JP2021196172A - Specimen inspection device - Google Patents

Abstract

To improve the accuracy of measurement.SOLUTION: A specimen inspection device according to an embodiment comprises: an optical waveguide; a magnetic field generator; a light source; a photodetector; and a detection unit. The optical waveguide has a sensing area in which a first substance is immobilized which is specifically joined to a measurement target substance. The magnetic field generator generates a magnetic field that moves magnetic fine particles to which a second substance is joined which is specifically joined to the measurement target substance. The light source makes light incident on the optical waveguide. The photodetector detects light emitted from or reflected by the optical waveguide. The detection unit detects a shortage of the magnetic particles based on a light signal detected by the photodetector.SELECTED DRAWING: Figure 1

Description

The embodiments disclosed in this specification and drawings relate to a sample testing apparatus.

Techniques for measuring test substances are known. For example, in the above technique, particles non-specifically adsorbed on the surface of an optical waveguide are removed by applying a magnetic field using magnetic particles and an optical waveguide on which an antibody or the like specifically bound to a test substance is immobilized. do. Thereby, for example, the antigen concentration or the like can be measured as the amount of the test substance. However, in the above technique, if the concentration of the magnetic particles is insufficient, it may affect the measurement of the test substance. For example, as a result of measuring the test substance, it may be erroneously determined that there is a high possibility of being positive.

Japanese Unexamined Patent Publication No. 2012-215553

One of the problems to be solved by the embodiments disclosed in the present specification and the drawings is to improve the measurement accuracy. However, the problems solved by the embodiments disclosed in the present specification and the drawings are not limited to the above problems. The problem corresponding to each effect by each configuration shown in the embodiment described later can be positioned as another problem.

The sample inspection device according to the embodiment includes an optical waveguide, a magnetic field generator, a light source, a photodetector, and a detection unit. The optical waveguide has a sensing area in which a first substance that specifically binds to the substance to be measured is immobilized. The magnetic field generator generates a magnetic field for moving magnetic fine particles to which a second substance specifically bound to the substance to be measured is bound. The light source causes light to enter the optical waveguide. The photodetector detects light emitted or reflected from the optical waveguide. The detection unit detects the shortage of the magnetic particles based on the optical signal detected by the photodetector.

FIG. 1 is a block diagram showing an example of the configuration of the sample inspection device according to the present embodiment. FIG. 2 is a diagram showing an example of the configuration of the reaction unit shown in FIG. FIG. 3 is a graph showing an example of time-series changes in the light intensity of the emitted light. FIG. 4 is an explanatory diagram when the mixed solution is not accurately injected into the reaction vessel. FIG. 5 is an explanatory diagram of processing by the sample inspection device according to the present embodiment. FIG. 6A is a flowchart showing a procedure of processing by the sample inspection device according to the present embodiment. FIG. 6B is a flowchart showing a procedure of processing by the sample inspection device according to the present embodiment. FIG. 7 is an explanatory diagram of processing by the sample inspection device according to the modified example of the present embodiment. FIG. 8 is a flowchart showing a procedure of processing by the sample inspection device according to the modified example of the present embodiment.

Hereinafter, embodiments of the sample testing apparatus will be described in detail with reference to the attached drawings. The embodiment is not limited to the following embodiments. Further, in principle, the contents described in one embodiment are similarly applied to other embodiments.

FIG. 1 is a block diagram showing an example of the configuration of the sample inspection device 1 according to the present embodiment. FIG. 2 is a diagram showing an example of the configuration of the reaction unit 2 shown in FIG. As shown in FIG. 1, the sample inspection device 1 includes a reaction unit 2 and a measurement system 3. The reaction unit 2 is removable from the sample inspection device 1.

First, the reaction unit 2 will be described with reference to FIG.

As shown in FIG. 2, the reaction unit 2 has a housing 21, a transparent substrate 22, an optical waveguide 23, and a protective member 24. A part of the lower surface of the housing 21 is open, and a chip in which the optical waveguide 23 and the protective member 24 are formed by thin film technology is fitted on the transparent substrate 22 in the opening. A part of the protective member 24 is open (open end 24a). Further, the reaction vessel 201 is formed by the housing 21, the optical waveguide 23, the protective member 24, and the like. The reaction unit 2 is configured to accommodate a sample solution containing a test object (test substance) inside the reaction unit 2, that is, in the reaction vessel 201.

The housing 21 is made of, for example, resin. A first recess is formed on the lower surface of the housing 21. A second recess constituting the upper surface and the side surface of the reaction vessel 201 is formed in a part of the upper surface of the first recess. A protective member 24, an optical waveguide 23, and a transparent substrate 22 are arranged in the first recess in order from the top. Further, a hole 21a for introducing a sample solution, a reagent, etc. is formed in the reaction vessel 201 inside the housing 21 so as to penetrate upward near one end of the upper surface of the second recess, and near the other end. A hole 21b is formed so as to penetrate the housing 21 upward and allow air to escape from the reaction vessel 201. A plurality of holes 21a and 21b may be formed.

The transparent substrate 22 is made of, for example, resin or optical glass. The transparent substrate 22 allows light incident from the light source 311 provided in the measurement system 3 to pass through the optical waveguide 23. Further, the transparent substrate 22 passes the light incident from the optical waveguide 23 to the photodetector 312 provided in the measurement system 3.

The optical waveguide 23 is formed of a material that allows light to pass through, such as resin or optical glass. As the resin, for example, a phenol resin, an epoxy resin, an acrylic resin, or the like can be used. The optical waveguide 23 is an optical path for light incident from the transparent substrate 22 and emitted to the transparent substrate 22. That is, the optical waveguide 23 fulfills the same role and function as the core (core material) in the optical fiber. The protective member 24 and the transparent substrate 22 are formed of a material having a refractive index different from that of the optical waveguide 23, totally reflect light at the interface with the optical waveguide 23, and confine the light in the optical waveguide 23. It functions as a clad. Further, the protective member 24 and the transparent substrate 22 physically protect the optical waveguide 23.

The optical waveguide 23 propagates the light incident from the measurement system 3 through the transparent substrate 22. In the optical waveguide 23, light affected by the concentration of the test substance contained in the reaction vessel 201, that is, the reaction state is propagated.

Further, a grating 23a is arranged on the protective member 24 side in the vicinity where light is incident on the optical waveguide 23. The grating 23a diffracts the incident light L1 incident on the optical waveguide 23 at a predetermined angle. The light diffracted in the grating 23a is incident on the interface between the optical waveguide 23 and the surface composed of the transparent substrate 22, the protective member 24, or the mixed solution 202 at an angle equal to or less than the supplementary angle of the critical angle. As a result, the incident light L1 propagates (waveguides) while being repeatedly reflected in the optical waveguide 23 at the interface of the optical waveguide 23.

A grating 23b is arranged on the protective member 24 side in the vicinity where light is emitted from the optical waveguide 23. The grating 23b diffracts the light optical waveguided by the optical waveguide 23 at a predetermined angle. The light diffracted by the grating 23b is emitted from the optical waveguide 23 to the outside at a predetermined angle.

The protective member 24 has an opening at the position of the second recess of the housing 21. The protective member 24 is arranged in close contact with the upper surface of the optical waveguide 23. The protective member 24 is arranged in close contact with the upper surface of the optical waveguide 23 to form a planar protective layer. Further, as shown in FIG. 2, the protective member 24 has an open end 24a for exposing the main surface (for example, the upper surface) of the optical waveguide 23. The opening end 24a is a vertical surface that forms an opening inside the protective member 24. The upper surface of the optical waveguide 23 is exposed by the open end 24a.

The upper surface of the reaction vessel 201 is composed of the upper surface of the second recess of the housing 21, the side surface is composed of the side surface of the second recess of the housing 21 and the open end 24a of the protective member 24, and the lower surface is the optical waveguide 23. It is composed of the upper surface of.

The reaction vessel 201 contains the sample solution and the reagent, and reacts the test substance contained in the sample solution with the reagent. A plurality of first antibodies 211 are immobilized on the lower surface of the surface forming the reaction vessel 201, that is, the upper surface of the optical waveguide 23. The first antibody 211 is a substance that specifically reacts with the antigen 212 contained in the test substance by an antigen-antibody reaction. The first antibody 211 is fixed to the upper surface of the optical waveguide 23, for example, by a hydrophobic interaction or a chemical bond that occurs with the upper surface of the optical waveguide 23. The first antibody 211 is an example of the “first substance”.

The reaction vessel 201 is, for example, empty in advance. At the time of measuring the test substance, for example, the mixed solution 202 of the sample solution and the reagent is injected into the reaction vessel 201 from the outside through the hole 21a. The sample solution contains a test substance containing the antigen 212. The reagent contains reagent component 213. The reagent component 213 includes, for example, a second antibody 214 that specifically reacts with the antigen 212 by an antigen-antibody reaction, and magnetic particles 215 to which the second antibody 214 is bound. At least a part of the magnetic particles 215 is made of a magnetic material such as magnetite. In the magnetic particles 215, for example, the surface of particles formed of a magnetic material is coated with a polymer material. The magnetic particles 215 may be configured to cover the surface of the particles made of a polymer material with a magnetic material. Further, the magnetic particles 215 may be replaced with any magnetic particles 215 as long as they are configured to be dispersible in the mixed liquid 202. The second antibody 214 is an example of a “second substance”.

By injecting the mixed solution 202, the reaction vessel 201 is filled with the antigen 212 contained in the test substance in the sample solution and the reagent contained in the reagent, in addition to the first antibody 211 immobilized on the upper surface of the optical waveguide 23. Ingredients 213 are housed. When the mixed solution 202 is injected into the reaction vessel 201, the air in the reaction vessel 201 is discharged to the outside through the hole 21b.

The reagent component 213 moves in a dispersible manner in the mixed solution 202 filled in the reaction vessel 201. At this time, the magnetic particles 215 are selected so that the gravity applied to the magnetic particles 215 is larger than the buoyancy in the mixed liquid 202 applied in the direction opposite to the gravity. The magnetic particles 215 to which the second antibody 214 is bound are fixed near the upper surface of the optical waveguide 23 by binding the second antibody 214 to the first antibody 211 via the antigen 212. The second antibody 214 may be the same as or different from the first antibody 211.

In the reaction unit 2, the first antibody 211 fixed on the upper surface of the optical waveguide 23 reacts with the antigen 212 contained in the test substance, so that the magnetic particles 215 to which the second antibody 214 is bound are formed on the upper surface of the optical waveguide 23. Fixed in the vicinity. The light guided through the optical waveguide 23 is scattered and absorbed by the magnetic particles 215 fixed in the vicinity of the upper surface of the optical waveguide 23. As a result, the light guided through the optical waveguide 23 is attenuated and emitted from the optical waveguide 23. That is, the incident light L1 is attenuated according to the amount of the antigen 212 that binds the first antibody 211 and the second antibody 214 immobilized on the magnetic particles 215. In other words, the incident light L1 is attenuated according to the amount of the antigen 212 contained in the reaction vessel 201.

Hereinafter, in the reaction vessel 201, a region separated by a distance L in the vertical upward direction from the surface of the optical waveguide 23, that is, a region extending to the vicinity of the surface of the optical waveguide 23 is defined as a sensing area 205.

When light propagates in the optical waveguide 23, near-field light (hereinafter referred to as evanescent light) is generated on the upper surface of the optical waveguide 23. The sensing area 205 is an area where evanescent light can be generated. In the sensing area 205, the first antibody 211 immobilized on the upper surface of the optical waveguide 23 is immobilized on the magnetic particles 215 contained in the reagent component 213 via the antigen 212 contained in the test substance in the sample solution. 2 Binds to antibody 214. As a result, the magnetic particles 215 to which the second antibody 214 is bound are held in the vicinity of the upper surface of the optical waveguide 23.

Next, the influence of the light propagating on the optical waveguide 23 due to the antigen-antibody reaction or the like occurring in the reaction vessel 201 will be described. The first antibody 211, the second antibody 214, and the antigen 212 are very small as compared with the magnetic particles 215. In FIG. 2, in order to schematically show the binding reaction, the first antibody 211, the antigen 212, the second antibody 214, and the magnetic particles 215 are shown as having the same size.

When the magnetic particles 215 enter the sensing area 205, the second antibody 214 immobilized on the magnetic particles 215 binds to the first antibody 211 immobilized on the upper surface of the optical waveguide 23 via the antigen 212. As a result, the magnetic particles 215 to which the second antibody 214 is bound remain in the sensing area 205. When evanescent light is generated on the upper surface of the optical waveguide 23 while the magnetic particles 215 remain in the sensing area 205, the magnetic particles 215 remaining in the sensing area 205 scatter and absorb the evanescent light, and attenuate the evanescent light. .. Scattering and absorption of evanescent light in the sensing area 205 affect the light propagating in the optical waveguide 23. That is, as the evanescent light is attenuated in the sensing area 205, the light optical waveguided in the optical waveguide 23 is also attenuated. Therefore, when the evanescent light is strongly scattered and absorbed in the sensing area 205, the intensity of the light propagating in the optical waveguide 23 decreases. In other words, the larger the amount of magnetic particles 215 that stays in the sensing area 205, the lower the intensity of the light output from the optical waveguide 23.

However, the magnetic particles 215 that remain in the sensing area 205 include the first antibody 211 immobilized on the upper surface of the optical waveguide 23 via the antigen 212 to be measured, and the second antibody 214 immobilized on the magnetic particles 215. Is not limited to the combined one. Therefore, in order to measure the accurate concentration of the antigen 212 contained in the test substance, the magnetic particles 215 to which the second antibody 214 that is not involved in the measurement, that is, not bound to the antigen 212, is bound is measured in the sensing area 205. You need to stay away from it. As a specific method, for example, there is a method of moving the magnetic particles 215 in which the second antibody 214 is not bound to the antigen 212 by the proximity action by a magnetic field.

As a result, the magnetic particles 215 that finally stay in the sensing area 205 are bound to the first antibody 211 fixed on the upper surface of the optical waveguide 23 via the antigen 212 and the second antibody 214. Therefore, the value of the intensity of the light emitted from the reaction unit 2 and the time-series change in the intensity correspond to the amount and concentration of the magnetic particles 215 remaining in the sensing area 205.

The reaction unit 2 may be configured to be capable of simultaneously measuring the same test substance on a plurality of channels in parallel for the same measurement item. At this time, the reaction unit 2 has, for example, an independent optical waveguide for each channel.

Next, the measurement system 3 will be described with reference to FIG.

As shown in FIG. 1, the measurement system 3 includes a detection unit 31, a magnetic field generator 32, an output unit 33, an input interface circuit 34, a storage circuit 35, and a processing circuit 36.

The detection unit 31 has a light source 311 and a photodetector 312.

The light source 311 is, for example, a diode such as an LED (Light Emitting Diode) or a lamp such as a xenon lamp. The light source 311 is arranged at a position where light can be incident in the optical waveguide 23 toward the grating 23a. The light source 311 incidents the incident light L1 into the optical waveguide 23 via the transparent substrate 22 of the reaction unit 2. The incident light L1 enters the optical waveguide 23 and is diffracted by the grating 23a. The incident light L1 diffracted by the grating 23a propagates while being totally reflected in the optical waveguide 23 and reaches the grating 23b. The light that has reached the grating 23b is diffracted by the grating 23b and is emitted from the optical waveguide 23 to the outside as emitted light L2 at a predetermined angle. Instead of the light source 311, a light source that generates electromagnetic waves other than light may be used.

The photodetector 312 outputs an electrical signal based on the reaction state in the reaction vessel 201 containing the mixture 202. Specifically, the photodetector 312 detects the emitted light L2 emitted to the outside of the optical waveguide 23, and generates an electric signal indicating the intensity of the detected emitted light L2, that is, digital data regarding the optical detection intensity. .. Digital data regarding the photodetection intensity generated by the photodetector 312 is supplied to the processing circuit 36.

The detection unit 31 may be configured to be capable of simultaneously measuring the same test substance on a plurality of channels in parallel for the same measurement item. At this time, the detection unit 31 may have a light source and a photodetector for each channel, for example, or may share the light source and the photodetector.

The magnetic field generator 32 promotes the reaction in the reaction vessel 201, that is, the binding of the second antibody 214 immobilized on the magnetic particles 215 and the first antibody 211 immobilized on the upper surface of the optical waveguide 23 via the antigen 212. Generates energy. Specifically, the magnetic field generator 32 has an upper magnetic field generator 32a and a lower magnetic field generator 32b, as shown in FIG. Further, the magnetic field generator 32 has a drive circuit (not shown). The magnetic field generator 32 applies a magnetic field to the reaction vessel 201 under the control of the processing circuit 36.

The lower magnetic field generator 32b is composed of, for example, a permanent magnet, an electromagnet, or the like. The lower magnetic field generator 32b is provided below the reaction unit 2. The lower magnetic field generator 32b uniformly generates a vertically downward magnetic field, which is energy for promoting the reaction in the reaction vessel 201, in the horizontal direction. Due to the generated vertical downward magnetic field, the magnetic particles 215 to which the second antibody 214 is bound are lowered by receiving the vertical downward force. At this time, the lower magnetic field generator 32b generates the magnetic field of a predetermined strength to bring the magnetic particles 215 to which the second antibody 214 is bound closer to the optical waveguide 23. The lower magnetic field generator 32b is an example of a “magnetic field generator”.

The upper magnetic field generator 32a is composed of, for example, a permanent magnet, an electromagnet, or the like. The upper magnetic field generator 32a is provided above the reaction unit 2 as shown in FIG. The upper magnetic field generator 32a uniformly generates a vertically upward magnetic field in the reaction vessel 201 in the horizontal direction. Due to the generated vertical upward magnetic field, the magnetic particles 215 to which the second antibody 214 is bound rise under the force of the vertically upward direction. At this time, the upper magnetic field generator 32a selectively moves the magnetic particles 215 to which the second antibody 214 is bound from the sensing area 205 by generating a magnetic field having a predetermined strength. That is, the upper magnetic field generator 32a binds the first antibody 211, which is fixed to the upper surface of the optical waveguide 23, and the second antibody 214, which binds via the antigen 212, by adjusting the strength of the generated magnetic field. It is possible to keep only the magnetic particles 215 in the sensing area 205.

The output unit 33 has a display 331, a speaker 332, and a printer 333.

The display 331 displays various information. For example, the display 331 displays various images generated by the processing circuit 36, and displays a GUI (Graphical User Interface) for receiving various operations from the user. For example, the display 331 is a liquid crystal display, an OLED (Organic Light Emitting Diode) display, a CRT (Cathode Ray Tube) display, or the like. The display 331 is controlled by the processing circuit 36, and has various operation screens, information indicating the light intensity of the emitted light L2 supplied from the photodetector 312, time-series data of information indicating the light intensity, and measurement results of the test substance. Etc. are displayed. The measurement result is, for example, the concentration, weight, number, etc. of the antigen 212.

The speaker 332 notifies the user of the measurement result of the test substance and the like under the control of the processing circuit 36.

Under the control of the processing circuit 36, the printer 333 has various operation screens displayed on the display 331, information indicating the light intensity of the emitted light L2 supplied from the photodetector 312, and time-series data of information indicating the light intensity. , And print the measurement results of the test substance.

The input interface circuit 34 is realized by, for example, a trackball, a switch button, a mouse, a keyboard, a touch pad for performing an input operation by touching an operation surface, a touch panel display in which a display screen and a touch pad are integrated, and the like. The input interface circuit 34 outputs an operation input signal corresponding to the user's operation to the processing circuit 36. In the present embodiment, the input interface circuit is not limited to the one provided with physical operation parts such as a mouse and a keyboard. For example, an example of an input interface circuit includes an electric signal processing circuit that receives an electric signal corresponding to an input operation from an external input device provided separately from the device and outputs the electric signal to the processing circuit 36. ..

The storage circuit 35 has a recording medium that can be read by a processor, such as a magnetic or optical recording medium or a semiconductor memory. The storage circuit 35 stores a program executed by the circuit of the sample inspection device 1 according to the present embodiment. A part or all of the program and data in the storage medium of the storage circuit 35 may be configured to be downloaded via an electronic network.

The storage circuit 35 stores information indicating the light intensity of the emitted light L2 supplied from the photodetector 312, time-series data of information indicating the light intensity, measurement results of the test substance to be measured, and the like.

The storage circuit 35 stores the setting information for measuring the target test substance. The setting information includes, for example, information that defines the timing for executing a predetermined process required for measurement. The timing for executing the predetermined process required for the measurement is, for example, the start and stop timing of the application of the lower magnetic field, the start and stop timing of the period described later, the start and stop timing of the application of the upper magnetic field, and the determination process. The timing. These timings are obtained empirically and experimentally in advance.

The storage circuit 35 stores preset threshold values _ST1 and _ST2 . Threshold S _T1, S _T2 is a predetermined value for the amount of change of light intensity corresponding to the concentration of the test substance (hereinafter referred to as an integrated value of the variation rate). The threshold _{values ST1} and _ST2 are used to determine whether or not to continue the measurement of the test substance. Threshold _{S T1, S T2,} respectively, are set in a period _T 1, _{T 2,} which will be described later. The threshold value _ST1 is an example of the “first threshold value”, and the threshold value _ST2 is an example of the “second threshold value”. The period T ₁ is an example of the "first period", and the period T ₂ is an example of the "second period".

Storage circuit 35 stores the preset allowable value I _A. Tolerance I _A is a prescribed value for the light intensity corresponding to the concentration of the analyte. Tolerance I _A is used to a process to determine whether there is a high possibility of positive or negative as a result of measurement of the analyte.

The processing circuit 36 is, for example, a processor that controls each constituent circuit of the sample inspection device 1. The processing circuit 36 functions as the center of the sample inspection device 1. The processing circuit 36 calls each operation program from the storage circuit 35 and executes the called program to provide a light source control function 361, a magnetic field control function 362, a measurement function 363, a detection function 364, a determination function 365, and an output control function 366. Realize.

The light source control function 361 is a function of controlling the light source 311 to generate light under predetermined conditions. In the light source control function 361, the processing circuit 36 continuously or intermittently generates incident light L1 from the light source 311 from the start of measurement to the end of measurement.

The magnetic field control function 362 controls the magnetic field generator 32 according to the time schedule stored in the storage circuit 35, and switches the application state of the energy for promoting the reaction in the reaction vessel 201. Specifically, the magnetic field control function 362 reads setting information from the storage 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. The magnetic field control function 362 is an example of a “control unit”.

The measurement function 363 measures the amount (for example, antigen concentration, etc.) or the presence or absence of the test substance from the optical signal detected by the photodetector 312. The measurement function 363 is an example of a “measurement unit”.

The processing of the detection function 364 and the determination function 365 will be described later. The detection function 364 is an example of a “detection unit”. The determination function 365 is an example of a "determination unit".

The output control function 366 controls the output unit 33 and outputs the measurement result regarding the amount or presence / absence of the test substance to the user. Specifically, the output control function 366 controls the display 331 or the printer 333 and presents the measurement result to the user. For example, the measurement result is presented to the user by displaying it on the display 331 or printing it with a printer. The output control function 366 controls the speaker 332 and notifies the user of the measurement result. For example, the user is notified by notifying the measurement result by sound or the like from the speaker 332.

The word "processor" used in the above description is, for example, a CPU (Central Processing Unit), a GPU (Graphics Processing Unit), an application specific integrated circuit (ASIC)), or a programmable logic device (for example, simple). It means a circuit such as a programmable logic device (Simple Programmable Logic Device: SPLD), a complex programmable logic device (CPLD), and a field programmable gate array (FPGA). When the processor is, for example, a CPU, the processor realizes the function by reading and executing the program stored in the storage circuit 60. On the other hand, when the processor is, for example, an ASIC, the program is directly incorporated in the circuit of the processor instead of storing the program in the storage circuit 60. It should be noted that each processor of the present embodiment is not limited to the case where each processor is configured as a single circuit, and a plurality of independent circuits may be combined to form one processor to realize its function. good. Further, the plurality of components in FIG. 1 may be integrated into one processor to realize the function.

Next, the timing at which the magnetic field is applied will be described with reference to FIG.

FIG. 3 is a graph showing an example of time-series changes in the light intensity of the emitted light L2. In FIG. 3, the horizontal axis indicates the time t [seconds], and the vertical axis indicates the intensity [%] of the optical signal of the emitted light L2. Here, the timing for starting the application of the lower magnetic field, the timing for stopping the application of the lower magnetic field, the timing for starting the application of the upper magnetic field, and the like are predetermined. For example, the timing for starting the application of the lower magnetic field is set to _{time t = t 0.} For example, the timing for stopping the application of the lower magnetic field is set to _{time t = t 2.} For example, the timing for starting the application of the upper magnetic field is set to _{time t = t 5.} The time t = t ₀ , t = t ₂ , and t = t ₅ are acquired in advance empirically and experimentally.

First, the injection of the mixed solution 202 composed of the sample solution and the reagent into the reaction vessel 201 is started. The injection of the mixed solution 202 into the reaction vessel 201 may be performed automatically or manually.

Here, the measurement function 363 starts measuring the test substance. Specifically, for example, when the injection of the mixed solution 202 into the reaction vessel 201 is started, the light source 311 continuously injects light of a constant intensity into the optical waveguide 23. The light emitted from the light source 311 is incident on the optical waveguide 23 via the transparent substrate 22. The light incident on the optical waveguide 23 propagates while being totally reflected in the optical waveguide 23, and is emitted to the photodetector 312 via the transparent substrate 22. The photodetector 312 receives the light emitted from the optical waveguide 23 and supplies light intensity data to the processing circuit 36 at predetermined time intervals. The measurement function 363 of the processing circuit 36 collects the light intensity data supplied from the photodetector 312, and measures the test substance from the light intensity data.

The light intensity increases during the period _{from t = 0 to t = t 0 when} the injection of the mixed solution 202 into the reaction vessel 201 is started and the incident of light is started. This is because when the reaction vessel 201 is filled with the sample solution and the reagent, the sugar-containing water-soluble film previously adhered to the upper surface of the optical waveguide 23 in order to improve the storage stability is dissolved. The sugar is, for example, a disaccharide.

Here, in the present embodiment, _{the value of the light intensity at time t = t 0} is standardized as an initial value of 100 [%]. For example, the value of light intensity increases significantly from time t = 0 to t = t ₀ , and reaches 100 [%] as an initial value at time t = t _0. The initial value of the light intensity is used when determining whether or not there is a high possibility of being positive or negative as a measurement result of the test substance.

The magnetic field control function 362 controls _{the lower magnetic field generator 32b at time t = t 0} to start applying the lower magnetic field.

After the application of the lower magnetic field is started, the value of the light intensity decreases significantly _{from time t = t 0} to t = t _{1, for example.}

At this time, the plurality of magnetic particles 215 to which the second antibody 214 in the reaction vessel 201 filled with the sample solution is bound receives a vertically downward magnetic force due to a lower magnetic field, and a part of the magnetic particles is attracted to the magnetic force lines. It begins to align along the lines of magnetic force. The magnetic particles 215 to which the second antibody 214 aligned along the magnetic force lines is bound gradually settles according to gravity and magnetic force, and enters the sensing area 205. The second antibody 214 immobilized on the magnetic particles 215 that has entered the sensing area 205 binds to the first antibody 211 immobilized on the upper surface of the optical waveguide 23 via the antigen 212.

On the other hand, the magnetic particles 215 to which the second antibody 214 not aligned along the magnetic force lines is bound gradually settles according to gravity and enters the sensing area 205. The second antibody 214 immobilized on the magnetic particles 215 that has entered the sensing area 205 binds to the first antibody 211 immobilized on the upper surface of the optical waveguide 23 via the antigen 212.

From time t = t ₀ to t = t ₁ , the magnetic particles 215 to which the second antibody 214 is bound enter the sensing area 205 one after another, so that the light intensity decreases. The light intensity starts to decrease at a large decrease rate (inclination) immediately after the time t = t _0. The rate of decrease in light intensity decreases with the passage of time. For example, the value of light intensity _{decreases significantly from time t = t 0} to t = t ₁ , and then slightly decreases from time t = t ₁ to t = t _2. Here, the time t = t ₂ is a time point at which the light intensity starts to become constant. At this point, the effect of applying the lower magnetic field becomes smaller. In other words, it is a time when the application of the lower magnetic field may be stopped. The value of the light intensity of the time t = t ₂ is set as I _{s [%]} is a reference value, the value of the light intensity of the other time points are normalized using the reference value I _s. I s _[%] is either the light intensity of the time t = t ₀ is reduced how much the value of the light intensity at time t = t _2, empirical, from experimentally obtained knowledge, is set It is a relative value.

Thus, ingress stops of the magnetic particles 215 in which the second antibody 214 is coupled to the sensing area 205, the value of the light intensity at time t = t _2, down to a certain intensity, a value I _s. Even at time t = t ₁ to t = t ₂ , a part of the antigen 212 contained in the reaction vessel 201 is sequentially bound to the second antibody 214.

The magnetic field control function 362 controls the lower magnetic field generator 32b to stop the application of the lower magnetic field at _{time t = t 2.} Here, when the application of the lower magnetic field is stopped, the magnetic particles 215 to which the second antibody 214 is bound are released from the binding by the lower magnetic field and start spontaneous sedimentation.

As shown in FIG. 3, the light intensity draws a spike-like waveform that changes from an increase to a decrease in the graph because an overshoot OS occurs at _{time t = t 2} to t = t _3. Since a part of the reagent component 213 is momentarily separated from the sensing area 205, floats, and then settles, an overshoot OS occurs at _{time t = t 2} to t = t _{3, as shown in FIG.} The time t = t ₃ is a time during which the occurrence of the overshoot OS is settled, and is acquired in advance empirically and experimentally.

Here, when the generation of the noise current in the overshoot OS is settled, the value of the light intensity is significantly reduced _{, for example, from time t = t 3} to t = t _4.

At this time, the magnetic particles 215 to which the second antibody 214 aligned along the magnetic force lines is bound are released from the binding by the lower magnetic field, so that the aligned state is broken and the particles are directed toward the upper surface of the optical waveguide 23. It sinks in a disorderly manner. The light intensity decreases at a large reduction rate because the magnetic particles 215 to which the second antibody 214 is bound enter the sensing area 205 one after another from time t = t ₃ to t = t _4. The rate of decrease in light intensity decreases with the passage of time. For example, the value of light intensity _{decreases significantly from time t = t 3} to t = t ₄ , and then slightly decreases, for example, from time t = t ₄ to t = t _5.

Thus, entry of the magnetic particles 215 in which the second antibody 214 is coupled to the sensing area 205 is stopped, the light intensity at time t = t _5, down to some strength. At this time, a part of the plurality of magnetic particles 215 to which the second antibody 214 in contact with the upper surface of the optical waveguide 23 is bound is specifically the first antibody 211 immobilized on the upper surface of the optical waveguide 23 via the antigen 212. Join. The magnetic particles 215 to which the second antibody 214 is bound are aligned and deposited on the upper surface of the optical waveguide 23. That is, the inside of the sensing area 205 is occupied almost without gaps by the magnetic particles 215 to which the second antibody 214 is bound. Incidentally, of the first antibody 211 and a plurality of magnetic particles 215 in which the second antibody 214 is coupled which has not bound through the antigen 212 that is fixed to the upper surface of the optical waveguide 23 at the stage of time t = t ₄ Some bind via antigen 212 to the first antibody 211 immobilized on the upper surface of the optical waveguide 23 at time t = t ₄ to t = t _5.

The magnetic field control function 362 controls _{the upper magnetic field generator 32a at time t = t 5} to start applying the upper magnetic field.

Here, the magnetic particles 215 to which the second antibody 214 is bound are aligned and deposited on the upper surface of the optical waveguide 23. At this time, most of the magnetic particles 215 to which the second antibody 214 in contact with the upper surface of the optical waveguide 23 is bound are specifically bound to the first antibody 211 fixed to the upper surface of the optical waveguide 23. Further, the magnetic particles 215 to which the second antibody 214 in the reaction vessel 201 filled with the sample solution is bound to receive a vertically upward magnetic force due to an upward magnetic field, the entry into the sensing area 205 is stopped, and the light intensity is increased. The value increases significantly from time t = t ₅ to t = t _6.

That is, when the value of the light intensity is significantly increased, only the magnetic particles 215 to which the second antibody 214 specifically bound to the first antibody 211 fixed on the upper surface of the optical waveguide 23 is bound are in the sensing area 205. It will be in an existing state. Here, by setting the magnetic field strength of the upper magnetic field to an appropriate value, the magnetic particles 215 bound to the sensing area 205 via the antigen 212 by the antigen-antibody reaction are not peeled off, and the sensing area 205 is not mediated by the antigen 212. The magnetic particles 215 adsorbed on the can be removed.

When the measurement function 363 of the processing circuit 36 _{reaches the time t = t 6} , the measurement function 363 derives a measurement result regarding the amount or presence / absence of the test substance from the optical signal detected by the photodetector 312. For example, the measurement function 363 measures the difference between the initial value of the intensity of the optical signal collected at _{time t = t 0} , which is 100 [%], and the value of the intensity of the optical signal collected at _{time t = t 6.} By doing so, the antigen concentration in the sample solution is measured.

Further, for example, at time t = t ₆ , the measurement function 363 performs a determination process as a measurement of the test substance. For example, the measurement function 363 determines whether the sample solution is likely to be positive or negative. Specifically, the measurement function 363 determines _{the intensity of the optical signal collected at time t = t 6} from 100 [%], which is the initial value of the intensity of the optical signal collected at _{time t = t 0.} obtaining a difference value I _B obtained by subtracting the value, the difference value I _B it is determined whether the allowable value I _a is smaller than or not stored in the memory circuit 35.

As an example of the determination processing, measurement function 363 determines, for example, if the difference value I _B is the allowable value I _A above, and likely positive as a measurement result of a test substance. On the other hand, the measurement function 363 determines, for example, if the difference value I _B is less than the allowable value I _A, to be likely negative as a measurement result of a test substance. In the example shown in FIG. 3, the difference value _{I B} of 100 [%] is the initial value of the light intensity at time t = _{t 0,} the value of the light intensity at time t = _{t 6,} the allowable value I _It shall be smaller than A. In this case, the measurement function 363 determines that the measurement result of the test substance is likely to be negative.

After that, the magnetic field control function 362 controls the upper magnetic field generator 32a to stop the application of the upper magnetic field.

In the present embodiment, the timing for starting the application of the lower magnetic field, the timing for stopping the application of the lower magnetic field, the timing for starting the application of the upper magnetic field, etc. are the time t = t ₀ , t = t ₂ , t = t. _Although it is predetermined as 5, these timings may be appropriately determined by measuring the amount of change in light intensity in real time.

Further, in the present embodiment, a standardized relative value is used as the value of the light intensity, but an absolute value may be used.

In the example shown in FIG. 3, when the reference value of I _s, the value of the light intensity at time t = t ₀ is a value close to 100% of the initial value, the time t = t ₆ The value of the light intensity in is close to 100 [%]. In this case, _{since there is no difference between the initial value of the light intensity at time t = t 0} and the value of the light intensity at time t = t ₆ , the measurement function 363 may be negative as the measurement result of the test substance. Judged as high.

By the way, in order for the light intensity value to reach the initial value of 100 [%] at the time of measuring the test substance, the mixed solution 202 of the sample solution and the reagent must be accurately injected into the reaction vessel 201. .. For example, as described above, the reaction vessel 201 is emptied in advance, and the mixed solution 202 is injected into the reaction vessel 201 from the hole 21a at the time of measuring the test substance. However, if the mixed solution 202 is not accurately injected into the reaction vessel 201, the reagent will be insufficient in the reaction vessel 201.

Further, as described above, in the mixed solution 202, the sample solution contains the test substance containing the antigen 212, and the reagent contains the reagent component 213. The reagent component 213 includes a second antibody 214 that specifically reacts with the antigen 212 by an antigen-antibody reaction, and magnetic particles 215 to which the second antibody 214 is bound. For example, if the reagent is insufficient in the reaction vessel 201 because the mixed solution 202 is not accurately injected into the reaction vessel 201, the magnetic particles 215 are also insufficient. Here, when the magnetic particles 215 are insufficient, the test substance cannot be accurately measured for the following reasons.

FIG. 4 is an explanatory diagram when the mixed liquid 202 is not accurately injected into the reaction vessel 201, and is a graph showing an example of time-series changes in the light intensity of the emitted light L2. In FIG. 4, the horizontal axis indicates the time t [seconds], and the vertical axis indicates the intensity [%] of the optical signal of the emitted light L2. FIG. 4 is an example in which the test substance is measured without the user noticing that the mixed solution 202 has not been accurately injected into the reaction vessel 201.

In the example shown in FIG. 4, the measured light intensity value increases significantly because the reagent (mainly magnetic particles 215) is insufficient because the mixed solution 202 is not accurately injected into the reaction vessel 201. In reality, the initial value of 100 [%] has not been reached at time t = t _0. Even if the measurement of the test substance was carried out in this situation, the normalization described above, is initiated the application of the lower magnetic field at time t = t _0, the time value of the optical intensity to decrease to a value I _{s [%]} The application of the lower magnetic field is stopped at t = t ₂ , and the application of the upper magnetic field is started at _{time t = t 5.} Further, the measurement function 363 has a time t = t from the standardized value of 100 [%] even though the initial value of 100 [%] has not been reached at the _{time t = t 0.} obtaining a difference value I _B obtained by subtracting the value of the light intensity at _6. Therefore, measurement function 363 is actually even sample solution was negative, for example, by the difference value I _B is the allowable value I _A above, can be determined to be positive as a measurement result of a test substance There is sex. Therefore, in the example shown in FIG. 4, there arises a problem that the measurement of the test substance cannot be accurately performed.

Further, in the example shown in FIG. 4, a standardized relative value is used as the value of the light intensity, but even when an absolute value is used, the test substance cannot be measured accurately. Problems arise. For example, since _{the difference between the light intensity value at time t = t 0 and} the light intensity value at time t = t ₆ is not sufficient, there arises a problem that a negative determination becomes difficult. Further, even when a relative value standardized with the value of the light intensity at time t = t ₀ as 100 [%] is used, if the reagent is insufficient, for example, the value of the light intensity at _{time t = t 0 and the value of light intensity at time t = t 0.} Since the difference from the value of the light intensity at time t = t ₆ is not sufficient, there arises a problem that it becomes difficult to determine negative.

Therefore, the sample inspection device 1 according to the present embodiment performs the following processing so as to improve the measurement accuracy. The sample inspection device 1 according to the present embodiment includes an optical waveguide 23, a magnetic field generator 32, a light source 311, a photodetector 312, a measurement function 363, and a determination function 365. The optical waveguide 23 has a sensing area 205 in which a first substance that specifically binds to the test substance is immobilized. The magnetic field generator 32 generates a magnetic field that moves the magnetic particles 215 on which the second substance specifically bound to the test substance is immobilized. The light source 311 causes light to enter the optical waveguide 23. The photodetector 312 detects the light emitted or reflected from the optical waveguide 23. The detection function 364 detects the shortage of the magnetic particles 215 based on the optical signal.

FIG. 5 is an explanatory diagram of processing by the sample inspection device 1 according to the present embodiment, and is a graph showing an example of time-series changes in the light intensity of the emitted light L2. In FIG. 5, the horizontal axis indicates the time t [seconds], and the vertical axis indicates the intensity [%] of the optical signal of the emitted light L2.

As shown in FIG. 5, in the present embodiment, the detection function 364 observes the amount of change in the optical signal over time for a plurality of periods. For example, the detection function 364 calculates the cumulative integration of the fluctuation rate of the optical signal for a plurality of periods, and describes the integrated value of the calculated fluctuation rate of the optical signal (hereinafter, referred to as the amount of change over time of the optical signal). ), It is detected whether or not the magnetic particles 215 are insufficient. Then, the determination function 365 determines whether or not to continue the measurement performed by the measurement function 363 based on the result detected by the detection function 364.

Here, it is assumed that the amount of change in the optical signal over time in the currently observed period is equal to or less than the threshold value set in the period. In this case, the detection function 364 detects that the magnetic particles 215 are insufficient. At this time, since the result detected by the detection function 364 indicates the shortage of the magnetic particles 215, the determination function 365 stops the measurement performed by the measurement function 363. On the other hand, it is assumed that the amount of change in the optical signal over time in the currently observed period is larger than the threshold value set in the period. In this case, the detection function 364 detects that the magnetic particles 215 are not insufficient, and observes the amount of change in the optical signal over time for the next period. At this time, since the result detected by the detection function 364 does not indicate the shortage of the magnetic particles 215, the determination function 365 continues the measurement performed by the measurement function 363.

Specifically, the detection function 364, first, for the period T _1, observing a temporal change amount S ₁ of the optical signal. The period T ₁ is a period after the start of application of the lower magnetic field. For example, the period T ₁ corresponds to the time zone from the time t = t ₀ the applied has started under the magnetic field, until the time t = t ₁ a first set time has elapsed.

Here, the temporal change amount S ₁ of the optical signal in the period T ₁ is assumed to be equal to or less than the period T ₁ set threshold S _T1. In this case, the detection function 364 detects that the magnetic particles 215 are insufficient. At this time, since the result detected by the detection function 364 indicates the shortage of the magnetic particles 215, the determination function 365 stops the measurement performed by the measurement function 363. On the other hand, it is assumed temporal change amount S ₁ of the optical signal is greater than the threshold S _T1 in the period T _1. In this case, the detection function 364 detects that the magnetic particles 215 are not insufficient, and observes the amount of change in the optical signal over time for the next period. At this time, since the result detected by the detection function 364 does not indicate the shortage of the magnetic particles 215, the determination function 365 continues the measurement performed by the measurement function 363.

Determination function 365, the next period, the period T _2, to observe a temporal change amount of the optical signal. The period T ₂ is a period after the overshoot OS occurs when the application of the lower magnetic field is stopped. For example, the period T ₂ corresponds to a time zone _{from the time t = t 3} after the overshoot OS occurs when the application of the lower magnetic field is stopped _{to the time t = t 4} where the second set time elapses. ..

Here, the temporal change amount S ₂ of the optical signal in the period T ₂ is assumed to be equal to or less than the period T ₂ set in the threshold S _T2. In this case, the detection function 364 detects that the magnetic particles 215 are insufficient. At this time, since the result detected by the detection function 364 indicates the shortage of the magnetic particles 215, the determination function 365 stops the measurement performed by the measurement function 363. On the other hand, it is assumed that the temporal change amount S ₂ of the optical signal in the period T 2 is larger than the threshold value _{ST 2.} In this case, the detection function 364 detects that the magnetic particles 215 are not insufficient. At this time, since the result detected by the detection function 364 does not indicate the shortage of the magnetic particles 215, the determination function 365 continues the measurement performed by the measurement function 363.

6A and 6B are flowcharts showing a procedure of processing by the sample inspection apparatus 1 according to the present embodiment.

First, in the processing circuit 36, the measurement function 363 starts measuring the test substance. Specifically, the measurement function 363 collects light intensity data supplied from the photodetector 312, and measures the test substance based on the light intensity data.

In step S101 of FIG. 6A, the magnetic field control function 362 determines whether or not it is the timing to start applying the lower magnetic field. Here, when the magnetic field control function 362 determines that it is not the timing to start applying the lower magnetic field (step S101; No), the process of step S101 is performed again. On the other hand, when the magnetic field control function 362 determines that it is the timing to start applying the lower magnetic field (step S101; Yes), step S102 is executed.

In step S102 of FIG. 6A, the magnetic field control function 362 controls _{the lower magnetic field generator 32b at time t = t 0} to start applying the lower magnetic field.

In step S103 of FIG. 6A, the detection function 364 _{determines the amount of change S 1} (of the intensity of the optical signal) of the optical signal over time for the _{period T 1} which is the time zone _{from the time t = t 0} to the time t = t _1. Observe the integrated value of the fluctuation rate).

In step S104 of FIG. 6A, detection 364 determines the temporal change amount _{S 1} of the optical signal in the period _{T 1} is, whether the period _{T 1} to greater than the threshold value _{S T1} that is set. Further, the determination function 365 determines whether or not to continue the measurement performed by the measurement function 363 based on the result detected by the detection function 364.

Here, if the temporal change amount _{S 1} of the optical signal in the period _{T 1} is a detection function 364 is below the threshold value _{S T1} is determined (Step S104; No), the detection function 364, the magnetic particles 215 is insufficient Detects that. At this time, step S120 is executed.

In step S120 of FIG. 6A, the determination function 365 stops the measurement performed by the measurement function 363 because the result detected by the detection function 364 indicates a shortage of the magnetic particles 215. At this time, the output control function 366 notifies the user of a message indicating that the measurement of the test substance has been stopped because the mixed liquid 202 has not been accurately injected into the reaction vessel 201. For example, the output control function 366 notifies the user by displaying the message on the display 331. For example, the output control function 366 notifies the user by notifying the message from the speaker 332 by sound or the like.

On the other hand, if the temporal change amount _{S 1} of the optical signal in the period _{T 1} is greater than the detection function 364 threshold _{S T1} is determined (step S104; Yes), the detection function 364, the magnetic particles 215 is not insufficient Detect that. At this time, step S105 is executed.

In step S105 of FIG. 6A, the magnetic field control function 362 determines whether or not it is the timing to stop the application of the lower magnetic field. Here, when the magnetic field control function 362 determines that it is not the timing to stop the application of the lower magnetic field (step S105; No), the process of step S105 is performed again. On the other hand, when the magnetic field control function 362 determines that it is the timing to stop the application of the lower magnetic field (step S105; Yes), step S106 is executed.

In step S106 of FIG. 6A, the magnetic field control function 362 controls _{the lower magnetic field generator 32b at time t = t 2} to stop the application of the lower magnetic field.

In step S107, the detection function 364 in FIG. 6A, the period _{T 2} is a time period from the time t = _{t 3} to time t = _{t 4,} the strength of the temporal change amount _{S 2} (optical signal of the optical signal Observe the integrated value of the fluctuation rate).

In step S108 of FIG. 6A, detection 364 determines the temporal change amount _{S 2} of the optical signal in the period _{T 2} is, whether the period _{T 2} to or greater than the threshold _{S T2} that has been set. Further, the determination function 365 determines whether or not to continue the measurement performed by the measurement function 363 based on the result detected by the detection function 364.

Here, if the temporal change amount _{S 2} of the optical signal in the period _{T 2} is the detection function 364 is below the threshold value _{S T2} is determined (step S108; No), the detection function 364, the magnetic particles 215 is insufficient Detects that. At this time, step S120 is executed.

On the other hand, if the temporal change amount _{S 2} of the optical signal in the period _{T 2} is larger than the detection function 364 threshold _{S T2} is determined (step S108; Yes), the detection function 364, the magnetic particles 215 is not insufficient Detect that. At this time, step S109 is executed.

In step S109 of FIG. 6A, the measurement after the _{time t = t 4 is continued.} That is, the determination function 365 continues the measurement performed by the measurement function 363.

In step S110 of FIG. 6B, the magnetic field control function 362 determines whether or not it is the timing to start applying the upper magnetic field. Here, when the magnetic field control function 362 determines that it is not the timing to apply the upper magnetic field (step S110; No), the process of step S109 is performed again. On the other hand, when the magnetic field control function 362 determines that it is the timing to apply the upper magnetic field, that is, when the time t = t ₅ for applying the upper magnetic field is reached (step S110; Yes), step S111 is executed.

In step S111 of FIG. 6B, the magnetic field control function 362 controls _{the upper magnetic field generator 32a at time t = t 5} to start applying the upper magnetic field.

In step S111 of FIG. 6B, the measurement function 363 performs a determination process as a measurement of the test substance at _{time t = t 6.} For example, the measurement function 363 has a difference value I obtained by subtracting the value of the intensity of the optical signal collected at _{time t = t 6} from 100 [%] which is the initial value of the intensity of the optical signal collected at _{time t = t 0. B} is, by determining whether or not stored in the memory circuit 35 is less than the allowable value I _a, determines whether the sample solution is likely positive or negative. For example, measurement function 363, if the difference value I _B is the allowable value I _A above, was determined to be likely positive as a measurement result of a test substance, if the difference value I _B is less than the allowable value I _A , It is judged that there is a high possibility that the measurement result of the test substance is negative.

In step S112 of FIG. 6B, the magnetic field control function 362 controls the upper magnetic field generator 32a to stop the application of the upper magnetic field.

As a result, the measurement function 363 ends the measurement of the test substance.

According to the above description, in the sample inspection device 1 according to the present embodiment, the optical waveguide 23 has a sensing area 205 on which the first antibody 211 that specifically binds to the test substance is immobilized. The magnetic field generator 32 generates a magnetic field that moves the magnetic particles 215 to which the second antibody 214 specifically bound to the test substance is bound. The light source 311 causes light to enter the optical waveguide 23. The photodetector 312 detects the light emitted or reflected from the optical waveguide 23. The measurement function 363 measures the amount or presence / absence of the test substance from the optical signal. The detection function 364 detects the shortage of the magnetic particles 215 based on the optical signal. For example, the detection function 364 detects whether or not the magnetic particles 215 are insufficient based on the amount of change in the optical signal over time, and when the amount of change in the optical signal over time is equal to or less than the threshold value, the detection function 364 is magnetic. It is detected that the particles 215 are deficient, and when the amount of change over time of the optical signal is larger than the threshold value, it is detected that the magnetic particles 215 are not deficient.

Specifically, the detection function 364 for the period T ₁ of the after starting the application of the lower magnetic field is moved in a direction closer to the magnetic particles 215 to the optical waveguide 23, to observe the temporal change amount S ₁ of the optical signal. Here, by mixing liquid 202 is not accurately injected into the reaction vessel 201, when the reagent (mainly magnetic particles 215) is insufficient, the temporal change amount S ₁ of the optical signal in the period T ₁ , It becomes equal to or less than the threshold value S _T1 set in the period T _1. In this case, the detection function 364 detects that the magnetic particles 215 are insufficient. At this time, since the result detected by the detection function 364 indicates a shortage of the magnetic particles 215, the determination function 365 stops the measurement.

The detection function 364, when the temporal variation amount S ₁ of the optical signal in the period T ₁ is greater than the threshold S _T1, the period T ₂ of the after overshoot OS has occurred at the time of stop of the lower magnetic field, the optical signal observing a temporal change amount S ₂ of. Here, when the reagent is insufficient, the temporal change amount S ₂ of the optical signal in the period T ₂ is equal to or less than the threshold value S _T2 which is set to a period T _2. In this case, the detection function 364 detects that the magnetic particles 215 are insufficient. At this time, since the result detected by the detection function 364 indicates a shortage of the magnetic particles 215, the determination function 365 stops the measurement.

As described above, according to the above configuration, the sample inspection device 1 according to the present embodiment has a period T _{1 after the start of application of the lower magnetic field and a period T 2} after the overshoot occurs when the lower magnetic field is stopped. When the amount of change over time of the optical signal is less than or equal to the threshold value, the measurement is stopped by detecting that the magnetic particles 215 are insufficient, and when the amount of change over time of the optical signal is larger than the threshold value. Since the measurement is continued, the measurement of the test substance can be performed accurately.

(Other embodiments)
Although the embodiments have been described so far, various different embodiments may be implemented in addition to the above-described embodiments.

In the above embodiment, detection function 364 for the period T _1, the temporal change amount S ₁ of the optical signal observed, when the change amount S ₁ is greater than the threshold S _T1, the next period, the period T ₂ However, the present embodiment is not limited to this, although the amount of change in the optical signal over time is observed. As a modification of the present embodiment, the detection function 364 provides an _{optical signal for the period T 3 in} which the overshoot OS occurs when the temporal change amount S _{1 of the optical signal in the period T 1} is larger than the threshold value S _{T 1.} observing temporal variation S ₃ of. The period T ₃ is an example of a "third period".

FIG. 7 is an explanatory diagram of processing by the sample inspection device 1 according to a modified example of the present embodiment, and is a graph showing an example of time-series changes in the light intensity of the emitted light L2. In FIG. 7, the horizontal axis indicates the time t [seconds], and the vertical axis indicates the intensity [%] of the optical signal of the emitted light L2. FIG. 8 is a flowchart showing a procedure of processing by the sample inspection device according to the modified example of the present embodiment. In FIG. 8, a part of the processing of steps S107 and S108 is different from that of FIG. 6A.

In step S107 of FIG. 8, the detection function 364, when the temporal variation amount _{S 1} of the optical signal in the period _{T 1} is greater than the threshold _{S T1,} the period _T 2, _{T 3,} respectively, of the optical signal temporal Observe the changes S ₂ and S _3. As shown in FIG. 7, the period T ₃ is a period during which the overshoot OS occurs when the application of the lower magnetic field is stopped. For example, the period T ₃ corresponds to the time zone from the time t = t _{2 to the time t = t 3} when the overshoot OS occurs. The period T ₂ corresponds to the time zone from the time t = t ₃ to the time t = t _{4 after the overshoot OS occurs.}

Since overshoot OS is generated instantaneously, for example, the temporal change amount S ₃ of the optical signal in the period T ₃ is not the cumulative value of the rate of change in intensity of the optical signal, the peak value of the overshoot OS Let it be _POS . Specifically, the peak value P _OS overshoot OS is the difference between the value of the light intensity in the value of the light intensity and time t = t ₃ at time t = t _4. The storage circuit 35 further stores a preset threshold value _ST3 . For example, the threshold S _T3 is used for the period T _3. The threshold value S _T3 is an example of a “third threshold value”.

In step S108 of FIG. 8, the detection function 364, a period temporal change amount _{S 2} of the optical signal in _{T 2} may determine whether the period _{T 2} to or greater than the threshold _{S T2} that is set, the period T temporal variation S ₃ of the optical signal in ₃ determines whether the period T ₃ to greater than the threshold value S _T3 that is set. Further, the determination function 365 determines whether or not to continue the measurement performed by the measurement function 363 based on the result detected by the detection function 364.

For example, a large temporal change amount _{S 3} of the optical signal from the threshold _{S T3} in the period _{T 3,} the temporal change amount _{S 2} the threshold _{S T2} is larger than the detection function 364 of the optical signal in the period _{T 2} is determined In the case (step S108; Yes), the detection function 364 detects that the magnetic particles 215 are not deficient. At this time, step S109 is executed. That is, the determination function 365 continues the measurement performed by the measurement function 363.

On the other hand, for example, if the detection function 364 temporal change amount _{S 2} of the optical signal is equal to or less than the threshold value _{S T2} in the period _{T 2} is determined (Step S108; No), the detection function 364, insufficient magnetic particles 215 Detect what you are doing. In this case, regardless of the magnitude of temporal variation S ₃ of the optical signal in the period T _3, step S120 is executed. That is, the determination function 365 stops the measurement performed by the measurement function 363. At this time, the output control function 366 notifies the user of a message indicating that the measurement of the test substance has been stopped because the mixed liquid 202 has not been accurately injected into the reaction vessel 201.

In the embodiment described above, using the normalized light intensity, but also the threshold value _{S T1,} S _T2, S _T3 is used standardized relative value may be used absolute value. When the absolute value of the light intensity is used, for example, the _{threshold values ST1} , _ST2 , and _ST3 are set according to the value of the light intensity at _{time t = t 0.}

Further, in the above-described embodiment, the detection function 364 detects the shortage of the magnetic particles 215 based on the optical signal during application of the magnetic field and the optical signal after the magnetic field is stopped. For example, the detection function 364 for the period T ₁ of the during application of a magnetic field, the temporal change amount S ₁ of the optical signal observed, when the change amount S ₁ is equal to or less than the threshold value S _T1, the lack of magnetic particles 215 To detect. Further, when the change amount S ₁ is larger than the threshold value S _T1 , the detection function 364 observes the temporal change amount S _{2 of the optical signal for the period T 2} after the magnetic field is stopped, and the change amount S ₂ is the threshold value S. _When it is T2 or less, the shortage of the magnetic particles 215 is detected. However, the present embodiment is not limited to this.

For example, as a modification of the present embodiment, for example, the detection function 364, for only the period T ₂ of the after cessation of the magnetic field, the temporal change amount S ₂ of the optical signal observed, the amount of change S ₂ the threshold S _T2 In the following cases, the shortage of the magnetic particles 215 may be detected. That is, the detection function 364 detects the shortage of the magnetic particles 215 based on at least one of the optical signal during application of the magnetic field and the optical signal after the magnetic field is stopped.

According to at least one embodiment described above, the measurement accuracy can be improved.

Although some embodiments have been described, these embodiments are presented as examples and are not intended to limit the scope of the invention. These embodiments can be implemented in various other embodiments, and various omissions, replacements, changes, and combinations of embodiments can be made without departing from the gist of the invention. These embodiments and variations thereof are included in the scope of the invention described in the claims and the equivalent scope thereof, as are included in the scope and gist of the invention.

1 Specimen inspection device 23 Optical wave guide 32 Magnetic field generator 311 Light source 312 Photodetector 364 Detection function

Claims (8)

An optical waveguide having a sensing area in which the first substance that specifically binds to the test substance is immobilized,
A magnetic field generator that generates a magnetic field that moves magnetic particles to which a second substance specifically bound to the test substance is bound,
A light source that causes light to enter the optical waveguide,
A photodetector that detects light emitted or reflected from the optical waveguide,
Based on the optical signal detected by the photodetector, the detector that detects the shortage of the magnetic particles and the detector
Specimen testing device equipped with. The detection unit detects the shortage of the magnetic particles based on at least one of the optical signal during application of the magnetic field and the optical signal after the magnetic field is stopped.
The sample inspection device according to claim 1. The detection unit
Based on the amount of change in the optical signal over time, it is detected whether or not the magnetic particles are insufficient.
When the amount of change over time of the optical signal is equal to or less than the threshold value, it is detected that the magnetic particles are insufficient, and the magnetic particles are detected.
When the amount of change in the optical signal with time is larger than the threshold value, it is detected that the magnetic particles are not insufficient.
The sample testing apparatus according to claim 1 or 2. The detection unit
The amount of change in the optical signal over time was observed for the first period after the start of application of the magnetic field for moving the magnetic particles in the direction closer to the optical waveguide.
When the amount of change in the optical signal over time in the first period is equal to or less than the first threshold value set in the first period, it is detected that the magnetic particles are deficient.
The sample inspection device according to claim 3. The detection unit
When the amount of change in the optical signal over time in the first period is larger than the first threshold value, the time of the optical signal is about the second period after the overshoot occurs when the magnetic field is stopped. Observe the amount of change
When the amount of change in the optical signal over time in the second period is equal to or less than the second threshold value set in the second period, it is detected that the magnetic particles are deficient.
The sample inspection device according to claim 4. The detection unit
When the amount of change in the optical signal over time in the first period is larger than the first threshold value, the amount of change in the optical signal in time is observed for the third period in which the overshoot occurs. death,
The amount of time change of the optical signal in the third period is larger than the third threshold value set in the third period, and the amount of time change of the optical signal in the second period is said. If it is larger than the second threshold value, it is detected that the magnetic particles are not deficient.
The sample inspection device according to claim 5. A measuring unit that measures the amount or presence / absence of the test substance from the optical signal detected by the photodetector, and
A determination unit that determines whether or not to continue the measurement based on the result detected by the detection unit, and a determination unit.
The sample inspection apparatus according to any one of claims 1 to 6, further comprising. The determination unit
If the result detected by the detection unit indicates that the magnetic particles are insufficient, the measurement is stopped and the measurement is stopped.
If the result detected by the detection unit indicates that the magnetic particles are not insufficient, the measurement is continued.
The sample inspection apparatus according to claim 7.

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