JP7101810B2 - Measuring device and measuring method - Google Patents

Description

The present invention relates to a measuring device and a measuring method.

Conventionally, a surface acoustic wave sensor device is known (Patent Document 1).

Japanese Unexamined Patent Publication No. 2008-286606

In such a sensor, improvement in measurement accuracy is required.

The measuring device according to the embodiment of the present invention is the sensor obtained by a sensor capable of detecting the detection target by a signal change caused by the detection target in the sample and a sensor having the same configuration as the sensor. A storage unit that stores a reference signal change caused by a correction body used for calibration and having a known specific measured value, and a calculation for deriving the measured value to be detected based on the signal change and the reference signal change. It is equipped with a department. Then, the calculation unit calculates a correction value based on the reference signal change and the first signal change caused by the correction body, and corrects with the correction value from the second signal change caused by the detection target. After calculating the third signal change, the measured value is derived based on the third signal change.

The measurement method according to the embodiment of the present invention was acquired by a step of preparing a sensor capable of detecting the detection target by a signal change caused by the detection target in the sample and a sensor having the same configuration as the sensor. , A step of storing a reference signal change caused by a correction body used for calibrating the sensor and having a known specific measured value, a step of acquiring a first signal change caused by the correction body, and the reference signal change. A step of calculating a correction value based on the first signal change, a step of acquiring a second signal change caused by the detection target, and a step of correcting the second signal change with the correction value to obtain a third signal change. It includes a step of acquiring and a step of deriving a measured value of the detection target included in the sample based on the change in the third signal.

According to the measuring device and the measuring method according to the present invention, the measurement accuracy can be improved.

FIG. 1 is a schematic diagram schematically showing a measuring device according to an embodiment. FIG. 2 is a block diagram showing an outline of the measuring device. FIG. 3 is a plan view of a part of the measuring device. FIG. 4 is a cross-sectional view taken along the line AA of a part of the measuring device shown in FIG. FIG. 5A is a diagram showing an example of measurement results of the measuring device shown in FIG. FIG. 5B is a diagram showing an example of measurement results of the measuring device shown in FIG. FIG. 6 is a flow chart showing an example of processing of the measuring device.

(measuring device)
(One embodiment)
Hereinafter, the measuring device 1 according to the embodiment of the present invention will be described with reference to the drawings.

FIG. 1 shows an outline of the measuring device 1 according to the embodiment. Further, FIG. 2 shows each functional unit included in the measuring device 1 shown in FIG.

The measuring device 1 can detect a detection target from a measurement target (sample) including a specific substance (detection target) to be detected. The measuring device 1 includes a sensor 2 capable of detecting a detection target and a control device 3 for controlling the sensor 2. As a result, the measuring device 1 can measure a specific measured value of the detection target by comparing the signal change acquired by the sensor 2 with the calibration data prepared in advance by the control device 3.

The measured value may be, for example, the concentration or mass of the detection target, the reaction rate between the detection target and the reactant, the equilibrium constant, the binding constant or the specificity constant. Further, the calculation unit 32 may identify the detection target based on the derived measured value. If the calibration data prepared in advance is related to the measured value to be measured, any measured value can be measured.

In the measuring device 1 of the present disclosure, the sensor 2 has an external terminal 21, and the control device 3 has a recess 30 having a connection terminal 31 on the bottom surface. The sensor 2 is arranged in the recess 30 of the control device 3 so that the external terminal 21 and the connection terminal 31 are connected to each other. As a result, the sensor 2 is electrically connected to the control device 3.

The sensor 2 can detect the detection target by the signal change caused by the detection target in the sample. That is, the sensor 2 can output a signal that changes due to the detection target to the control device 3. Then, the measuring device 1 can derive the measured value by comparing the signal change acquired by the sensor 2 with the calibration data prepared in advance.

The change in the signal output by the sensor 2 may be, for example, a phase change, a frequency change, a voltage value change, a current value change, a weight value change, or the like.

The sensor 2 of the present disclosure is a surface acoustic wave sensor that detects a detection target based on a signal change of a surface acoustic wave. In this case, the signal change is a phase change. Specifically, the output of the sensor 2 indicates the amount of change in the phase difference of the surface acoustic wave. Here, the phase difference is the difference between the phase of the transmitted elastic surface wave and the phase of the received elastic surface wave, and the amount of change in the phase difference is how much the phase difference has changed due to the detection of the detection target. It is a value representing.

The sensor 2 can output a signal according to the detection of the detection target. The sensor 2 may use, for example, an elastic surface wave, a QCM (Quartz Crystal Microbalance), an SPR (Surface Plasmon Resonance), a FET (Field Effect Transistor), or the like.

FIG. 3 shows a plan view of the sensor 2.

The sensor 2 includes a substrate 22, a detection unit 23 located on the substrate 22, and a pair of IDT (Inter Digital Transducer) electrodes 24 arranged so as to sandwich the detection unit 23 on the substrate 22. The substrate 22 can support the IDT electrode 24 and the like. The detection unit 23 can react with the detection target. The pair of IDT electrodes 24 can generate surface acoustic waves between the pair of IDT electrodes 24.

The sensor 2 can be manufactured by a conventionally known method.

The substrate 22 is a piezoelectric substrate. For example, the substrate 22 may be a substrate containing a single crystal having piezoelectricity such as lithium tantalate or quartz.

A part of the surface of the substrate 22 can function as a detection unit 23. In other words, the detection unit 23 is a region forming a part of the surface of the substrate 22. A substance (reactant) that reacts with the detection target is fixed to the detection unit 23 (a part of the surface of the substrate 22). When the detection target reacts with the reactant in the detection unit 23, the sensor 2 can detect the detection target. Then, the signal caused by the reaction with the detection target is output from the sensor 2 to the control device 3.

The reaction between the detection target and the reactant may be any reaction that causes a change in the output of the sensor 2. As such a reaction, for example, by a reaction in which a detection target and a reactant are bound by an oxidation-reduction reaction, an enzymatic reaction, an antigen-antibody reaction, a chemical adsorption, an intermolecular interaction, an ion-to-ion interaction, or the like, or an enzymatic reaction. Examples include reactions that produce new substances.

The reactant to be fixed to the detection unit 23 may be appropriately selected according to the detection target. For example, when the detection target is a specific protein, DNA, cell, or the like in a sample, an antibody, peptide, aptamer, or the like may be used as the reactant. Further, for example, when the detection target is an antibody, an antigen may be used as the reactant. Further, for example, when the detection target is a substrate, an enzyme may be used as the reactant.

The pair of IDT electrodes 24 can transmit a surface acoustic wave propagating from one toward the detection unit 23 and receive the surface acoustic wave that has passed through the detection unit 23 on the other side. The pair of IDT electrodes 24 may be made of a metal material such as gold, chromium or titanium. Further, the pair of IDT electrodes 24 may be a single-layer electrode made of a single material or a multi-layer electrode made of a plurality of materials.

By having the above configuration, the sensor 2 can detect the detection target. That is, the detection target can be detected by changing the viscosity or density of the surface of the detection unit 23 and changing the phase of the surface acoustic wave passing through the detection unit 23. Specifically, the sensor 2 can detect the detection target by the reaction between the detection target and the reactant in the detection unit 23.

Further, the larger the reaction between the detection target and the reactant and the larger the change in viscosity or density, the larger the phase change. In other words, the phase change of surface acoustic waves depends on the detection target and the reactants. Therefore, it is possible not only to detect the detection target but also to measure the content or concentration of the detection target.

FIG. 4 shows a cross-sectional view of the sensor 2 at the cutting plane line AA of FIG.

The sensor 2 further has a flow path member 25. The flow path member 25 can function as a path for the sample. The flow path member 25 has an opening on the upper surface of the flow path member 25, and has a supply port 26 for supplying a sample and a discharge port 27 for discharging the sample. When the sample supplied from the supply port 26 reaches the detection unit 23, the sensor 2 detects the detection target by the detection unit 23, and then discharges the sample from the discharge port 27.

The measuring device 1 can flow a sample in the flow path member 25 by, for example, pressing by a pump or a capillary phenomenon. When the sample is a solid or a substance having low fluidity, the measuring device 1 may supply a medium (flow medium) for flowing the sample together with the sample to the flow path member 25. As a result, the measuring device 1 can improve the convenience of measurement. The fluid medium is, for example, water, PBS (Phosphate Buffered Saline), TBS (Tris Buffered Saline), or MES (2-Morpholinoethanesulfonic acid, monohydrate) buffer and HEPES (2- [4- (2-hydroxyethyl) -1-). piperazinyl] ethanesulfonic acid) Good buffer such as buffer may be used.

The control device 3 can control the measuring device 1. The control device 3 has a calculation unit 32 and a storage unit 33. The calculation unit 32 can receive a signal from the sensor 2 at any time during the measurement and acquire a waveform representing a temporal change in the output. Then, the calculation unit 32 can derive the measured value to be detected based on the acquired waveform. The storage unit 33 can store a program or the like for the calculation of the calculation unit 32.

The control device 3 has a plurality of electronic components. Thereby, the control device 3 can configure each functional unit of the control device 3. That is, the control device 3 constitutes each functional unit of the control device 3 by integrating a plurality of electronic components to form at least one IC (Integrated Circuit) or LSI (Large Scale Integration). can do. The control device 3 of the present disclosure integrates a plurality of electronic components to form a calculation unit 32, a storage unit 33, and the like.

The plurality of electronic components may be, for example, an active element such as a transistor or a diode, or a passive element such as a capacitor. It should be noted that a plurality of electronic components and an integrated circuit formed by integrating them can be formed by a conventionally known method.

Specifically, the storage unit 33 has, for example, a RAM (Random Access Memory) or a ROM (Read-Only Memory). Firmware is stored in the storage unit 33. As a result, the processor of the calculation unit 32 can execute one or more data calculation procedures or processes according to the firmware of the storage unit 33.

Further, the storage unit 33 of the present disclosure can store the calibration data. The calibration data is data obtained by measuring a detection target (standard substance) having a known measured value by the sensor 2, and refers to the relationship between the output of the sensor 2 and the measured value. The storage unit 33 of the present disclosure can store the relationship between the concentration of the detection target contained in the sample and the signal change as calibration data. The sensor 2 for acquiring calibration data and the sensor 2 for performing actual measurement may be separate parts. Further, the measuring device 1 can shorten the measuring time by storing the calibration data in the storage unit 33 in advance.

Specifically, the calculation unit 32 has, for example, a processor. Processors may include, for example, one or more processors, controllers, microprocessors, or combinations of these devices or arbitrary calibrations, or other known devices or combinations of calibrations.

The calculation unit 32 can derive a specific measured value by comparing the signal change acquired by the sensor 2 with the calibration data. The calculation unit 32 of the present disclosure can derive the concentration to be detected as a measured value. Further, the calculation unit 32 can correct the measurement result of the measuring device 1 before or during the measurement.

The correction of the measuring device 1 can be performed by using the correction body. Specifically, first, a reference signal change indicating the relationship between the output of the sensor 2 and the measured value, which is obtained by measuring the correction body having a known measured value by the sensor 2, is prepared in advance. Then, at the time of measurement by the measuring device 1, the correction body can be measured, and the measurement result of the sample can be corrected based on the deviation between the measurement result and the reference signal change.

That is, the calculation unit 32 of the measuring device 1 first calculates the correction value based on the reference signal change and the first signal change caused by the correction body. Then, after calculating the third signal change corrected by the correction value from the second signal change caused by the detection target, the measured value can be derived based on the third signal change.

Here, conventionally, even if the detection target having the same concentration is measured, the detection sensitivity may be different for each sensor, and different results may be obtained for each sensor. Therefore, the measurement accuracy of the measuring device has been reduced.

On the other hand, the measuring device 1 according to the present invention can detect the difference in detection sensitivity based on the degree of signal change of the corrector by having the above configuration. Specifically, since the concentration of the correction body is constant, the measuring device 1 can detect the difference in sensitivity of the sensor 2 by comparing the change in the reference signal with the change in the first signal. As a result, since the measuring device 1 can calibrate the sensitivity of the sensor 2 by the correction value, the influence of the variation in the sensitivity for each sensor 2 can be reduced, and the measurement accuracy can be improved.

It will be described in more detail below.

FIG. 5A shows an example of measurement results when a correction body having a known concentration is measured together with a standard substance containing detection targets (X, Y, Z) having different concentrations by one sensor 2. In FIG. 5A, the signal change that appears first is the signal change caused by the measurement of the corrector, and the signal change that appears next is the signal change caused by the measurement of the sample. The signal change caused by the measurement of the sample differs depending on the concentration of the detection target.

FIG. 5B shows an example of measurement results when a corrector having the same concentration as the concentration at which the reference signal change was acquired is measured together with a sample whose detection target concentration is unknown by a sensor 2 different from the sensor 2 from which the calibration data is acquired. Is shown. In FIG. 5B, the signal change that appears first is the signal change caused by the measurement of the corrector, and the signal change that appears next is the signal change caused by the measurement of the sample.

When the sensitivity of the sensor 2 used for the measurement is different from that of the sensor 2 from which the calibration data is acquired, the signal change (first signal change) caused by the detection of the corrector is different from the reference signal change. For example, the maximum value of the first signal change in FIG. 5B is smaller than the maximum value of the reference signal change in FIG. 5A. In this case, the control device 3 corrects the signal change (second signal change) caused by the detection of the detection target based on the error between the reference signal change and the first signal change, so that the difference in sensitivity of the sensor 2 is different. It is possible to reduce the measurement error caused by the above. That is, the measurement accuracy of the measuring device 1 can be improved.

The measurement result (reference signal change) of the correction body is stored in the storage unit 33 as a part of the calibration data. The calibration data refers to the relationship between the output of the sensor 2 and the measured value obtained by measuring the correction body. The measured values of the calibration data and the calibration data may be of the same type. Specifically, when the measured value of the sample is the concentration of the detection target contained in the sample, the measured value of the corrected body may be the concentration of the substance contained in the corrected body. The storage unit 33 of the present disclosure can store the relationship between the concentration of the substance contained in the correction body and the change in the reference signal as calibration data. Further, since the calibration data is stored in the storage unit 33 in advance, the measuring device 1 can shorten the measurement time.

The corrector may contain a substance having a density or viscosity different from that of the flow medium. The substance contained in the corrector may be, for example, an organic compound such as glycerin, ethylene glycol, or ethanol. Further, the corrector may be an inorganic compound such as sodium chloride or potassium chloride.

Further, the signal change acquired by the detection unit 23 depends on the performance of the detection unit 23, for example, the amount of the reactant fixed on the surface of the detection unit 23 or the thickness of the detection unit 23. Therefore, the measuring device 1 can acquire a signal change according to the state of the reactant fixed on the surface of the detection unit 23 by measuring the corrector before the measurement of the sample. That is, the measuring device 1 can improve the measurement accuracy regardless of the surface quality of the detection unit 23.

The control device 3 may calculate the ratio of the first signal change to the reference signal change as a correction value. As a result, the measuring device 1 can calculate the product of the correction value and the second signal change as the third signal change. Specifically, the difference in sensitivity between the sensor 2 from which the calibration data has been acquired and the sensor 2 used for the actual measurement can be detected as a ratio. Then, by applying a correction value to the second signal change, the measuring device 1 can bring the third signal change closer to the signal change that can be acquired when the sensor 2 has acquired the calibration data. As a result, the measuring device 1 can reduce the error between the signal change included in the calibration data and the actually measured signal change, so that the measurement accuracy can be improved.

FIG. 6 shows a processing procedure of the measuring device 1. The calculation unit 32 measures the standard substance and the corrective body (step S101). In step S101, measurements may be made for a plurality of concentrations of the standard substance. The storage unit 33 stores the relationship between the output and the density (calibration data) acquired in the step S101 and the relationship between the reference signal change and the density of the corrector (calibration data) (step S102). The calculation unit 32 measures the correction body and acquires the first signal change (step S103). The calculation unit 32 measures the sample and acquires the second signal change (step S104). The calculation unit 32 calculates the correction value based on the reference signal change and the first signal change (step S105). The calculation unit 32 calculates the third signal change by applying the correction value to the second signal change (step S106). Then, the calculation unit 32 derives the concentration to be detected by comparing the change in the third signal with the change in the signal included in the calibration data (step S107).

In the above description, some embodiments have been described in order to clearly disclose the present disclosure. However, the accompanying claims are not limited to the above embodiments, and all modifications and alternatives that can be created by those skilled in the art within the scope of the basic matters set forth herein. It should be configured to embody a unique configuration. In addition, the requirements shown in some embodiments can be freely combined. For example, a measuring device, a measuring method, or a program may be configured by appropriately combining each component / process of the above-described embodiment.

For example, in the above embodiment, the case where the detection unit 23 is one has been described as an example, but the present invention is not limited to this case. For example, the sensor may have two or more detection units. According to this, it is possible to measure a plurality of types of detection targets.

Further, the sensor 2 may be a disposable cartridge. According to this, the step of cleaning the sensor 2 after the measurement becomes unnecessary, and it is possible to eliminate the influence on the measurement result due to insufficient cleaning.

Further, in the above embodiment, an example of acquiring calibration data based on the output of the measured standard substance is shown, but the present invention is not limited to this case as long as the data can derive the concentration to be detected. .. For example, the calibration data may be data based on theoretical or statistical values if the relationship between the output of the sensor 2 and the concentration to be detected is clear theoretically or statistically, and is not necessarily data of actual measurement values. It is not necessary to use. As a result, the measuring device 1 does not need to actually measure the measurement data, so that the measuring time can be shortened.

Further, in the above embodiment, the preparation of the calibration data and the measurement of the sample can be performed in the same flow, but the present invention is not limited to this case. For example, the calibration data may be stored in the storage unit 33 before starting the measurement of the sample. Therefore, the creation and storage of the calibration data do not necessarily have to be performed in the same flow as the measurement of the sample, and the calculation unit 32 derives the concentration of the detection target using the calibration data stored in advance in the storage unit 33. be able to. As a result, since the measuring device 1 can be started from the process S103 in the processing flow shown in FIG. 6, the measuring time can be shortened. Further, since the measuring device 1 does not need to insert a step of cleaning the sensor 2 or the like between the step of measuring the standard substance and the step of measuring the sample, the measurement of the sample can be performed more easily.

Further, in the above embodiment, an example in which the detection unit 23 is a part of the surface of the substrate 22 has been described, but the present invention is not limited to this case. For example, a metal film such as Ti-Au or Cr-Au, an organic polymer, or the like may be provided on the surface of a part of the substrate 22 to serve as the detection unit 23. In this case, the reactant may be fixed to the surface of a metal film or the like. As a result, the stability of the reactants can be improved.

(Measuring method)
Each step performed in the above measuring device 1 may be interpreted as an invention of a measuring method.

Specifically, the measurement method according to the embodiment of the present invention has a step of preparing a sensor 2 capable of detecting a detection target by a signal change caused by a detection target in a sample, and a configuration similar to that of the sensor 2. A step of storing a reference signal change caused by a corrector having a known specific measured value used for calibrating the sensor 2 acquired by the sensor, and a step of acquiring a first signal change caused by the corrector. The step of calculating the correction value based on the reference signal change and the first signal change, the step of acquiring the second signal change caused by the detection target, and the step of correcting the second signal change with the correction value to correct the third signal change. It includes a step of acquiring and a step of deriving the measured value of the detection target included in the sample based on the change in the third signal. As a result, the measuring method can improve the measuring accuracy.

In the above measurement method, the correction value is the ratio of the first signal change to the reference signal change, and the product of the second signal change and the correction value may be calculated as the third signal change.

In the above measuring method, the correction body may have a different density or viscosity from the flow medium supplied to the sensor 2 and flowing the sample and the correction body. As a result, the detection unit 23 can acquire the signal change caused by the correction body.

The above-mentioned measuring method further includes a step of storing the relationship between the second signal change and the known concentration of the sample acquired together with the reference signal change, and the second signal change included in the relationship and the third signal change. The concentration may be derived by comparing it with the signal change.

It should be noted that each step executed in the above-mentioned measuring device 1 may be interpreted as an invention of a control method of a program for executing each step in an electronic device.

1 Measuring device 2 Sensor 21 External terminal 22 Board 23 Detection unit 24 IDT electrode 25 Flow path member 26 Supply port 27 Discharge port 3 Control device 30 Recessed 31 Connection terminal 32 Calculation unit 33 Storage unit

Claims (7)

A sensor in which a substance that reacts with a detection target in a sample is immobilized and the detection target can be detected by a signal change caused by the detection target.
A storage unit that stores a reference signal change caused by a corrector having a known specific measured value used for calibration of the sensor acquired by a sensor having the same configuration as the sensor.
A calculation unit for deriving the measured value to be detected based on the signal change and the reference signal change is provided.
The calculation unit calculates a correction value based on the reference signal change and the first signal change caused by the correction body, and corrects the second signal change caused by the detection target with the correction value. A measuring device that derives the measured value based on the third signal change after calculating the three signal changes. The measuring device according to claim 1.
The calculation unit calculates the ratio of the first signal change to the reference signal change as the correction value, and calculates the product of the second signal change and the correction value as the third signal change. .. The measuring device according to claim 1 or 2.
The storage unit further stores the relationship between the second signal change and the known measured value of the sample acquired together with the reference signal change.
The calculation unit is a measuring device that derives the measured value by comparing the second signal change included in the relationship with the third signal change. A step of preparing a sensor capable of detecting the detection target by immobilizing a substance that reacts with the detection target in the sample and using a signal change caused by the detection target.
A step of storing a reference signal change caused by a corrector having a known specific measured value used for calibration of the sensor acquired by a sensor having the same configuration as the sensor.
The process of acquiring the first signal change caused by the corrector and
A step of calculating a correction value based on the reference signal change and the first signal change, and
The process of acquiring the second signal change caused by the detection target and
The step of correcting the second signal change with the correction value and acquiring the third signal change, and
A measuring method comprising a step of deriving a measured value of the detection target contained in the sample based on the third signal change. The measuring method according to claim 4.
The correction value is the ratio of the first signal change to the reference signal change, and the product of the second signal change and the correction value is calculated as the third signal change. The measuring method according to claim 4 or 5.
A measuring method in which the correction body is supplied to the sensor and has a different density or viscosity from the flow medium through which the sample and the correction body are flown. The measuring method according to any one of claims 4 to 6.
Further comprising a step of storing the relationship between the second signal change and the known measured value of the sample acquired together with the reference signal change.
A measuring method for deriving the measured value by comparing the change in the second signal included in the relationship with the change in the third signal.

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