral surface 102c1 first adjacent side surface 102c2 second Adjacent side surface 102e Second region 102q First part 102r Second part 102re Capillary space 102s Recess 103, 103A Third holding chamber 103Aa Outermost peripheral side 103Ac Adjacent side 103B Fourth Holding chamber 103Ba outermost peripheral side 103Bc adjacent side 103a outermost peripheral side 103b innermost peripheral side 104 first storage chamber 104a outermost peripheral side

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Abstract

La présente invention concerne un substrat d'analyse d'échantillon qui est destiné à transférer un liquide comprenant un échantillon et à analyser une substance spécifique dans l'échantillon et qui comprend : un substrat ; une chambre principale qui est positionnée dans le substrat et qui a un espace pour contenir un composite obtenu par liaison d'une substance spécifique dans l'échantillon, une substance d'étiquette et des particules magnétiques ; un aimant qui est disposé à proximité de la chambre principale ; une chambre de récupération qui est positionnée dans le substrat et qui a un espace pour contenir un liquide transféré depuis la chambre principale, l'espace étant au moins partiellement positionné plus près du côté circonférentiel radialement externe que l'espace de la chambre principale ; un passage d'écoulement qui est positionné dans le substrat et qui a des première et seconde ouvertures qui sont respectivement reliées à la chambre principale et à la chambre de récupération ; et un inhibiteur d'activité qui est maintenu dans la chambre de récupération et qui réduit l'activité de la substance d'étiquette.
PCT/JP2019/025833 2018-07-02 2019-06-28 Substrat d'analyse d'échantillon et procédé d'analyse d'échantillon WO2020009023A1 (fr)

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JP2010522866A (ja) * 2006-10-13 2010-07-08 セラノス， インコーポレイテッド 流体装置における光学干渉の減少
JP2009258013A (ja) * 2008-04-18 2009-11-05 Rohm Co Ltd マイクロチップ
JP2013029444A (ja) * 2011-07-29 2013-02-07 Brother Ind Ltd 検査システム、及び検査方法
JP2014167390A (ja) * 2013-02-28 2014-09-11 Brother Ind Ltd 検査チップ及び検査システム
JP2015105891A (ja) * 2013-11-29 2015-06-08 ブラザー工業株式会社 検査チップ
WO2017115733A1 (fr) * 2015-12-28 2017-07-06 パナソニックヘルスケアホールディングス株式会社 Substrat d'analyse d'échantillons, dispositif d'analyse d'échantillons, système d'analyse d'échantillons, et programme pour système d'analyse d'échantillons

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CN113009136A (zh) * 2020-08-21 2021-06-22 东莞东阳光医疗智能器件研发有限公司 小型多指标检测样本分析装置
CN113009136B (zh) * 2020-08-21 2024-04-05 东莞东阳光医疗智能器件研发有限公司 小型多指标检测样本分析装置

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