Testing devices, test kits, and testing systems

Abstract

To improve the convenience and efficiency of testing. [Solution] The inspection device according to this embodiment includes a reaction vessel and a reaction detection unit. The reaction vessel has an opening into which a liquid droplet is dropped and contains the liquid droplet. The reaction detection unit is located below the opening in the reaction vessel and has a substance on its surface that binds with the substance to be detected. The capacity of the reaction vessel is approximately the same as twice the volume of the liquid droplet or less than or equal to twice the volume of the liquid droplet.

Description

[Technical Field]

[0001] Embodiments disclosed herein and in the drawings relate to testing devices, testing kits, and testing systems. [Background technology]

[0002] Infectious disease tests and blood tests require the collection of specimens such as mucosal epithelium and blood, and since these are invasive medical procedures, it is desirable to perform them only when absolutely necessary. Furthermore, in tests targeting newborns, only minute specimens can often be collected, requiring testing with minute specimens. Thus, for tests that require invasive specimen collection or tests that can only obtain minute specimens, it is necessary to perform the test with a minute sample. However, when using minute samples, there is a problem in that it is difficult to deliver the minute sample to the reaction detection area due to the surface tension of the liquid. [Prior art documents] [Patent Documents]

[0003] [Patent Document 1] Patent No. 5424610 [Patent Document 2] Patent No. 6359348 [Overview of the project] [Problems that the invention aims to solve]

[0004] One of the problems that the embodiments disclosed herein and in the drawings aim to solve is to improve the convenience and efficiency of inspection. However, the problems that the embodiments disclosed herein and in the drawings aim to solve are not limited to the above problem. Problems corresponding to the effects of each configuration shown in the embodiments described later can also be positioned as other problems. [Means for solving the problem]

[0005] The inspection device according to this embodiment includes a reaction vessel and a reaction detection unit. The reaction vessel has an opening into which a liquid droplet is dropped and contains the liquid droplet. The reaction detection unit is located below the opening in the reaction vessel and has a substance on its surface that binds with the substance to be detected. The capacity of the reaction vessel is approximately the same as twice the volume of the liquid droplet or less than or equal to twice the volume of the liquid droplet. [Brief explanation of the drawing]

[0006] [Figure 1] Figure 1 shows an example of the appearance of the inspection device according to the first embodiment. [Figure 2] Figure 2 shows an example of the appearance of the inspection device according to the first embodiment. [Figure 3A] Figure 3A shows an example of a sensor chip according to the first embodiment. [Figure 3B] Figure 3B shows an example of a sensor chip according to the first embodiment. [Figure 4] Figure 4 shows an example of a dropper device according to the first embodiment. [Figure 5] Figure 5 shows a first design example of an inspection device according to the first embodiment. [Figure 6] Figure 6 shows a second design example of the inspection device according to the first embodiment. [Figure 7] Figure 7 shows a third design example of the inspection device according to the first embodiment. [Figure 8] Figure 8 shows a fourth design example of the inspection device according to the first embodiment. [Figure 9] Figure 9 shows a fifth design example of the inspection device according to the first embodiment. [Figure 10] Figure 10 shows the state transition of a droplet when a sample liquid is dropped onto the inspection device according to the first embodiment. [Figure 11] Figure 11 is a block diagram showing an inspection system according to the second embodiment. [Figure 12]FIG. 12 is a flowchart showing the operation of the inspection system according to the second embodiment. [Figure 13] FIG. 13 is a flowchart showing an example of the time-series change of the light intensity of the emitted light according to the second embodiment. **[Embodiments for Carrying Out the Invention]**

[0007] Hereinafter, the inspection device, inspection kit, and inspection system according to the present embodiment will be described with reference to the drawings. In the following embodiments, parts with the same reference numerals are assumed to perform the same operations, and overlapping descriptions will be omitted as appropriate.

[0008] (First Embodiment) An example of the appearance of the inspection device according to the first embodiment will be described with reference to FIGS. 1 and 2. FIG. 1 is a top view showing the upper surface (front surface) of the inspection device 1, and FIG. 2 is a bottom view showing the lower surface (back surface) of the inspection device 1.

[0009] The inspection device 1 has an opening 10 and four holes 12 on the upper surface of the inspection device 1. The opening 10 is provided for dropping a sample liquid into the inspection device using a dropping device described later. Near the center of the reaction detection part of the sensor chip 2 described later is disposed directly below the opening 10. The four holes 12 are provided to discharge the internal air that is pushed out in response to the dropping when the sample liquid is dropped from the opening 10. Therefore, the holes 12 may be called air holes. In the example of FIG. 1, four holes 12 are arranged, but the present invention is not limited to this, and the holes 12 may be absent, or the number of holes 12 may be from 1 to 3, or may be 5 or more.

[0010] A first auxiliary structure 14 is formed around the opening 10. The first auxiliary structure 14 is a structure that assists in guiding the sample liquid to the opening 10 using a dropping device, and will be described later with reference to FIG. 5. The label area 16 provided on the front surface of the inspection device 1 is an area for writing the inspection items to be inspected by the inspection device 1 and information such as the name of the provider (subject) who provided the specimen for specifying the provider. The sensor chip 2 is a chip for determining whether the measurement result of the detection target substance contained in the sample liquid is positive or negative. The sensor chip 2 is attached from the back surface of the inspection device 1 by an adhesive substance such as double-sided tape to form a reaction tank described later.

[0011] More specifically, an example of the sensor chip 2 according to the first embodiment will be described with reference to FIGS. 3A and 3B. FIG. 3A is a top view of the sensor chip 2, and FIG. 3B is a cross-sectional view when the sensor chip 2 is cut along the line B-B'. The sensor chip 2 includes a transparent substrate 20, an optical waveguide 22, a reaction detection unit 24 (also referred to as a detection area), a grating 26a, a grating 26b, and a non-reaction detection unit 28 (also referred to as a non-detection area).

[0012] The transparent substrate 20 has a structure for extracting light from the reaction detection unit 24. For example, it is formed of resin or optical glass. The transparent substrate 20 passes the incident light to the optical waveguide. In addition, the transparent substrate 20 passes the light that has passed through the optical waveguide 22 to the outside. Note that the transparent substrate is formed of a material having a refractive index different from that of the optical waveguide 22, and totally reflects light at the interface with the optical waveguide 22. That is, it serves as a cladding for confining light within the optical waveguide 22. In addition, the transparent substrate 20 physically protects the optical waveguide 22.

[0013] The optical waveguide 22 is laminated on the transparent substrate 20, and light passes through the inside. That is, the optical waveguide 22 serves the same role as the core (core material) in an optical fiber. It is formed of a material through which light can pass, for example, resin or optical glass. As the resin, for example, phenol resin, epoxy resin, or acrylic resin can be used. The reaction detection unit 24 is located in the center of the sensor chip 2 and is the region where the antibody is fixed (coated) to the upper surface of the optical waveguide 22. The reaction detection unit 24 also has a substance on its surface that binds to the substance to be detected. The surface of the reaction detection unit 24 may also be treated to be hydrophilic. Hydrophilicity refers to the property of having a contact angle with a liquid that is less than approximately 90 degrees, and when the liquid is water, it is also called hydrophilicity.

[0014] The grating 26a has a structure that reflects (diffracts) light and is positioned to direct light into the optical waveguide 22. The grating 26b has a structure that reflects (diffracts) light and is positioned to reflect light from within the optical waveguide 22 to the outside. The non-reaction detection section 28 is the portion of the upper surface of the optical waveguide 22 other than the reaction detection section 24, and is formed to make each reaction detection section 24 an independent region. That is, in the examples of Figures 3A and 3B, since there are two rows of reaction detection sections, the non-reaction detection section 28 is the region surrounding each row of reaction detection section 24. Furthermore, the non-reaction detection section 28 is formed to be hydrophobic (liquid-repellent). Liquid repellency refers to the property of having a contact angle with a liquid that is greater than approximately 90 degrees, and when the liquid is water, it is also called water repellency. Because the liquid is repelled in the region of the non-reaction detection section 28, the non-reaction detection section 28 plays the role of retaining the sample liquid in the reaction detection section 24, which is hydrophilic.

[0015] Furthermore, while the examples in Figures 3A and 3B assume the formation of two rows of reaction detection units 24, the reaction detection units 24 may consist of one row or three or more rows. The antibodies coated on the reaction detection units 24 may be different for each row or the same for each row. In particular, if three or more rows of reaction detection units 24 are formed, at least two rows may use the same antibody.

[0016] Next, Figure 4 shows an example of a dispensing device used to dispense the sample solution onto the inspection device 1. Figure 4 shows the cross-sectional shape of the tip of the dispensing device 40. The outer diameter 41 of the tip of the dispensing device 40 is designed to a predetermined size, such as 3.9 mm. In the example shown in Figure 4, the tip of the dispensing device 40 is designed to be tapered in order to make the droplet larger than the outer diameter 41 of the tip, but it is not limited to this and a general nozzle shape may also be used. The combination of the testing device 1 and the dispensing device 40 is also called a testing kit.

[0017] Next, a first design example of the inspection device 1 according to the first embodiment will be described with reference to Figure 5. Figure 5 is a cross-sectional view of the inspection device 1 when it is cut along the line A-A' in Figure 1. Note that in cases where the reaction detection unit 24 is arranged in two rows, the opening 10 may not be present in the cross-sectional view along line A-A'. However, for the sake of explanation, the opening 10 is shown in the cross-sectional view to indicate its position relative to the reaction detection unit 24 when viewed from the Y direction.

[0018] Figure 5 shows a transparent substrate 20, a housing 21, an optical waveguide 22, a reaction detection unit 24, gratings 26a and 26b, and a first auxiliary structure 14. The housing 21 is made of, for example, resin. The bottom surface of the housing 21 is open, and a sensor chip 2, on which the optical waveguide 22 is formed using thin-film technology, is fitted onto the transparent substrate 20 from the bottom side of the housing 21. In this way, the housing 21 and sensor chip 2 of the inspection device 1 form a reaction chamber 51. The top surface of the reaction chamber 51 is formed by the top surface of the housing 21, the sides are formed by the housing 21, and the bottom surface is formed by the top surface of the optical waveguide 22 including the reaction detection unit 24 (the front surface of the sensor chip 2). The inspection device 1 can contain a sample liquid inside, i.e., in the reaction chamber 51.

[0019] The size of the opening 10 is determined according to the outer diameter of the tip of the dispensing device 40. For example, the lower limit of the size of the opening 10 should be designed to be larger than the diameter of the sample liquid droplet dispensed from the dispensing device and larger than the outer diameter 41 of the tip of the dispensing device 40. The upper limit of the size of the opening should be appropriately determined from the outer diameter 41 of the tip of the dispensing device and the reaction detection state, because if the opening is too large, it may be affected by external light during reaction detection. For example, if the shape of the opening 10 is circular, a diameter of 3.0 to 7.0 mm, more preferably 4.0 to 6.0 mm (5.0 ± 1.0 mm), is preferable. Note that the shape of the opening 10 is not limited to a circle; any shape such as a triangle, a square, or other polygon, or a star shape is acceptable as long as it is larger than the diameter of the sample liquid droplet dispensed. If the shape of the opening 10 is not circular, it should have the same opening area as the circular case.

[0020] The distance between the inner wall side of the upper surface of the inspection device 1 (i.e., the top surface of the reaction vessel 51) and the reaction detection unit 24 (in other words, the height of the reaction vessel 51) is designed so that the inner wall side of the upper surface of the inspection device 1 and the reaction detection unit 24 are in close proximity. For example, this distance is designed to be approximately 1 ± 0.2 mm. This makes it possible to reduce the volume of the reaction vessel 51. Here, the volume of the reaction vessel 51 is the volume assuming that the opening 10 is closed by a plane at the same height as the top surface. For example, the volume of the reaction vessel 51 should be designed to be approximately the same as twice the volume of liquid droplets dispensed by the dropping device 40, or less than or equal to twice that volume. Specifically, the reaction vessel 51 should be designed to have a volume equivalent to, for example, one or two drops of sample liquid dispensed by the dropping device 40. That is, when the sample liquid is dispensed into the reaction vessel 51 from the opening 10 by the dropping device 40, the reaction vessel 51 will be filled with a small amount of liquid droplets (one or two drops of sample liquid). A filled state is, for example, a state in which the upper and lower surfaces of the reaction vessel 51 are in contact with the droplets. Furthermore, if the height of the reaction vessel 51 is too low, the droplets may not enter the reaction vessel 51, and if the height of the reaction vessel 51 is too high, the droplets may not spread properly to the reaction detection unit 24. Therefore, it is desirable that the height of the reaction vessel 51 be appropriately designed, for example, based on the above-mentioned 1 ± 0.2 mm, so that the reaction vessel 51 is filled with the sample liquid with a small amount of droplets.

[0021] The first auxiliary structure 14 protrudes from the surface of the housing 21 toward the outside of the housing 21 and is positioned around the opening 10. The first auxiliary structure 14 has a structure that guides or drops the sample liquid droplet toward the opening 10 even if the sample liquid droplet from the dropping device 40 is dropped outside the opening 10. For example, in the example of Figure 5, the first auxiliary structure 14 has a concave structure centered on the opening. Furthermore, because the first auxiliary structure 14 has a concave structure, even if the sample liquid is dropped to the point of overflowing from the reaction vessel 51, the concave structure of the first auxiliary structure 14 acts as a receptacle, and there is a high possibility that the sample liquid can be contained within the concave structure.

[0022] Next, a second design example of the inspection device 1 according to the first embodiment will be described with reference to Figure 6. The first auxiliary structure 14 in the second design example has a tapered shape that widens from the opening 10 toward the upper surface of the inspection device 1. This allows the sample liquid to be contained within the tapered shape of the first auxiliary structure 14 even if it overflows from the reaction vessel 51, and also makes it easier to drop droplets into the opening 10 compared to the first design example.

[0023] Next, a third design example of the inspection device 1 according to the first embodiment will be described with reference to Figure 7. In the third design example, in addition to the first auxiliary structure 14 related to the first design example shown in Figure 5, a second auxiliary structure 71 is arranged extending from the opening 10 toward the reaction vessel 51 to assist in guiding the droplet to the reaction detection unit 24. Specifically, the second auxiliary structure 71 is formed in a cylindrical shape extending from the opening 10 toward the reaction vessel 51. As a result, even when the sample liquid is dropped closer to the outer edge of the opening, the droplet falls along the second auxiliary structure 71, making it easier for the droplet to be guided to the reaction detection unit 24 within the reaction vessel 51.

[0024] Next, a fourth design example of the inspection device 1 according to the first embodiment will be described with reference to Figure 8. The fourth design example includes, in addition to the first auxiliary structure 14 related to the first design example shown in Figure 5, a third auxiliary structure 81 formed on the side of the hole 12 on the top surface of the reaction vessel 51 and protruding into the reaction vessel 51 from the top surface. In other words, it has a concave structure inward from the opening 10 towards the reaction vessel 51. The third auxiliary structure 81 helps to retain as much of the sample liquid as possible in the reaction detection unit 24 located on the lower surface of the reaction vessel 51.

[0025] Next, a fifth design example of the inspection device 1 according to the first embodiment will be described with reference to Figure 9. In the fifth design example, the third auxiliary structure 81 has a tapered shape, similar to the first auxiliary structure 14 shown in Figure 6. This tapered shape helps to retain as much of the sample liquid as possible in the reaction detection unit 24, similar to the fourth design example.

[0026] The first auxiliary structure 14, the second auxiliary structure 71, and the third auxiliary structure 81 may be formed by integral molding with the inspection device, or the auxiliary structures may be formed from synthetic resin or the like and then bonded to the inspection device 1. Furthermore, at least one of the first auxiliary structure 14 and the second auxiliary structure 71 may have a surface structure that suppresses the surface tension of the sample liquid droplets. For example, it may have at least one of a minute uneven structure and a hydrophilic structure. This prevents droplets from remaining on each auxiliary structure, allowing the auxiliary structure to guide the droplets more effectively to its intended destination.

[0027] Furthermore, the top surface of the reaction vessel 51 may also have a surface structure that suppresses the surface tension of the sample liquid droplets, such as at least one of a microscopic uneven surface and a hydrophilic structure. This similarly makes it easier for the liquid to wet and spread on the reaction vessel 51, that is, to spread in the xy-plane direction.

[0028] Next, the state transition of the droplet when the sample liquid is dropped into the reaction vessel 51 of the inspection device 1 will be explained with reference to the conceptual diagram in Figure 10. The left side of Figure 10 shows the situation immediately after the sample solution 101 has been dispensed using the dispensing device 40. Because the opening 10 of the inspection device 1 is larger than the outer diameter 41 of the tip of the dispensing device 40, the user can easily dispense the sample solution 101 into the opening 10. The central diagram of Figure 10 shows the state in which the sample liquid 101 is spread within the reaction vessel 51 after it has been dropped. Due to the hydrophilicity of the reaction detection unit 24 surface, and further due to capillary action caused by the thinness of the reaction vessel 51, the sample liquid 101 quickly wets and spreads across the entire surface of the reaction detection unit 24. The right-hand figure of Figure 10 shows the reaction vessel 51 filled with the sample solution 101. In this way, one drop dispensed from the dispensing device 40 is enough to fully fill the reaction vessel 51 with the sample solution 101.

[0029] According to the first embodiment described above, the opening of the inspection device is designed to be larger than the outer diameter of the tip of the dispensing device, and the volume of the reaction vessel formed by the housing of the inspection device and the sensor chip is designed to be large enough to be filled by a small amount of liquid droplet dispensed from the dispensing device, that is, approximately the same as or less than the volume of liquid in the droplet. Furthermore, the reaction detection part on the surface of the sensor chip is treated to be hydrophilic. As a result, by dispensing one or two drops of sample liquid from the opening, the sample liquid wets and spreads over the reaction detection part, filling the reaction vessel with the sample liquid. Consequently, the dispensing operation of the sample liquid by the dispensing device is only required once or twice, improving convenience. Moreover, since there is no need for other droplet guidance mechanisms, and a small amount of sample liquid can be quickly guided into the reaction vessel, the efficiency of inspection and analysis can be improved.

[0030] (Second embodiment) In the second embodiment, an inspection system for inspecting a sample solution using the inspection device according to the first embodiment will be described. A second embodiment of the inspection system will be described with reference to the block diagram in Figure 11. The inspection system includes an inspection device 1 according to the first embodiment and a measuring device 3. The inspection device 1 is detachable from the measuring device 3.

[0031] Here, multiple first antibodies are immobilized on the reaction detection unit 24 of the inspection device 1, or in other words, on the upper surface of the optical waveguide 22. The first antibodies are substances that react specifically with antigens contained in the substance to be detected through an antigen-antibody reaction.

[0032] Furthermore, it is assumed that the sample solution dropped onto the testing device 1 is a mixture of the sample solution and the reagent. The sample solution contains the target substance, including the antigen. The reagent contains reagent components. The reagent components include, for example, a secondary antibody that specifically reacts with the antigen through an antigen-antibody reaction, and magnetic particles on which the secondary antibody is immobilized. At least a portion of the magnetic particles are formed from a magnetic material such as magnetite. For example, the surface of the magnetic particles formed from the magnetic material is coated with a polymer material. The magnetic particles may also be configured such that the surface of particles composed of a polymer material is coated with a magnetic material. In addition, the magnetic particles may be replaced with anything that is dispersible in the sample solution.

[0033] The reagent components move in a dispersible manner within the sample solution filling the reaction vessel 51. Therefore, the magnetic particles are selected such that the gravitational force acting on them is greater than the buoyant force in the sample solution acting in the opposite direction to that gravity. The magnetic particles to which the second antibody is immobilized are fixed near the upper surface of the optical waveguide 22 by the binding of the second antibody to the first antibody via the antigen. The second antibody may be the same as or different from the first antibody.

[0034] The measuring device 3 includes a detection unit 31, a magnetic field generator 32, an output unit 33, an input interface circuit 34, a memory circuit 35, and a system control circuit 36.

[0035] The detection unit 31 includes a light source 311 and a photodetector 312. The light source 311 is a diode such as an LED (Light Emitting Diode) or a lamp such as a xenon lamp. The light source 311 is positioned so that light can be incident into the optical waveguide 22 toward the grating 26a of the inspection device 1. The light source 311 causes incident light L1 to enter the optical waveguide 22 through the transparent substrate 20 of the inspection device 1. The incident light L1 enters the optical waveguide 22 and is diffracted by the grating 26a. The incident light L1 diffracted by the grating 26a propagates through the optical waveguide 22 while undergoing total internal reflection and reaches the grating 26b. The light that reaches the grating 26b is diffracted by the grating 26b and is emitted from the optical waveguide 22 to the outside at a predetermined angle as emitted light L2. Note that a device that generates electromagnetic waves other than light may be used instead of the light source 311.

[0036] The photodetector 312 outputs an electrical signal based on the reaction state in the reaction vessel 51 containing the sample liquid. Specifically, the photodetector 312 detects the emitted light L2 that is emitted outside the optical waveguide 22 and generates an electrical signal indicating the intensity of the detected emitted light L2, i.e., digital data relating to the light detection intensity. The digital data relating to the light detection intensity generated by the photodetector 312 is supplied to the system control circuit 36.

[0037] The magnetic field generator 32 applies a magnetic field to the reaction vessel 51 of the testing device 1 in accordance with the control of the system control circuit 36, thereby promoting the reaction of the sample solution in the reaction vessel 51. The magnetic field generator 32 generates energy that promotes antigen-mediated binding between the second antibody, which is fixed to magnetic particles, and the first antibody, which is fixed to the upper surface of the optical waveguide 22. Specifically, the magnetic field generator 32 has an upper magnetic field generator and a lower magnetic field generator. The magnetic field generator 32 also has a drive circuit (not shown). The upper magnetic field generator and the lower magnetic field generator are composed of, for example, a permanent magnet and an electromagnet, respectively.

[0038] The output unit 33 includes a display circuit 331, an alarm 332, and a printer 333. The display circuit 331 outputs data to a general external display device, such as a liquid crystal display or an OLED (organic LED) display. The display circuit 331 displays various operation screens, information indicating the light intensity of the emitted light L2 supplied from the photodetector 312, time-series data of the light intensity information, and measurement results of the detected substance, etc., according to the control of the system control circuit 36. The measurement results are, for example, the concentration, weight, or number of antigens. The alarm 332 is, for example, a speaker. Under the control of the system control circuit 36, the alarm 332 notifies the operator of the determination result of the detected substance, etc. Under the control of the system control circuit 36, the printer 333 prints various operation screens output from the display circuit 331, information indicating the light intensity of the emitted light L2 supplied from the photodetector 312, time-series data of the light intensity information, and measurement results of the detected substance.

[0039] The input interface circuit 34 can be implemented by, for example, a trackball, a switch button, a mouse, a keyboard, a touchpad that allows input operations by touching the operating surface, or a touch panel display that integrates a display screen and a touchpad. The input interface circuit 34 outputs an operation input signal corresponding to the operator's operation to the system control circuit 36. In this embodiment, the input interface circuit 34 is not limited to those equipped with physical operating components such as a mouse or keyboard. For example, an electrical signal processing circuit that receives an electrical signal corresponding to an input operation from an external input device provided separately from the device and outputs this electrical signal to the system control circuit 36 ​​is also included as an example of an input interface circuit.

[0040] The memory circuit 35 has a recording medium that can be read by the processor, such as a magnetic or optical recording medium or a semiconductor memory. The memory circuit 35 stores a program that is executed by the circuit of the measuring device 3 according to this embodiment. Note that some or all of the program and data in the storage medium of the memory circuit 35 may be configured to be downloaded via an electronic network.

[0041] The memory circuit 35 stores information indicating the light intensity of the emitted light L2 supplied from the photodetector 312, time-series data of the light intensity information, and measurement results of the target substance to be measured.

[0042] The memory circuit 35 is, for example, a storage medium such as an HDD or SSD, and stores setting information for measuring the substance to be detected. The setting information includes, for example, information that defines the timing for executing predetermined processes necessary for measurement. The timing for executing predetermined processes necessary for measurement is, for example, the timing when the application of the lower magnetic field is started, the timing when the application of the lower magnetic field is stopped, the timing when the application of the upper magnetic field is started, and the timing when the judgment is performed. The information that defines these timings includes the relative elapsed time from a predetermined time or the absolute time for executing the predetermined process. The relative elapsed time from a predetermined time or the absolute time for executing the predetermined process may be obtained in advance empirically or experimentally.

[0043] The memory circuit 35 has a preset threshold T A It remembers the threshold T. A This is the threshold value for light intensity corresponding to the concentration of the substance to be detected. Threshold T A This is used to determine the qualitative state of the substance being detected. The qualitative state refers to, for example, the degree of positive or negative result indicated by the measurement. Threshold T A This is used to make a final determination of whether the measurement result of the substance being detected is likely to be positive. A The threshold can be one of several steps. In other words, by comparing the light intensity contained in the digital data with multiple steps of thresholds, it becomes possible to make judgments that represent more detailed measurement results.

[0044] The system control circuit 36 ​​is, for example, a processor that controls each component circuit of the measuring device 3. The system control circuit 36 ​​functions as the central hub of the measuring device 3. The system control circuit 36 ​​recalls each operation program from the memory circuit 35 and executes the recalled program to realize the light source control function 361, the magnetic field control function 362, the calculation function 363, the judgment function 364, and the output control function 365.

[0045] The light source control function 361 controls the light source 311 and generates light under predetermined conditions. In the light source control function 361, the system control circuit 36 ​​generates incident light L1 from the light source 311 continuously or intermittently, at least from the start of measurement to the end of measurement.

[0046] The magnetic field control function 362 controls the magnetic field generator 32 according to a time schedule pre-stored in the memory circuit 35, and switches the energy application state to promote the reaction in the reaction vessel 51. Specifically, in the magnetic field control function 362, the system control circuit 36 ​​reads setting information from the memory circuit 35, controls the magnetic field generator 32 based on the read setting information, and generates a magnetic field in the magnetic field generator 32.

[0047] The calculation function 363 performs various calculations based on the time-series digital data of light intensity supplied from the photodetector 312. In the calculation function 363, the system control circuit 36 ​​uses the supplied time-series digital data of light intensity to perform calculations such as the average value of light intensity, the rate of change of light intensity, and the integrated value of the rate of change.

[0048] The determination function 364 determines the qualitative state of the substance to be detected based on digital data of light intensity supplied from the photodetector 312 while the upper magnetic field described later is applied. In the determination function 364, the system control circuit 36 ​​receives setting information and threshold T from the memory circuit 35. A The system control circuit 36 ​​reads out the settings information. The system control circuit 36 ​​determines the qualitative state of the target substance in accordance with the execution timing included in the read-out settings information. The system control circuit 36 ​​determines that the light intensity included in the supplied time-series digital data of light intensity is the threshold T A If the following conditions are met, for example, the measurement result of the substance to be detected is likely to be positive. The system control circuit 36 ​​determines that the light intensity contained in the digital data is at threshold T A If the result is larger, for example, the measurement result for the detected substance is likely to be weakly positive or negative.

[0049] The output control function 365 controls the output unit 33 and outputs the determination result, such as the qualitative state of the substance to be detected, to the operator. In the output control function 365, the system control circuit 36 ​​controls the display circuit 331 or the printer 333 to present the determination result to the operator. Presentation includes displaying via a display and printing using a printer. The system control circuit 36 ​​controls the alarm 332 to notify the operator of the determination result. Notification includes notifying by sound or other means.

[0050] Next, an example of specimen testing using the testing system according to the second embodiment will be described with reference to the flowchart in Figure 12. In step S1, the inspection device 1 is set in the measuring device 3, and the sample liquid is dispensed by the dispensing device 40. As a result, the reaction vessel 51 is filled with the sample liquid. At the time the sample liquid is dispensed into the opening 10 of the inspection device 1, a downward magnetic field may be applied by the magnetic field generator 32. Alternatively, the magnetic field may be fluctuated by intermittently applying an upward or downward magnetic field alternately or randomly using the magnetic field generator 32. By applying a magnetic field in this way, the droplets are encouraged to fall into the reaction vessel 51, and the time until the sample liquid is filled can be shortened.

[0051] Furthermore, whether or not the sample solution is filled in the reaction tank 51 can be determined, for example, by whether or not the sample solution is filled up to the hole 12 of the inspection device 1. In other words, if the sample solution is filled up to the position of the hole 12 of the inspection device 1, it can be determined that the sample solution is filled in the reaction tank 51, and if the sample solution is not filled up to the position of the hole 12, it can be determined that the sample solution is not filled in the reaction tank 51. Therefore, the system control circuit 36 ​​may use the determination function 364 to determine whether or not the sample solution is filled up to the position of the hole 12 using image information obtained from an imaging device such as a camera, or distance information obtained from a distance measuring device such as a laser, and if it is determined that the sample solution is not filled in the reaction tank 51, it may notify the user to drop additional sample solution. Alternatively, if a dropping device 40 can also be set in the measuring device 3, the system control circuit 36 ​​may, for example, control the system to automatically drop additional sample solution into the opening 10.

[0052] In step S2, a constant intensity of light is irradiated from the light source 311 of the detection unit 31 toward the optical waveguide 22 of the inspection device 1, thereby causing a constant intensity of light to enter the optical waveguide 22. The constant intensity of light is continuously incident from the light source 311. The magnetic field generator 32 begins applying the lower magnetic field. Light incident on the optical waveguide 22 propagates through the optical waveguide 22 while undergoing total internal reflection, and is emitted to the photodetector 312 via the transparent substrate 20.

[0053] When light propagates through the optical waveguide 22, near-field light (evanescent light) is generated on the upper surface of the optical waveguide 22. The region near the surface of the optical waveguide 22 in the reaction vessel 51 where near-field light can be generated is also called the sensing region. In the reaction vessel 51, the first antibody, fixed to the upper surface of the optical waveguide 22, reacts with the antigen contained in the target substance in the sample solution. The reaction between the first antibody and the antigen also causes the second antibody, which is immobilized on magnetic particles contained in the reagent components, to bind. As a result, magnetic particles with the second antibody immobilized on them are held near the reaction detection section 24 on the upper surface of the optical waveguide 22.

[0054] The light guiding through the optical waveguide 22 is scattered and absorbed by magnetic particles fixed near the upper surface of the optical waveguide 22. As a result, the light guiding through the optical waveguide 22 is attenuated and emitted from the optical waveguide 22. In other words, the incident light L1 is attenuated according to the amount of antigen that binds the first antibody and the second antibody immobilized on the magnetic particles, or in other words, the amount of antigen contained in the reaction vessel 51. The photodetector 312 receives light emitted from the optical waveguide 22 and supplies light intensity data to the system control circuit 36 ​​at predetermined time intervals.

[0055] In step S3, the magnetic field generator 32 begins applying a downward magnetic field according to the control of the system control circuit 36. Specifically, the downward magnetic field generator, located below the inspection device 1, uniformly generates a vertically downward magnetic field horizontally, which is the energy that promotes the reaction in the reaction vessel 51. According to the generated vertically downward magnetic field and gravity, the magnetic particles to which the second antibody is immobilized align along the magnetic field lines and descend under the vertically downward force. The second antibody binds to the first antibody, which is immobilized in the reaction detection unit 24 located on the lower surface of the reaction vessel 51, via the light source.

[0056] In step S4, the magnetic field generator 32 stops applying the lower magnetic field at a predetermined timing in accordance with the control from the system control circuit 36. In step S5, the magnetic field generator 32 starts applying the upper magnetic field according to the control from the system control circuit 36. Specifically, when the inspection device is set in the measuring device 3, the upper magnetic field generator is located above the inspection device 1. The upper magnetic field generator uniformly generates a vertically upward magnetic field in the horizontal direction in the reaction tank 51. Due to the generated vertically upward magnetic field, the magnetic particles immobilized with the second antibody receive a vertically upward force and rise. At this time, the upper magnetic field generator selectively moves the magnetic particles immobilized with the second antibody away from the sensing region by generating a magnetic field of a predetermined strength. That is, the upper magnetic field generator can retain only the magnetic particles immobilized with the second antibody that bind via the first antibody and the antigen and are fixed to the upper surface of the optical waveguide 22 in the sensing region by adjusting the strength of the generated magnetic field.

[0057] In step S6, at a timing when it is considered that the reaction in the reaction tank 51 has converged, the system control circuit 36 acquires one value of the light intensity data continuously supplied from the photodetector 312 as a measured value. In step S7, the system control circuit 36 compares the measured value obtained in step S7 with the threshold value T stored in the storage circuit 35 by the determination function 364 A to determine, for example, positive or negative. In step S8, the system control circuit 36 presents or notifies the determination result to the user by the output control function 365.

[0058] Next, an example of the time-series change of the light intensity of the emitted light will be described with reference to FIG. 13. FIG. 13 is a graph C of the time-series change of the light intensity, where the vertical axis represents the light intensity and the horizontal axis represents the time. When the sample liquid is dropped onto the reaction tank 51 of the inspection device 1 and the reaction tank 51 is filled with the sample liquid, the measured light intensity increases. This is because the water-soluble film attached to the upper surface of the optical waveguide including the reaction detection part dissolves.

[0059] Subsequently, when a lower magnetic field is applied, as described above, the magnetic particles to which the second antibody is immobilized in the sample solution of the reaction vessel 51 bind to the first antibody immobilized on the reaction detection unit 24 via the light source. Also, as the magnetic particles to which the second antibody is immobilized successively enter the sensing region, the light intensity decreases. The rate of decrease in light intensity decreases over time, and a certain light intensity value, in this case A, is reached. 01 It converges to [a certain point].

[0060] Subsequently, when the application of the lower magnetic field is stopped, the magnetic particles to which the second antibody is immobilized are released by the lower magnetic field and begin to settle naturally. For a predetermined period after the application of the lower magnetic field is stopped, a so-called overshoot occurs, where the light intensity increases and then decreases rapidly. Once the overshoot subsides, the light intensity decreases. This is because the rate of decrease increases as the magnetic particles to which the second antibody is immobilized successively enter the sensing region. After a certain period, the natural settling of the magnetic particles to which the second antibody is immobilized also subsides, reaching a certain light intensity value, in this case, light intensity value A. 03 It converges to [a certain point].

[0061] Light intensity value A 03 In the converged state, the magnetic particles immobilized with the second antibody remain in the sensing region. When near-field light is generated on the upper surface of the optical waveguide 22 while the magnetic particles remain in the sensing region, the magnetic particles remaining in the sensing region scatter and absorb this near-field light, attenuating it. In other words, the attenuation of the near-field light in the sensing region also attenuates the light guided within the optical waveguide 22. To put it another way, the more magnetic particles remain in the reaction vessel 51, the lower the intensity of the light output from the optical waveguide 22.

[0062] However, the magnetic particles remaining in the reaction vessel 51 are not limited to those to which the first antibody, fixed to the upper surface of the optical waveguide 22 via the antigen being measured, and the second antibody, immobilized on the magnetic particles, have bound. Therefore, in order to accurately measure the concentration of the antigen contained in the substance to be detected, it is necessary to move away from the reaction vessel 51 magnetic particles to which the second antibody, which is not involved in the measurement and is not bound to the antigen, has been immobilized. Thus, by applying an upper magnetic field, the magnetic particles to which the second antibody, which were not aligned, have been immobilized can be moved away from the sensing region and allowed to float again in the reaction vessel 51. As a result, the magnetic particles that ultimately remain in the sensing region are those to which the first antibody, fixed to the upper surface of the optical waveguide 22 via the antigen, and the second antibody are bound, and a certain light intensity value, in this case light intensity value A 02 It converges to [a certain point].

[0063] According to the second embodiment described above, the inspection system using the inspection device according to the first embodiment can perform inspection of the target substance even with a minute sample liquid.

[0064] In the above description, the term "processor" refers to circuits such as a CPU (Central Processing Unit), a GPU (Graphics Processing Unit), an Application Specific Integrated Circuit (ASIC), or a programmable logic device (e.g., a Simple Programmable Logic Device (SPLD), a Complex Programmable Logic Device (CPLD), and a Field Programmable Gate Array (FPGA)). When the processor is a CPU, for example, it performs its functions by reading and executing a program stored in a memory circuit. On the other hand, when the processor is an ASIC, for example, instead of the program being stored in a memory circuit, the function is directly incorporated as a logic circuit within the processor's circuit. In this embodiment, each processor is not limited to being configured as a single circuit; multiple independent circuits may be combined to form a single processor and perform its functions. Furthermore, multiple components shown in the figure may be integrated into a single processor to perform its functions.

[0065] According to at least one embodiment described above, the convenience and efficiency of the inspection can be improved.

[0066] While several embodiments have been described, these embodiments are presented as examples only and are not intended to limit the scope of the invention. These embodiments can be implemented in a variety of other forms, and various omissions, substitutions, modifications, and combinations of embodiments can be made without departing from the spirit of the invention. These embodiments and their variations are included in the scope and spirit of the invention, as well as in the claims and their equivalents. [Explanation of symbols]

[0067] 1. Inspection device 2 Sensor chips 3. Measuring device 10 aperture 12 holes 14 1st auxiliary structure 16 Label area 20 Transparent substrates 21 cabinets 22 Optical waveguide 24 Reaction detection unit 26a, 26b Grating 28 Non-reaction detection unit 31 detection unit 32 Magnetic field generator 33 Output Units 34 Input Interface Circuit 35 Memory circuit 36 System Control Circuits 40 Droplet dispensing devices 41 Tip outer diameter 51 Reaction vessel 71 Second auxiliary structure 81 Third auxiliary structure 311 Light source 312 Photodetector 331 Display circuit 332 Alarm 333 Printer 361 Light source control function 362 Magnetic field control function 363 arithmetic functions 364 Judgment Function 365 Output control function

Claims

1. A reaction vessel having a top surface and an opening formed in the top surface, A reaction detection unit is located below the opening in the reaction vessel and has a substance on its surface that binds to the substance to be detected. It is equipped with, The reaction detection unit has a surface that is hydrophilic, The height of the reaction vessel is designed such that the distance between the top surface and the reaction detection unit is 1 ± 0.2 mm. Inspection device.

2. The reaction vessel becomes filled with the droplet when a droplet is dropped into the reaction vessel. The inspection device according to claim 1.

3. The inspection device according to claim 2, wherein the filled state is a state in which the upper and lower surfaces of the reaction vessel are in contact with the droplets.

4. The reaction detection unit includes a plurality of detection regions, Each of the plurality of detection regions contains an antibody for measuring whether or not the droplet contains the substance to be detected. The inspection device according to any one of claims 1 to 3.

5. The reaction detection unit further includes a hydrophobic non-detection region formed such that each of the plurality of detection regions is an independent region. The inspection device according to claim 4.

6. The diameter of the opening is 3.0 mm to 7.0 mm. The inspection device according to any one of claims 1 to 5.

7. The diameter of the opening is 4.0 mm to 6.0 mm. The inspection device according to any one of claims 1 to 5.

8. The opening is formed in a position where a droplet is dropped near the center of the reaction detection unit. The inspection device according to any one of claims 1 to 7.

9. The device further comprises a first auxiliary structure that protrudes outward from the surface of the housing and is positioned around the opening, assisting in guiding droplets into the opening. The inspection device according to any one of claims 1 to 8.

10. The system further comprises a second auxiliary structure positioned toward the reaction vessel from the opening, which assists in guiding the droplet to the reaction detection unit. The inspection device according to any one of claims 1 to 9.

11. The system further comprises a third auxiliary structure that protrudes from the top surface toward the inside of the reaction vessel. The inspection device according to any one of claims 1 to 10.

12. At least one of the first auxiliary structure and the third auxiliary structure includes a concave structure centered on the opening. The inspection device according to claim 9 or claim 11.

13. At least one of the first auxiliary structure and the second auxiliary structure has a surface structure that suppresses the surface tension of the droplet. The inspection device according to claim 9 or claim 10.

14. The surface structure includes at least one of a micro-uneven structure and a hydrophilic structure. The inspection device according to claim 13.

15. The top surface has at least one of a micro-uneven structure and / or hydrophilicity. The inspection device according to any one of claims 1 to 14.

16. The droplets in the reaction vessel spread to the surface due to their hydrophilic nature and capillary action due to their height. The inspection device according to any one of claims 1 to 15.

17. An inspection device according to any one of claims 1 to 16, A dropping device for dropping a liquid droplet into the opening of the inspection device, A test kit equipped with the following.

18. An inspection system comprising an inspection device according to any one of claims 1 to 16 and a measuring device, The aforementioned inspection device, The apparatus further includes a first grating through which light is incident, using a region filled with droplets inside the reaction vessel as an optical waveguide, and a second grating through which light transmitted through the optical waveguide is emitted to the outside. The measuring device is, Light source and A light detection unit that receives light from the second grating, The system includes a detection unit that, in accordance with the detection intensity of light received by the light detection unit, detects as an optical change the reaction between the target substance contained in the droplet in the reaction vessel and the substance having a reaction detection unit, and generates a measurement result for the target substance. Inspection system.

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