Detector, detection device, and detection method

Abstract

A detector (1, 1A, 1B, 1C, 1D) comprises a sensor accommodation part (3), a sample introduction part (2), a movement passage (7), and a change material supply part (11, 11A). The sensor accommodation part accommodates a sensor for measuring ions. A sample is introduced into the sample introduction part. The movement passage connects the sample introduction part and the sensor accommodation part and supplies the sample to the sensor accommodation part. The change material supply part supplies an ion concentration change material (C) that changes the ion concentration of the sample to the sensor accommodation part.

Description

Detector, detection device, and detection method CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This international application claims priority based on Japanese Patent Application No. 2024-033954, filed with the Japan Patent Office on March 6, 2024, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure relates to a detector, a detection device, and a detection method.

[0003] Patent Document 1 discloses a technique for detecting with high sensitivity changes in ion concentration of a sample in a solution by using a buffer solution with a low concentration (i.e., low buffer capacity) or a solution that does not contain a buffer material.

[0004] International Publication No. 2014 / 031783

[0005] However, as a result of detailed investigation by the inventors, it was found that the technology of Patent Document 1 has a problem in that when the change in ion concentration derived from the specimen is small, the change in ion concentration may not be detected sufficiently.

[0006] In one aspect of the present disclosure, it is preferable to provide a technology for improving the detection sensitivity of changes in ion concentration in a specimen. One aspect of the present disclosure is a detector comprising a sensor housing portion, a specimen input portion, a migration flow path, and a changing substance supply portion. The sensor housing portion houses a sensor for measuring ions. The specimen input portion receives the specimen. The migration flow path connects the specimen input portion and the sensor housing portion and supplies the specimen to the sensor housing portion. The changing substance supply portion supplies an ion concentration changing substance that changes the ion concentration of the specimen to the sensor housing portion.

[0007] With this configuration, it is possible to improve the detection sensitivity of changes in ion concentration in a specimen. One aspect of the present disclosure is a detection device, the detection device comprising: a detector; and a control unit. The detector comprises a sensor housing portion, a specimen input portion, a movement flow path, and a changing substance supply portion. The sensor housing portion houses a sensor for measuring ions. The specimen input portion receives the specimen. The movement flow path connects the specimen input portion and the sensor housing portion and supplies the specimen to the sensor housing portion. The changing substance supply portion supplies an ion concentration changing substance that changes the ion concentration of the specimen to the sensor housing portion. The control unit comprises: a specimen supply portion, an ion concentration changing substance adding portion, and a measurement portion. The specimen supply portion supplies the input specimen to the sensor housing portion. The ion concentration changing substance adding portion supplies the ion concentration changing substance contained in the changing substance housing portion to the sensor housing portion. The measurement portion measures the ion concentration in the specimen.

[0008] With this configuration, it is possible to improve the detection sensitivity of changes in ion concentration in a sample. One aspect of the present disclosure is a detection device, the detection device comprising: a detector; and a control unit. The detector comprises a sensor housing portion, a sample input portion, a movement flow path, a changing substance supply portion, and a mixing portion. The sensor housing portion houses a sensor for measuring ions. The sample input portion receives the sample. The movement flow path connects the sample input portion and the sensor housing portion and supplies the sample to the sensor housing portion. The changing substance supply portion supplies an ion concentration changing substance that changes the ion concentration of the sample to the sensor housing portion. The mixing portion mixes the beads, linker-enzyme fusion, and substrate with the sample input from the sample input portion before the sample reaches the sensor housing portion. The control unit comprises a bead supply portion, a linker-enzyme fusion supply portion, a substrate supply portion, a reaction portion, an ion concentration changing substance addition portion, and a measurement portion. The bead supply unit supplies beads to the input sample, generating a first conjugate in which the sample and the beads are bound. The linker-enzyme fusion supply unit supplies a linker-enzyme fusion to the first conjugate, generating a second conjugate in which the first conjugate and the linker-enzyme fusion are bound. The substrate supply unit supplies a substrate to the second conjugate. The reaction unit supplies the second conjugate and the substrate to the sensor storage unit, causing a chemical reaction in which the enzyme contained in the second conjugate consumes the substrate. The ion concentration changing substance addition unit supplies the ion concentration changing substance stored in the changing substance storage unit to the sensor storage unit. The measurement unit measures the ion concentration in the sample.

[0009] This configuration can improve the detection sensitivity of changes in ion concentration in a specimen. One aspect of the present disclosure is a detection method using a detector. The detector includes a sensor housing portion, a specimen input portion, a movement flow path, and a changing substance supply portion. The sensor housing portion houses a sensor for measuring ions. The specimen input portion receives the specimen. The movement flow path connects the specimen input portion and the sensor housing portion and supplies the specimen to the sensor housing portion. The changing substance supply portion supplies an ion concentration changing substance that changes the ion concentration of the specimen to the sensor housing portion. The detection method includes inputting the specimen to the specimen input portion, supplying the input specimen to the sensor housing portion, supplying the ion concentration changing substance contained in the changing substance housing portion to the sensor housing portion, and measuring the ion concentration in the specimen.

[0010] By carrying out such a method, it is possible to improve the detection sensitivity of changes in ion concentration in a sample. One aspect of the present disclosure is a detection method using a detector. The detector includes a sensor containing section, a sample input section, a transfer flow path, a change substance supply section, and a mixing section. The sensor containing section contains a sensor for measuring ions. The sample is input into the sample input section. The transfer flow path connects the sample input section and the sensor containing section and supplies the sample to the sensor containing section. The change substance supply section supplies an ion concentration change substance that changes the ion concentration of the sample to the sensor containing section. The mixing section mixes the beads, linker-enzyme fusion, and substrate with the sample input from the sample input section before the sample reaches the sensor containing section. The detection method includes introducing a sample into a sample introduction section, supplying beads to the introduced sample to prepare a first conjugate in which the sample and the beads are bound, supplying a linker-enzyme fusion to the first conjugate to prepare a second conjugate in which the first conjugate and the linker-enzyme fusion are bound, supplying a substrate to the second conjugate, supplying the second conjugate and the substrate to a sensor storage section to cause a chemical reaction in which the enzyme contained in the second conjugate consumes the substrate, supplying an ion concentration changing substance stored in the changing substance storage section to the sensor storage section, and measuring the ion concentration in the sample.

[0011] By implementing such a method, the sensitivity of detecting changes in ion concentration in a sample can be improved.

[0012] FIG. 1A is a schematic diagram of a second conjugate of the present disclosure. FIG. 1B is another schematic diagram of a second conjugate of the present disclosure. The figure shows the results of an experiment confirming the effect of an ion concentration changing substance on the enzyme-substrate reaction of the present disclosure when an acid is used as the ion concentration changing substance. When air (i.e., CO ２ 13A, 13B, and 13C are schematic diagrams showing variations of the mixing section.

[0041] FIG. 13A shows the configuration of a detector in the first embodiment.

[0042] FIG. 13B shows the configuration of a detector in the third embodiment.

[0043] FIG. 13C shows the configuration of a detector in the fourth embodiment.

[0044] FIG. 13C shows the configuration of a detector in the fifth embodiment.

[0045] FIG. 13A shows the configuration of a changing substance supply section in another embodiment.

[0046] FIG. 13B shows the configuration of a detector in the fourth embodiment.

[0047] FIG. 13C shows the configuration of a changing substance supply section in another embodiment.

[0048] FIG. 13C shows the configuration of a mixing section.

[0013] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, embodiments of the present disclosure will be described with reference to the accompanying drawings. 1. Detection Method An outline of the detection method employed in the present disclosure will be described.

[0014] The detection method of the present disclosure can be used to detect changes in ion concentration in a sample. The detection method of the present disclosure can also be used to detect a target contained in a sample. The sample may be a liquid or a solid. When the sample is a solid, a mixture of the solid and any liquid may be used in the detection method of the present disclosure. As an example, the target may contain a virus (e.g., SARS-CoV-2).

[0015] The main principle of the detection method of the present disclosure is to detect changes in ion concentration due to an enzyme-substrate reaction. Therefore, to perform the detection method of the present disclosure, at least an enzyme and a substrate are required. That is, an enzyme and a substrate may be added to a sample, and a change in ion concentration caused by a chemical reaction in which the enzyme consumes the substrate may be detected. However, to more effectively perform the detection method of the present disclosure, the following detection method may be used.

[0016] First, beads are bound to a sample to prepare a first conjugate. The beads may be capable of specifically binding to a target in the sample. For example, the beads may be bound to an antibody that specifically recognizes the surface of a virus (e.g., the spike protein in SARS-CoV-2). The antibody may then specifically bind to a viral protein in the sample. Note that any type of beads may be used as long as they bind to a target in the sample. As an example, the beads may be magnetic beads.

[0017] Next, a linker-enzyme fusion, in which a linker and an enzyme are fused, is bound to the first conjugate to prepare a second conjugate. Schematic diagrams of the second conjugate are shown in Figures 1A and 1B. In Figure 1A, magnetic beads (beads MB) are bound to protein VP on the surface of a virus in a sample via antibody IB, which specifically binds to the protein VP. In other words, in Figure 1A, the beads MB, antibody IB, and virus form first conjugate A. Then, a linker LK fused with enzyme EZ binds to protein VP on the surface of the virus belonging to first conjugate A to prepare second conjugate B. The linker-enzyme fusion may exist in solution. The linker LK may also specifically bind to a target in the sample. Examples of linker LK include DNA aptamers, RNA aptamers, peptide aptamers, antibodies, antibody fragments, modified antibodies, peptides, and nucleic acids. Examples of enzyme EZ include alkaline phosphatase (ALP).

[0018] As shown in Figure 1B, the antibody IB in the second conjugate B shown in Figure 1A may be replaced with a linker LK. That is, in the present disclosure, the bead MB may be bound to the linker LK, and the linker LK may be bound to the protein VP on the surface of the virus. Then, the second conjugate B may be prepared by further binding the linker LK fused with the enzyme EZ to the protein VP on the surface of the virus.

[0019] Next, after removing excess solution other than the second conjugate B, a substrate solution is added to the second conjugate B. Then, a chemical reaction occurs in which the enzyme contained in the second conjugate B consumes the substrate. The chemical reaction changes the ion concentration in the reaction solution. Note that, for example, p-nitrophenyl phosphate can be used as the substrate.

[0020] The sensor is an ion sensor for measuring ions. The sensor may be a semiconductor sensor that measures the ion concentration (e.g., hydrogen ion concentration) in the sample. Specifically, as described above, the sensor may be configured to detect, as the ion concentration in the sample, the hydrogen ion concentration that changes in association with a chemical reaction that consumes a substrate, caused by an enzyme contained in the second bond B containing the sample. Note that measurement using the sensor is preferably performed after eliminating external factors that may affect the ion concentration of the sample as much as possible. For example, measurement using the sensor may be performed in a nitrogen environment, which is a gas that is inert to the sample and the substrate.

[0021] A washing solution may be used in the steps of preparing the first conjugate A and the second conjugate B and in the step of adding a substrate solution to the second conjugate B. The washing solution is used to remove components that were not used as constituent elements of the first conjugate A and the second conjugate B. Examples of the washing solution include phosphate buffer.

[0022] A buffer solution may also be used in the above-described detection method. A buffer solution is a solution for stabilizing ion concentrations. Various types of buffer solutions (e.g., acetate buffer solution, phosphate buffer solution, citrate buffer solution, borate buffer solution, and Tris buffer solution) can be used as long as they can stabilize ion concentrations. A buffer solution having any buffer range suitable for the detection method of the present disclosure can also be used. The buffer solution may be mixed with a sample to form a mixture. The buffer solution may also be mixed with a reaction solution in which a substrate solution is added to the second conjugate B. By using a buffer solution, various reactions are carried out under more stable conditions.

[0023] An ion concentration changing substance C is further added to the reaction solution obtained by adding the substrate solution to the second bond B. The ion concentration changing substance C is a substance that changes the ion concentration of the specimen when mixed with the specimen. Specifically, it is a substance that acts to further increase the change in hydrogen ion concentration that occurs in the reaction solution due to the chemical reaction of the enzyme and the substrate. This causes an even greater change in the hydrogen ion concentration in the reaction solution. Examples of the ion concentration changing substance C include acids, bases, and air (i.e., CO ２ ) and the like. Note that, for example, when a buffer solution is used in the above detection method, the addition of the ion concentration changing substance C may be performed by mixing the ion concentration changing substance C with a mixture of the buffer solution and the sample, thereby changing the ion concentration of the sample contained in the mixture to outside the buffer range of the buffer solution. Furthermore, the addition of the ion concentration changing substance C may be performed by mixing the ion concentration changing substance C with a reaction solution obtained by adding a substrate solution to the second conjugate B mixed with the buffer solution, thereby changing the ion concentration of the sample contained in the reaction solution to outside the buffer range of the buffer solution.

[0024] As described above, the detection method of the present disclosure may be used to determine whether a sample contains a target (e.g., a virus). Specifically, the presence of a target contained in a sample can be detected by comparing the measurement results of the ion concentration in a reaction solution to which a substrate solution has been added to a second conjugate B and / or the measurement results of the ion concentration in the reaction solution after adding an ion concentration changing substance C to the reaction solution with reference data. The reference data is the measurement results of the ion concentration in a reference sample that does not contain the target, measured under the same conditions.

[0025] Here, the following experiment was conducted to verify the effect of the ion concentration-changing substance C on the above-mentioned detection method. [Experimental Example 1] An enzyme was added to a substrate to initiate a chemical reaction. p-Nitrophenyl phosphate was used as the substrate, and ALP was used as the enzyme. The enzyme concentrations were set to 0 pM, 0.01 pM, 0.1 pM, 1 pM, and 10 pM, and the change in hydrogen ion concentration generated by the chemical reaction between the enzyme and substrate was measured using a sensor for each case. As shown in Figure 2, the hydrogen ions generated by low concentrations of enzyme alone were not detectable as a change in hydrogen ion concentration. However, by adding acid to the reaction solution of the enzyme and substrate and shifting the hydrogen ion concentration to a steeper region of the pH titration curve, minute changes in hydrogen ion concentration could be amplified and detected. Furthermore, by adding more acid to the reaction solution each time the sensor signal stabilized, changes in hydrogen ion concentration could be further amplified and detected.

[0026] [Experimental Example 2] An enzyme was added to a substrate to initiate a chemical reaction. p-Nitrophenyl phosphate was used as the substrate, and ALP was used as the enzyme. The enzyme concentration was set to 0 pM, 0.1 pM, and 10 pM, and for each case, the change in hydrogen ion concentration generated by the chemical reaction of the enzyme and substrate was measured using a sensor. As shown in Figure 3, the hydrogen ions generated by the low concentration of enzyme alone could not be detected as a change in hydrogen ion concentration. However, by exposing the reaction solution of the enzyme and substrate to air, the CO in the air ２As a result, the hydrogen ion concentration was shifted to a steeper region of the pH titration curve, allowing for the amplification and detection of minute changes in hydrogen ion concentration.

[0027] [Experimental Example 3] An enzyme was added to a substrate to initiate a chemical reaction. p-Nitrophenyl phosphate was used as the substrate, and ALP was used as the enzyme. The enzyme concentrations were set to 0 pM, 0.01 pM, 0.1 pM, 1 pM, and 10 pM. In each case, acid was added to the reaction solution of the enzyme and substrate, and changes in hydrogen ion concentration were detected by the sensor. Each time the sensor signal stabilized, additional acid was added to the reaction solution.

[0028] As shown in Figure 4, the sensor output value and the detected hydrogen ion concentration increased according to the amount of acid added. By using samples with known enzyme concentrations as standard samples and adding multiple amounts of acid to these samples, a standard titration curve showing the relationship between enzyme concentration and sensor output value could be created.

[0029] Such a titration curve may be used when detecting a target substance contained in a sample according to the detection method of the present disclosure. Specifically, the enzyme concentration in the sample may be quantitatively evaluated by applying the sensor output value obtained when a predetermined amount of acid is dropped into the sample to this standard titration curve. This allows for quantitative and accurate evaluation of the enzyme concentration in the sample, i.e., the amount of target substance in the sample bound to the enzyme.

[0030] The sensor output values ​​obtained when multiple amounts of acid are added to the standard sample may be stored in any recording medium, or machine learning may be performed using the sensor output values ​​as training data to generate a trained model. By using such sensor output values, a standard titration curve can be created, for example, when a detection method according to the present disclosure is subsequently performed, even if a smaller number of acids (e.g., one) are added to the standard sample. Furthermore, the sensor can be calibrated based on the difference between such sensor output values ​​and a new sensor output value obtained when a detection method according to the present disclosure is subsequently performed.

[0031] 2. First Embodiment A detector 1 that realizes the above-described measurement method and a detection device 100 will be described. 2-1. Configuration of the detector 1 The configuration of the detector 1 will be described with reference to FIG.

[0032] As shown in Fig. 5, the detector 1 includes a substrate 10. The detector 1 is also referred to as a cartridge. The substrate 10 is a plate-like member having a rectangular plate surface. When the detector 1 is mounted in the detection device 100, the upper plate surface is referred to as the front surface of the substrate 10, and the lower plate surface is referred to as the back surface of the substrate 10. The material of the substrate 10 is, for example, acrylic resin, polycarbonate resin, or polystyrene resin.

[0033] The detector 1 comprises a specimen input section 2 and a sensor housing section 3. The specimen input section 2 is a hole having an opening on the surface of the substrate 10 for inputting a specimen. The sensor housing section 3 is formed within the substrate 10 and is a space for holding an object to be detected by the sensor. A semiconductor sensor 31 for measuring ion concentration is disposed in the sensor housing section 3.

[0034] The detector 1 includes a pressure inlet 4, a pressure outlet 5, a first flow path 6, a second flow path 7, a third flow path 8, and a waste flow path 9. The first flow path 6 is a passage for flowing a fluid, which is formed in the substrate 10 so as to connect the pressure inlet 4 and the specimen input section 2.

[0035] The second flow path 7 is a passage for flowing a fluid, which is formed in the substrate 10 so as to connect the specimen input section 2 and the sensor containing section 3. The second flow path 7 serves to supply the specimen input into the specimen input section 2 to the sensor containing section 3.

[0036] The third flow path 8 is a path for flowing a fluid, which is formed in the substrate 10 so as to connect the sensor housing 3 and the pressure exhaust port 5. The waste flow path 9 is a path used to discharge fluid (hereinafter, waste fluid) that is no longer needed in the second flow path 7, etc., to the outside of the detector 1.

[0037] The pressure input port 4 has an opening at a first end 10A in the longitudinal direction of the plate surface. The pressure input port 4 is a portion that receives a fluid pressurized by a pump 104 or the like provided outside the detector 1 (described later), and flows the fluid toward the first flow path 6. The fluid flowing into the first flow path 6 may be, for example, a cleaning liquid, an inert gas, or the like.

[0038] The pressure outlet 5 has an opening at a first end 10A in the longitudinal direction of the plate surface, similar to the pressure input port 4. The pressure outlet 5 is a portion for discharging the fluid that reaches the pressure outlet 5 via the third flow path 8 to the outside of the substrate 10. A negative pressure may be applied to the pressure outlet 5 by a pump 104 or the like that is provided outside the detector 1, which will be described later.

[0039] The first flow path 6 includes a bead storage section 61. Magnetic beads are stored in the bead storage section 61. The second flow path 7 includes a first mixing section 71, a holding section 72, a second mixing section 73, a separation section 74, and an adjustment section 75.

[0040] The first mixing section 71 is a crank-shaped passageway that thoroughly mixes the magnetic beads and the specimen supplied from the specimen input section 2 by turbulence that occurs when the fluid passes through a section that bends at a right angle.

[0041] The holding section 72 is a space that temporarily holds the substances mixed in the first mixing section 71. The holding section 72 is connected to the waste liquid flow path 9 via a first discharge valve 92. The holding section 72 is connected to the second mixing section 73 via a first control valve 76.

[0042] The second mixing section 73 is a crank-shaped passage, similar to the first mixing section 71. The second mixing section 73 thoroughly mixes the substances supplied from the holding section 72. The separation section 74 is a space that temporarily holds the substances mixed in the second mixing section 73. The separation section 74 is connected to the waste liquid flow path 9 via a second discharge valve 93. The separation section 74 is connected to the adjustment section 75 via a second control valve 77.

[0043] The adjustment section 75 is a linear passage leading to the sensor accommodating section 3. The adjustment section 75 may be set to a length that allows the time required for the mixed substance supplied from the separation section 74 to react sufficiently (i.e., enzyme-substrate reaction).

[0044] The waste liquid flow path 9 has a waste liquid storage section 91. The waste liquid storage section 91 is a space formed in the substrate 10 for temporarily storing waste liquid. In the waste liquid flow path 9, the waste liquid discharged from the holding section 72 via a first discharge valve 92 and the waste liquid discharged from the separation section 74 via a second discharge valve 93 are stored in the waste liquid storage section 91. The waste liquid storage section 91 is connected to the third flow path 8 via a third discharge valve 94.

[0045] The sensor housing 3 is connected to the third flow path 8 via a fourth discharge valve 95. The third flow path 8 is a passage leading to a pressure discharge port 5 formed in the substrate 10. The third flow path 8 is configured so that the waste liquid discharged from the waste liquid housing 91 via the third discharge valve 94 and the waste liquid discharged from the sensor housing 3 via the fourth discharge valve 95 can be discharged from the pressure discharge port 5.

[0046] The first discharge valve 92, the second discharge valve 93, the third discharge valve 94, the fourth discharge valve 95, and the first control valve 76 and the second control valve 77 are all electromagnetic valves that are opened and closed by electric signals. The detector 1 includes a first operation unit 11, a second operation unit 12, a third operation unit 13, a fourth operation unit 14, and a fifth operation unit 15. The first operation unit 11, the second operation unit 12, the third operation unit 13, the fourth operation unit 14, and the fifth operation unit 15 each have a space formed within the substrate 10, and each have a connection flow path 17. The first operation unit 11, the second operation unit 12, the third operation unit 13, the fourth operation unit 14, and the fifth operation unit 15 are configured so that when a pressing force is applied from the surface side of the substrate 10, the contained contents are supplied to the connection destination of the connection flow path 17.

[0047] The first operating unit 11 contains an ion concentration changing substance C and is connected to the sensor containing unit 3 via a connecting flow path 17. The second operating unit 12 contains a linker-enzyme fusion product and is connected to the holding unit 72 via a connecting flow path 17.

[0048] The third operating unit 13 contains a substrate solution and is connected to the separation unit 74 via a connecting flow path 17. The fourth operating unit 14 contains a cleaning solution and is connected to the holder 72 via a connecting flow path 17. The fifth operating unit 15 contains a cleaning solution and is connected to the separation unit 74 via a connecting flow path 17.

[0049] In the present disclosure, when a buffer solution is used, the buffer solution may be contained in at least one of the specimen input section 2, the sensor accommodating section 3, the first operation section 11, the second operation section 12, the third operation section 13, the fourth operation section 14, and the fifth operation section 15. For example, the buffer solution may be contained in at least one of the specimen input section 2 and the sensor accommodating section 3.

[0050] The detector 1 of the present disclosure can be disposed of after a single use, but can also be reused. The detector 1 can be reused by cleaning the specimen insertion section 2, the sensor housing section 3, the operation sections 11 to 15, and the flow paths 6 to 9, and then filling them with the necessary substance or liquid after removing any influence from the previous use.

[0051] 6, the configuration of the detection device 100 will be described. The detection device 100 includes a slit-shaped insertion section 101 into which the detector 1 is inserted. At the back of the insertion section 101, the detection device 100 includes a pressure inlet 102 to which the pressure input section of the detector 1 is connected, and a pressure outlet 103 to which the pressure output section of the detector 1 is connected.

[0052] The detection device 100 includes a pump 104, a heating unit 105, a control unit 106, a magnetic force generating unit 107, and a pressing operation unit 108. The pump 104 pressurizes the fluid to be introduced into the pressure inlet 4 and outputs it from the pressure inlet 102. The pump 104 may also generate negative pressure to be applied to the pressure outlet 5, thereby sucking the fluid from the outlet 103. The pump 104 operates according to instructions from the control unit 106.

[0053] The heating unit 105 heats one or more locations in the detection device 100. The heating unit 105 operates in accordance with instructions from the control unit 106. For example, the control unit 106 controls the heating unit 105 to maintain the temperature of one or more locations in the detection device 100 within a suitable temperature range (for example, about 25°C).

[0054] The magnetic force generating unit 107 is disposed at a position facing the surface of the substrate 10 at which a portion of the detector 1 attached to the insertion unit 101 where magnetic force needs to be generated is located. In FIG. 6 , only one magnetic force generating unit 107 is shown for ease of viewing. However, in reality, there are two locations where magnetic force needs to be generated: the holding unit 72 and the separation unit 74, and a magnetic force generating unit 107 is disposed at each of these locations. The magnetic force generating unit 107 is an electromagnet that generates magnetic force when energized in accordance with instructions from the control unit 106. Hereinafter, the magnetic force generating unit 107 disposed opposite the holding unit 72 will be referred to as the first electromagnet M1, and the magnetic force generating unit 107 disposed opposite the separation unit 74 will be referred to as the second electromagnet M2. The first electromagnet M1 and the second electromagnet M2 will be collectively referred to as the magnetic force generating unit 107.

[0055] For example, when the first electromagnet M1 arranged opposite the holder 72 is activated, the magnetic beads are attracted to the first electromagnet M1. Therefore, even if the first discharge valve 92 or the first control valve 76 is opened, the magnetic beads remain in the holder 72, and only the fluid supplied to the holder 72 together with the magnetic beads is discharged via the first discharge valve 92. When the first electromagnet M1 is stopped, the magnetic beads are released from the magnetic force of the first electromagnet M1, and the magnetic beads can be discharged from the first control valve 76. Note that the same effect occurs when the second electromagnet M2 arranged opposite the separator 74 is activated as when the first electromagnet M1 is activated.

[0056] The pressing operation unit 108 is disposed at a position facing the surface of the substrate 10 where the portions of the detector 1 attached to the insertion unit 101 that require a pressing operation are located. In Fig. 6, for ease of viewing the drawing, the pressing operation unit 108 is shown in only one location, similar to the magnetic force generating unit 107. However, in reality, there are a first operation unit 11, a second operation unit 12, a third operation unit 13, a fourth operation unit 14, and a fifth operation unit 15 that require a pressing operation. The pressing operation unit 108 has a mechanism that uses a pressing member to press each of the operation units 11 to 15 individually in accordance with instructions from the control unit 106.

[0057] The control unit 106 is mainly composed of a microcomputer including a CPU 110, ROM, RAM, etc. The various functions of the microcomputer are realized by the CPU 110 executing a program stored in a non-transitory tangible recording medium. In this example, the ROM corresponds to the non-transitory tangible recording medium storing the program. Furthermore, the execution of this program executes a method corresponding to the program. Note that some or all of the functions executed by the CPU 110 may be configured as hardware using one or more ICs, etc. Furthermore, the number of microcomputers constituting the control unit 106 may be one or more.

[0058] The control unit 106 at least executes a detection process for detecting a substance to be detected from a sample. In the detection process, control signals for operating the detector 1 are sequentially generated to control the operations of the pump 104, the heating unit 105, the magnetic force generating unit 107, the pressing operation unit 108, the first discharge valve 92, the second discharge valve 93, the third discharge valve 94, the first control valve 76, and the second control valve 77. This enables the semiconductor sensor 31 to detect changes in ion concentration with high sensitivity.

[0059] [2-3. Processing] Next, the processing executed by the detection device 100 will be described using the flowchart in FIG. 7 . Note that the following processing may be executed by the CPU 110 of the detection device 100. In the initial state, the first discharge valve 92, the second discharge valve 93, the third discharge valve 94, the first control valve 76, and the second control valve 77 are all closed, and the pump 104, the magnetic force generating unit 107, and the pressing operation unit 108 are all stopped. Note that the "initial state" in this disclosure refers to, for example, the state before the detection device 100 is used to measure ion concentration.

[0060] In S10, a sample is introduced into the sample introduction section 2. However, the introduction of the sample may be performed by an operator. In S20, the CPU 110 performs a first mixing process. The first mixing process is a process in which magnetic beads and a sample are mixed to generate a first combined entity A, which is then held in the holding section 72. In the first mixing process, the CPU 110 activates the first electromagnet M1, opens the first discharge valve 92, and drives the pump 104. The magnetic beads contained in the bead holding section 61 pass through the first flow path 6 and pass through the first mixing section 71 together with the sample introduced into the sample introduction section 2 in S10. This causes the magnetic beads and the sample to mix, generating a first combined entity A in which they are bound together. The first combined entity A moves to the holding section 72. The magnetic beads are attracted to the first electromagnet M1, and the first combined entity A is maintained in the holding section 72. The components that did not form the first bond A pass through the waste liquid flow path 9 and move to the waste liquid storage section 91. After a predetermined time has elapsed since the pump 104 was driven, the CPU 110 closes the first discharge valve 92 to stop the pump 104.

[0061] In S30, the CPU 110 performs a first cleaning process. The first cleaning process is a process for cleaning the holder 72. In the first cleaning process, the CPU 110 activates the pressing operation unit 108 and presses the fourth operation unit 14. As a result, the cleaning liquid contained in the fourth operation unit 14 passes through the connection flow path 17 and is supplied to the holder 72. The supplied cleaning liquid cleans the holder 72. The CPU 110 then opens the first discharge valve 92 and drives the pump 104. As a result, components that did not form the first combined body A pass through the waste liquid flow path 9 and move to the waste liquid storage unit 91. After a predetermined time has elapsed since the pump 104 was driven, the CPU 110 closes the first discharge valve 92, stops the first electromagnet M1, and stops the pump 104.

[0062] In S40, the CPU 110 performs a second mixing process. The second mixing process is a process in which the first conjugate A and the linker-enzyme fusion are mixed to generate a second conjugate B, which is then retained in the separation unit 74. In the second mixing process, the CPU 110 activates the second electromagnet M2 to open the first control valve 76 and the second discharge valve 93, and activates the pressing member to press the second operation unit 12. As a result, the linker-enzyme fusion solution contained in the second operation unit 12 passes through the connection flow path 17 and is supplied to the holding unit 72. The CPU 110 then drives the pump 104. The first conjugate A and the linker-enzyme fusion solution present in the holding unit 72 pass through the second mixing unit 73 and move to the separation unit 74. As a result, the first conjugate A and the linker-enzyme fusion are mixed, and a second conjugate B is generated by binding them. The magnetic beads are attracted to the second electromagnet M2, thereby maintaining the second bond B in the separation section 74. Components that do not form the second bond B pass through the waste liquid flow path 9 and move to the waste liquid storage section 91. After a predetermined time has elapsed since the pump 104 was driven, the CPU 110 closes the first control valve 76 and the second discharge valve 93 to stop the pump 104.

[0063] In S50, the CPU 110 performs a second cleaning process. The second cleaning process is a process for cleaning the separation unit 74. In the second cleaning process, the CPU 110 activates the pressing operation unit 108 and presses the fifth operation unit 15. As a result, the cleaning liquid contained in the fifth operation unit 15 passes through the connection flow path 17 and is supplied to the separation unit 74. The supplied cleaning liquid cleans the separation unit 74. The CPU 110 then opens the second discharge valve 93 and drives the pump 104. As a result, the components that did not form the second combined body B pass through the waste liquid flow path 9 and move to the waste liquid storage unit 91. After a predetermined time has elapsed since the pump 104 was driven, the CPU 110 closes the second discharge valve 93, stops the second electromagnet M2, and stops the pump 104.

[0064] In S60, the CPU 110 performs a third mixing process. The third mixing process is a process in which the second bond B and the substrate solution are mixed to cause a chemical reaction between the enzyme and the substrate. In the third mixing process, the CPU 110 opens the second control valve 77, activates the pressing operation unit 108, and presses the third operation unit 13. As a result, the substrate solution contained in the third operation unit 13 passes through the connecting flow path 17 and is supplied to the separation unit 74. The CPU 110 then drives the pump 104. As a result, the second bond B and the substrate solution present in the separation unit 74 pass through the adjustment unit 75 and move to the sensor housing unit 3. During this movement, the second bond B and the substrate solution are mixed, and a chemical reaction occurs in which the enzyme contained in the second bond B consumes the substrate. This chemical reaction changes the hydrogen ion concentration in the mixture of the second bond B and the substrate solution. After a predetermined time has elapsed since the pump 104 started to operate, the CPU 110 closes the second control valve 77 to stop the pump 104 .

[0065] In S70, the CPU 110 performs a first ion concentration measurement process. The CPU 110 measures the ion concentration using the semiconductor sensor 31. Note that the first ion concentration measurement process can be omitted as necessary.

[0066] In S80, the CPU 110 performs an ion concentration change process. After a predetermined time has elapsed since the first ion concentration measurement process, the CPU 110 activates the pressing operation unit 108 and presses the first operation unit 11. As a result, the acid, which is the ion concentration change substance C contained in the first operation unit 11, passes through the connection flow path 17 and is supplied to the sensor containing unit 3.

[0067] In S90, the CPU 110 performs a second ion concentration measurement process. The CPU 110 measures the ion concentration using the semiconductor sensor 31. After the second ion concentration measurement process, the CPU 110 opens the fourth discharge valve 95 and drives the pump 104. This causes the liquid in the sensor housing 3 to pass through the third flow path 8 and be discharged.

[0068] The presence of a target contained in a sample can be detected by comparing the results obtained by the first ion concentration measurement process in S70 and / or the second ion concentration measurement process in S90 with the reference data. To acquire the reference data, two identical sets of detectors 1 may be provided, one for measuring a sample and the other for measuring a reference sample not containing the target. The above-described processing may then be performed in each set. Alternatively, to acquire the reference data, two detectors 1 may be used, one for measuring a sample and the other for measuring a reference sample, and the above-described processing may be performed independently on each set.

[0069] When a buffer solution is used in the present disclosure, the buffer solution may be mixed with the sample at any point in the process (S10 to S60) from when the sample is introduced into the sample input section 2 until when the sample moves to the sensor housing section 3. Alternatively, the buffer solution may be mixed with the mixture of the second conjugate B and the substrate solution at any point in time after the sample moves to the sensor housing section 3 (S70 to S90).

[0070] [2-4. Effects] The first embodiment described above in detail provides the following effects. (2a) According to the above embodiment, the detector 1 measures the ion concentration of a specimen after adding the ion concentration changing substance C. The ion concentration changing substance C is a substance that changes the ion concentration of the specimen when mixed with the specimen. This increases the change in ion concentration in the specimen. This improves the detection sensitivity of changes in ion concentration in the specimen.

[0071] (2b) Furthermore, according to the above embodiment, an acid is used as the ion concentration changing substance C. This allows the ion concentration of the sample to be changed in a simple manner, thereby advantageously improving the detection sensitivity of changes in ion concentration in the sample.

[0072] (2c) According to the above embodiment, magnetic beads are bound to a sample to prepare a first conjugate A, and a linker-enzyme fusion is bound to the first conjugate A to prepare a second conjugate B. A substrate solution is added to the second conjugate B, and an enzyme contained in the second conjugate B causes a chemical reaction that consumes the substrate, changing the hydrogen ion concentration in the reaction solution. After adding the ion concentration-changing substance C, the change in hydrogen ion concentration is measured as the ion concentration in the sample. Therefore, the ion concentration of a specific target bound to the linker in the sample is measured. This can advantageously improve the detection sensitivity of ion concentration changes. Furthermore, by comparing the ion concentration measurement results with reference data, it is possible to determine whether the target is contained in the sample.

[0073] (2d) Furthermore, according to the above embodiment, the detector 1 includes the specimen insertion section 2, the sensor housing section 3, the first operation section 11, the second operation section 12, the third operation section 13, the fourth operation section 14, and the fifth operation section 15, as well as the above-mentioned flow paths, within the substrate 10. Therefore, by using the detector 1 of the present disclosure, it is not necessary to change the container for each process, and ion concentration measurement can be performed easily and simply. Furthermore, the detector 1 can be made smaller.

[0074] (2e) Furthermore, according to the above embodiment, when a buffer solution is used in the present disclosure, the ion concentration of the sample may be changed to a level outside the buffer range of the buffer solution by mixing the ion concentration changing substance C with the sample. Therefore, outside the buffer range, the change in ion concentration of the sample becomes larger. This can advantageously improve the detection sensitivity of changes in ion concentration.

[0075] [3. Second Embodiment] [3-1. Differences from First Embodiment] The second embodiment has the same basic configuration as the first embodiment, so differences will be described below. Note that the same reference numerals as in the first embodiment indicate the same configuration, and the preceding description will be referred to.

[0076] The detector 1A of the second embodiment differs from the first embodiment in the configuration of the first flow path 6, the configuration of the waste liquid flow path 9, and the attachment positions of the second operation unit 12, the third operation unit 13, the fourth operation unit 14, and the fifth operation unit 15. As shown in Fig. 8 , in the detector 1, the first flow path 6 does not include the bead storage unit 61, and instead includes a sixth operation unit 16.

[0077] Magnetic beads are stored in the sixth operating unit 16. Like the other operating units 11 to 15, the sixth operating unit 16 supplies the contents to the destination of the connection flow channel 17 when pressed. The sixth operating unit 16 is connected to the first flow channel 6 via the connection flow channel 17.

[0078] The second operating unit 12, the third operating unit 13, the fourth operating unit 14, and the fifth operating unit 15 are all connected to the first flow path 6 via a connecting flow path 17. In the second flow path 7, the holding unit 72 is not connected to the first discharge valve 92 and the waste liquid flow path 9, and the first control valve 76 is also omitted.

[0079] The third discharge valve 94 is omitted from the waste liquid flow path 9. In the detection device 100, the pressing operation unit 108 is provided with a mechanism for pressing the first operation unit 11, the second operation unit 12, the third operation unit 13, the fourth operation unit 14, the fifth operation unit 15, and the sixth operation unit 16 at a position facing the respective operation units 11 to 16.

[0080] The magnetic force generating unit 107 includes a second electromagnet M2 that is disposed opposite the separating unit 74. The first electromagnet M1 that was disposed opposite the holding unit 72 is omitted. However, in the second embodiment, the magnetic force generating unit 107 may include the first electromagnet M1 that is disposed opposite the holding unit 72, in addition to the second electromagnet M2.

[0081] That is, in the detection device 100, the pressing operation unit 108 is arranged according to the positions of the first to sixth operation units 11 to 16 in the detector 1A, and the magnetic force generation unit 107 is arranged according to the position where magnetic force needs to be generated. The same applies to the following embodiments.

[0082] [3-2. Processing] Next, the processing executed by the detection device 100 of the second embodiment will be described based on the flow in the first embodiment shown in Fig. 7. Note that a description of the processing common to the first embodiment will be omitted.

[0083] In S20, the CPU 110 activates the pressing operation unit 108 and presses the sixth operation unit 16. As a result, the magnetic beads contained in the sixth operation unit 16 pass through the connection flow path 17 and are supplied to the first flow path 6. The CPU 110 then drives the pump 104. The magnetic beads pass through the first flow path 6 and pass through the first mixing unit 71 together with the specimen that was input into the specimen input unit 2 in S10. As a result, the magnetic beads and the specimen are mixed, and a first combined entity A is generated by combining them. The first combined entity A moves to the holding unit 72. After a predetermined time has elapsed since the pump 104 was driven, the CPU 110 stops the pump 104.

[0084] In S30, the CPU 110 activates the pressing operation unit 108 to press the fourth operation unit 14. As a result, the cleaning liquid contained in the fourth operation unit 14 is supplied to the first flow path 6 via the connection flow path 17. The CPU 110 then drives the pump 104. The cleaning liquid passes through the first flow path 6 and the first mixing unit 71 and is supplied to the holding unit 72. The supplied cleaning liquid cleans the holding unit 72. After a predetermined time has elapsed since the pump 104 was driven, the CPU 110 stops the pump 104.

[0085] In S40, the CPU 110 activates the second electromagnet M2 to open the second discharge valve 93, activates the pressing operation unit 108, and presses the second operation unit 12. As a result, the linker-enzyme fusion solution contained in the second operation unit 12 is supplied to the first flow path 6 via the connection flow path 17. The CPU 110 then drives the pump 104. The linker-enzyme fusion solution passes through the first flow path 6 and the first mixing unit 71 and is supplied to the holding unit 72. Furthermore, the first conjugate A and the linker-enzyme fusion solution present in the holding unit 72 pass through the second mixing unit 73 and move to the separation unit 74. Note that other processing in S40 is similar to that in the first embodiment.

[0086] In S50, the CPU 110 activates the pressing operation unit 108 to press the fifth operation unit 15. As a result, the cleaning liquid stored in the fifth operation unit 15 is supplied to the first flow path 6 via the connection flow path 17. The CPU 110 then opens the second discharge valve 93 and drives the pump 104. The cleaning liquid passes through the first flow path 6, the first mixing unit 71, the holding unit 72, and the second mixing unit 73, and is supplied to the separation unit 74. The supplied cleaning liquid cleans the separation unit 74. Note that other processing in S50 is the same as in the first embodiment.

[0087] In S60, the CPU 110 activates the pressing operation unit 108 and presses the third operation unit 13. As a result, the linker-enzyme fusion solution contained in the second operation unit 12 is supplied to the first flow path 6 via the connecting flow path 17. The CPU 110 then drives the pump 104. The substrate solution passes through the first flow path 6, first mixing unit 71, holding unit 72, and second mixing unit 73 via the connecting flow path 17, and is supplied to the separation unit 74. Furthermore, the second conjugate B and the substrate solution present in the separation unit 74 pass through the adjustment unit 75 and move to the sensor storage unit 3. Note that other processing in S60 is similar to that in the first embodiment.

[0088] [3-3. Effects] According to the second embodiment described above in detail, in addition to the effects of the first embodiment described above, the following effects are also achieved.

[0089] (3a) The detector 1A of the second embodiment differs in the configuration of the first flow path 6, the configuration of the waste liquid flow path 9, and the mounting positions of the second operation unit 12, the third operation unit 13, the fourth operation unit 14, and the fifth operation unit 15. Even if the configuration and mounting positions of the detector 1A differ in this way, the same effects as those of the first embodiment described above can be achieved.

[0090] (3b) Furthermore, depending on the arrangement of the components, the configuration of detector 1A can be simplified compared to detector 1. [4. Third Embodiment] [4-1. Differences from First Embodiment] The basic configuration of the third embodiment is similar to that of the first embodiment, so differences will be described below. Note that the same reference numerals as those in the first embodiment indicate the same components, and reference is made to the preceding description.

[0091] The detector 1B of the third embodiment differs from the first embodiment in the configuration of the second flow path 7 and the configuration of the waste liquid flow path 9. Furthermore, in the detector 1B, the first operation unit 11, the second operation unit 12, and the third operation unit 13 are omitted, and the connection destinations of the fourth operation unit 14 and the fifth operation unit 15 differ from those of the first embodiment.

[0092] 9 , the specimen input section 2 is connected to the waste liquid flow path 9 via a fifth discharge valve 96. The second flow path 7 includes a first connection section 711, a linker enzyme storage section 712, a second connection section 713, a substrate liquid storage section 714, and an adjustment section 75.

[0093] The first connection part 711 is a flow path connecting the specimen input part 2 and the linker-enzyme storage part 712, and is provided with a third control valve 78 at its upstream end connected to the specimen input part 2. The linker-enzyme storage part 712 is a space that initially stores the linker-enzyme fusion product. The linker-enzyme storage part 712 is connected to the waste liquid flow path 9 via a sixth discharge valve 97.

[0094] The second connection part 713 is a flow path connecting the linker enzyme storage part 712 and the substrate liquid storage part 714, and is provided with a fourth control valve 79 at the upstream end connected to the linker enzyme storage part 712. In the initial state of the detector 1B, the ion concentration changing substance C is stored in the sensor storage part 3.

[0095] The substrate liquid storage section 714 is a space that stores the substrate liquid in the initial state. The adjustment section 75 is a flow path that connects the substrate liquid storage section 714 and the sensor storage section 3. The length of the flow path is set in the same way as the adjustment section 75 described in the first embodiment.

[0096] In the detection device 100, the magnetic force generation unit 107 has a third electromagnet M3 at a position facing the specimen insertion unit 2, and a fourth electromagnet M4 at a position facing the linker enzyme storage unit 712. [4-2. Processing] Next, the processing executed by the detection device 100 of the third embodiment will be described based on the flow in the first embodiment shown in Figure 7. Note that a description of processing common to the first embodiment will be omitted.

[0097] In S20, the CPU 110 activates the third electromagnet M3, opens the fifth discharge valve 96, and drives the pump 104. The magnetic beads contained in the bead container 61 pass through the first flow path 6 and move to the specimen input section 2. The magnetic beads are then mixed with the specimen input into the specimen input section 2, and a first conjugate A is generated by the combination of the magnetic beads and the specimen. The magnetic beads are attracted to the third electromagnet M3, and the first conjugate A is maintained in the specimen input section 2. Components that did not form the first conjugate A pass through the waste liquid flow path 9 and move to the waste liquid container 91. After a predetermined time has elapsed since the pump 104 was driven, the CPU 110 closes the fifth discharge valve 96 and stops the pump 104.

[0098] In S30, the CPU 110 activates the pressing operation unit 108 to press the fourth operation unit 14. As a result, the cleaning liquid contained in the fourth operation unit 14 passes through the connection flow path 17 and is supplied to the specimen insertion unit 2. The supplied cleaning liquid cleans the specimen insertion unit 2. The CPU 110 then opens the fifth discharge valve 96 and drives the pump 104. After a predetermined time has elapsed since the pump 104 was driven, the CPU 110 closes the fifth discharge valve 96, stops the third electromagnet M3, and stops the pump 104.

[0099] In S40, the CPU 110 activates the fourth electromagnet M4, opens the third control valve 78 and the sixth discharge valve 97, and drives the pump 104. The first conjugate A present in the specimen input section 2 moves to the linker-enzyme storage section 712 via the first connection section 711, where it is mixed with the second conjugate B and the linker-enzyme fusion product, generating a second conjugate B by combining them. The magnetic beads are attracted to the fourth electromagnet M4, so that the second conjugate B is maintained in the linker-enzyme storage section 712. After a predetermined time has elapsed since the pump 104 was driven, the CPU 110 closes the third control valve 78 and the sixth discharge valve 97 and stops the pump 104.

[0100] In S50, the CPU 110 activates the pressing operation unit 108 to press the fifth operation unit 15. As a result, the cleaning solution contained in the fifth operation unit 15 passes through the connection flow path 17 and is supplied to the linker enzyme storage unit 712. The supplied cleaning solution cleans the linker enzyme storage unit 712. The CPU 110 then opens the sixth discharge valve 97 and drives the pump 104. After a predetermined time has elapsed since the pump 104 was driven, the CPU 110 closes the sixth discharge valve 97, stops the fourth electromagnet M4, and stops the pump 104.

[0101] In S60, the CPU 110 opens the fourth control valve 79 and drives the pump 104. As a result, the second bond B present in the linker enzyme storage section 712 moves to the substrate solution storage section 714 via the second connection section 713, passes through the adjustment section 75 together with the substrate solution, and moves to the sensor storage section 3. These are then mixed with the acid, which is the ion concentration changing substance C, stored in the sensor storage section 3. After a predetermined time has elapsed since the pump 104 was driven, the CPU 110 closes the fourth control valve 79 and stops the pump 104.

[0102] In the third embodiment, the processes of S70 and S80 are omitted. [4-3. Effects] According to the third embodiment described above in detail, in addition to the effects of the first embodiment described above, the following effects are also achieved.

[0103] (4a) In the detector 1B of the third embodiment, the first operation unit 11, the second operation unit 12, and the third operation unit 13 are omitted, and the operation of pressing these operation units 11 to 13 by the CPU 110 is omitted. This simplifies the structure and processing of the detector 1B compared to the detector 1 of the present disclosure.

[0104] [5. Fourth Embodiment] [5-1. Differences from the Third Embodiment] The basic configuration of the fourth embodiment is the same as that of the third embodiment, so differences will be described below. Note that the same reference numerals as those in the third embodiment indicate the same configuration, and reference is made to the preceding description.

[0105] 10, in a detector 1C of the fourth embodiment, the bead storage section 61 is omitted from the first flow path 6. In the detector 1, magnetic beads are stored in the specimen insertion section 2 in the initial state.

[0106] 5-2. Processing Next, the processing executed by the detection device 100 of the fourth embodiment will be described below, focusing on differences from the first and third embodiments.

[0107] In the detector 1 of the fourth embodiment, the bead storage section 61 is omitted from the first flow path 6, and magnetic beads are stored in the specimen input section in the initial state. Therefore, in the detector 1 of the fourth embodiment, at the stage in S10 when the specimen is input into the specimen input section 2, the specimen is mixed with the magnetic beads stored in the specimen input section 2, and a first conjugate A is generated in which the specimen and the magnetic beads are bound to each other.

[0108] Other processing is the same as in the third embodiment. [5-3. Effects] According to the fourth embodiment described above in detail, in addition to the effects of the first embodiment and the third embodiment described above, the following effects are also achieved.

[0109] (5a) In the detector 1C of the fourth embodiment, the bead storage section 61 is omitted. Therefore, it is possible to provide a detector 1C with a simpler structure compared to the detector 1. [6. Fifth Embodiment] [6-1. Differences from the First Embodiment] The fifth embodiment has the same basic configuration as the first embodiment, so differences will be explained below. Note that the same reference numerals as in the first embodiment indicate the same configuration, and reference will be made to the preceding explanation.

[0110] As shown in Fig. 11, the detector 1D of the fifth embodiment does not include the third operation unit 13. In the initial state of the detector 1, the substrate liquid is contained in the sensor container 3. [6-2. Processing] Next, the processing executed by the detection device 100 of the second embodiment will be described based on the flow of the first embodiment shown in Fig. 7. Note that a description of processing common to the first embodiment will be omitted.

[0111] In S60, the CPU 110 opens the second control valve 77 and drives the pump 104. As a result, the second bound substance B present in the separation section 74 passes through the adjustment section 75 and moves to the sensor housing section 3. In the sensor housing section 3, the second bound substance B and the substrate solution are mixed, and a chemical reaction occurs in which the enzyme contained in the second bound substance B consumes the substrate. After a predetermined time has elapsed since the pump 104 was driven, the CPU 110 closes the second control valve 77 and stops the pump 104.

[0112] Other processes are the same as those in the third embodiment. [6-3. Effects] According to the fifth embodiment described above in detail, in addition to the effects of the first embodiment described above, the following effects are also achieved.

[0113] (6a) In the detector 1D of the fifth embodiment, the third operating unit 13 is omitted. Therefore, it is possible to provide a detector 1D with a simpler structure compared to the detector 1. [7. Other Embodiments] Although the embodiments of the present disclosure have been described above, the present disclosure is not limited to the above-described embodiments and can be implemented in various modifications.

[0114] (7a) The detector 1 may have a specimen insertion section 2, a sensor storage section 3, and a first operation section 11. In other words, the second operation section 12, the third operation section 13, the fourth operation section 14, and the fifth operation section 15 may be omitted.

[0115] As an exemplary process, first, a specimen may be introduced into the specimen receiving section 2. Next, the CPU 110 may drive the pump 104. As a result, the specimen introduced into the specimen receiving section 2 may pass through the second flow path 7 and move to the sensor containing section 3. The CPU 110 may then optionally measure the ion concentration of the specimen using the semiconductor sensor 31. Thereafter, the CPU 110 may actuate the pressing operation unit 108 and press the first operation unit 11, thereby supplying the acid, which is the ion concentration change substance C contained in the first operation unit 11, to the sensor containing section 3 through the connecting flow path 17. The CPU 110 may then measure the ion concentration of the specimen using the semiconductor sensor 31. This allows the detector 1 to improve its detection sensitivity for changes in ion concentration in the specimen, even with a minimal configuration.

[0116] (7b) In the above embodiment, an acid is used as the ion concentration changing substance C. However, the ion concentration changing substance C may be, for example, a base or air (i.e., CO ２ ) may be used. When air is used as the ion concentration changing substance C, the detector 1 may have an ion concentration changing substance supply passage 11A. Specifically, as shown in FIG. 12 , the ion concentration changing substance supply passage 11A may be a passage extending from the sensor housing portion 3 to the surface of the substrate 10. Furthermore, an opening / closing mechanism 11B (e.g., a valve 11B) for the ion concentration changing substance supply passage 11A may be provided on the surface of the substrate 10 to which the ion concentration changing substance supply passage 11A is connected. The ion concentration changing process may be performed by opening the opening / closing mechanism 11B from the surface side of the substrate 10, thereby allowing the ion concentration changing substance supply passage 11A to take in air from outside the detector 1 and supply the air to the sensor housing portion 3.

[0117] (7c) In the above embodiment, a pressurized fluid is used as a method for moving the specimen, etc., within the detector 1. However, the method for moving the specimen, etc., is not limited to this. In particular, when mixing the specimen with magnetic beads, the specimen, etc., may be moved together with the magnetic beads by generating a magnetic force that attracts the magnetic beads so that they move along the flow path. In addition to the magnetic force, the specimen, etc., may be moved by combining it with negative pressure applied to the pressure outlet 5.

[0118] (7d) In the above embodiment, several patterns were shown in which the magnetic beads, linker-enzyme fusion product, substrate solution, and ion concentration changing substance C were initially stored in the operation units 11 to 16, or in the spaces in the first flow path 6 and the second flow path 7, the specimen input unit 2, and the sensor storage unit 3. However, these configurations are not limited to the above patterns, and various patterns can be used.

[0119] (7e) In the above embodiment, crank-shaped flow paths are used as the first mixing section 71 and the second mixing section 73 of the second flow path 7, but this is not limited thereto. For example, as shown in FIGS. 13A, 13B, and 13C, solutions may be mixed by generating turbulence in the flow path by erecting pillars or providing micro-ribs in the flow path. Solutions may also be mixed by employing a vibrator mechanism that applies vibrations to the detector 1 or a vortex mechanism that generates vortexes in the flow path. Solutions may also be mixed by employing a stirrer mechanism that mixes the solution with a rotor containing a magnet and rotates the rotor with magnetic force. Additionally, solutions may be mixed in the detector 1 by generating ultrasound waves using an ultrasonic device.

[0120] (7f) The control unit 106 and its method described herein may be implemented by a special-purpose computer configured by configuring a processor and memory programmed to perform one or more functions embodied in a computer program. Alternatively, the control unit 106 and its method described herein may be implemented by a special-purpose computer configured by configuring a processor with one or more dedicated hardware logic circuits. Alternatively, the control unit 106 and its method described herein may be implemented by one or more special-purpose computers configured by combining a processor and memory programmed to perform one or more functions with a processor configured with one or more hardware logic circuits. Furthermore, the computer program may be stored as instructions executed by a computer on a computer-readable non-transitory tangible recording medium. The method for implementing the functions of each unit included in the control unit 106 does not necessarily need to include software; all of the functions may be implemented using one or more hardware devices.

[0121] (7g) Multiple functions possessed by one component in the above embodiments may be realized by multiple components, or one function possessed by one component may be realized by multiple components. Also, multiple functions possessed by multiple components may be realized by one component, or one function realized by multiple components may be realized by one component. Also, part of the configuration of the above embodiments may be omitted. Also, at least part of the configuration of the above embodiments may be added to or substituted for the configuration of another of the above embodiments.

[0122] (7h) In addition to the above-described detection device 100, the present disclosure can also be realized in various forms, such as a system including the detection device 100 as a component, a program for causing a computer to function as the control unit 106 of the detection device 100, a non-transient physical recording medium such as a semiconductor memory on which this program is recorded, a detection method, and a method for detecting a target in a specimen.

[0123] [7. Correspondence of Words] In this embodiment, the second flow path 7 corresponds to the movement flow path. Furthermore, the first operation unit 11 and the ion concentration change substance supply passage 11A correspond to the change substance supply unit. Furthermore, the first operation unit 11 corresponds to the change substance storage unit. Furthermore, the second operation unit 12, the third operation unit 13, the sixth operation unit 16, the bead storage unit 61, the first mixing unit 71, the second mixing unit 73, the adjustment unit 75, the linker enzyme storage unit 712, and the substrate liquid storage unit 714 correspond to the mixing unit. Furthermore, the sixth operation unit 16 and the bead storage unit 61 correspond to the bead storage unit. Furthermore, the second operation unit 12 and the linker enzyme storage unit 712 correspond to the enzyme storage unit. Furthermore, the third operation unit 13 and the substrate liquid storage unit 714 correspond to the substrate storage unit. Furthermore, the fourth operation unit 14 and the fifth operation unit 15 correspond to the washing unit. Furthermore, the first flow path 6 corresponds to the drive flow path. Furthermore, S20, S40, and S60 in the process of the present disclosure correspond to a specimen supply unit. Furthermore, S80 in the process of the present disclosure corresponds to an ion concentration changing substance addition unit. Furthermore, S90 in the process of the present disclosure corresponds to a measurement unit. Furthermore, S20 in the process of the present disclosure corresponds to a bead supply unit. Furthermore, S40 in the process of the present disclosure corresponds to a linker-enzyme fusion supply unit. Furthermore, S60 in the process of the present disclosure corresponds to a substrate supply unit. Furthermore, S60 and S70 in the process of the present disclosure correspond to a reaction unit. [Technical Ideas Disclosed in the Present Specification] [Item 1] A detector (1, 1A, 1B, 1C, 1D) comprising: a sensor housing (3) that houses a sensor for measuring ions; a specimen input section (2) into which a specimen is input; a transfer flow path (7) that connects the specimen input section and the sensor housing section and supplies the specimen to the sensor housing section; and a changing substance supply section (11, 11A) that supplies an ion concentration changing substance (C) that changes the ion concentration of the specimen to the sensor housing section. [Item 2] The detector according to Item 1, wherein the changing substance supply section comprises a changing substance housing section (11) that houses the ion concentration changing substance, and has a structure (11) that pushes the ion concentration changing substance toward the sensor housing section by pressing the changing substance housing section.[Item 3] The detector according to Item 1, wherein the changing substance supply unit includes an ion concentration changing substance supply passage (11A) communicating with the sensor housing unit and a structure (11B) for taking in outside air into the sensor housing unit. [Item 4] The detector according to any one of Items 1 to 3, wherein at least one of the specimen input unit and the sensor housing unit contains a buffer solution, the buffer solution and the specimen form a mixture, and the ion concentration changing substance has a property of changing the ion concentration of the specimen contained in the mixture to outside the buffer range of the buffer solution. [Item 5] The detector according to any one of Items 1 to 4, further including a mixing unit (12, 13, 16, 61, 71, 73, 75, 712, 714) for mixing an enzyme and a substrate with the specimen input from the specimen input unit before the specimen reaches the sensor housing unit. [Item 6] The detector according to Item 5, wherein the enzyme is provided as a linker-enzyme fusion complex fused to a linker, and the linker has a property of binding to the specimen. [Item 7] The detector according to Item 6, wherein the mixing unit has a structure (16, 61) for mixing beads with the sample input from the sample input unit before the sample reaches the sensor storage unit. [Item 8] The detector according to Item 7, wherein the mixing unit comprises a bead storage unit (16, 61) for storing the beads, an enzyme storage unit (12, 712) for storing the linker-enzyme fusion, and a substrate storage unit (13, 714) for storing the substrate, and at least one of the bead storage unit, the enzyme storage unit, and the substrate storage unit is provided on the migration flow path. [Item 9] The detector according to Item 7, wherein the mixing unit comprises a bead storage unit for storing the beads, an enzyme storage unit for storing the linker-enzyme fusion, and a substrate storage unit for storing the substrate, and at least one of the bead storage unit, the enzyme storage unit, and the substrate storage unit supplies at least one of the beads, the linker-enzyme fusion, and the substrate to either the sample input unit or the migration flow path. [Item 10] The detector according to item 8 or 9, wherein the sensor accommodating section and the substrate accommodating section are integrally provided.[Item 11] The detector according to any one of items 1 to 10, further comprising a driving flow path (6) for applying fluid pressure to the specimen input portion to move the specimen from the specimen input portion toward the sensor accommodating portion.

Claims

1. A detector (1, 1A, 1B, 1C, 1D) comprising: a sensor housing (3) that houses a sensor for measuring ions; a specimen input section (2) into which a specimen is input; a transfer flow path (7) that connects the specimen input section and the sensor housing and supplies the specimen to the sensor housing; and a change substance supply section (11, 11A) that supplies an ion concentration change substance (C) that changes the ion concentration of the specimen to the sensor housing section.

2. A detector as described in claim 1, wherein the change substance supply section includes a change substance storage section (11) that stores the ion concentration change substance, and has a structure (11) that pushes the ion concentration change substance toward the sensor storage section by pressing the change substance storage section.

3. A detector as described in claim 1, wherein the change substance supply section has an ion concentration change substance supply passage (11A) connected to the sensor accommodating section, and has a structure (11B) for taking in outside air into the sensor accommodating section.

4. A detector as claimed in any one of claims 1 to 3, wherein at least one of the specimen input section and the sensor storage section contains a buffer solution, the buffer solution and the specimen form a mixture, and the ion concentration changing substance has the property of changing the ion concentration of the specimen contained in the mixture to outside the buffer range of the buffer solution.

5. A detector as described in any one of claims 1 to 3, further comprising a mixing section (12, 13, 16, 61, 71, 73, 75, 712, 714) for mixing an enzyme and a substrate with the sample input from the sample input section before the sample reaches the sensor accommodating section.

6. The detector of claim 5, wherein the enzyme is provided as a linker-enzyme fusion fused to a linker, the linker having the property of binding to the analyte.

7. A detector as described in claim 6, wherein the mixing section has a structure (16, 61) for mixing beads with the sample introduced from the sample introduction section before the sample reaches the sensor accommodating section.

8. The detector of claim 7, wherein the mixing section comprises a bead storage section (16, 61) for storing the beads, an enzyme storage section (12, 712) for storing the linker-enzyme fusion, and a substrate storage section (13, 714) for storing the substrate, and at least one of the bead storage section, the enzyme storage section, and the substrate storage section is provided on the transport flow path.

9. The detector of claim 7, wherein the mixing section comprises a bead storage section for storing the beads, an enzyme storage section for storing the linker-enzyme fusion, and a substrate storage section for storing the substrate, and at least one of the bead storage section, the enzyme storage section, and the substrate storage section supplies at least one of the beads, the linker-enzyme fusion, and the substrate to either the sample input section or the transport flow path.

10. The detector according to claim 9, wherein the sensor housing and the substrate housing are integrally provided.

11. A detector as described in any one of claims 1 to 3, further comprising a driving flow path (6) for applying fluid pressure to the specimen input portion to move the specimen from the specimen input portion toward the sensor accommodating portion.

12. A detection device (100) comprising: a detector; and a control unit (106); the detector comprising: a sensor housing portion that houses a sensor for measuring ions; a specimen input portion into which a specimen is input; a transfer flow path that connects the specimen input portion and the sensor housing portion and supplies the specimen to the sensor housing portion; and a changing substance supply portion that supplies an ion concentration changing substance that changes the ion concentration of the specimen to the sensor housing portion; and the control portion comprising: a specimen supply portion (S20, S40, S60) that supplies the input specimen to the sensor housing portion; an ion concentration changing substance adding portion (S80) that supplies the ion concentration changing substance stored in the changing substance housing portion to the sensor housing portion; and a measurement portion (S90) that measures the ion concentration in the specimen.

13. A detection device comprising a detector and a control unit, the detector comprising: a sensor housing section that houses a sensor for measuring ions; a specimen input section into which a specimen is input; a transfer flow path that connects the specimen input section and the sensor housing section and supplies the specimen to the sensor housing section; a changing substance supply section that supplies an ion concentration changing substance that changes the ion concentration of the specimen to the sensor housing section; and a mixing section that mixes beads, a linker-enzyme fusion, and a substrate with the specimen input from the specimen input section before the specimen reaches the sensor housing section, and the control unit comprises: a bead supply section (S20) that supplies the beads to the input specimen and generates a first conjugate (A) in which the specimen and the beads are bound; and a linker-enzyme fusion supply section (S40) that supplies the linker-enzyme fusion to the first conjugate and generates a second conjugate (B) in which the first conjugate and the linker-enzyme fusion are bound; a substrate supply unit (S60) that supplies the substrate to the second conjugate; a reaction unit (S60, S70) that supplies the second conjugate and the substrate to the sensor housing unit and causes a chemical reaction in which an enzyme contained in the second conjugate consumes the substrate; an ion concentration changing substance adding unit (S80) that supplies the ion concentration changing substance contained in the changing substance housing unit to the sensor housing unit; and a measurement unit (S90) that measures the ion concentration in the sample.

14. A detection method using a detector, the detector comprising: a sensor housing portion that houses a sensor for measuring ions; a specimen input portion into which a specimen is input; a transfer flow path that connects the specimen input portion and the sensor housing portion and supplies the specimen to the sensor housing portion; and a changing substance supply portion that supplies an ion concentration changing substance that changes the ion concentration of the specimen to the sensor housing portion, the detection method comprising: inputting the specimen into the specimen input portion; supplying the input specimen to the sensor housing portion; supplying the ion concentration changing substance stored in the changing substance storage portion to the sensor housing portion; and measuring the ion concentration in the specimen.

15. A detection method using a detector, the detector comprising: a sensor housing portion that houses an ion sensor for measuring ions; a specimen input portion into which a specimen is input; a transfer flow path that connects the specimen input portion and the sensor housing portion and supplies the specimen to the sensor housing portion; a changing substance supply portion that supplies an ion concentration changing substance that changes the ion concentration of the specimen to the sensor housing portion; and a mixing portion for mixing beads, a linker-enzyme fusion, and a substrate with the specimen input from the specimen input portion before the specimen reaches the sensor housing portion, the detection method comprising: inputting the specimen into the specimen input portion; supplying the beads to the input specimen to prepare a first conjugate in which the specimen and the beads are bound; supplying the linker-enzyme fusion to the first conjugate to prepare a second conjugate in which the first conjugate and the linker-enzyme fusion are bound; and supplying the substrate to the second conjugate. A detection method comprising: supplying the second conjugate and the substrate to the sensor housing portion, and causing a chemical reaction in which an enzyme contained in the second conjugate consumes the substrate; supplying the ion concentration changing substance contained in a changing substance housing portion to the sensor housing portion; and measuring the ion concentration in the sample.

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