JPH1031025A - Biochemical analyzer - Google Patents

Abstract

(57) [Summary] [PROBLEMS] To provide a simple semi-automatic analyzer capable of accurate time management. A hand-held nozzle device for at least semi-manually aspirating and discharging a sample liquid, a pump device connected to the hand-held nozzle device directly or via a pipe, a reaction container from which a sample liquid is discharged, a plurality of reactions A biochemical analyzer comprising a reaction container transfer device for holding and transferring a container along a transfer path, a timer, and a controller for controlling the device in conjunction with the timer.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a biochemical analyzer for chemically, enzymatically or immunochemically analyzing a specific component in a liquid sample derived from a living body such as serum or urine.

[0002]

2. Description of the Related Art In general biochemical analysis, a sample and a reagent are mixed and reacted at a predetermined temperature for a certain period of time, and a change resulting from the reaction is measured, for example, by an optical method. Measure several times before and after or during the course of the reaction. After mixing the sample and the reagent, the second and third reagents may be further dispensed during the reaction.

For example, in an immunochemical analysis method, a homogeneous measuring system and a heterogeneous measuring system are known. The former is performed in the same manner as general biochemical analysis, and the latter is called B / F
A step of separation (separation of Bound and Free) is added. This step is a step of separating the binding component bound to the water-insoluble carrier and the component not bound to the carrier present in the solution by washing the inside of the reaction vessel with a washing liquid.

[0004]

The conventional biochemical analysis is
It is implemented by a semi-automatic analyzer that performs some operations by hand and a fully automatic analyzer that performs all operations automatically,
Since the progress of the reaction depends on time, it is necessary to perform each analysis operation within a certain time. In a fully automatic analyzer, since all operations are commanded by a control device or the like, it is possible to always analyze a plurality of samples under the same conditions. On the other hand, in the semi-automatic analyzer, it is necessary for the operator to operate while watching the clock so that the reaction time and the like become constant.

[0005] The fully automatic analyzer requires many complicated mechanisms to automatically perform all operations, and has a problem that the apparatus is large and the cost is high. On the other hand, in a semi-automatic analyzer, it is possible to simplify the mechanism of the apparatus as compared with a fully automatic analyzer, but not only the reaction time becomes inaccurate because manual operation is included in a part of the operation, There is a problem that once the analysis is started, the hand cannot be released during the analysis.

[0006]

SUMMARY OF THE INVENTION The present invention has been made in view of the above-mentioned problems, and has been made to provide a simple semi-automatic analyzer capable of accurate time management. A hand-held nozzle device for sucking / discharging the sample liquid, a pump device connected to the hand-held nozzle device directly or via a pipe, a reaction container from which the sample liquid is discharged, and holding a plurality of reaction containers along a transfer path. It is a biochemical analyzer comprising a reaction vessel transfer device for transferring by means of a timer, a timing device, and a control device for controlling the device in conjunction with the timing device. Hereinafter, the present invention will be described in detail.

[0007] As the hand-held nozzle device, those used in the field of ordinary biochemistry can be used. For example, there is a pipette device using a thin tube or a disposable tip connected directly to a pump device or via a pipe. Then, it is sufficient that a sample, a solution of a sample and a sample, a solution of a sample and a diluent of the sample, and the like necessary for such a thin tube and a chip are sucked and then discharged into the reaction vessel. The number of nozzle devices need not be one, but may be, for example, a plurality of nozzle devices connected to the same or different pump devices directly or via piping.
It is preferable to wash the thin tube and the like every time the sample liquid is replaced, and in the case of a disposable tip, replace it with a new one every time the sample liquid is replaced in order to prevent contamination between the sample liquids. As a pump device connected to the nozzle device, for example, a normal syringe pump, a plunger pump, or the like can be used. This pump device may be incorporated in the nozzle device and may be integrally formed, or may be separately formed from the nozzle device and connected by piping.

The hand-held nozzle device may be completely manually operated, but is preferably connected to a control device via a timer device from the viewpoint of time management described later. That is, for example, a switch for aspirating and discharging a liquid sample is provided in the handheld nozzle device, and when this switch is pressed, the timekeeping operation of the timekeeping device is started, and the control device receives the input and the sample is supplied to the handheld nozzle device. The pump device may be driven to suck or discharge the liquid, or an electromagnetic valve may be installed between the driving device and the handheld nozzle device, and the control device may open and close the electromagnetic valve in response to an input. Can be illustrated. However, as will be described later, when the timekeeping operation of the timekeeping device is started using a switch provided separately or a sensor provided on the transfer device, when this switch is pressed, suction and / or discharge of the sample liquid or the like is performed. It is also possible to adopt a configuration that is only performed.

[0009] The discharge of the sample liquid in the hand-held nozzle device usually means the start of analysis. For example, when performing analysis on a plurality of samples in immunochemical analysis, B
/ F separation, detection operation, etc., which need to be performed after a certain time from the start of the reaction for each reaction vessel,
If the ejection of the sample liquid by the hand-held nozzle is performed irregularly, the processing of the analyzer may be affected. For example, B / F
A certain period of time is required to perform the separation operation, etc., but if the sample liquid is discharged to two or more reaction containers within the certain period to start the analysis, an appropriate time is required for the reaction container that started the analysis later. In some cases, B / F separation cannot be performed. In order to avoid this, the handheld nozzle device is connected to the control device, and if there is a possibility that the above-mentioned obstacle may occur in the subsequent operation, even if the discharge switch is pressed, the control device rejects this and the sample liquid is rejected. It is preferable to make a configuration such that the liquid is not discharged, or to prohibit the pressing of the switch itself. In addition, a configuration in which an operator can be visually or audibly notified that a discharge switch can be pressed (or conversely, that the switch cannot be pressed) by using a display device described later can be exemplified. Of course, whether or not a failure occurs in a later operation depends on the processing capability of the entire apparatus and the content of analysis, and therefore, it is necessary to appropriately determine the details. For example, in the above example, B / F
The situation is different between the case where the separation device can process two or more reaction vessels at the same time and the case where only one reaction vessel can be processed at the same time, and depending on the analysis contents, delays in each operation are not affected because the analysis results are not affected. This is because there are cases where

As described above, in the case where it is possible that the control device refuses the operation even if the operator presses the switch for discharging the sample liquid or prohibits the pressing of the switch itself, the operator can easily recognize the situation. For this reason, it is preferable that a display device connected to the control device be installed and displayed to indicate the fact. This display device can also have a function to be described later, other than displaying whether or not the sample liquid can be discharged to the reaction container.

When switches are provided in the hand-held nozzle device, the number and the like are not limited at all. For example, two single-press buttons are provided, one for aspirating sample liquid and the other for discharging, or one for aspirating and discharging sample liquid and the other for aspirating and discharging other liquid. Can be exemplified.
When one switch is used, suction and discharge may be performed by pressing down once and continuously pressing down twice. Such a switch does not necessarily need to be provided on the handheld nozzle main body, and can be provided separately from the main body. For example, the switch may be a foot-operated pedal.

Examples of the liquid sample in the present invention include, but are not particularly limited to, a sample prepared from blood derived from a living body such as human serum and urine. A certain amount of the biological sample is aspirated by the hand-held nozzle device and discharged to the reaction container. The reaction vessel may be charged with a reagent necessary for analyzing the sample liquid in advance. For example, when performing an immunochemical analysis, it may contain an antibody against a specific substance in a sample liquid bound to a water-insoluble carrier and an antibody against a specific substance bound to a labeling substance such as an enzyme. This is a reagent configuration when performing analysis using a so-called one-step sandwich method (simultaneous sandwich method or Simultaneous sandwich method). It is also possible to use a container in which only the antibody to the specific substance in the bound sample liquid is charged, and to subsequently charge the antibody to the specific substance bound to the labeling substance such as an enzyme. In the case of performing analysis using a so-called competitive method, for example, a reaction in which an antibody to a specific substance in a sample liquid bound to a water-insoluble carrier and a specific substance analog in which a specific substance and a labeling substance such as an enzyme are bound in advance is input. A container may be used.

The reaction vessel into which the sample liquid has been charged is placed on a transfer device. The transfer device is not particularly limited as long as it can hold a plurality of reaction vessels and can transfer these along the transfer path. Further, for example, other than the reaction container, a reagent or the like used in the subsequent analysis operation may be held. Examples of such a reagent include an antibody against a specific substance bound to a labeling substance such as an enzyme when the above-described two-step sandwich method is used, and an enzyme substrate when an enzyme is used as a labeling substance.

The transfer device may be composed of, for example, a reaction vessel holding section for holding the reaction vessel, a driving means for moving the reaction vessel holding section, a transfer path, and the like. It may be configured to rotate this. The former case is effective in that the transfer path can be made straight or curved. The latter is effective in that the transfer path itself is limited in the circumferential direction of the disk, but the apparatus itself can be downsized. In addition to such a configuration, for example, a configuration may be adopted in which the reaction container is moved from the reaction container holding portion to a separately configured transfer path using a means capable of capturing the reaction container such as an arm.

A number or the like is assigned to the reaction container holding portion of the transfer device so that the control device described later manages the reaction container. Based on the numbers and the like, the control device performs time management such as the reaction time for each reaction vessel, and manages so that a predetermined operation is performed at a predetermined time. After dispensing the sample liquid into the reaction container, the operator places the sample liquid at an arbitrary position in the reaction container holding section of the transfer device, and automatically inputs the above-mentioned number and the like to the control device, and thereafter, automatically. The analysis is performed at
On the contrary, for example, a suitable mounting place for performing time management in the control device is output in the form of the above-mentioned number or the like, or an indicator lamp is provided for each reaction vessel holding portion, and the suitable mounting place is provided. It is also possible to adopt a configuration in which the reaction vessel is placed at a designated site by turning on a display lamp at the location. In this case, the control device controls the time for a plurality of reaction vessels and facilitates parallel processing. It is also possible to exemplify a configuration in which a placement place separated from the placement place is designated. In addition, a sensor that detects whether or not the reaction vessel is placed on the reaction vessel holding part of the transfer device is installed, and the operator automatically places the reaction vessel that has discharged the sample liquid on the transfer device, and the control device automatically operates. It is also possible to adopt a configuration in which the place where the robot is placed is grasped and time management is performed.

In the case where the control device outputs a place where the reaction container is suitable for time management, a display device for displaying whether or not the sample liquid can be ejected by the hand-held nozzle device can also be used as the output destination. Further, according to this display device, for example, when the disk-shaped reaction vessel transfer device is to start rotating under the instruction of the control device,
It is also possible to display a time until the start of rotation and an indication to the operator that loading of the reaction container is prohibited. This display device may display these items visually, for example, or may display these items by a warning sound or the like. The display device can further display the place where the container has been analyzed and the like with the above-mentioned number. This allows the operator to easily identify unnecessary reaction vessels and discard them.

In the transfer path, for example, a B / F separation device, a reagent dispensing device, a detection device and the like are installed in an immunochemical analyzer. The B / F separation device is a device for discharging the washing solution to the reaction vessel and discharging the liquid from the reaction vessel. In the heterogeneous immunoassay using a water-insoluble carrier, the B / F separation device binds to the label component bound to the carrier and the carrier. This is for separating unlabeled components. The device includes, for example, a pipe for discharging a cleaning liquid and a pipe for discharging a liquid in a reaction vessel,
And a drive means for moving these tubes up and down. As the reagent dispensing device, an ordinary dispensing device composed of a thin tube, a disposable tip and the like connected directly to the pump device or via a pipe can be used.
With this device, for example, as described above, an antibody against a specific substance bound to a labeling substance such as an enzyme in the case of using a two-step sandwich method, or a certain amount of an enzyme substrate or the like when using an enzyme as a labeling substance, is aspirated, Discharge into the reaction vessel. In this case, as long as the same reagent is dispensed, it can be used without washing the thin tube and without changing the disposable tip. The detection device installed on the transfer path is appropriately selected depending on the content of the analysis and the like. For example, a colorimeter or the like may be selected when a color is generated by the reaction, a fluorometer is used when the reaction solution emits fluorescence by the reaction, and a luminescence detector is selected when the reaction solution emits light by the reaction. Besides such an optical detection device,
Depending on the contents of the reaction, for example, an ammeter or the like can be used. The detection by the detection device may be performed, for example, while the reaction solution is maintained in the reaction vessel, or a certain amount of the reaction solution may be collected and detected. in this way,
A device for performing various operations required for performing the analysis is disposed in the transfer path.

In many cases, it is preferable to install a temperature control device for controlling the temperature of the reaction solution in the reaction vessel in the transfer path. For example, a water bath may be arranged below the transfer path, or the path itself may be formed of a heating element. As a result, the analysis can always be performed at a constant temperature, and an analysis with higher reproducibility can be realized. Further, it is preferable that a stirrer for stirring the reaction solution in the reaction vessel is provided in the transfer path. For example, the use of a stirrer that can be moved up and down can be exemplified,
For example, a stirrer that moves with a magnet device may be previously introduced into the reaction vessel. In particular, in immunochemical analysis using a water-insoluble carrier, it is convenient to use a resin or the like in which ferrite or the like is embedded as the carrier. A stirring operation can be realized by installing a magnet device below the transfer device and reciprocating the magnet device. This makes it possible to accelerate the reaction.

The above-described various devices do not necessarily need to be installed on the transfer path of the reaction vessel. For example, a structure in which the reaction vessel on the transfer apparatus is moved to each apparatus by using a reaction vessel capturing means such as an arm. It is good.

The control device according to the present invention comprises a microprocessor and peripheral parts, and is connected to various devices. The microprocessor includes, for example, driving means such as a motor of a transfer device, a driver circuit for driving a tube for B / F separation up and down, a hand-held nozzle device, a reagent dispensing device,
A pump circuit for sucking (discharging) or discharging the liquid and a driving circuit for driving an electromagnetic valve installed between these devices are connected to the B / F separation device or the like. Further, it is preferable that the control device is also connected to the detection device, and outputs the final analysis result based on the detection result. To achieve this effect, it is preferable to connect an operation panel having display means and keys for input, a printer for outputting analysis results, and the like to the control device. By connecting such a peripheral device, it is possible to immediately display the analysis result and output it to paper by a printer. Here, the display device described so far can also be used as an output destination of the analysis result. If a communication port with an external computer is provided, the final analysis result can be output to the external computer. In order to output an analysis result, it is preferable that calibration curve information used for calculating the concentration of an analyte and the like be stored or input.

As described above, if the hand-held nozzle device and the control device are connected and various information such as the sample liquid amount required according to the analysis content is input to the control device,
The operator can complete a necessary operation only by pressing a switch provided on the nozzle device.
For this purpose, the control device should be configured to store in advance the sample liquid amount, the reagent amount, the diluent amount of the liquid sample, etc. required for each analysis item, or be configured to be able to input as needed. Is preferred.

The microprocessor may have the function of the microprocessor, but if it is installed separately, it is connected to the microprocessor. The timer measures the elapsed time for each reaction vessel. In order to measure the elapsed time for each reaction container, the transfer device is provided with a number or the like at the place where the reaction container is placed. The control device controls each reaction vessel
Time management is performed based on the elapsed time for each reaction vessel measured by the timer. Therefore, it is preferable that the control device stores various parameters corresponding to the analysis contents, for example, a reaction time, a reagent dispensing volume, and the like, or enables input from a key or the like. For example, in the case of immunochemical reaction, even if the analysis is performed on the same sample, if the analysis target is different, the reaction time between the antibody bound to the carrier or the antibody bound to the label and the sample liquid and the amount of the reagent to be dispensed later are reduced. It may be different or the reaction time itself may be different. Therefore, for example, it is preferable to adopt a configuration in which the contents of the analysis are input to the control device prior to the analysis, and the reaction conditions including the reaction time are managed in accordance with the input information.

In order to measure the elapsed time for each reaction vessel, for example, it is possible to exemplify a configuration of a time-measuring device which measures the time from the time when the liquid sample is started to be discharged into the reaction vessel. For example, as described above, the handheld nozzle device is provided with a switch for sucking and discharging the liquid sample,
When a configuration in which the liquid sample is sucked and discharged through the control device is employed, the point in time when the discharge switch is pressed can be used as the starting point of the timing device. Such a configuration is particularly preferable when the reaction according to the analysis content is started at the same time when the sample liquid is discharged into the reaction container. However,
For example, when the amount of sample liquid to be ejected is about several tens of μl, such as in immunochemical analysis, the time required to eject the sample liquid is extremely short. Time measurement may be performed with the completion point as a starting point. In order to operate the timing device in this way,
For example, a configuration may be provided in which a switch for starting the operation of the timing device (timing operation) is provided, and the switch is pressed when the operator discharges the sample liquid into the reaction liquid.
In order to reduce the burden on the operator and prevent mistakes such as forgetting to press the switch, a sensor for detecting the presence or absence of a container is preferably provided on the container holder, and the operator places the reaction container on the holder after discharging the sample liquid. It is preferable to have a configuration in which the placement is automatically sensed and the timing operation of the timing device is started. This sensor can also be used as a sensor for automatically detecting the place where the reaction vessel is placed.

The switch provided on the hand-held nozzle as described above, the switch provided separately from the hand-held nozzle, or the sensor provided on the container holding unit is connected to a time-measuring device, and is used when the operator presses the switch. The timekeeping operation is started from the starting point. The timing device is connected to the control device as described above, and the container holding portion of the transfer device is assigned a number or the like, so the control device manages the reaction time for each reaction container, and according to the analysis content. After the reaction is performed for a time stored or input in advance, for example, in the case of immunochemical analysis, a B / F separation operation, a reagent dispensing operation, a detection operation, and the like can be automatically performed. Also, different from such control, the timer may be always operated, and the controller may be configured to permit the discharge of the sample liquid only when it is convenient to control the reaction. For example, a configuration in which ejection is permitted for 5 seconds every 30 seconds can be exemplified.
If the permitted time width (5 seconds in the above example) is sufficiently short with respect to the actual reaction time (for example, 10 minutes) performed subsequently, the case where ejection is performed in the initial stage of the time width and the time width The time difference when the ejection is performed in the latter stage can be ignored.

Hereinafter, the apparatus of the present invention will be described with reference to the drawings. FIG. 1 is a block diagram showing an example of an immunochemical analyzer to which the device of the present invention is applied. 1 is a hand-held nozzle device provided with a switch, 2 is a pump device, 3 is a reaction container holding part of a transfer device, 4 is a B / F separation device, 5 reagent dispensing device,
6 is a detection device, 7 is a control device also serving as a timing device, 8 is a display device, 9 is an operation panel (input device), and 10 is an output device (printer). It is. In this example, the container holding section of the transfer device is moved in the lateral direction by the action of the driving means (not shown), and the reaction container placed on the container holding section is moved by the B / F separation device, the reagent dispensing device, and the detection device. It can be transported directly below. Although not shown in this example, a temperature control device for controlling the temperature of the solution in the reaction container and a magnet device for stirring the container are attached immediately below the transfer path of the container holding unit by the transfer device. ing. In the reaction vessel, a carrier having a diameter of about 1.5 mm in which ferrite, which is a paramagnetic substance, is embedded, and a carrier on which an antibody to an antigen to be analyzed is immobilized is previously placed. The solution is agitated by moving the carrier by the action.

In the analyzer according to the present embodiment, the reaction vessel contains the carrier on which the first antibody to the antigen to be measured is immobilized, and an antibody that recognizes a site different from the first antibody, A second antibody coupled to the enzyme is pre-loaded,
Lyophilized. Therefore, a switch provided on the hand-held nozzle 1 is operated to aspirate a reagent solution and a sample liquid for dissolving the lyophilized reagent, and discharge the sample solution to the reaction container, thereby simultaneously starting an immune reaction. Therefore, when the discharge switch of the handheld nozzle 1 is pressed, or before or after the discharge switch, the control device 7 starts the timekeeping operation for the reaction vessel. At the same time, the control device 7 designates a holding unit on the transfer device on which the reaction container is to be mounted and outputs the same to the display device 8 in order to realize time management for the reaction container. Therefore, the operator can perform the immunochemical analysis only by placing the reaction container on the designated holding part after discharging the sample liquid.

In the apparatus of this embodiment, B / F separation operation, dispensing operation of a reagent (enzyme substrate) for measuring the activity of the enzyme bound to the antibody, detection of the enzyme activity after 10 minutes from the start of the immune reaction. Parameters are input to the control device 7 so that a series of operations called operations are started. For this reason, the controller 7 operates 9 minutes 3 after the immune reaction is started as described above.
When 0 seconds have elapsed, the transfer device is driven to sequentially transfer the corresponding reaction vessels to the B / F separation device, the reagent dispensing device, and the detection device. A warning is displayed on the display device 8 so as not to discharge the sample liquid to the reaction vessel, and the switching of the hand-held nozzle for discharging the sample liquid is invalidated to prevent an operator's mistake.

In addition to this, the control device 7 displays a similar warning when the container holding portion on the transfer device becomes full or when it may hinder the subsequent operation, and performs the discharge switching of the hand-held nozzle. Disable.

When the operation by the B / F separation device, the reagent dispensing device, and the detection device is completed, the control device 7 compares the detection result from the detection device with the calibration curve data input in advance, and determines the antigen to be measured. Is calculated and output to an output device (printer, 10). The control device 7 displays an indication on the display device 8 to permit the disposal of the reaction container after the operation by each device is completed. When the control device 7 determines that the operator has discarded the unnecessary reaction container and made a space in the holding portion of the transfer device or that there is no obstacle to a series of operations following the B / F separation,
The warning that the ejection of the sample liquid is prohibited is released, and the switching of the handheld nozzle device 1 is enabled.

[0030]

According to the apparatus of the present invention, since the suction and discharge of the sample liquid are manually performed by the operator, the operation is performed in addition to the mechanism for holding and transferring the sample container and the mechanism for holding and moving the nozzle device. The mechanism for automatically detecting the liquid level of the sample liquid, which is required when the automatic measurement is performed, can be omitted. As a result, the apparatus of the present invention can have a simple configuration as compared with a fully automatic analyzer, and can be provided in a small size and at low cost.

According to the apparatus of the present invention, the reaction time and the like can be managed for each reaction container starting from the time when the operator discharges the sample liquid into the reaction container. As a result, the apparatus of the present invention can improve the reproducibility of analysis results and the like through accurate time management in analysis.

[Brief description of the drawings]

FIG. 1 is a diagram showing an example of an analyzer according to the present invention.

[Explanation of symbols]

 Reference Signs List 1 hand-held nozzle device 2 pump device 3 transfer device (container holding part of transfer device) 4 B / F separation device 5 reagent dispensing device 6 detection device 7 control device 8 display device 9 operation panel 10 output device (printer)

Claims (13)

[Claims] 1. A hand-held nozzle device for sucking and discharging a sample liquid at least semi-manually, a pump device connected directly or via a pipe to the hand-held nozzle device, a reaction container from which a sample liquid is discharged, A biochemical analyzer comprising a reaction vessel transfer device for holding and transferring a reaction container along a transfer path, a timing device, and a control device that controls the device in conjunction with the timing device. 2. The apparatus according to claim 1, wherein the handheld nozzle device is provided with a switch for sucking and discharging the liquid sample. 3. A temperature control device for controlling a temperature of a reaction solution in a reaction vessel in a transfer path of the reaction vessel.
Equipment. 4. The apparatus according to claim 1, further comprising a stirrer for stirring the reaction solution in the reaction vessel in a transfer path of the reaction vessel. 5. The apparatus according to claim 1, further comprising a B / F separation device in a transfer path of the reaction vessel. 6. The apparatus according to claim 1, further comprising a reagent dispensing device in a transfer path of the reaction container. 7. The apparatus according to claim 1, wherein the reaction vessel transfer device includes a detection means for detecting whether or not the reaction vessel has been placed. 8. The apparatus according to claim 1, wherein the time measuring device measures the reaction time starting from the time when the liquid sample is started to be discharged into the reaction container. 9. The apparatus according to claim 1, wherein the timer measures the reaction time starting from a point in time when the discharge of the liquid sample to the reaction container is completed. 10. The apparatus according to claim 1, wherein the timer measures the reaction time starting from the time when the reaction container from which the liquid sample has been discharged is held on the holding table. 11. A control device controls a hand-held nozzle device so as to permit ejection of a liquid sample to a reaction vessel at a time within a certain range, and a timer measures a time point when the liquid sample is ejected or within the certain range or within the certain range. The apparatus according to claim 1, wherein the reaction time is measured starting from an arbitrary time before and after the range. 12. The apparatus according to claim 1, further comprising a display device for displaying whether or not the liquid sample can be ejected. 13. The apparatus according to claim 1, further comprising a display device for displaying at which position in the reaction container transfer device the reaction container from which the sample liquid has been discharged is to be mounted and held.