JP7819466B2 - Calibration method and calibration device - Google Patents

Description

This disclosure relates to a calibration method for calibrating an analytical device, a calibration standard sample used to calibrate an analytical device, and a calibration device for calibrating an analytical device.

Analytical devices are known that irradiate a sample with light, detect scattered light from substances in the sample, and analyze the properties of the sample from the detection results obtained.

JP 2020-060586 A (Patent Document 1) discloses a blood coagulation analyzer that analyzes blood coagulation ability by irradiating a measurement sample prepared by adding a reagent to a specimen such as plasma with light and detecting and analyzing the resulting scattered light.

Japanese Patent Application Laid-Open No. 2020-060586

In such analytical devices, there are individual differences in the light source and the detection unit that detects scattered light. Therefore, analytical devices must be calibrated using a standard reference material. Calibration of analytical devices is performed, for example, when the analytical device is manufactured or during maintenance.

However, there has been insufficient consideration given to standard samples and calibration methods used in analytical instruments that analyze sample properties based on scattered light from the sample.

An object of the present disclosure is to provide a calibration method, a calibration standard sample, and a calibration device suitable for an analytical device that analyzes the properties of a sample based on scattered light from the sample.

The calibration method disclosed herein is a method for calibrating an analytical device that includes a storage unit for storing a sample, a light source for irradiating light onto the sample stored in the storage unit, and a detection unit for measuring scattered light from the sample. The calibration method includes the steps of storing a standard sample in the storage unit, in which standard particles prepared so that the particle size distribution falls within a predetermined range are dispersed in a liquid; acquiring the detection value obtained by the detection unit when the standard sample is stored in the storage unit; and calibrating the analytical device so that the detection value becomes a predetermined value.

The standard sample disclosed herein is a calibration standard sample used to calibrate an analytical instrument that includes a light source that irradiates a sample with light and a detection unit that detects scattered light from the sample. The calibration standard sample contains standard particles dispersed in a liquid, the standard particles being prepared so that the particle size distribution range falls within a predetermined range.

The calibration device of the present disclosure also calibrates an analytical instrument that includes a storage unit for storing a sample, a light-emitting element that irradiates the sample stored in the storage unit with light , an adjustment mechanism for adjusting the luminance of the light -emitting element, and a detection unit that measures scattered light from the sample. The calibration device includes a processor and a communication port for communicating with the analytical instrument, and the processor receives, from the analytical instrument via the communication port, a value detected by the detection unit when a standard sample, in which standard particles prepared so that the particle size distribution falls within a predetermined range are dispersed in a liquid, is stored in the storage unit, and the processor outputs, to the analytical instrument via the communication port, a signal for adjusting the luminance of the light-emitting element so that the detection unit obtains a predetermined detection value when the standard sample is stored in the storage unit.

According to the present disclosure, standard particles prepared so that the particle size distribution range falls within a predetermined range are used, thereby providing a standard sample with consistent scattering properties. Furthermore, by performing calibration using such a standard sample, a calibration method is provided that minimizes the impact on measurement results caused by differences in the standard sample used during calibration, and a calibration device is provided that is capable of performing calibration that minimizes the impact on measurement results caused by differences in the standard sample used during calibration. As a result, the reproducibility of measurement values is improved.

FIG. 1 is a diagram functionally illustrating an overall configuration of an analysis device 1000 according to an embodiment. FIG. 2 is a plan view showing an example of the configuration of an analysis table of the analysis device 1000. FIG. 2 is a diagram illustrating an example of the configuration of a photometry unit 130. FIG. 10 is a plan view showing an example of the configuration of the coagulation port P3a. FIG. 2 is a block diagram showing an example of a system configuration of an analysis device 1000 and a control device 500. FIG. 2 is a diagram illustrating an example of the hardware configuration of a control device 500. 10 is a flowchart illustrating an example of a calibration procedure for the coagulation port P3a. FIG. 10 shows the change in scattering intensity of control plasma after the addition of a reagent. 10 is a graph showing the results of measuring scattered light from a sample. FIG. 2 is a block diagram showing the configurations of a measuring device 300 and a control device 500. FIG. 2 is a block diagram showing in more detail the hardware configuration of the measurement device 300 and the control device 500. 10 is a flowchart showing a procedure in which the control device 500 calibrates the measurement device 300 included in the analysis device 1000. 10 is a flowchart showing a procedure in which the control device 500 receives input of a reference value used for calibration (modification); 10 is a flowchart showing a procedure in which the control device 500 calibrates the measurement device 300 included in the analysis device 1000 based on a reference value (variation).

Embodiments of the present disclosure will now be described in detail with reference to the drawings. Note that identical or equivalent parts in the drawings will be designated by the same reference numerals and their descriptions will not be repeated.

The analytical device of the present disclosure is configured to dispense a sample into a cuvette using a probe (nozzle) and optically measure the reaction state within the cuvette. In this disclosure, "sample" can include not only the "measurement sample" that is the object of measurement, but also a "standard sample" used for calibration. The "measurement sample" may also be referred to as a "specimen," such as a blood component (plasma). In addition, in this disclosure, disposable cuvettes are used.

[Overall configuration of the analysis device 1000]
1 is a diagram functionally illustrating the overall configuration of an analyzer 1000 according to an embodiment. The analyzer 1000 described in this embodiment can function as an automatic blood coagulation (fibrinolysis) analyzer.

Referring to FIG. 1, the analytical device 1000 includes a cuvette supplying device 110, a cuvette transporting device 120, a stirring device 200, a measuring device 300, and a cuvette waste container 400. Note that, hereinafter, the cuvette supplying device 110, the cuvette transporting device 120, and the cuvette waste container 400 will be simply referred to as the "supplying device 110," the "transporting device 120," and the "waste container 400," respectively.

The analytical device 1000 further includes a sample dispensing port P1. The supply device 110 includes a cuvette storage unit 111 (hereinafter simply referred to as "storage unit 111") and a supply mechanism 112. The storage unit 111 is configured to be able to store a large number of cuvettes (for example, up to 1,000). The supply mechanism 112 supplies the cuvettes stored in the storage unit 111 to the sample dispensing port P1. Details of the storage unit 111 and the supply mechanism 112 will be explained later with reference to Figure 2.

The sample dispensing port P1 is positioned so that a sample can be dispensed into a cuvette by a sample dispensing device (not shown). When a cuvette is set in the sample dispensing port P1, the sample is dispensed into the cuvette by the sample dispensing device.

The transfer device 120 includes an arm 121 with a chuck (hereinafter simply referred to as "arm 121") and a drive device 122. The arm 121 has a chuck configured to grip a cuvette. The arm 121 is configured to removably hold the cuvette with the chuck. The drive device 122 is configured to operate the arm 121 (chuck) to change the position of the chuck. Details of the arm 121 and drive device 122 will also be explained later with reference to Figure 2.

The analytical device 1000 further includes multiple ports through which cuvettes can be transferred by the transfer device 120, specifically, an agitation port P2, a photometry port P3, and a waste port P5. The photometry port P3 includes multiple coagulation ports P3a and multiple colorimetric ports P3b. The sample dispensing port P1 is provided with a port sensor that detects the presence or absence of a cuvette. Port sensors may also be provided in other ports (such as the agitation port P2, photometry port P3, and waste port P5).

Agitation port P2 is positioned at the agitation position of agitation device 200. When a cuvette is set in agitation port P2, agitation device 200 is configured to agitate the contents of the cuvette under predetermined conditions (e.g., agitation speed and agitation time).

The coagulation port P3a and the colorimetric port P3b are each located in a photometric unit (not shown). Light is irradiated from a light source onto each of the coagulation port P3a and the colorimetric port P3b, and a detector (not shown) is provided to detect the irradiated light.

The measuring device 300 receives the light intensity detection results from the detectors of the coagulation port P3a and colorimetric port P3b, and performs a predetermined measurement on the contents of the cuvette set in each port. That is, for the coagulation port P3a, the measuring device 300 uses the amount of scattered light detected by the detector to perform a coagulation measurement of the sample in the cuvette. For the colorimetric port P3b, the measuring device 300 uses the amount of transmitted light detected by the detector to measure the absorbance in the cuvette.

The light source for the coagulation port P3a can be, for example, a light-emitting diode, and the detector provided in the coagulation port P3a can be, for example, a photodiode. The detector in the coagulation port P3a is positioned to detect the amount of 90° scattered light (light scattered in a direction perpendicular to the light irradiation direction).

The light source for colorimetric port P3b can be, for example, a halogen lamp. The wavelength of light supplied to colorimetric port P3b can be switched using a filter depending on the analysis conditions. The detector provided at colorimetric port P3b can be, for example, a photodiode. The detector at colorimetric port P3b is positioned to detect the amount of transmitted light.

The analytical device 1000 further includes a reference port P4 for measuring the absorbance in a cuvette set in the colorimetric port P3b. The reference port P4 has the same configuration as each colorimetric port P3b, but no cuvette is set in it, and it is shielded by a lid or the like to prevent light other than that from the light source from entering the reference port P4. The absorbance is then measured from the ratio (light intensity ratio) between the amount of light detected by the detector provided in the colorimetric port P3b and the amount of light detected by the detector provided in the reference port P4, and colorimetric analysis of the sample is performed.

The waste port P5 is configured to collect used cuvettes. The waste port P5 is connected to the waste container 400, for example, via piping. When a cuvette is inserted into the waste port P5, the cuvette is guided into the waste container 400.

[Analysis table configuration]
Fig. 2 is a plan view showing an example of the configuration of the analysis table of the analysis device 1000. Fig. 2 shows three mutually orthogonal axes (X-axis, Y-axis, and Z-axis), where the X-axis and Y-axis indicate the width and depth directions of the analysis device 1000, respectively, and the Z-axis indicates the vertical direction (i.e., the up-down direction). The direction indicated by the arrow on the Z-axis is the upward direction, and the opposite direction is the downward direction (i.e., the direction of gravity).

Referring to Figures 2 and 1, the storage unit 111 stores a large number of cuvettes 100. A user can replenish the storage unit 111 with cuvettes 100 through an inlet (not shown) in the storage unit 111. The cuvettes 100 can be made of any material that is light-transmitting, and for example, transparent acrylic can be used.

The supply mechanism 112 is configured to remove cuvettes 100 one by one from the storage section 111 and supply them to the sample dispensing port P1. The supply mechanism 112 may transport the cuvettes 100 in any manner, including, for example, a slide system (gravity system), a belt conveyor system, a roller system, or a slide system. The supply mechanism 112 is configured to receive the detection results of the port sensor of the sample dispensing port P1, and supply the next cuvette 100 to the port P1 when the sample dispensing port P1 becomes empty. However, the present invention is not limited to this, and the supply mechanism 112 may also be configured to supply cuvettes 100 to the sample dispensing port P1 in accordance with instructions from the control device described below.

The arm 21 is a device (sample dispensing device) for dispensing the sample aspirated from the sample suction port P21 into the cuvette 100 set in the sample dispensing port P1, and includes a probe 21a and an arm body 21b. The arm body 21b is configured to be rotatable around a rotation axis 23a, and as the arm body 21b rotates, the probe 21a attached to the tip of the arm body 21b can move along an arc-shaped trajectory L2 in the XY plane.

By rotating the arm body 21b, the probe 21a can move to each of the sample dispensing port P1, sample suction port P21, S port P22 (more specifically, ports P22a to P22i), and washing port P23, which are provided on the track L2. Regarding the S port P22, for example, ports P22a and P22b are detergent ports, ports P22c, P22d, and P22e are buffer solution ports, and ports P22f, P22g, P22h, and P22i are plasma-deficient ports.

Although not shown, a movable sample rack is provided below the sample aspiration port P21. A plurality of sample containers are placed on the sample rack. When analyzing a sample, a blood component (e.g., plasma) or urine sample is placed in each of these sample containers, and when calibrating the analyzer 1000, a standard sample (described below) is placed in each of these sample containers. Prior to dispensing a sample into a cuvette 100 set in the sample dispensing port P1, the sample rack operates to position the sample container to be dispensed directly below the sample aspiration port P21. The CTS mechanism 24 is provided near the sample aspiration port P21 and is configured to pierce the cap of the sample container to be dispensed if it has a cap.

The photometry unit 130 has multiple photometry ports P3 (multiple coagulation ports P3a and colorimetric ports P3b) arranged in an arc. In this example, 14 coagulation ports P3a and 6 colorimetric ports P3b are arranged. The arm 11 is an instrument for dispensing reagent aspirated from the suction port P11 into the target cuvette 100 set in the photometry port P3, and includes a probe 11a and an arm body 11b. The arm body 11b is configured to be rotatable around a rotation axis 13a, and by rotating the arm body 11b, the probe 11a attached to the tip of the arm body 11b can move in an arc-shaped trajectory L1 in the XY plane.

By rotating the arm body 11b, the probe 11a can move to each of the coagulation ports P3a, colorimetric ports P3b, suction ports P11 and P12, and washing port P13 provided on the track L1. Although not specifically shown, in reality, the probe 11a is composed of two probes to prevent contamination between reagents, and the reagent tray 31a (described below) has an outer tray and an inner tray, allowing the reagent (or washing solution) on the outer tray and the reagent (or washing solution) on the inner tray to be aspirated from the suction ports P11 and P12 using two probes, respectively. The washing port P13 is a port for washing the probe 11a.

The reference port P4 is provided in a location separate from the photometric port P3 (photometric unit 130). As described above, the reference port P4 has the same configuration as each colorimetric port P3b, but because there is no need to set the cuvette 100, it is placed, for example, inside the analysis device 1000 rather than on the analysis table.

Below the suction ports P11 and P12, a reagent tray 31a on which multiple reagent containers 1 and multiple detergent containers 1a are placed is provided, and the reagent tray 31a is provided inside the reagent refrigerator 31. The multiple reagent containers 1 contain different reagents, and the multiple detergent containers 1a contain different detergents. The reagent tray 31a is composed of a disc-shaped turntable, and by driving the turntable, the desired reagent container 1 or detergent container 1a can be positioned directly below the suction ports P11 and P12.

The arm 121 includes a chuck 121a and an arm body 121b. The chuck 121a is configured to be able to grip the cuvette 100. The chuck 121a may hold the cuvette 100 in any manner, and the chuck 121a may be a mechanical chuck, a magnetic chuck, or a vacuum chuck. The arm body 121b is configured to be able to rotate together with the rotating body 122a around the rotation axis 13a. When the rotating body 122a rotates, the arm body 121b rotates integrally with the rotating body 122a, and the chuck 121a provided at the tip of the arm body 121b can move in a circular arc-shaped trajectory L1 on the XY plane.

As described above, arm 11 and arm 121 share the same center of rotation. On orbit L1, there are provided a sample dispensing port P1, an agitation port P2, a waste port P5, multiple photometric ports P3 (multiple coagulation ports P3a and multiple colorimetric ports P3b), suction ports P11 and P12, and a cleaning port P13. Arm 121 can move chuck 121a to sample dispensing port P1, agitation port P2, each photometric port P3, and waste port P5, while arm 11 can move probe 11a to aspiration ports P11 and P12, cleaning port P13, agitation port P2, and each photometric port P3.

[Configuration of photometry unit 130]
FIG. 3 is a diagram showing an example of the configuration of the photometry unit 130. Referring to FIG. 3, the photometry unit 130 has a plurality of coagulation ports P3a and colorimetric ports P3b arranged in an arc. More specifically, the plurality of coagulation ports P3a and colorimetric ports P3b are arranged so that the storage portions of each port are aligned along an arc-shaped trajectory L1. In this example, 14 coagulation ports P3a and 6 colorimetric ports P3b are arranged. Note that the number and arrangement order of the coagulation ports P3a and colorimetric ports P3b are not limited to those shown in the figure.

Figure 4 is a plan view showing an example configuration of the coagulation port P3a. The coagulation port P3a includes a storage section 312, a light-emitting diode 316 serving as an example of a light source, and a photodiode 314 serving as an example of a detector or light-receiving element. In Figure 4, the optical axis Li of the light emitted from the light-emitting diode 316 toward the storage section 312 is schematically shown by a dashed line.

The storage unit 312 is configured to allow the cuvette 100 transferred by the transfer device 120 (arm 121) to be detached, and is a specific example of a "storage unit" for storing samples.

The light-emitting diode 316 irradiates light onto the sample (cuvette 100) stored in the storage section 312. The light-emitting diode 316 is, for example, a red light-emitting diode that irradiates light with a wavelength of 660 nm. However, the light-emitting diode 316 is not limited to this. For example, a light-emitting diode 316 that irradiates light with a wavelength of 405 nm, 570 nm, 730 nm, or 800 nm may also be used.

The photodiode 314 detects light scattered in a predetermined direction from the sample. Specifically, the photodiode 314 is disposed in a direction perpendicular to the optical axis Li of the light emitted from the light-emitting diode 316, and detects light scattered at a 90° angle from the sample. In this embodiment, the photodiode 314 is configured to detect light scattered at a 90° angle from the sample, but it may also be configured to detect light scattered at other angles.

The coagulation port P3a is used to measure the coagulation time in order to analyze the coagulation function of a sample. Specifically, when a reagent is added to a blood component (e.g., plasma) that serves as the sample, a coagulation reaction occurs, converting fibrinogen in the sample to fibrin. While fibrinogen is soluble in water, fibrin is insoluble in water, causing a change in the turbidity of the reaction solution. The photodiode 314 measures the scattered light generated when light is irradiated onto the reaction solution as an indicator of the turbidity of the reaction solution. The photodiode 314 measures the scattered light over time. The coagulation time is calculated by applying an algorithm to the reaction curve indicated by the change in scattered light over time.

[System configuration]
Fig. 5 is a block diagram showing an example of a system configuration of analysis device 1000 and control device 500. Fig. 5 conceptually illustrates only the configuration related to measurement using light, among the configuration of analysis device 1000 shown in Fig. 1. Referring to Fig. 5, analysis device 1000 includes photometry unit 130, robot unit 150, and measurement device 300. Control device 500 is connected to analysis device 1000.

The photometry unit 130 includes multiple coagulation ports P3a, multiple colorimetric ports P3b, and a reference port P4.

The robot unit 150 collectively refers to movable devices such as the arms 11, 21, 121, cuvette supply device 110, CTS mechanism 24, reagent refrigerator 31, reagent tray 31a (see Figure 2), and sample rack. The robot unit 150 handles samples using the arm 21, sample rack, and CTS mechanism 24, handles reagents using the arm 11, reagent refrigerator 31, and reagent tray 31a, and transports and handles cuvettes 100 using the supply device 110 and arm 121. The robot unit 150 is fully automatically controlled by the transport control unit 376 of the measuring device 300.

The measurement device 300 includes a photometry control unit 370, a data collection unit 372, an AD conversion unit 374, and a transport control unit 376. The photometry control unit 370 controls all photometry in the photometry unit 130 in accordance with instructions from the data collection unit 372. For example, the photometry control unit 370 controls the light-emitting diode 316 when performing measurements using the coagulation port P3a.

The data collection unit 372 determines the coagulation port P3a from which measurement data will be acquired in accordance with data collection instructions from the control unit 500, and outputs instructions to the photometry control unit 370 to perform measurements at that coagulation port P3a. The data collection unit 372 then acquires measurement data (measurement signals) of scattered light detected by the photodiode 314 of the coagulation port P3a from the AD conversion unit 374, and outputs the collected data to the control unit 500.

The AD conversion unit 374 converts the detection signal from the photodiode 314 of each coagulation port P3a into a digital signal and outputs it as a measurement signal to the data collection unit 372. The transfer control unit 376 generates commands for controlling various operations of the robot unit 150 in accordance with instructions from the data processing unit 510 of the control device 500, and controls the various operations of the robot unit 150.

The control device 500 includes a data processing unit 510 and a memory unit 512. A display device 520 and a keyboard 530 are connected to the control device 500. The control device 500 is configured, for example, by a personal computer. The control device 500 is an example of a calibration device that calibrates the analysis device 1000.

The display device 520 displays various information related to measurement and calibration. The user inputs various instructions from the keyboard 530 while looking at the screen of the display device 520. The keyboard 530 is an example of an operation unit. In addition to the keyboard, a mouse, which is another example of an operation unit, may also be connected to the control device 500.

The data processing unit 510 generates various instructions for performing measurements in accordance with measurement instructions from the user, and outputs the various generated instructions to the data collection unit 372 and transport control unit 376 of the measuring device 300. The data processing unit 510 also performs various data processing for performing colorimetric analysis and coagulation analysis based on the various measurement data received from the data collection unit 372 of the measuring device 300.

The data processing unit 510 also generates commands to measure the standard sample in accordance with a user's instruction to calibrate the analytical device 1000, and outputs the generated commands to the measuring device 300. The data processing unit 510 then receives the measurement results of the standard sample from the measuring device 300, and calibrates each coagulation port P3a so that the output values from each photodiode 314 included in each coagulation port P3a become predetermined values (hereinafter also referred to as reference values). The calibration method and the standard sample used for calibration will be described below.

The memory unit 512 stores control programs and various information (data) for executing various processes by the control device 500, and outputs various control programs and information (data) to the data processing unit 510 in response to requests from the data processing unit 510.

[Hardware configuration of the control device]
Fig. 6 is a diagram showing an example of the hardware configuration of the control device 500. Referring to Fig. 6, the control device 500 includes a CPU (Central Processing Unit) 531, a RAM (Random Access Memory) 532, a storage device 534, and a communication port 535 for communicating with external devices. The data processing unit 510 and the storage unit 512 shown in Fig. 5 are realized by the hardware shown in Fig. 6.

The CPU 531 loads into the RAM 532 a control program stored in the storage device 534 and executes it. This control program is a program that describes the procedures for various processes executed by the control device 500. In addition to the control program, the storage device 534 also stores various information and data used in the various processes. The control device 500 executes various processes in the analysis device 1000 in accordance with these control programs and various information and data. Note that the processes are not limited to those executed by software, and can also be executed by dedicated hardware (electronic circuits).

In addition, the storage device 534 stores information or data such as a control program that describes processing procedures, as well as reagent information, analysis schedules, analysis history, and calibration information. The reagent information is information about each reagent prepared in the reagent tray 31a (Figure 2) (e.g., reagent ID, reagent type, expiration date, etc.).

The analysis schedule is determined based on sample information (e.g., the analysis items for each sample) and the availability of each port, in order to efficiently analyze all reserved samples. For example, the analysis schedule includes the timing of each dispensing and measurement, the sample and reagent to be dispensed, and the photometric port P3 (coagulation port P3a and/or colorimetric port P3b) where the measurement will be performed. The analysis schedule is managed for each sample ID (each sample container).

The analysis history indicates the progress of the analysis, including intermediate steps, and is updated sequentially as the analysis progresses. The analysis history includes, for example, the cuvette's movement path (including its current position), the sample and reagent dispensed into the cuvette, the photometric port P3 where the measurement was performed, and the measurement results. The analysis history is managed for each cuvette. By referencing the analysis history, the control device 500 and the user can confirm whether the analysis was performed (or is progressing) according to the analysis schedule.

The calibration information includes information necessary to calibrate each coagulation port P3a included in the analyzer 1000, and information indicating the calibration results. The information necessary for calibration is, for example, a reference value for the output value from the photodiode 314 that is used as a reference during calibration. The information indicating the calibration results is, for example, a predetermined value set for each light-emitting diode 316, and a correction value set for each photodiode 314 to correct the detection results.

Calibration Procedure
7 is a flowchart showing an example of a procedure for calibrating the coagulation port P3a. Referring to FIG. 7, a user such as a manufacturer of the analytical device 1000, a user of the analytical device 1000, or a service technician prepares a standard sample (S10). More specifically, the user prepares the standard sample by diluting a sample (stock solution) containing standard particles prepared so that the particle size distribution range falls within a predetermined range with a liquid (dilution solution).

Next, the user stores each of the standard samples in the respective storage units 312 (S20). For example, the user dispenses the standard sample into a sample container and places the sample container with the dispensed standard sample on the sample rack. The arm 21 of the analytical device 1000 aspirates the standard sample from the sample container into the cuvette 100 set in the sample dispensing port P1. Note that the maximum amount of liquid that the arm 21 can aspirate is limited, so the arm 21 repeats the operation of aspirating the standard sample from the sample container and dispensing it into the cuvette 100 until the required amount of standard sample has been dispensed into the cuvette 100. The arm 121 then stores the cuvette 100 containing the standard sample set in the sample dispensing port P1 in the storage unit 312 of the coagulation port P3a. This achieves the processing of S20. Alternatively, the process of S20 may be performed by the user dispensing a standard sample into each of multiple cuvettes 100, and then setting the cuvettes 100 containing the standard sample in the storage section 312 of each of the coagulation ports P3a.

The control device 500 controls each light-emitting diode 316 to irradiate light onto the standard samples stored in each storage section 312 (S30).

The control device 500 acquires the detection values from each photodiode 314 (S40).

The control device 500 calibrates the analysis device 1000 so that the detection value from each photodiode 314 matches a predetermined reference value (S50). For example, the control device 500 sets a command value for adjusting the amount of light emitted from the light-emitting diode 316 so that the detection value from the photodiode 314 matches the reference value. Alternatively, the control device 500 determines a correction value for adjusting the detection value from the photodiode 314 to the reference value. Specific examples of the calibration procedure of the control device 500 will be described in detail later.

The calibration procedure for the coagulation port P3a shown in Figure 7 includes the step of preparing a standard sample. The standard sample may also be prepared in advance.

The step (S10) of preparing a standard sample may be performed by the analytical device 1000, rather than by a user. Specifically, the step (S10) of preparing a standard sample may be realized by the analytical device 1000 executing a step of dispensing a stock solution into a cuvette and a step of dispensing a diluent into the cuvette into which the stock solution has been dispensed. In this case, the stock solution is set in a sample rack, for example, in a sample container. The diluent is set in the S port 22 or the reagent container 1, for example. As an example, the analytical device 1000 may prepare a standard sample as follows: First, the arm 21 dispenses a predetermined amount of the stock solution contained in the sample container into the cuvette 100 supplied to the sample dispensing port P1. Next, the arm 121 moves the cuvette 100 into which the stock solution has been dispensed from the sample dispensing port P1 to the coagulation port P3a. Then, the arm 11 dispenses a predetermined amount of the diluent contained in the reagent container 1 into the cuvette 100 containing the stock solution stored in the coagulation port P3a. At this time, the arm 11 dispenses the dilution solution so that the concentration of the standard particles in the cuvette 100 stored in the coagulation port P3a is within a predetermined concentration range.

[Standard sample]
The standard sample will now be described in detail. The standard sample is configured by dispersing standard particles, which have been prepared so that the particle size distribution range falls within a predetermined range, in a liquid. The liquid is, for example, water. To easily disperse the standard particles, the viscosity of the liquid is preferably equal to or less than that of water. For example, a user may add water to a sample consisting of standard particles and water to create a standard sample in which the standard particles are dispersed in the liquid.

The particle diameter of the particles used as standard particles is selected, for example, based on the wavelength of light from the light-emitting diode 316 and the angle of scattered light detected by the photodiode 314. Preferably, the standard particles used are those whose particle diameter distribution peaks at a particle diameter that scatters most in the direction detected by the photodiode 314 when irradiated with light of the wavelength of the light-emitting diode 316.

For example, if the photodiode 314 is positioned to detect 90° scattered light, the smaller the particle diameter at the peak of the particle diameter distribution, the better. For example, if the wavelength of the light emitted from the light-emitting diode 316 is 660 nm and the photodiode 314 is positioned to detect 90° scattered light, the standard particles preferably have a particle diameter at the peak of the particle diameter distribution of 350 nm or less.

In this way, by selecting a sample as the standard particle with a particle diameter that is the peak of the particle diameter distribution and that scatters a lot in the direction detected by the photodiode 314 when irradiated with light of the wavelength of the light-emitting diode 316, the amount of standard particle required to obtain a predetermined scattering intensity can be reduced. From this perspective, it is preferable that the above-mentioned standard particle has a particle diameter that is the peak of the particle diameter distribution of 350 nm or less.

Furthermore, if there is a large variation in the particle diameters of the particles contained in the standard particles, it will be difficult to intentionally create samples with the same scattering intensity, so it is preferable that there is a small variation in the particle diameters of the particles contained in the standard particles.

For example, the CV (Coefficient of Variation) value, which is an index of particle size distribution (uniformity of particle size) and indicates the ratio of standard deviation to the average particle size, is preferably less than 3%. A CV value of less than 3% indicates that a population with a narrow distribution has been formed around the average diameter.

A possible standard sample to use for calibration is one in which a pigment is mixed into epoxy resin. However, pigments are not prepared so that the particle size distribution falls within a specified range, and there is a problem in that it is not possible to intentionally create a standard sample that will produce the same scattering intensity as a standard sample that has already been created.

The standard samples disclosed herein are created using standard particles that have been prepared so that the particle size distribution range falls within a specified range, making it possible to intentionally create standard samples that provide similar scattering intensities.

Furthermore, when attempting to create a standard sample that will provide a similar scattering intensity (scattering intensity within a specified range), if a sample with a wide particle size distribution is used, it will be necessary to dilute the sample using the reference analytical device 1000 while checking the scattering intensity so that the scattering intensity falls within the specified range. In contrast, by using a sample with a narrow particle size distribution, the scattering intensity obtained using the reference analytical device 1000 can be kept within the specified range by fixing the dilution rate (concentration of standard particles in the standard sample) without having to check the scattering intensity.

Next, the scattering intensity of a standard sample will be described. The analytical device 1000 according to this embodiment is used to observe the coagulation factor activity in blood. Therefore, it is preferable that the standard sample provide a scattering intensity similar to that obtained when measuring a sample in the middle of a coagulation reaction. In other words, the intensity of scattered light detected when light is irradiated onto the standard sample is preferably within the range of the scattered light intensity distribution obtained by measuring the change over time in scattered light detected when light is irradiated onto a sample obtained by adding a reagent for inducing a coagulation reaction to a specimen containing at least plasma. From another perspective, it is also preferable that the intensity of scattered light detected when light is irradiated onto a standard sample is within a predetermined range. This range is preferably set, for example, according to the scattered light intensity distribution obtained by measuring the change over time in scattered light detected when light is irradiated onto a sample obtained by adding a reagent for inducing a coagulation reaction to a specimen containing at least plasma.

Figure 8 shows the change in scattering intensity of control plasma after the addition of a reagent. More specifically, the change in scattering intensity shown in Figure 8 represents the change in voltage detected by the detector due to the change in scattering intensity after adding a reagent to control plasma (Coagpia Control P-N I, manufactured by Sekisui Medical Co., Ltd.) using an analyzer 1000 (CP3000, manufactured by Shimadzu Corporation) with prothrombin time and fibrinogen as the measurement items. The change in scattering intensity shown by the solid line in Figure 8 represents the result obtained when prothrombin time was the measurement item and the reagent (Coagpia PT-N, manufactured by Sekisui Medical Co., Ltd.) was added to the control plasma. The change in scattering intensity shown by the dashed line in Figure 8 represents the result obtained when fibrinogen was the measurement item and the reagent (Coagpia Fbg Thrombin Reagent, manufactured by Sekisui Medical Co., Ltd.) and diluent (Coagpia Fbg Sample Diluent, manufactured by Sekisui Medical Co., Ltd.) were added to the control plasma. As shown in Figure 8, the median output voltage for all measurement items is between 250mV and 500mV.

For this reason, it is preferable that the standard sample be prepared so that the output voltage detected by the detector of the analytical device 1000 (CP3000, manufactured by Shimadzu Corporation) is between 250 mV and 500 mV.

Next, we will explain the relationship between the concentration of standard particles and scattering intensity. The standard particles used were a sample with an average particle diameter of approximately 270 nm, a CV value of 1.6%, and a particle concentration of 1 wt% (product number 3269A, Thermo Fisher Scientific), a sample with an average particle diameter of approximately 300 nm, a CV value of 1.6%, and a particle concentration of 1 wt% (product number 3300A, Thermo Fisher Scientific), and a sample with an average particle diameter of approximately 350 nm, a CV value of 1.9%, and a particle concentration of 1 wt% (product number 3350A, Thermo Fisher Scientific). Here, particle concentration is the ratio of particle mass to sample mass. A stock solution was prepared by diluting the sample 251 times with water (for example, 1 mL of sample diluted with 250 mL of water). The stock solution was further diluted to create multiple samples. The scattered light from the sample was measured using an analytical instrument 1000 (CP3000, manufactured by Shimadzu Corporation).

Figure 9 is a graph showing the results of measuring the scattered light of a sample. The horizontal axis of Figure 9 shows the dilution series of the stock solution (volume of stock solution / (volume of stock solution + volume of water)), and the vertical axis shows the output voltage corresponding to the scattering intensity. The value of 0 in the dilution series shows the output voltage obtained when measuring water. The measurement results shown by the dotted line in Figure 9 are the results for a sample made using standard particles with an average particle size of 270 nm. The measurement results shown by the solid line in Figure 9 are the results for a sample made using standard particles with an average particle size of 300 nm. The measurement results shown by the dashed line in Figure 9 are the results for a sample made using standard particles with an average particle size of 350 nm.

If the specific gravity of a sample with a particle concentration of 1 wt% is equal to the specific gravity of water, the particle concentration of the standard particles contained in the sample in dilution series 1 is approximately 0.004 wt% (= 1 wt% / 251). Similarly, if the specific gravity of a sample with a particle concentration of 1 wt% is equal to the specific gravity of water, the particle concentration of the standard particles contained in the sample in dilution series 0.2 is approximately 0.0008 wt% (= 1 wt% / 251 x 0.2). Below, the particle concentrations of the standard samples are calculated assuming that the specific gravity of a sample with a particle concentration of 1 wt% is equal to the specific gravity of water.

As shown in Figure 9, the smaller the dilution series, the lower the output voltage detected as scattered light. Note that the smaller the dilution series, the lower the particle concentration of the standard particles. In other words, the lower the particle concentration of the standard particles, the lower the output voltage detected as scattered light.

As shown in Figure 9, the output voltage obtained when measuring water was 29.6 mV. Therefore, to reduce the effects of scattering from water, it is preferable that the standard sample be prepared to a concentration that will result in an output value above a predetermined value. For example, it is preferable that the standard sample be prepared to a concentration that will result in an output value of 200 mV or more.

When using standard particles with an average particle size of 270 nm, the output voltage obtained when measuring a sample in the dilution series of 0.4 (particle concentration: approximately 0.0016 wt%) is 228.1 mV. Therefore, when using standard particles with an average particle size of 270 nm, it is preferable to adjust the particle concentration to 0.0016 wt% or higher.

When using standard particles with an average particle size of 300 nm, the output voltage obtained when measuring a sample in the dilution series of 0.4 (particle concentration: approximately 0.0016 wt%) is 207.5 mV. Therefore, when using standard particles with an average particle size of 300 nm, it is preferable to adjust the particle concentration to 0.0016 wt% or higher.

When using standard particles with an average particle size of 350 nm, the output voltage obtained when measuring a sample in the dilution series of 0.5 (particle concentration: approximately 0.002 wt%) is 192.9 mV, which is approximately 200 mV. Therefore, when using standard particles with an average particle size of 350 nm, it is preferable to adjust the particle concentration to 0.002 wt% or higher.

Furthermore, as mentioned above, it is preferable that the standard sample be prepared so that the median output voltage detected by the detector of the analytical device 1000 (CP3000, manufactured by Shimadzu Corporation) is between 250 mV and 500 mV.

When using standard particles with an average particle size of 270 nm, the output voltage obtained when measuring samples in the dilution series 0.5 (particle concentration: approximately 0.002 wt%) to 1.0 (particle concentration: approximately 0.004 wt%) is approximately 250 mV to approximately 500 mV. Therefore, when using standard particles with an average particle size of 270 nm, it is preferable to adjust the particle concentration to between 0.002 wt% and 0.004 wt%.

When using standard particles with an average particle size of 300 nm, the output voltage obtained when measuring samples in the dilution series 0.5 (particle concentration: approximately 0.002 wt%) to 1.0 (particle concentration: approximately 0.004 wt%) is approximately 250 mV to approximately 500 mV. Therefore, when using standard particles with an average particle size of 300 nm, it is preferable to adjust the particle concentration to between 0.002 wt% and 0.004 wt%.

When using standard particles with an average particle size of 350 nm, the output voltage obtained when measuring a sample in dilution series 0.7 (particle concentration: approximately 0.0028 wt%) is 261 mV, and the output voltage obtained when measuring a sample in dilution series 1 (particle concentration: approximately 0.004 wt%) is 375.8 mV. Therefore, when using standard particles with an average particle size of 350 nm, it is preferable that the particle concentration be adjusted to at least 0.0028 wt% or higher.

In this way, by adjusting the concentration of the standard sample, it is possible to simulate the state during the clotting reaction, and calibration can be performed using a standard sample similar to the sample being measured.

[Procedure for the control device 500 to calibrate the analytical device 1000 using a standard sample]
Before describing the calibration procedure, we will explain the background art. Light-emitting diodes (LEDs) have been widely used as light sources in analytical instruments. However, to ensure a wide measurement range that can accommodate samples of various concentrations, it is necessary to maintain the emission intensity of the light source used in the analytical instrument within a certain range. Therefore, it is extremely important to calibrate the emission intensity of the light source to an appropriate value in the analytical instrument.

However, because the brightness of light-emitting diodes varies greatly from one to another, some production lots may have brightness that deviates from the standard. Analytical devices are sometimes equipped with a correction circuit that corrects the output value of the light-receiving element. However, if the light-emitting diode's brightness deviates significantly from the standard, the output value of the light-receiving element cannot be adjusted to the standard value, even with the correction circuit. Therefore, even taking into account the existence of a correction circuit, it is still time-consuming to select light-emitting diodes that have a certain range of brightness. This can also be a factor in reducing production yields.

Furthermore, the brightness of light-emitting diodes gradually decreases over time due to deterioration. Therefore, to maintain the output value of the light-receiving element at a reference value, calibration is required after each analysis process. The more light-emitting diodes used in an analytical device, the more time-consuming calibration becomes. Furthermore, in the past, correction using a correction circuit was often only performed during the manufacturing of the analytical device, and this did not adequately address the deterioration of light-emitting diodes over time.

The luminous efficiency of light-emitting diodes tends to increase year by year. As a result, the brightness of standard light-emitting diodes in circulation also increases year by year. As a result, it is becoming more and more difficult to obtain light-emitting diodes with the same level of luminous performance as light-emitting diodes used in the past. Because the luminous brightness of newly obtained light-emitting diodes is too high, the correction circuit installed in the analytical device at the time is unable to correct the output value of the light-receiving element to the appropriate value, which is a problem.

In light of these background art issues, the following describes the procedure by which the control device 500 calibrates the analytical device 1000 using a standard sample, with reference to Figures 11 to 14.

Figure 10 is a block diagram showing the configuration of the measuring device 300 and the control device 500. The measuring device 300, which constitutes part of the analytical device 1000, includes a board 310 corresponding to each of the 14 coagulation ports P3a. Connected to the board 310 are light-emitting diodes 316, which are an example of light-emitting elements, and photodiodes 314, which are an example of light-receiving elements. The measuring device 300 is configured to be able to communicate with the control device 500, which is an example of a calibration device. As also shown in Figure 5, the control device 500 is connected to a display device 520 and a keyboard 530.

The control device 500 outputs a measurement or calibration command to the substrate 310 corresponding to the coagulation port P3a to be measured or calibrated. The user selects the coagulation port P3a to be measured or calibrated by operating the keyboard 530.

Figure 11 is a block diagram showing the hardware configuration of the measurement device 300 and the control device 500 in more detail. Figure 11 illustrates one of the multiple boards 310 included in the measurement device 300. The various components of the measurement device 300 shown in Figure 5 are realized by the hardware shown in Figure 11.

The measuring device 300 includes a board 310 on which a microcomputer 311, an I/V conversion circuit 313, an amplifier circuit 315, and a current control circuit 319 are mounted. The current control circuit 319 is connected to a light-emitting diode 316. The I/V conversion circuit 313 is connected to a photodiode 314. The light-emitting diode 316 and the photodiode 314 are stored in the coagulation port P3a together with the storage section 312 (see FIG. 4). The measuring device 300 shown in FIG. 10 is provided with multiple microcomputers 310. Each microcomputer 311 corresponds to a respective combination of the light-emitting diodes 316 and the photodiodes 314. However, all of the light-emitting diodes 316 and the photodiodes 314 may be connected to a single microcomputer 311 provided in the measuring device 300.

When calibrating the analytical device 1000, a standard sample is stored in the storage unit 312. For example, the standard sample described above in this embodiment may be used as the standard sample.

The current control circuit 319 controls the forward current If flowing through the light-emitting diode 316. The amplifier circuit 315 is configured to amplify the input voltage within a predetermined range of magnification.

The microcomputer 311 communicates with the control device 500. The control device 500 outputs various commands to the microcomputer 311 via the communication port 535. The various commands include commands regarding the value of the forward current If to be passed through the light-emitting diode 316 and commands regarding the amplification factor of the amplifier circuit 315. The value of the forward current If and the amplification factor of the amplifier circuit 315 are specified, for example, by the user. The user specifies the value of the forward current If and the amplification factor of the amplifier circuit 315, for example, by operating the keyboard 530. The values specified by the user are stored in the memory device 534 as part of the calibration information.

Based on instructions from the control device 500, the microcomputer 311 sets the value of the forward current If to be passed by the current control circuit 319 and sets the amplification factor of the amplifier circuit 315. The current control circuit 319 passes the set magnitude of forward current If through the light-emitting diode 316. This causes the light-emitting diode 316 to emit light at a brightness that corresponds to the brightness characteristics of the light-emitting diode 316 and the magnitude of the forward current If.

Light from the light-emitting diode 316 is irradiated onto the standard sample in the storage section 312. A portion of the scattered light generated by the standard sample is incident on the photodiode 314. A current corresponding to the magnitude of the incident light flows through the photodiode 314. The I/V conversion circuit 313 converts the current output by the photodiode 314 into a voltage Vout.

The I/V conversion circuit 313 transmits the voltage Vout to the amplifier circuit 315. The amplifier circuit 315 amplifies the voltage Vout by a set magnification. As a result, the voltage Vout is amplified to the voltage Vgout. The voltage Vgout is input to the microcomputer 311. The microcomputer 311 A/D converts the input voltage Vgout. The microcomputer 311 outputs the A/D converted value to the control device 500 as the detection value of the detection unit.

The control device 500 acquires the detection value from the measurement device 300. The control device 500 stores the acquired detection value in the storage device 534 as part of the calibration information. The control device 500 also displays the acquired detection value on the display device 520. The user determines whether the detection value matches the reference value. Of course, if the detection value falls within a range with a certain width around the reference value, it may be determined that the analysis device 1000 has been properly calibrated.

If the user determines that the detected value does not match the reference value or is not within a certain reference range, they can reset the forward current If and amplification factor and instruct the control device 500 to calibrate the analysis device 1000 again.

Figure 12 is a flowchart showing the procedure by which the control device 500 calibrates the measuring device 300 included in the analytical device 1000. First, the control device 500 detects the input of the target photometric port number (step S101). In step S101, a port corresponding to a storage unit in which a standard sample has been previously stored is selected. A notification may be sent to the user to confirm whether or not a standard sample has been stored in the storage unit corresponding to the selected photometric port. The photometric port number is input to the control device 500, for example, by the user operating the keyboard 530. Based on the input photometric port number, the control device 500 identifies the board 310 from which to output a calibration command, from among the multiple boards 310 provided in the measuring device 300.

Next, the control device 500 displays on the display device 520 a screen for setting the forward current If to be passed through the light-emitting diode 316 and the amplification factor of the amplifier circuit 315 (step S102). At this time, the control device 500 may also display on the screen the photometry port number to be calibrated.

Next, the control device 500 receives the input of the forward current If and outputs a command signal to the measuring device 300 to adjust the forward current If (step S103). The measuring device 300 sets the forward current If corresponding to this command signal in the target current control circuit 319.

Next, the control device 500 receives the input of the amplification factor and outputs a command signal to the measuring device 300 to adjust the amplification factor (step S104). The measuring device 300 sets the amplification factor corresponding to this command signal in the target amplifier circuit 315.

Next, the control device 500 detects an instruction to emit light (step S105). The instruction to emit light is input to the control device 500, for example, by the user operating the keyboard 530. Next, the control device 500 outputs a command to the measurement device 300 to emit light to the storage section of the target photometry port number (step S106).

As a result, a forward current If of the set magnitude flows through the light-emitting diode 316. The light from the light-emitting diode 316 is irradiated onto the standard sample in the storage section 312, generating scattered light. A signal corresponding to the magnitude of the scattered light is detected by the photodiode 314. The detected signal is output to the control device 500 via the I/V conversion circuit 313, amplifier circuit 315, and microcomputer 311. The amplifier circuit 315 amplifies the signal by the set magnification.

The control device 500 receives the detection value from the measuring device 300 (step S107). Next, the control device 500 displays the detection value on the screen (step S108) and ends the processing based on this flowchart. The user compares the detection value with the calibration reference value, and if necessary, reviews the forward current If and amplification factor, and causes the control device 500 to execute the processing based on this flowchart again. This allows the user to calibrate the detection value obtained for the standard sample to the reference value.

As described above, according to this embodiment, the forward current If of the light-emitting diode 316 can be adjusted to an appropriate value in relation to a reference value. Additionally, according to this embodiment, by adjusting the amplification factor of the amplifier circuit 315 to an appropriate value, the detection value output when a standard sample is used can be calibrated to the reference value.

For this reason, even when using light-emitting diodes 316 that vary in light emission intensity, the analytical device 1000 can be properly calibrated. Furthermore, because the calibration process can be performed using the control device 500, it is easy to calibrate the analytical device 1000 each time to address deterioration of the light-emitting diodes 316 over time. Furthermore, even if the only light-emitting diodes available are those that are deemed to have excessively high light emission brightness, the analytical device 1000 can be properly calibrated by adjusting the forward current If.

[Modification]
Next, a modified example will be described with reference to Figures 13 and 14. In the processing procedure of Figure 11 described above, the user must compare the detected value with the calibration reference value and, if necessary, revise the forward current If and the amplification factor. Here, as a modified example, a method will be described in which the detected value obtained for a standard sample is automatically calibrated to the reference value in order to reduce the burden on the user. The hardware configuration of this modified example is the same as that shown in Figures 10 and 11.

Figure 13 is a flowchart showing the procedure by which the control device 500 accepts input of a reference value to be used for calibration. First, the control device 500 displays a screen for setting the reference value on the display device 520 (step S201). The user can input the reference value on the screen of the display device 520 by operating the keyboard 530.

Next, the control device 500 detects the input of a reference value (step S202). Next, the control device 500 stores the reference value in the storage device 534 (step S203), and ends the processing based on this flowchart.

The control device 500 may display on the display device 520 a screen that allows the user to input a reference value for each photometry port number. The control device 500 may also display on the display device 520 a screen that allows the user to input the concentration of a standard sample to be used for calibration in addition to the reference value. The control device 500 may also display on the display device 520 the reference value (500 mV), Vout1, Vout2, scatterer concentration, and current voltage value for each photometry port number.

For example, when a standard sample of a first concentration is stored in storage unit 312 corresponding to photometry port number 1, a user may set a first reference value as the detection value obtained when light is irradiated onto the standard sample of the first concentration. In this case, the user can input the first concentration as the concentration of the standard sample corresponding to photometry port number 1 on the screen of display device 520 by operating keyboard 530, and input the first reference value as the reference value corresponding to photometry port number 1. It is desirable that control device 500 stores this first concentration and first reference value as calibration information in memory device 534, correlating them with photometry port number 1. Furthermore, it is desirable that control device 500 be able to read out calibration information for each photometry port number and calibrate the detection value for each photometry port number.

Figure 14 is a flowchart showing the procedure by which the control device 500 calibrates the measurement device 300 included in the analysis device 1000 based on the reference value. The control device 500 automatically performs calibration according to the procedure described below, based on the reference value stored in step S203 of Figure 13.

First, the control device 500 determines whether it is time to calibrate (step S211). The calibration timing can be set in various ways. For example, a specific date and time may be set as the calibration timing. Alternatively, the timing when the analysis device 1000 is initialized may be set as the calibration timing.

If the control device 500 determines that it is not time to perform calibration, it terminates processing based on this flowchart. If the control device 500 determines that it is time to perform calibration, it selects the target photometry port number (step S212). For example, the control device 500 may initially select photometry port number 1. In this case, the next time calibration is performed, the selected photometry port number may be updated to 2. The control device 500 may also select the photometry port number to be calibrated in accordance with user instructions stored in the storage device 534.

Next, the control device 500 sets the amplification factor of the amplifier circuit 315 to a predetermined value (step S213). Here, for example, the amplification factor may be set to 2. The amplification factor set here may be stored in advance in the storage device 534.

Next, the control device 500 sets the forward current If to a predetermined value (step S214). The predetermined value may be a standard value that takes into account the characteristics of the light-emitting diode, etc. The value of the forward current If set here may be stored in advance in the memory device 534. Next, the control device 500 outputs a command to the measurement device 300 to irradiate light onto the storage unit 312 of the target photometry port number (step S215).

As a result, a forward current If of the set magnitude flows through the light-emitting diode 316. The light from the light-emitting diode 316 is irradiated onto the standard sample in the storage section 312, generating scattered light. A signal corresponding to the magnitude of the scattered light is detected by the photodiode 314. The detected signal is output to the control device 500 via the I/V conversion circuit 313, amplifier circuit 315, and microcomputer 311.

Next, the control device 500 receives the detection value from the measurement device 300 (step S216). Next, the control device 500 determines whether the detection value is within the target range (step S217). The control device 500 determines whether the detection value is within the target range using the reference value and the amplification performance of the amplifier circuit 315.

A specific example will be used to explain how to determine whether a detection value is within the target range. A standard sample according to this embodiment is used for calibration. The reference value for the detection value obtained when using the standard sample is set to, for example, 500 mV. The amplifier circuit 315 is capable of amplifying the input signal by, for example, 2 to 22 times.

In this case, in order to use the amplification function of amplifier circuit 315 to adjust the value of voltage Vgout output from amplifier circuit 315 to 500 mV, the voltage Vout output from I/V conversion circuit 313 to amplifier circuit 315 must be 500/22 mV or higher. This voltage is referred to as Vout1.

Furthermore, if the voltage Vout output from the I/V conversion circuit 313 to the amplifier circuit 315 is too high, the detected value cannot be adjusted to the reference value. For example, when the amplification factor of the amplifier circuit 315 is set to twice the minimum factor, if the voltage Vout exceeds "500/2", the voltage Vgout output from the amplifier circuit 315 will exceed the reference value. Therefore, in order to be able to adjust the value of the voltage Vgout output from the amplifier circuit 315 to 500 mV, the voltage Vout output from the I/V conversion circuit 313 to the amplifier circuit 315 must be "500/2" mV or less. This voltage is referred to as Vout2.

For example, if the amplification factor set in step S213 is 2 and the value (Vgout) detected in step S217 is 40 mV, the voltage Vout output from the I/V conversion circuit 313 to the amplifier circuit 315 is 40/2 mV. In this case, "(40/2) < Vout1" holds. Currently, the voltage Vout output from the I/V conversion circuit 313 to the amplifier circuit 315 is too low, so adjusting the amplification factor of the amplifier circuit 315 does not allow the detected value to be calibrated to the reference value. In this case, the control device 500 determines that the detected value is not within the target range. On the other hand, if the voltage Vout output from the I/V conversion circuit 313 to the amplifier circuit 315 satisfies "Vout1 ≦ Vout ≦ Vout2," the control device 500 determines that the detected value is within the target range. Note that the reference value Vout1≦Vout≦Vout2 (for example, 500 mV) changes linearly depending on the concentration of scatterers.

The control device 500 may be configured so that the user can freely set the range of the reference value within the range of Vout1 to Vout2. Because minimizing the forward current If extends the life of the LED, it is generally desirable for Vout to be closer to Vout1. However, with LEDs that inherently have a low light output, it has been observed that if the forward current If is small (light output is low), noise occurs in the photodiode output when the LED is turned on and when it switches from OFF to ON and ON to OFF. For this reason, there is a demand to set the forward current If of LEDs with a low light output closer to Vout2, rather than positioning it near Vout1. If the range of the reference value can be freely set, the weighting of the forward current If and amplification degree can be freely changed, allowing for greater flexibility.

In this way, the control device 500 determines whether the detection value received in step S216 is within the target range based on the reference value and the amplification factor set in step S213 (step S217). Note that a tolerance may be set for the reference value. For example, a range of 500 ± 25 mV may be adopted as the reference range with a tolerance.

If the control device 500 determines in step S216 that the detected value received is not within the target range, it outputs a command signal to the measuring device 300 to adjust the forward current If of the light-emitting diode 316 (step S218). Specifically, the control device 500 takes into account the determination result of step S217 and outputs to the measuring device 300 a value of the forward current If adjusted so that the detected value falls within the target range. The measuring device 300 resets the value of the forward current If based on the command received from the control device 500. This adjusts the brightness of the light-emitting diode 316 to an appropriate value. The control device 500 then outputs a command to irradiate light again in step S215. This causes the light-emitting diode 316 to irradiate the standard sample with light again. The control device 500 again determines in step S217 whether the detected value is within the target range.

If the control device 500 determines that the detected value is within the target range, it calculates the amplification factor to match the detected value with the reference value (step S219). The calculated value is obtained, for example, by dividing the reference value by the detected value. Next, the control device 500 sets the calculated amplification factor in the amplifier circuit 315 (step S220), and ends the processing based on this flowchart. By performing the above processing, the brightness of the light-emitting diode 316 and the amplification factor of the amplifier circuit 315 are calibrated to appropriate values.

In the modified example described above, the calibration process is automatically performed by the control device 500, further reducing the workload on the user. As a result, it becomes easier to perform calibration processes regularly. In addition, by increasing the number of calibrations, the analytical accuracy of the analyzer 1000 can be maintained. Furthermore, by performing calibration processes periodically for each of the multiple coagulation ports P3a, it is possible to maintain a low level of accuracy discrepancy between the coagulation ports.

In addition, according to the modified example, because calibration is performed automatically, it is easy to obtain measurement results for a dilution series such as that shown in Figure 9 using standard samples of various concentrations. As a result, it is possible to create a dilution series such as that shown in Figure 9 using standard samples of various concentrations, and adjust and maintain the linearity of the graph shown in Figure 9 at multiple points. Furthermore, rather than manually adjusting the scatterer, it is possible to set the original solution of the scatterer in the device and perform multi-point calibration using automatic dilution, thereby achieving automatic calibration, multi-point calibration, and regular calibration all at once.

So far, with reference to Figures 11 to 14, we have described the procedure by which the control device 500, which is an example of a calibration device, calibrates the analytical device 1000 using a standard sample. By using a standard sample containing standard particles as described above, it is possible to provide a calibration device for obtaining measurements that are traceable to NIST, and as a result, it is possible to maintain the analytical device 1000 in a state that is traceable to NIST.

In this embodiment, an example has been given in which one light-emitting diode 316 is housed within one coagulation port P3a. However, multiple light-emitting diodes may be housed within one coagulation port P3a. In this case, a first light-emitting diode that emits light of a first wavelength and a second light-emitting diode that emits light of a second wavelength different from the first wavelength may be housed within one coagulation port P3a. In such a configuration, it is desirable to configure the control device 500 so that the forward current If for each of the multiple light-emitting diodes can be adjusted.

The control device 500 may also have the ability to apply the calibration procedure for the coagulation port P3a to the colorimetric port P3b, enabling calibration of the colorimetric port P3b as the target.

In this embodiment, the current control circuit 319 is given as an example of a mechanism that allows the brightness of the light-emitting diode 316 to be adjusted. Another example of a mechanism that allows the brightness of the light-emitting diode 316 to be adjusted is a variable resistor provided in the light-emitting diode 316.

For example, the variable resistor may be provided with an operating unit for adjusting the resistance value of the variable resistor. Operating the operating unit changes the resistance value, thereby adjusting the forward current If flowing through the light-emitting diode 316. This makes it possible to adjust the brightness of the light-emitting diode 316. The light-emitting diode 316 may be provided with a digital variable resistor device that can receive command signals from the control device 500. In this case, the digital variable resistor device adjusts the variable resistance value in response to the command signal from the control device 500. As a result, the forward current If flowing through the light-emitting diode 316 is adjusted. This makes it possible to adjust the brightness of the light-emitting diode 316.

In this embodiment, the control device 500 connected to the analysis device 1000 is given as an example of a calibration device. However, the control device 500 having the above-mentioned calibration function may also be provided in the analysis device 1000. For example, the calibration function of the control device 500 may be built into the measurement device 300.

[Aspects]
It will be understood by those skilled in the art that the above-described embodiments are specific examples of the following aspects.

(Section 1) One aspect of the calibration method is a method for calibrating an analytical device that includes a storage unit for storing a sample, a light source for irradiating light onto the sample stored in the storage unit, and a detection unit for measuring scattered light from the sample. The calibration method includes the steps of: storing a standard sample in the storage unit, in which standard particles prepared so that the particle size distribution falls within a predetermined range are dispersed in a liquid; acquiring a detection value obtained by the detection unit when the standard sample is stored in the storage unit; and calibrating the analytical device so that the detection value is a predetermined value.

Calibrating using a standard sample with consistent scattering characteristics reduces the impact on measurement results caused by differences in the standard sample used during calibration, and improves the reproducibility of measurement values. Standard particles adopted as standards by the National Institute of Standards and Technology (NIST) may also be used as standard particles. Using a standard sample containing such standard particles provides a calibration method for obtaining measurements that are traceable to NIST.

(Section 2) In the calibration method described in Section 1, the concentration of standard particles in the standard sample is 0.002 wt% or more.

This configuration reduces the influence of scattered light from the liquid other than the standard particles.

(Section 3) In the calibration method described in Section 2, the concentration of standard particles in the standard sample is 0.002 wt% or more and 0.004 wt% or less.

This configuration makes it possible to simulate the state of the clotting reaction in progress, and calibration can be performed using a standard sample similar to the sample being measured.

(4) In the calibration method described in 2, the concentration of standard particles in the standard sample is 0.004% or more.

This configuration reduces the influence of scattered light from the liquid other than the standard particles.

(Section 5) In the calibration method described in Section 1, the intensity of scattered light detected when a standard sample is irradiated with light is within the range of scattered light intensity distribution obtained by measuring the change over time in scattered light detected when a sample obtained by adding a reagent for inducing a coagulation reaction to a specimen containing at least plasma is irradiated with light.

This configuration makes it possible to simulate the state of the clotting reaction in progress, and calibration can be performed using a standard sample similar to the sample being measured.

(Item 6) In the calibration method described in any one of Items 1 to 5, the ratio of standard deviation (CV value) to the average particle diameter of the standard particles is less than 3%.

This configuration makes it possible to intentionally create samples with the same scattering intensity. Furthermore, even without checking the scattering intensity, by fixing the dilution rate (concentration of standard particles in the standard sample), the scattering intensity obtained using the reference analytical device can be kept within a specified range, thereby improving work efficiency when creating standard samples.

(Item 7) In the calibration method described in any one of Items 1 to 6, the peak particle size of the standard sample is 350 nm or less.

This configuration reduces the amount of standard particles required to obtain a given scattering intensity, thereby reducing the cost of standard samples.

(Item 8) The calibration method described in any one of Items 1 to 7 further includes a step of preparing a standard sample by diluting a sample containing standard particles with water.

By further including a step of diluting the sample with water, a liquid that is readily available, this type of calibration means that only the sample containing the standard particles needs to be prepared, which reduces the amount of luggage a service technician must carry when visiting the installation site of an analytical instrument to perform maintenance.

(Item 9) In the calibration method described in any one of Items 1 to 8, the analytical device includes a plurality of reaction units, each including a light source, a detection unit, and a storage unit. In the step of storing a standard sample in the storage unit of the calibration method, the standard sample is stored in the storage unit of each of the plurality of reaction units. In addition, in the step of calibrating the analytical device of the calibration method, each of the plurality of reaction units is calibrated so that the detection value of the detection unit of each of the plurality of reaction units becomes a predetermined value.

This type of calibration reduces the time required for calibration when calibrating an analytical device with multiple reaction units, as there is no need to calibrate each reaction unit one by one.

(Item 10) Furthermore, a calibration standard sample according to one embodiment is a standard sample used to calibrate an analytical device that includes a light source that irradiates light onto a sample and a detection unit that detects scattered light from the sample, and is made by dispersing standard particles in a liquid, the standard particles being prepared so that the particle size distribution range falls within a predetermined range.

The standard sample for calibration described in paragraph 10 uses standard particles prepared so that the particle size distribution range falls within a predetermined range, thereby providing a standard sample with consistent scattering characteristics. As a result, calibration using such a standard sample provides a calibration method that minimizes the impact on measurement results caused by differences in the standard sample used during calibration, and improves the reproducibility of measurement values. Note that standard particles adopted as NIST standards may also be used as the standard particles used in the standard sample, and using a standard sample containing such standard particles provides a calibration method for obtaining measurement values traceable to standards established by NIST.

(Section 11) Furthermore, a calibration device according to one embodiment calibrates an analytical device that includes a storage unit for storing a sample, a light-emitting element that irradiates light onto the sample stored in the storage unit, an adjustment mechanism for adjusting the brightness of the light-emitting element, and a detection unit that measures scattered light from the sample. The calibration device includes a processor and a communication port for communicating with analytical device 1000. When a standard sample, in which standard particles prepared so that the particle size distribution falls within a predetermined range are dispersed in a liquid, is stored in the storage unit, the processor receives from the analytical device via the communication port a value detected by the detection unit, and outputs a signal to the analytical device via the communication port to adjust the brightness of the light-emitting element so that the detection unit obtains a predetermined detection value when the standard sample is stored in the storage unit.

The calibration device described in paragraph 11 makes it possible to calibrate the analytical device, including the luminance of the light-emitting element, using a standard sample made of standard particles prepared so that the particle size distribution range falls within a predetermined range. This makes it possible to provide a calibration device that can perform calibration while minimizing the impact on measurement results that may occur due to differences in the standard sample used during calibration.

(Item 12) The calibration device described in Item 11 further includes a memory that stores a reference value for the detection value measured by the detection unit when the standard sample is stored in the storage unit, and the processor outputs a signal to the analysis device that adjusts the brightness of the light-emitting element so that the reference value is detected by the detection unit.

The calibration device described in paragraph 12 automatically adjusts the brightness of the light-emitting elements based on reference values stored in memory, thereby reducing the burden of calibration work on the user.

(Clause 13) In the calibration device described in Clause 12, the detection unit includes a light-receiving element that receives scattered light and an amplifier circuit configured to amplify the magnitude of a signal determined based on the output of the light-receiving element within a predetermined range, and the processor outputs a signal to the analysis device that adjusts the brightness of the light-emitting element so that a reference value is obtained when the signal determined based on the output of the light-receiving element is amplified within the predetermined range.

In the calibration device described in paragraph 13, the luminance of the light-emitting element and the amplification factor of the amplifier circuit can be adjusted to properly calibrate the analytical device.

The embodiments disclosed herein are intended to be combined as appropriate within the scope of any technical inconsistency. The embodiments disclosed herein should be considered in all respects to be illustrative and not restrictive. The scope of the present invention is indicated by the claims, not by the description of the above-described embodiments, and is intended to include all modifications within the meaning and scope of the claims.

100 cuvette, 130 photometric unit, 150 robot unit, 300 measuring device, 310 substrate, 311 microcomputer, 312 storage unit, 313 I/V conversion circuit, 314 photodiode (detector), 315 amplifier circuit, 316 light-emitting diode (light source), 319 current control circuit, 370 photometric control unit, 372 data collection unit, 374 conversion unit, 376 transport control unit, 500 control device, 510 data processing unit, 512 memory unit, 520 display device, 530 keyboard, 531 CPU, 532 RAM, 534 memory device, 535 communication port, 1000 analyzer, P3a coagulation port.

Claims (10)

1. A calibration method for calibrating an analytical device, comprising:
the analytical device comprises a storage unit for storing a sample, a light-emitting element for irradiating light onto the sample stored in the storage unit, an adjustment mechanism for adjusting the luminance of the light-emitting element, and a detection unit for measuring scattered light from the sample;
The detection unit
a light receiving element that receives the scattered light;
an amplifier circuit configured to amplify the magnitude of an output signal determined based on the output of the light receiving element by an amplification factor set within a predetermined range;
a step of storing a standard sample in the storage unit, the standard sample being prepared by dispersing standard particles in a liquid, the standard particles being adjusted so that the particle size distribution falls within a predetermined range;
acquiring a detection value of the detection unit obtained when the standard sample is stored in the storage unit;
a step of determining whether an acquired detection value is within a target range using the reference value and the predetermined magnification range so that a predetermined reference value can be obtained from the detection unit when the output signal is amplified within the predetermined magnification range, adjusting the luminance of the light-emitting element so that the acquired detection value falls within the target range when the acquired detection value is not within the target range , and setting an amplification magnification in the amplifier circuit to adjust the acquired detection value to the reference value when the acquired detection value is within the target range . The calibration method described in claim 1, wherein the concentration of the standard particles in the standard sample is 0.002 wt% or more. The calibration method described in claim 2, wherein the concentration of the standard particles in the standard sample is 0.002 wt% or more and 0.004 wt% or less. The calibration method described in claim 2, wherein the concentration of the standard particles in the standard sample is 0.004 wt% or more. The calibration method described in claim 1, wherein the intensity of scattered light detected when the standard sample is irradiated with light is within a scattered light intensity distribution range obtained by measuring the change over time in scattered light detected when a sample obtained by adding a reagent for inducing a coagulation reaction to a specimen containing at least plasma is irradiated with light. A calibration method according to any one of claims 1 to 5, wherein the ratio of the standard deviation to the average particle diameter of the standard particles is less than 3%. A calibration method according to any one of claims 1 to 6, wherein the peak particle diameter of the standard particles is 350 nm or less. The calibration method of any one of claims 1 to 7, further comprising the step of preparing the standard sample by diluting a sample containing the standard particles with water. the analysis device includes a plurality of reaction units, each of which includes the light-emitting element, the detection unit, and the storage unit;
In the step of storing the standard sample in the storage unit, the standard sample is stored in the storage unit of each of the plurality of reaction units,
A calibration method according to any one of claims 1 to 8, wherein in the step of calibrating the analytical device, each of the plurality of reaction units is calibrated so that the detection value of the detection unit of each of the plurality of reaction units becomes a predetermined value. A calibration device for calibrating an analytical device, comprising:
the analytical device comprises a storage unit for storing a sample, a light-emitting element for irradiating light onto the sample stored in the storage unit, an adjustment mechanism for adjusting the luminance of the light-emitting element, and a detection unit for measuring scattered light from the sample;
The detection unit
a light receiving element that receives the scattered light;
an amplifier circuit configured to amplify the magnitude of an output signal determined based on the output of the light receiving element by an amplification factor set within a predetermined range;
The calibration device
a processor;
a communication port for communicating with the analytical device;
a memory for storing a reference value of the detection value measured by the detection unit when a standard sample in which standard particles prepared so that the particle diameter distribution falls within a predetermined range are dispersed in a liquid is stored in the storage unit,
the processor receives the detection value detected by the detection unit from the analysis device via the communication port when the standard sample is stored in the storage unit;
The processor:
a signal for adjusting the brightness of the light-emitting element so that the detection value detected by the detection unit falls within the target range when the output signal is amplified within the range of the predetermined magnification is output to the analysis device via the communication port, the signal being used to determine whether the received detection value is within the target range, so that the detection value detected by the detection unit falls within the target range ,
A calibration device that outputs, when the received detection value is within the target range, a signal to the analysis device via the communication port to set an amplification factor in the amplifier circuit to adjust the received detection value to the reference value .