JPH06265559A - Automatic immunoanalyzer - Google Patents

Abstract

PURPOSE:To enhance efficiency in measurement by modifying the arrangement of reagent dispensers and B/F separators to be used depending on the reaction time of each reagent thereby improving the handling. CONSTITUTION:Reaction containers B held in a rack C are transferred one by one on an endless transfer path D. A sample/reagent dispenser E, reagent dispensers F, G1-G3, B/F separators H, I, a photometric unit J and a reaction container disposer K are arranged sequentially from the upstream. The reagent dispensers G1-G3 comprise containers 8A-8C containing enzyme-labeled antibody liquids for 5, 10 and 15min reaction, and buffer detergent containers 9A-9C. The dispensers G1-G3 are selected depending on the required reaction time and the reagents are dispensed to the reaction container B at respective dispensational positions C1-C2. The B/F separators H, I move to positions n1-n3 depending on a reaction time being selected and suck the antibody liquid from the container B thus performing B/F separation. This constitution improves handling and enhances efficiency in processing.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an enzyme immunoassay method (EIA method) utilizing an antigen-antibody reaction, an immunoturbidimetric method or a light scattering assay method or a chemiluminescence method (CL method) utilizing latex agglutination. The present invention relates to a high-sensitivity automatic immunoanalyzer using an electrochemiluminescence method (ECL method), and in particular, it is possible to perform dispensing timing of labeled reagents and B / F separation according to the reaction time after the reagents. The present invention relates to an automatic analyzer.

[0002]

2. Description of the Related Art Conventionally, various highly sensitive immunoassay devices using the immunoturbidimetric method or the light scattering measuring method utilizing the EIA method or latex agglutination, or the CL method or the ECL method have been proposed. In the conventional immunoassay device, the sample dispensing device, the plurality of reagent dispensing devices, the B / F separating device, and the measuring device are arranged at fixed positions. For example, depending on the reagent used for the measurement item, Has a reaction time of 5
There are various types such as minutes, 10 minutes, 15 minutes, etc., but it is not designed to deal with this, it is very inconvenient, and the reaction time is 5 minutes. If all of the 10 minute, 15 minute and 15 minute immuno-automated analyzers were prepared, the equipment cost would be very high and it would be impractical.

The present invention was devised in view of the present situation, and its purpose is to respond to the difference in the reaction time of each reagent and to dispense the reagent and the B / F.
It is an object of the present invention to provide an automatic immunoanalyzer that can greatly improve the usability and practicality of this type of device by configuring the separation time so that it can be easily changed.

[0004]

In order to achieve the above object, in the present invention, the reaction vessels are configured to be sequentially transferred along a transfer path, and the reaction path is moved from the upstream side to the downstream side. Along with sample dispenser, multiple reagent dispensers,
A B / F separating device and a measuring device are provided, and at least one reagent dispensing device and B / F among the plurality of reagent dispensing devices are provided.
It is characterized in that the arrangement position of the F separation device can be changed according to the reaction time.

[0005]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described in detail below with reference to an embodiment shown in the accompanying drawings.

An automatic immune analyzer A shown in FIG. 1 shows a case where the present invention is applied to an automatic immune analyzer of the ECL method using magnetic particles. Of course, the automatic immunoassay device to which the present invention is applied is not limited to the one shown in the figure, and for example, an immunoturbidimetric method using an EIA method or latex aggregation, a light scattering measurement method, or a chemiluminescence method can be used. It can also be applied to the used automatic immune analyzer.

That is, the automatic immunoassay apparatus A according to this embodiment has a rack C for holding reaction vessels B one by one, an endless transfer path D for intermittently transferring the rack C, and a transfer path D for the transfer path D. Sample / first reagent dispensing device E, second / third reagent dispensing device F, fourth reagent dispensing device G ₁ , G ₂ , G ₃ , first B / F separating device arranged in order from the upstream side H, second
It comprises a B / F separation device I, an optical measurement device J, a reaction container disposal device K, and a control device (not shown) that drives and controls them in an organically related manner.

The reaction container B is housed in the reaction container stocker R, and the rack C is arranged in order from the reaction container B on the front side in FIG.
Held in. In this embodiment, the reaction container B is supplied from the reaction container stocker R to the empty rack C where the reaction container B is discarded at the reaction container disposal position g.

The rack C is constructed so as to heat the held reaction container B to a predetermined temperature via a heating device (not shown), and the sample / first reagent dispensing position a, second・ Third reagent dispensing position b, fourth reagent dispensing position c
₁ , c ₂ , c ₃ , first B / F separation positions d ₁ , d ₂ , d
₃ , the second B / F separation position e, the optical measurement position f, the reaction container discarding position g, the reaction container supply position h, and the sample
It is transferred to the first reagent dispensing position a. Since a known belt conveyor mechanism can be applied to the rack C transfer device, detailed description thereof is omitted here.

The transfer path D is a straight transfer path D ₁ on the front side,
Depth side linear transfer path D ₂ and these linear transfer paths D ₁ and D
It is composed of short paths D ₃ , D ₄ and D ₅ connecting the _two , and a short path D ₆ connecting the end portion of the straight transfer path D _{2 and} the start end of the straight transfer path D _1. Transfer route D
_Since a known belt conveyor mechanism can be applied to ₁ and D ₂ , detailed description thereof is omitted here. Moreover, short-path D _3, D ₄ which connects the linear transport path _{D 1, D 2, D 5} , D 6
Although not shown, the movement of the rack C in FIG. Further, a well-known heating device for performing incubation at 20 to 30 degrees is incorporated in the transfer path D.

The sample / first reagent dispensing apparatus E includes a chain belt type autosampler L for holding a plurality of sample containers 1, a first reagent table M, and a first reagent table M for holding the first reagent table M. A reagent container 3 and a chip 2 detachably held on the inner peripheral side of the first reagent container 3;
A drive unit (not shown) that rotationally controls the first reagent table M and a pipette unit N are included, and a reaction solution is contained in the first reagent container 3.

Therefore, in the sample / first reagent dispensing apparatus E, first, the arm 10 of the pipette apparatus N is rotated to the tip pickup position i, and at the position i, the arm 10 is moved.
Is lowered and the tip 2 is fitted on the tip of the pipette 11,
After this, the arm 10 moves up and rotates to the first reagent suction position j and moves down, and after inserting the pipette 11 into the first reagent container 3 to suck the reaction solution which is the first reagent, it moves up. The pipette 11 is swung down to the sample suction position k and lowered, and a certain amount of the sample is sucked from the sample container 1 and then moved up to rotate the pipette 11 to the sample / first reagent dispensing position a. The sample and the reaction solution, which are dynamically transferred and sucked at the position a, are dispensed into the reaction container B. After that, the chip 2 is discarded at a discarding position (not shown) to prevent cross contamination. Needless to say, although not shown, a new sampling pipette tip 1A is automatically provided in the tip holding hole of the first reagent table M holding the used tip 2 by a tip supply device configured by a known pickup robot or the like. Supplied. Although not shown, a reader device for reading an ID number such as a bar code label attached to the sample container 1 is provided at the sample suction position k.

The second / third reagent dispensing apparatus F includes an arm 13 whose one end is pivotally supported by a shaft, a second / third reagent pipette 12 arranged at the other end of the arm 13, and a second A third reagent table F, a second reagent container 5 and a third reagent container 7 held in the second and third reagent tables F, and a dedicated chip 4 for the second reagent container 5 and the third reagent container 7. , 6 and a drive device (not shown) for rotating the second and third reagent tables F forward and backward. In this embodiment, the second reagent container 5 contains the antibody-insoluble magnetic material liquid, and the third reagent container 7 contains the enzyme-labeled antibody liquid. Of course, this second reagent container 5 and the third
The contents of the reagent container 7 may be reversed.

Therefore, in the second / third reagent dispensing device F, first, the arm 13 is rotated to the chip pickup position 1 and lowered, and the driving device drives the second / third reagent suction positions. After fitting the dedicated tip 4 of the second reagent container 5 transferred to m to the tip of the second and third reagent pipettes 12, it is moved up to the second and third reagent pipettes 12 to the second position.
-After transferring to the third reagent suction position m and descending, sucking the antibody-insoluble magnetic body liquid from the inside of the second reagent container 5 that has reached the position m, then ascending to move the second and third reagent pipettes 12 to the second position.・
The solution is transferred to the third reagent dispensing position b and descends to dispense the antibody-insoluble magnetic substance liquid into the reaction container B.

After that, the arm 13 moves up to rotate to the chip pickup position 1 and then descends. After returning the chip 4 to its original position at the position 1, the arm 13 rises and stands by.

Next, the control device controls the rotation of the second and third reagent tables F to transfer the third reagent container 7 containing the third reagent to the second and third reagent suction positions m. To do.

After this, the second and third reagent pipettes 12 are
Is lowered and the dedicated chip 6 of the third reagent container 7 is moved to the second and third chips.
After fitting the tip portion of the reagent pipette 12, it moves up to move the second and third reagent pipettes 12 to the second and third reagent suction positions m.
To the second and third positions after the buffer solution is sucked from the inside of the third reagent container 7 that has reached the position m.
The reagent pipette 12 is transferred to the second / third reagent dispensing position b, and lowered to dispense the enzyme-labeled antibody solution into the reaction container B.

After that, the arm 13 is raised to rotate to the chip pickup position 1 and descend, and after returning the chip 6 to its original position at the position l, it is raised to stand by. ing.

The antibody-insoluble magnetic substance is a substance obtained by sensitizing a known magnetic fine particle with an antibody. The antibody-insoluble magnetic substance is not shown in the figure, but is reacted through a magnetic substance adsorbent composed of an electromagnet or a permanent magnet. Adsorbed on the inner surface of the container B. This magnetic adsorbent is disposed between the second and third reagent dispensing positions b to the fourth reagent dispensing positions c ₁ , c ₂ and c ₃ .

The second and third reagent containers 5 and 7 arranged in the reagent holder are set at predetermined positions, and these positions are stored in the controller S respectively. In addition, since the specific gravity of the antibody-insoluble magnetic substance liquid of the antibody-insoluble magnetic substance liquid is large, if it is left standing, it will settle to the bottom of the container, resulting in variation in measurement accuracy. It is desirable to stir.

The sample / first reagent dispensing position a
Although not shown, a stirring device is provided at the second and third reagent dispensing positions b, and the stirring rod is cleaned after the stirring.

The fourth reagent dispenser G ₁ , G ₂ , G ₃ comprises, for example, a fourth reagent container 8A containing an enzyme-labeled antibody solution for a 5-minute reaction and a container 9A containing a buffer washing solution.
A fourth reagent container 8B containing an enzyme-labeled antibody solution for 10-minute reaction and a container 9B containing a buffer washing solution;
Fourth reagent container 8C containing the enzyme-labeled antibody solution for the fractionation reaction
And a container 9C containing the buffer cleaning liquid, a slide pipette 14 for sucking a target reagent or buffer cleaning liquid from these containers and dispensing it into the reaction container B, and the slide pipette 14 is slid in the horizontal direction in FIG. 1, a horizontal rail member 15 for moving the rail member 15 in the vertical direction in FIG. 1, chips 17A, 17B and 17C dedicated to the fourth reagent, and chips 18A, 18B and 18C dedicated to the buffer cleaning solution. It consists of and. The configuration of the pipette portion of the slide pipette 14 is the same as that of a known pipette device, and the horizontal rail member 15 and the front-rear rail member 16 that slide the slide pipette 14 are the well-known XY transfer device (X -Y slider), the detailed description thereof will be omitted here.

As described above, the reagent container and the buffer washing liquid container are arranged in parallel in three sets, one pair for the purpose of promptly coping with the case where the reaction time differs depending on the measurement item or the specification of the reagent. Thus, for example, when using a reaction reagent for 5 minutes, the fourth reagent and the buffer cleaning liquid sucked from the fourth reagent container 8A and the container 9A containing the buffer cleaning liquid are placed at the fourth reagent dispensing position c ₁ . Dispense into reaction vessel B.

When using a reaction reagent for 10 minutes, the fourth reagent and the buffer cleaning liquid sucked from the fourth reagent container 8B and the container 9B containing the buffer cleaning liquid are
Dispense into the reaction container B at the fourth reagent dispensing position c ₂ .

Further, when a reagent for reaction for 15 minutes is used, the fourth reagent and the buffer cleaning liquid sucked from the fourth reagent container 8C and the container 9C containing the buffer cleaning liquid are supplied to the fourth reagent dispensing position c ₃ Dispense into reaction vessel B at.

When the fourth reagent or the buffer washing solution is aspirated by the slide pipette 14, a dedicated chip is attached to the pipette part (not shown) of the slide pipette 14 before aspirating by the slide pipette 14. Is mounted, and after the fourth reagent or the buffer washing solution is sucked and dispensed into the reaction container B, the chip is returned to its original position.

By the way, in the automatic immune analyzer according to the present embodiment, the fourth reagent dispensing work is configured to correspond to three types of 5 minutes, 10 minutes, and 15 minutes, and these reaction times have different reaction times. The 4 reagents are not mixed and dispensed corresponding to the measurement items, but first, after the analysis treatment in which the 4th reagent of the 5 minute reaction is used is finished, this analysis treatment line is used for the 10 minute reaction this time. The fourth reagent is selected and reset to be used, and the fourth reagent dispensing line for the other 5 minute reaction and 15 minute reaction is paused. Of course, 15
If the 4th reagent of the min reaction is used, select and reset the 4th reagent of the 15 min reaction to be used, and
Pause the 4th reagent dispensing line for the 1 minute and 10 minute reactions. Although not shown, this reaction time is selected by turning on each reaction time selection switch provided on the operation panel of the automatic immune analyzer.

Further, according to the present invention, the fourth reagent dispensing work is configured to correspond to three types of 5 minutes, 10 minutes, and 15 minutes, and the fourth reagent having a different reaction time is used as a measurement item. It is also possible to make a configuration in which they are made to correspond and mixed and dispensed.

In this way, the fourth reagent corresponding to the reaction time is dispensed by the fourth reagent dispensing device G ₁ or G ₂ or G _{3 at} the fourth reagent dispensing position c ₁ or c ₂ or c _3. Then, the reaction container B at the fourth reagent dispensing position c ₁ or c ₂ or c ₃ is pressed and transferred to the depth side transfer path D ₂ via a pressing rod (not shown), and Accordingly, the guide body Q also moves to the depth side of the transfer path D ₂ at each position n ₁ or n ₂ or n.
Move to ₃ and engage the rack C that reached each position,
The reaction container B is configured to be intermittently transferred rightward in FIG.

The first B / F separation device H and the second B / F separation device I are configured such that after sucking the antibody solution in the reaction container B, washing water is injected and stirred, and the antibody-insoluble magnetic substance is magnetized by the reaction container. After adsorbing to, for example, the bottom portion of B, the residual liquid in the reaction container B is sucked, and in the present embodiment, the first B / F separation device H corresponds to the depth of the depth side corresponding to the selected reaction time. Other than the structure that the transfer path D ₂ is moved to each position n ₁ , n ₂ , n ₃ and set, the other structure and action are the same as those of the known B / F separation device. However, detailed description thereof will be omitted here. The second B /
The F separation device I may not be used depending on the measurement item.

The reaction container B thus subjected to the B / F separation treatment is then sent to the optical measurement position f, and the reaction solution in the reaction container B is stirred at the position f, The reaction liquid is sucked by a measuring pipette (not shown) and sent to a flow cell (not shown), a predetermined voltage is applied, and the light emission state by this is measured by the optical measuring device J.
Since the photomultiplier tube and the quantitative measurement method by the photon counting method which constitute the optical measuring device J are known, detailed description thereof will be omitted here.

When the present immunoautomatic analyzer is used for optical measurement in accordance with the CL method, for example, polystyrene beads are used as a solid phase carrier, and the polystyrene beads are coated with an antibody or an antigen to react. In the case of encapsulating in a container B and measuring the antigen by the sandwich method, the target component (antigen) in the sample is reacted with an antibody coated on polystyrene beads to form a solid-phased antibody-antigen, and then the Other components are washed away, an acridinium ester labeled antibody is added and reacted to form a solid phase antibody-antigen-labeled antibody, and then unreacted labeled antibody is washed away.
The immobilized luminescent substance is made to emit light and quantitatively measured by the photon counting method.

In the above embodiment, optical measurement is performed by EIA.
Although the case of performing the method according to the method has been described as an example, when measuring and analyzing the latex agglutination reaction, it is optically measured by a known immunoturbidimetric method or a light scattering method.

Further, in the case of performing optical measurement corresponding to the ECL method, first, divalent ruthenium.
A tris-bi-pyridyl compound (hereinafter referred to as a Ru compound) is oxidized on the electrode surface (not shown) composed of the working electrode and the counter electrode arranged in the luminescence measuring container N to be in a trivalent state. At this time, the T present in a large excess in the sample
PA (tri-propylaminamine) is also simultaneously oxidized by the above electrode and converted into TPA cation radical.
This TPA cation radical is very unstable,
TPA, a strong reducing agent that releases protons in a short time
Change into radicals. The trivalent Ru compound is reduced by the TPA radical to be converted into a divalent Ru compound in the excited state, and photons emitted during the process in which this substance returns to a stable state are provided with PMTs arranged above the luminescence measuring container N. Measured with
After that, the electrode surface is electrochemically washed with an alkaline solution and a condition buffer. In this case, a reference electrode for controlling the excitation potential is incorporated in the luminescence measuring container N.

The discarding device K is a device for pulling out the reaction container B from the rack C and discarding it after all the optical measurements for the reaction container B held in each of the racks C are completed.
The discarded reaction container B is dropped and stored in the recovery container disposed at the reaction container disposal position g. Of course, in the present invention, instead of the discarding device K, a cleaning device having a known configuration may be arranged at the position.

The empty rack C is transferred again to the sample / first reagent dispensing position a via the reaction container supply position h of the short path D ₆ . Of course, the reaction container B may be configured to be newly supplied at the sample / first reagent dispensing position a.

The control device controls the drive of the above-mentioned devices / mechanisms in cooperation with each other, and arithmetically processes the analysis data by a predetermined method. The light received by the light receiving element is A / D.
The converted analysis value is sent to the control unit, and the analysis data is stored and stored in the storage unit (not shown).

Although not shown, the above-mentioned devices and mechanisms are drive-controlled by a known readable / writable IC card.

This IC card has a readable integrated circuit, and this integrated circuit is an electrically rewritable E-EPROM (Electrical Erasable Program).
ammable Read Only Memory),
The drive control means corresponding to the analysis items used in the facility where the automatic immune analyzer is installed are grouped and input, and the name, registration number, position, affiliation, etc. of the operator who uses the automatic analyzer are input. Various operation information is also entered.

[0040]

As described above, the present invention is configured so that the dispensing time of the reagent and the B / F separation time can be easily changed according to the difference in the reaction time of each reagent. By doing so, it is possible to greatly improve the usability and practicality of this type of device, and to achieve a number of excellent effects.

[Brief description of drawings]

FIG. 1 is a plan view schematically showing the overall configuration of an automatic immune analyzer according to an embodiment of the present invention.

[Explanation of sign]

A automatic immunoassay device B reaction container C rack D transfer path E sample / first reagent dispensing device F second / third reagent dispensing device G ₁ , G ₂ , G ₃ fourth reagent dispensing device H 1B / F separation device I Second B / F separation device J Optical measurement device

Claims (1)

[Claims] 1. A reaction container is configured to be sequentially transferred along a transfer path, and a sample dispenser, a plurality of reagent dispensers, and a B / F separator are sequentially arranged from an upstream side to a downstream side of the transfer path. A device and a measuring device are arranged, and the arrangement positions of at least one reagent dispensing device and B / F separating device among the plurality of reagent dispensing devices are configured to be variable according to the reaction time. An automatic immune analyzer characterized by the following.