JP2001074749A - Automatic analyzer - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an automatic analyzer that cancels the influence of specimen temperature fluctuation for a final detection value, and improves analysis accuracy. SOLUTION: An automatic analyzer 1 is equipped with a temperature sensor (thermocouple) that is provided at a second reagent supply part 60 for measuring luminescence reagent liquid temperature, a temperature sensor (thermocouple) that is provided at a BF separation washing part 50 for measuring BF separation wash temperature, and a control part that corrects a luminescence value that is a final detection value based on the luminescence reagent liquid temperature and BF separation wash temperature being measured by the temperature sensors. By the correction, the influence of specimen temperature fluctuation depending on luminescence reagent liquid temperature fluctuation and BF separation wash temperature fluctuation for the luminescence value is canceled.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an automatic analyzer for detecting a chemical reaction using a final reaction detection reagent such as a luminescent reagent.

[0002]

2. Description of the Related Art When chemiluminescence is detected by an automatic analyzer, it is desired to control the luminescence detection value so as to eliminate the temperature change because the luminescence detection value is very sensitive to the temperature change in the measurement environment. In reality, it is extremely difficult to eliminate the temperature change. Therefore, in Japanese Patent Application Laid-Open No. Hei 6-201585 (hereinafter, referred to as a conventional example), the temperature of the reaction cell environment at the time of detection (specifically, the ambient temperature of the space inside the integrating sphere in which the reaction cell is installed) is measured by a temperature sensor. And a method of correcting the emission detection value based on the measured temperature is proposed.

[0003]

Generally, since the measuring cell is always maintained at a constant temperature in a thermostat, the largest factor among the factors that cause the emission detection value to vary is the sample to be inspected. It is known that this is a temperature fluctuation of (sample) itself. The variation in the temperature of the sample depends on the temperature of the final reaction detection reagent such as the luminescent reagent dispensed into the container containing the sample, and the temperature of the BF separation / cleaning solution for performing BF (bound / free) separation and cleaning of the inside of the container. However, in the above conventional example, instead of directly measuring the temperature of the sample, since the ambient temperature near the reaction cell is measured by the sensor and it is regarded as the temperature of the sample, the sensor measures the actual sample temperature fluctuation. The sensitivity of the temperature fluctuation becomes low, and the response of the temperature fluctuation measured by the sensor to the actual specimen temperature fluctuation also becomes slow. Furthermore, in the above-mentioned conventional example, a luminescence reaction is performed using luminol, which is a luminescence reagent, but this luminescence reaction ends in a few seconds. It is difficult to correct for the effects of the reaction.

A method of measuring the sample temperature before detection with a temperature sensor and correcting the emission detection value based on the obtained sample temperature is also conceivable. However, the temperature of the sample in the reaction cell is measured in a non-contact manner by the temperature sensor. In the case of measuring with, the desired sensitivity cannot be obtained as a result. When a temperature sensor is inserted into a sample and the temperature of the sample is measured while the sample is in contact with the sample, not only a sensor driving mechanism is required, but also a sensor driving step and a sensor cleaning step are required. Required
Not realistic.

SUMMARY OF THE INVENTION It is an object of the present invention to provide an automatic analyzer which cancels the influence of a change in the sample temperature on the final detection value and improves the analysis accuracy.

[0006]

According to a first aspect of the present invention, a temperature measuring means for measuring a temperature of a final reaction detection reagent solution is provided. And correcting means for correcting the final detected value based on the detected value.

In order to achieve the above object, a second aspect of the present invention provides a temperature measuring means for measuring the temperature of the BF separation cleaning liquid, and corrects the final detected value based on the measured BF separation cleaning liquid temperature. Correction means.

According to a third aspect of the present invention, there is provided a temperature measuring means for measuring a temperature of a final reaction detection reagent solution and a temperature of a BF separation washing solution, respectively. And correcting means for correcting the final detected value based on each of the BF separation cleaning liquid temperatures.

According to a fourth aspect of the present invention, there is provided a thermostatic means for thermosetting at least one of the final reaction detection reagent solution and the BF separation washing solution.

In the first invention, when performing an analysis such as immunity, the temperature measuring means measures the temperature of the final reaction detection reagent solution, and the correction means determines the final detection value based on the measured temperature of the final reaction detection reagent solution. Since the correction is performed, the final detection value obtained by the analysis cancels the influence of the specimen temperature fluctuation depending on the final reaction detection reagent liquid temperature fluctuation, and the analysis accuracy is improved.

In the second invention, when performing an analysis such as immunity, the temperature measurement means measures the temperature of the BF separation washing solution, and the correction means corrects the final detected value based on the measured BF separation washing solution temperature. Therefore, the final detection value obtained by the analysis cancels the influence of the specimen temperature fluctuation depending on the BF separation washing liquid temperature fluctuation, and the analysis accuracy is improved.

In the third invention, when performing an analysis such as immunity, the temperature measuring means is used to determine the temperature of the final reaction detection reagent solution and the B
Since the temperature of the F separation washing solution is measured, and the correcting means corrects the final detection value based on the measured final reaction detection reagent solution temperature and BF separation washing solution temperature, respectively.
The final detection value obtained by the analysis cancels the influence of the specimen temperature fluctuation depending on the fluctuation of the final reaction detection reagent solution temperature and cancels the influence of the specimen temperature fluctuation depending on the fluctuation of the BF separation washing solution. The analysis accuracy is further improved by the synergistic effect of

According to the fourth aspect of the present invention, since the thermostatic means for thermosetting at least one of the final reaction detection reagent solution and the BF separation washing solution is provided, the analysis accuracy is improved by temperature correction and the temperature fluctuation itself is reduced by thermostating. The analysis accuracy is further improved by a synergistic effect with the improvement of the analysis accuracy by the method.

[0014]

Embodiments of the present invention will be described below in detail with reference to the drawings. FIG. 1 is a diagram illustrating the configuration of the automatic analyzer according to the first embodiment of the present invention. FIG.
Among them, 1 indicates an automatic analyzer, and this automatic analyzer 1
Around the reaction turntable 10 arranged at the center, the reaction container transfer section 20, the sample supply section 30, the first reagent supply section 40, the BF separation and cleaning section 50, the second reagent supply section 60, and the measurement section 70 Are arranged as shown in the figure.

The automatic analyzer 1 further includes a control unit (not shown) and output means (not shown) such as a display and a printer for outputting various information such as analysis data obtained as a result of the test. Can be configured. The respective components are controlled in operation in an order corresponding to a predetermined analysis item under the control of the control unit. The control unit includes a computer as a device controller, and includes an input circuit for various input information, an arithmetic processing circuit (CPU), a control program executed by the arithmetic processing circuit, measurement data, various arithmetic results, and the like. , And an output circuit for transmitting a control signal to a controlled object including a mechanical unit such as the above-described reaction turntable 10 and the like.

In FIG. 1, a reaction turntable 10 is constituted by a perfect circular table, and a large number of reaction vessels 11 are held on the same circumference near the outer periphery thereof and transferred at a predetermined operation timing. The rotation direction (in the illustrated example, the counterclockwise direction) and the amount of rotation are controlled.

The reaction container transfer section 20 includes a reaction container stocker 21 and a transfer device 22. The reaction vessel 11 stopped at the position where the stocker 21 is taken out is transferred to the transfer device 2.
By 2, it is supplied to a predetermined position of the reaction turntable 10. The reaction container 11 used in the present embodiment is, for example, a rectangular cuvette, and a specimen and a reagent can be sequentially dispensed into the reaction container 11 supplied to the reaction turntable 10.

The sample supply section 30 is a supply section for supplying a sample to the reaction container 11, and has a sample holding section 32 capable of holding a plurality of sample containers 31 each containing a sample, and a dispenser having a nozzle section at the tip end. (Sample dispenser) 33. When the sample holding unit 32 is sequentially conveyed from left to right in the figure, the dispenser 33 aspirates a sample from the sample container 31 on the holding unit 31 with a nozzle to dispense a predetermined amount, Container 1 on the reaction turntable 10
1 and dispenses the sample.

The first reagent supply section 40 is a supply section for supplying the first reagent to the reaction vessel 11, and has a perfectly circular reagent turntable 41 and a dispenser (reagent dispenser) having a nozzle section on the tip end side. Device 42). On the reagent turntable 41, a reagent storage container (first reagent storage container) 43 storing various first reagents corresponding to a plurality of desired analysis items is held at a position on the outer circumference. Can be. In this case, an enzyme-labeled reagent is arranged as the first reagent. The dispenser 42 dispenses a predetermined amount of the reagent from the corresponding reagent container 43 under the instruction and control of the control unit, and performs dispensing. Therefore, reaction turntable 1
By the rotation of 0, the first reagent can be supplied to the reaction container 11 that has been transferred to the corresponding position facing the first reagent supply unit 40 and stopped.

The BF separation and washing section 50 performs BF separation and washing on the reaction vessel 11 immediately before the final reaction step. As shown in FIG. 2, which is a detailed view of part A in FIG. A tank 51 to be housed, a syringe 52, a valve 54 provided in a pipe 53 connected to the tank 51,
In addition to a cleaning nozzle 55 for sucking the BF separation cleaning liquid, a heater 56 provided near the reaction vessel side end of the pipe 53 and a heater 56 provided near the reaction vessel side end of the heater 56 (instead of piping A thermocouple (which may be provided at the discharge nozzle at the end of 53) as a temperature sensor (a thermistor may be used instead). At the time of the BF separation cleaning operation, a predetermined amount of the BF separation cleaning liquid is sucked from the tank 51 by the syringe 52 and discharged to the reaction container 11 under the instruction and control of the control unit. Further, during the cleaning liquid suction operation after the completion of the BF separation cleaning, the BF separation cleaning liquid in the reaction vessel 11 is suctioned by the cleaning nozzle 55 driven by a drive mechanism (not shown) under the instruction and control of the control unit, and the external To be discharged.

The second reagent supply section 60 is a line dispensing section for supplying the second reagent to the reaction vessel 11, and as shown in FIG. 3, which is a detailed view of section B in FIG. A tank 61 for accommodating the second reagent, a syringe 62, a valve 64 provided in a pipe 63 connected to the tank 61, and a heater 65 provided in the vicinity of the reaction vessel side end of the pipe 63. And a thermocouple (or a thermistor may be used instead) as a temperature sensor provided near the end of the heater 65 on the side of the reaction vessel (alternatively, it may be provided at the discharge nozzle at the end of the pipe 63). Equipped. In this case, a luminescent reagent (for example, a luminol solution and a hydrogen peroxide solution) is stored in the tank 61 as the second reagent. During the line dispensing operation, the luminescent reagent solution is supplied from the tank 61 to the syringe 6 under the instruction and control of the control unit.
A predetermined amount is sucked in 2 and dispensed into the reaction vessel 11. Therefore, the first reagent dispensing by the first reagent supply unit 40 and the BF
After the BF separation and cleaning by the separation and cleaning unit 50, the reaction container 11 transferred to the corresponding position facing the second reagent supply unit 60 and stopped with the rotation of the reaction turntable 10.
, A second reagent can be supplied.

The measuring section 70 measures the luminescence value based on the luminescence reaction by the enzyme labeling reagent and the luminescent reagent. As shown in FIG. 4, which is a detailed view of the section C in FIG. The photomultiplier tube (PM) provided in the section 71
T) 72 and a transfer mechanism 73 for transferring the reaction vessel 11. During the measurement operation, first, the reaction turntable 1
The reaction container 11 on the zero is transferred by the transfer mechanism 73 into the photometric unit 71 as shown by the arrow in the figure, and the luminescence value is measured. After the measurement, the reaction container 11 in the photometric unit 71 is moved by the arrow as shown in the figure. It is transported and discarded in a waste box (not shown).

As described above, the automatic analyzer 1 basically dispenses a sample by the sample supply unit 30, dispenses the first reagent by the first reagent supply unit 40, and
BF separation washing is performed, the second reagent is dispensed by the second reagent supply unit 60, and the measurement is performed by the measurement unit 70, thereby performing the inspection.

In the present embodiment, when performing the above-described inspection, the luminescence reagent solution temperature and the BF
The correction based on the temperature of the separated washing solution is performed, and the outline is as follows.

(1) In the automatic analyzer 1, an immunocomplex is formed on the solid phase, an enzyme labeling reagent as a labeling substance is allowed to react, and after performing BF separation washing with a BF separation washing solution, the labeling substance is removed. A reagent solution (final reaction detection reagent solution, luminescence reagent solution in the above case) that specifically reacts with the above is dispensed, and the product obtained after the reaction is detected. (2) The temperature sensor 57 provided near the outlet of the heater 56 for keeping the temperature of the BF separation cleaning liquid constant on the reaction vessel side,
A temperature sensor provided in the vicinity of the reaction vessel side outlet of the heater 65 for measuring the liquid temperature (BF separation cleaning liquid temperature) Xb when the BF separation cleaning liquid is dispensed into the reaction container 11 and for keeping the luminescent reagent liquid constant. By 66, the liquid temperature (luminous reagent liquid temperature) X when the luminescent reagent liquid is dispensed into the reaction vessel 11
a is measured, and the obtained temperatures Xa and Xb are stored in the storage circuit of the control unit. (3) In each expression representing the relationship between the temperature change of the luminescent reagent solution and the BF separation and washing solution and the luminescence detection value stored in advance in the storage circuit, the temperature Xa of (2) is used.
And Xb are substituted to obtain a correction value. (4) The measured light emission value is corrected by the correction value, and the corrected light emission value is output as a final light emission value.

Next, the correction of the luminescence value in the present embodiment will be described in detail in the case of performing "luminescence detection by luminol reaction with POD (peroxidase) labeled substance". First, items common to both the correction based on the temperature of the luminescent reagent solution and the correction based on the temperature of the BF separation washing solution will be described. The fluctuation of the luminescence value with respect to the fluctuation of the temperature of the specimen (test solution) at the time of detecting the luminescence can be expressed by the following relational expression. dY = 0.025 × dX (1) where dY is the degree of fluctuation of the light emission value, and dX is the temperature fluctuation width (° C.).

Next, a relational expression used for correction based on the temperature of the luminescent reagent solution will be described. The automatic analyzer 1 is provided with a luminol solution and a hydrogen peroxide solution as luminescent reagents. A heater 65 is provided in the middle of a pipe 63 for discharging the luminescent reagent into the reaction vessel 11 by line dispensing. Is always thermostated. A thermocouple is mounted as a temperature sensor 66 near the outlet of the heater 65 provided in the middle of the pipe 63 near the reaction vessel side, and the temperature sensor 66 monitors the temperature of each luminescent reagent solution at the time of ejection. ing. Here, constant temperature control is performed so that the temperature of the luminescent reagent solution at the time of ejection is always around 37 ° C. Further, when performing a plurality of measurements, the deviation value of the luminescence reagent solution temperature from 37 ° C. in the n-th measurement is stored in the storage circuit of the control unit as dXan by the luminescence reagent solution temperature monitoring function. It has become.

It has been found that the following relational expression similar to the above expression (1) is established between the fluctuation of the luminescence reagent liquid temperature at the time of this ejection and the fluctuation of the luminescence value corresponding thereto. This relational expression is also stored in the storage circuit of the control unit in advance. dYa = 0.025 × dXa (2) where dYa is the degree of fluctuation of the luminescence value, and dXa is the fluctuation range (° C.) of the temperature of the luminescence reagent solution.

Next, a description will be given of a relational expression used for correction based on the temperature of the BF separation cleaning liquid. B just before the final reaction process
A heater 56 is provided in the middle of a pipe 53 for discharging the F separation cleaning liquid to the reaction vessel 11 by line dispensing, and the BF separation cleaning liquid is always kept at a constant temperature. In addition, a thermocouple is mounted as a temperature sensor 57 near the outlet of the heater 56 provided in the middle of the pipe 53 on the side of the reaction vessel, and the temperature sensor 57 monitors the temperature of the BF separation cleaning liquid at the time of discharge. I have. Here, the temperature of the BF separation cleaning liquid at the time of discharge is always 3
The temperature is controlled so as to be around 7 ° C. Further, when performing a plurality of measurements, the deviation value of the BF separation cleaning liquid temperature from 37 ° C. in the n-th measurement is stored in the storage circuit of the control unit as dXbn by the BF separation cleaning liquid temperature monitoring function. It has become.

It has been found that the following relational expression holds between the fluctuation of the BF separation cleaning liquid temperature at the time of discharge and the corresponding fluctuation of the emission value. This relational expression is also stored in the storage circuit of the control unit in advance. dYb = 0.010 × dXb (3) where dYb is the degree of fluctuation of the luminescence value, and dXb is the fluctuation range (° C.) of the temperature of the BF separation cleaning liquid.

Next, the correction of the light emission value using the above relational expressions (2) and (3) will be described. When performing a measurement for quantifying AFP (alpha fetoprotein), an immunoreaction for reacting AFP with an antibody in the form of magnetic particles as a solid phase is performed, and then BF separation washing is performed. Next, a POD-labeled AFP antibody reagent is added and reacted to form a sandwich immune complex, followed by BF separation and washing. Since the BF separation washing at this time corresponds to the BF separation washing immediately before the final reaction process, the temperature fluctuation width dX of the BF separation washing liquid is used.
bn is stored in the storage circuit. Next, when the luminescent reagent is dispensed, the temperature fluctuation width dXan of the luminescent reagent at this time is stored in the storage circuit. Thereafter, the POD in the immune complex reacts with the luminescent reagent, and the luminescent value Y is detected by the luminescent reaction.

From the derivation results of the above equations (1), (2) and (3), the temperature fluctuation of the luminescent reagent directly causes the temperature fluctuation of the specimen, but the temperature fluctuation of the BF separation washing solution causes indirect light emission. It can be presumed that the temperature fluctuation of the reagent is caused and the temperature fluctuation of the specimen is caused accordingly. Therefore, when these sample temperature fluctuation factors occur at the same time, it can be estimated that the light emission value Y is affected in a form in which the temperature fluctuation of the luminescent reagent due to each sample temperature fluctuation factor is added.

Therefore, the influence of the specimen temperature fluctuation on the luminescence value Y may be corrected using the following equation. The light emission value after correction (hereinafter referred to as corrected light emission value) is Y ′
Then, Y 'is expressed by the following equation. The unit of Y 'is cps (count per second). Y '= Y / (1 + 0.025dXa + 0.010dXb) (4)

Next, the principle of light emission value correction in the automatic analyzer according to the first embodiment will be described. The inventor of the present application
As a result of intensive studies, it has been found that the above-mentioned fluctuations in the sample temperature are closely related to fluctuations in the temperature of the BF separation washing solution immediately before the final reaction step and fluctuations in the temperature of the final reaction reagent solution such as the luminescent reagent solution. Therefore, the temperature of the BF separation washing solution and the temperature of the luminescent reagent solution are monitored by a temperature sensor to predict the sample temperature at the time of detecting the luminescence value, and correction based on the sample temperature at the time of detecting the luminescence value is easily added to the detected luminescence value. An accurate luminescence detection value was obtained.

More specifically, between the sample temperature and the count corresponding to the luminescence value, the count corresponding to the luminescence value linearly increases according to the increase in the sample temperature, as shown in FIG. 5 (b), the horizontal axis represents the temperature fluctuation around the sample temperature of 37 ° C. (X = 0), and the vertical axis represents the sample temperature 3
When the count variability when the count at 7 ° C. is centered (Y = 0) is represented, Y = 0.0253X +
It was confirmed by experiments that the relationship of 0.0007 was established. The above relational expression (1) is based on this relation. In addition, when measurement was performed on three types of samples having different concentrations (POD), the temperature fluctuation of the luminescent reagent solution (central temperature 3
7C) and the count fluctuation, a linear relationship as shown in FIG. 5C is established, and between the BF cleaning liquid temperature fluctuation (central temperature 37 ° C.) and the count fluctuation, FIG. It was confirmed by experiments that a linear relationship as shown in FIG. The relational expression (2) is based on the relation in FIG. 5C, and the relational expression (3) is based on the relation in FIG.

As described above, according to the automatic analyzer of this embodiment, based on each of the temperature of the luminescent reagent solution and the temperature of the BF separation washing solution measured at the time of analysis of immunity and the like, (2) and ( Since the luminescence value Y is corrected using the expression 3), the luminescence value obtained by the analysis is obtained by canceling the influence of the specimen temperature fluctuation depending on the luminescence reagent liquid temperature fluctuation and the BF separation washing liquid temperature fluctuation, respectively. And the analysis accuracy is improved. Further, the automatic analyzer according to the present embodiment only requires the provision of a temperature sensor for correcting the luminescence value and a heater for maintaining the temperature of the luminescent reagent solution and the BF separation and cleaning solution. Since it becomes possible, the apparatus configuration does not become complicated. Furthermore, the above-described measurement operation with improved analysis accuracy is also useful as a process monitor function from the final reaction process to photometry.

In the first embodiment, both the correction of the luminescence value based on the temperature of the luminescence reagent solution and the temperature of the BF separation cleaning solution and the constant temperature control of the luminescence reagent solution and the BF separation cleaning solution by the heater are performed. When cost is prioritized, the heater may be omitted so that the luminescent reagent solution and the BF separation cleaning solution are not kept at a constant temperature. in this case,
The effect of improving the detection accuracy due to the decrease in the temperature fluctuation range of the specimen as a result of the temperature fluctuation width of the luminescent reagent liquid and the BF separation cleaning liquid temperature being reduced by the constant temperature by the heater cannot be obtained. The effect of improving the detection accuracy due to the correction based on the temperature of the luminescent reagent solution and the temperature of the BF separation washing solution is obtained.

[0038]

As described above, according to the automatic analyzer of the present invention, the influence on the measurement data due to the fluctuation of the specimen temperature at the time of photometry, particularly the influence on the luminescence value data due to the fluctuation of the specimen temperature during the chemiluminescence measurement, Cancellation can be performed without complicating the device configuration, and highly accurate measurement can be performed.

[Brief description of the drawings]

FIG. 1 is a diagram illustrating a configuration of an automatic analyzer according to a first embodiment of the present invention.

FIG. 2 is a detailed view of a portion A in FIG.

FIG. 3 is a detailed view of a portion B in FIG. 1;

FIG. 4 is a detailed view of a part C in FIG. 1;

FIGS. 5A to 5D are diagrams illustrating a method of deriving a relational expression used for emission value correction in the automatic analyzer according to the first embodiment.

[Explanation of symbols]

 Reference Signs List 1 automatic analyzer 10 reaction turntable 11 reaction container 20 reaction container transfer unit 21 reaction container stocker 22 transfer unit 30 sample supply unit 31 sample container 32 sample holding unit 33 dispenser 40 first reagent supply unit 41 reagent turntable 42 Dispenser 43 First reagent storage container 50 BF separation and cleaning unit 51 Tank 52 Syringe 53 Pipe 54 Valve 55 Cleaning nozzle 56 Heater 57 Temperature sensor (thermocouple) 60 Second reagent supply unit 61 Tank 62 Syringe 63 Pipe 63 Valve 65 Heater 66 Temperature sensor (thermocouple) 70 Measuring unit 71 Photometry unit 72 Photomultiplier tube (PMT) 73 Transfer mechanism

Claims (4)

[Claims] 1. A temperature measuring means for measuring a temperature of a final reaction detection reagent solution, and a correction means for correcting a final detection value based on the measured temperature of the final reaction detection reagent solution. Automatic analyzer. 2. An automatic analyzer comprising: a temperature measuring means for measuring a temperature of a BF separation cleaning liquid; and a correction means for correcting a final detected value based on the measured BF separation cleaning liquid temperature. . 3. A temperature measuring means for measuring the temperature of the final reaction detection reagent solution and the temperature of the BF separation washing solution, respectively, and correcting the final detection value based on the measured final reaction detection reagent solution temperature and BF separation washing solution temperature, respectively. An automatic analyzer comprising: a correction unit for performing the correction. 4. The automatic analyzer according to claim 1, further comprising a thermostat for thermostatting at least one of the final reaction detection reagent solution and the BF separation washing solution.