JP2023128080A - Sample analyzer and sample analyzing method - Google Patents

Abstract

To generate a mixed state of a sample with a simple configuration prior to dispensing of the sample.SOLUTION: Suction discharge of a sample 68 by a nozzle 52 is repeated n times. Thereafter, the sample 68 is sucked into the nozzle 52, and the sucked sample is discharged into a cuvette that is a reaction container. Sample agitation and dispensing sample suction are performed at a same position. A nozzle tip 72 is replaced between sample agitation and subsequent sample suction.SELECTED DRAWING: Figure 2

Description

The present invention relates to a sample analyzer and a sample analysis method, and particularly to a technique for stirring a sample.

A sample analyzer is a device that analyzes blood, urine, etc. collected from a subject. As sample analyzers, immunoassay devices, biochemical analyzers, and the like are known.

When analyzing blood, for example, blood collected from a subject is stored in a blood collection tube containing an anticoagulant. The blood is the specimen, which is also called whole blood. In whole blood in a blood collection tube or whole blood transferred from a blood collection tube to another container, blood cell components (erythrocytes, white blood cells, etc.) settle to the bottom of the container over time. That is, a concentration gradient of blood cell components occurs within the blood collection tube or another container. When all or part of the substance to be analyzed is contained in blood cell components, if a portion of such non-uniform whole blood is aspirated and analyzed, the reliability of the analysis results will decrease. Even in samples other than whole blood, if a concentration gradient occurs in a specific substance to be quantified, that is, a substance to be analyzed, the same problem as described above occurs. The sample must be stirred to eliminate concentration gradients.

Patent Documents 1 and 2 disclose techniques for stirring a specimen by repeatedly aspirating and discharging the specimen. However, these patent documents do not disclose sample stirring that is performed immediately before dispensing the sample from the original container to the reaction container.

Japanese Patent Application Publication No. 2006-184009 International Publication 2017/006969

Prior to sample analysis, the sample in the original container is sucked into the nozzle, and the sucked sample is discharged from the nozzle into the reaction container. If a concentration gradient of the substance to be analyzed occurs in the original container when the sample is aspirated, the reliability of the analysis results will decrease.

An object of the present invention is to provide a sample analyzer and a sample analysis method that can obtain highly reliable analysis results. Alternatively, the object is to create a mixed state of the specimen with a simple configuration prior to specimen aspiration.

The sample analyzer according to the present invention includes a nozzle and a control unit that controls sample dispensing using the nozzle, and the nozzle is used prior to controlling the sample dispensing when a stirring execution condition is satisfied. In the sample dispensing, the sample in the original container transferred to the suction position is sucked into the nozzle, and the sucked sample is transferred from the nozzle to the reaction container. The sample stirring includes n (where n is an integer of 1 or more) suction and discharge operations performed at the suction position, and in each suction and discharge operation, the sample in the original container is moved into the nozzle. and the aspirated specimen is discharged from the nozzle into the original container.

The sample analysis method according to the present invention includes a step of dispensing a sample using a nozzle, a step of stirring the sample using the nozzle before dispensing the sample, and analyzing the sample after dispensing the sample. In the sample dispensing, the sample in the original container transferred to the suction position is sucked into the nozzle, the sucked sample is discharged from the nozzle into the reaction container, The sample stirring includes n (where n is an integer of 1 or more) suction and discharge operations performed at the suction position, and in each of the suction and discharge operations, the sample in the source container is sucked into the nozzle. , the aspirated specimen is discharged from the nozzle into the original container.

According to the present invention, it is possible to provide a sample analyzer and method that can obtain highly reliable analysis results. Alternatively, it is possible to create a mixed state of the specimen with a simple configuration prior to specimen aspiration.

FIG. 1 is a schematic diagram showing an analysis device according to an embodiment. FIG. 3 is a diagram for explaining suction and discharge control. FIG. 3 is a diagram illustrating a configuration example of an information processing section. It is a timing chart showing a first example of stirring and dispensing operation. It is a timing chart showing a second example of stirring and dispensing operation. It is a figure showing an example of composition of a management table. FIG. 3 is a diagram for explaining an appropriate liquid amount range. 3 is a flowchart showing a sample analysis method. It is a flowchart (Part 1) showing a stirring and dispensing process. FIG. 2 is a flowchart (Part 2) showing the stirring and dispensing process. FIG. FIG. 3 is a schematic diagram showing a sample analyzer according to a modified example. It is a figure which shows the change of stirring execution conditions based on elapsed time. FIG. 6 is a diagram showing changes in stirring execution conditions based on sample amount and container type.

Hereinafter, embodiments will be described based on the drawings.

(1) Overview of Embodiment A sample analyzer according to an embodiment includes a nozzle and a control section. The control unit controls sample dispensing using the nozzle. The control unit controls specimen stirring using the nozzle prior to controlling specimen dispensing when stirring execution conditions are satisfied. In sample dispensing, the sample in the original container transferred to the suction position is sucked into the nozzle, and the sucked sample is discharged from the nozzle into the reaction container. Specimen stirring includes n (where n is an integer greater than or equal to 1) suction and discharge operations performed at the suction position. In each suction/discharge operation, the sample in the original container is sucked into the nozzle, and the sucked sample is discharged from the nozzle into the original container.

According to the above configuration, when the stirring execution conditions are satisfied, sample stirring is performed prior to sample dispensing. This causes a mixed state of the specimen in the original container. In other words, even if a concentration gradient of the substance to be analyzed occurs in the original container, it is eliminated. By aspirating the sample for dispensing, that is, sampling, as soon as the sample has become homogeneous, the accuracy of the analysis of the substance to be analyzed can be improved, that is, the reliability of the analysis results of the substance to be analyzed can be increased. Since the sample is stirred using a nozzle, there is no need to provide special equipment, and there is an advantage that existing equipment can be used to stir the sample.

It is possible to make the position where the sample is stirred (stirring position) and the position where the sample is aspirated during sample dispensing (aspiration position for dispensing, sampling position) different; It is necessary to transport the original container between the two locations, and the time and process must be secured for this purpose. In the above configuration, since the stirring position and the aspiration position for dispensing are the same, the sample can be aspirated immediately after the sample is stirred. As will be described later, the nozzle tip may be replaced between sample agitation and sample suction. Since the time required to replace the nozzle tip is usually short, even in that case, it is possible to aspirate a sample in a mixed state.

For example, if a long period of time has passed since the original container was installed or installed in the specified position in the sample analyzer, the viscosity of the precipitated components has increased significantly, or if a large amount of specimen is stored in the original container. In some cases, the sample may not be sufficiently agitated by repeated suction and discharge using the nozzle. In such cases, it may be desirable to apply manual stirring or other methods of stirring as an adjunct or alternative. Furthermore, depending on the type or condition of the specimen, stirring may not be necessary. Taking various situations into consideration, in the above configuration, the sample is stirred by the nozzle when the stirring execution conditions are satisfied. After manual stirring or other methods of stirring are performed, sample stirring using a nozzle may be performed.

The sample analyzer according to the embodiment operates according to cycle time. Sample stirring and sample dispensing are performed for each cycle time unit consisting of a plurality of cycle times or for each cycle time. Cycle time is a basic unit of operation on the time axis, and each piece of equipment in a sample analyzer operates according to the cycle time. A cycle time unit is made up of a plurality of cycle times arranged in time.

In the embodiment, the control unit measures the elapsed time from the reference time determined based on the erection of the original container to the determination time before starting sample agitation, and controls the operation of the nozzle based on the elapsed time.

Generally, the source container is manually stirred before it is installed in the sample analyzer. After the original container is erected, sedimentation and aggregation of specific components progress within the original container. The degree of specimen change depends on the elapsed time, but the elapsed time actually varies depending on various conditions (number of specimens, presence or absence of interruption, etc.). Therefore, in the above configuration, the elapsed time is actually measured and the nozzle operation is controlled based on the elapsed time. The reference time may be the time when the original container is erected, or the reference time may be a predetermined time after the original container is erected. The determination time may be the start of the suction process, or the determination time may be the time immediately before the start of suction. Even when the sample container rack is installed on the sample analyzer, the reference time and determination time may be determined as appropriate.

In the embodiment, the control unit determines an error without causing the nozzle to stir the sample when the elapsed time exceeds a predetermined time. Alternatively, the control unit changes the conditions for stirring the sample depending on the elapsed time. For example, the control unit changes n depending on the elapsed time. Once an error has been determined, measures such as manually stirring the sample can be taken. By increasing n as the elapsed time increases, the possibility of insufficient stirring occurring can be reduced. Other parameters such as the amount of suction and discharge may be changed.

In an embodiment, the nozzle includes a nozzle body and a nozzle tip attached to the nozzle body. Nozzle tips are replaced between sample stirring and sample dispensing.

When stirring the sample, the sample adheres to the inner and outer surfaces of the nozzle tip. The residual sample may affect analytical accuracy. If the nozzle tip is replaced after the sample agitation is completed, the sample can be dispensed using a new nozzle tip, so problems caused by residual sample do not occur. Both specimen stirring and specimen dispensing may be performed using one type of nozzle tip. A nozzle tip for stirring the sample and a different nozzle tip for dispensing the sample may be used. When using one type of nozzle chip, cost reduction can be achieved. By preparing a dedicated nozzle tip for sample agitation, agitation efficiency can be increased. It is also conceivable to use a cleaning nozzle to stir the sample and dispense the sample.

The stirring execution conditions may include liquid amount conditions. The liquid volume condition is a condition that must be satisfied by the amount of the sample in the original container. The stirring execution conditions may include container conditions. Container conditions are conditions that the original container must satisfy. The stirring execution conditions may include specimen type conditions. The specimen type condition is a condition that must be satisfied by the specimen type in the original container. The stirring execution conditions may include specimen state conditions. The specimen state condition is a condition that the state of the specimen in the original container should satisfy. Examples of the specimen state conditions include hemolysis conditions and blood cell concentration conditions. The hemolysis condition is a condition that the degree of hemolysis in the sample should satisfy when the sample in the original container is whole blood. The blood cell concentration condition is a condition that the blood cell concentration in the sample should satisfy when the sample in the original container is whole blood. The stirring execution conditions may include a plurality of conditions, and stirring may be performed when all of the conditions are satisfied.

In the embodiment, during sample agitation, the nozzle is conveyed up and down in accordance with the vertical movement of the liquid level of the sample in the original container. By synchronizing the vertical movement of the nozzle with the vertical movement of the liquid level, it becomes possible to control the amount of entry of the nozzle into the sample in the original container to a constant value or within a certain range. For example, the amount of penetration of the nozzle into the sample in the original container in each suction/discharge operation is within the range of 0.5-15 mm.

In embodiments, a pressure sensor is provided to detect the pressure within the nozzle. During sample agitation, at least one of bubble suction, clogging, and leak is determined as an aspiration abnormality based on the output signal of the pressure sensor. Error processing is executed when a suction abnormality is determined. According to this configuration, it is possible to avoid a situation in which the suction and discharge operation proceeds under a situation where there is a possibility that a mixed state of the specimen cannot be formed appropriately. In the embodiment, the processor functions as a suction abnormality determining means and an error processing means.

In the embodiment, the height of the liquid level of the sample in the original container is determined prior to stirring the sample. If the height of the liquid level is outside the predetermined height range, error processing is executed. According to this configuration, it is possible to avoid a situation in which the suction and discharge operation proceeds in a situation where proper specimen agitation cannot be performed because the amount of liquid is too large or too small. The concept of liquid level includes liquid volume. In the embodiment, the processor functions as a liquid amount adequacy determining means and an error processing means.

The sample analysis method according to the embodiment includes a dispensing step, a stirring step, and an analysis step. The dispensing process is a process of dispensing a sample using a nozzle. The stirring step is a step performed before sample dispensing, and is a step of stirring the sample using a nozzle. The analysis step is a step of performing sample analysis after dispensing the sample. In sample dispensing, the sample in the original container transferred to the suction position is sucked into the nozzle, and the sucked sample is discharged from the nozzle into the reaction container. Specimen stirring includes n (where n is an integer greater than or equal to 1) suction and discharge operations performed at the suction position. In each suction/discharge operation, the sample in the original container is sucked into the nozzle, and the sucked sample is discharged from the nozzle into the original container.

According to the above method, the sample is agitated using a nozzle immediately before dispensing the sample for sample analysis. In other words, the sample is sampled after ensuring the uniformity or uniformity of the sample, so that analysis can be performed easily. The reliability of analysis results for target substances can be increased. There is also the advantage that there is no need to provide complicated equipment for stirring the specimen, and that existing equipment can be used to stir the specimen. Note that when the sample is whole blood, for example, if the blood cell sedimentation rate in the sample is slow or the degree of hemolysis is above a predetermined level, stirring may not be necessary depending on the type of substance to be analyzed. Sample agitation was postponed.

In embodiments, the specimen is whole blood. As long as the stirring execution conditions are satisfied, the stirring step is applied to all specimens. However, the necessity of stirring may be determined for each type of specimen. Specimen types include serum, plasma, urine, sweat, saliva, and the like.

(2) Details of Embodiment FIG. 1 shows a sample analyzer 10 according to an embodiment. FIG. 1 schematically shows the top surface of the sample analyzer 10. The sample analyzer 10 is an immunoassay device that analyzes a sample using an immune reaction, that is, an antigen-antibody reaction, and specifically, is an immunoassay device that follows chemiluminescent enzyme immunoassay (CLEIA). The technical matters described below may be applied to biochemical analyzers and the like.

In FIG. 1, the sample analyzer 10 includes a sample supply section 12, a reaction section 14, a reagent supply section 16, a light detection section 18, a cuvette supply section 20, a substrate cooler 22, cuvette transfer mechanisms 24 and 26, and a sample dispensing mechanism. 28, reagent dispensing mechanisms 30, 32, etc.

The sample supply unit 12 has a turntable 33 as a rotating table. A holding hole group 34 is formed in the turntable 33, and the holding hole group 34 is composed of a plurality of holding holes 34a. In the illustrated example, the holding hole group 34 includes an outer holding hole row consisting of a plurality of holding holes 34a arranged in an annular shape, and an inner holding hole row consisting of a plurality of holding holes 34a arranged in an annular shape. . Each holding hole 34a is a portion that accommodates a sample container as a source container. A specimen is contained within the specimen container.

In embodiments, the specimen is whole blood. Other liquids collected from living organisms may also be used as the specimen. The sample container (original container) is a blood collection tube containing whole blood or another container containing whole blood. For example, blood collected from a living body is contained in a blood collection tube containing an anticoagulant. In that case, the blood in the blood collection tube or the blood transferred from the blood collection tube to another container is the whole blood sample. As is well known, whole blood contains blood cell components, and if whole blood is allowed to stand still, the blood cell components will sediment. Sedimentation rates vary depending on the specimen.

In addition, in the case of whole blood in a hemolyzed state, most of the substance to be analyzed in the blood cell components may be eluted into the plasma depending on the degree of hemolysis (degree of hemolysis). Therefore, in the embodiment, as will be described later, the necessity of agitating the sample using the nozzle is determined based on the degree of hemolysis. The degree of hemolysis can be determined by measuring the hemoglobin value in the supernatant portion of the specimen. The degree of hemolysis may be determined by analyzing images obtained by imaging the specimen. On the other hand, depending on the level of blood cell concentration, the hemocyte sedimentation rate may become slower and the effect on the analysis may be reduced. Therefore, the necessity of agitating the sample using the nozzle may be determined based on the level of blood cell concentration. The level of blood cell concentration can be determined by measuring the hematocrit value. As the hematocrit value, a measured value obtained by a known method (such as the microhematocrit method) may be used. The degree of sedimentation may be determined by analyzing an image obtained by imaging the specimen.

Each specimen container is inserted into each holding hole 34a manually by the examiner. In other words, each sample container is constructed. Normally, prior to inserting each sample container, the sample in the sample container is stirred by repeatedly shaking the sample container, that is, by repeatedly mixing by overturning. An arbitrary number of sample containers can be installed in the sample supply section 12. The examiner can also arbitrarily determine the timing for erecting each sample container.

Prior to erection of the sample container, the button 36 is operated by the examiner. As a result, the operation of the sample supply section 12 is temporarily interrupted, and a state in which the sample container can be accepted is created in the sample supply section 12. After the specimen container is installed, the button 36 is operated again by the examiner. As a result, the operation of the sample supply section 12 is restarted. A virtual button may be displayed in place of the button 36 on a touch screen panel or the like. The button 38 is operated when it is desired to rotate the turntable 33. Button 36 and button 38 may be integrated.

The sample supply unit 12 is provided with a barcode reader (BCR), which is not shown. The BCR reads the contents of the barcode labels affixed to each sample container held by the holding hole group 34. Thereby, sample information such as sample ID is read for each sample. Based on the sample ID, subject information, analysis items, sample container type, etc. are specified.

The reaction section 14 has a turntable 39 as a rotating table. A holding hole group 40 is formed in the turntable 39, and the holding hole group 40 is composed of a plurality of holding holes 40a. In the illustrated example, the holding hole group 40 includes an outer holding hole row made up of a plurality of holding holes 40a arranged in an annular shape, and an inner holding hole row made up of a plurality of holding holes 40a arranged in an annular shape. . Each holding hole 40a is a portion that accommodates a cuvette as a reaction container. Reagents and specimens are injected stepwise into each cuvette. This generates an immune reaction within each cuvette.

In the embodiment, the analyte is measured based on, for example, a so-called two-step method. The two-step method included a first immunoreaction step using a first reagent containing a first antibody, a second immunoreaction step using a second reagent containing a second antibody, and a substrate (substrate solution). It includes an enzyme reaction step and a light detection step. In the reaction section 14, a first immune reaction step, a second immune reaction step, and an enzyme reaction step are performed. Further, in the reaction section 14, a stirring process, a B/F cleaning process, etc. are performed. In FIG. 1, illustration of the mechanism included in the reaction section 14 is omitted. Note that the stirring method in the reaction section 14 is a vortex stirring method in which a cuvette is rotated to generate a vortex within the cuvette.

The reagent supply unit 16 has a reagent tank 41 as a rotating cold storage. The reagent tank 41 accommodates a reagent bottle row 42 and a reagent bottle row 44 . The reagent bottle row 42 and the reagent bottle row 44 each include a plurality of reagent bottles. Each reagent bottle contains a reagent. Reagent dispensing mechanisms 30 and 32 are provided adjacent to the reagent supply section 16 and the reaction section 14. The reagent dispensing mechanism 30 has a rotating arm 60 and a nozzle 62 provided at the tip of the arm 60. The reagent dispensing mechanism 32 has a rotating arm 64 and a nozzle 65 provided at the tip of the arm 64. The nozzles 62 and 65 are each non-replaceable nozzles, that is, washable nozzles. The reagent dispensing mechanisms 30 and 32 aspirate a specific reagent and discharge the aspirated reagent into a specific cuvette.

The light detection section 18 is a unit that detects light emission generated within the cuvette after the enzyme reaction. The concentration of the substance to be analyzed is calculated based on the detected value. When transferring cuvettes, cuvette transfer mechanisms 24 and 26 function. In FIG. 1, numerals 56 and 58 indicate waste portions. Used cuvettes and used nozzle tips are discarded in the disposal section.

In the illustrated configuration example, the sample dispensing mechanism 28 includes a rail mechanism 46, a slide base 48, an arm 50, a nozzle 52, and the like. The rail mechanism 46 has a rail extending in a direction inclined with respect to the left-right direction of the device and the depth direction of the device. The slide base 48 slides along the rail (see reference numeral 53). The base end of the arm 50 is rotatably held by the slide base 48, and a nozzle 52 is disposed at the tip of the arm 50.

The nozzle 52 is composed of a nozzle body and a nozzle tip. A nozzle tip is removably attached to the nozzle body. The nozzle body is made of metal, and the nozzle tip is made of transparent, translucent, or non-transparent resin. After aspirating the sample, the nozzle tip is replaced. In the embodiment, the nozzle tip is replaced even after the sample is stirred by the nozzle.

In the sample supply section 12, a first suction position (outer suction position) and a second suction position (inner suction position) are defined. At each suction position, in addition to aspiration of the sample for dispensing, agitation of the sample is also performed. Specimen stirring will be described in detail later.

The movement area of the nozzle 52 is expanded by the combination of the sliding movement of the slide base 48 and the pivoting movement of the arm 50. Under the control of the control unit, which will be described later, during sample dispensing, the sample in the sample container (original container) at the aspiration position (first aspiration position or second aspiration position) is aspirated by the nozzle 52, and the aspirated sample is transferred to the nozzle. 52 into a specific cuvette on the reaction section 14. The discharge destination position may be fixedly determined, or the discharge destination position may be dynamically changed. In embodiments, the sample is dispensed into the cuvette after the first reagent is dispensed into the cuvette. When the sample is discharged, the sample and the first reagent are mixed.

The sample dispensing mechanism 28 shown in FIG. 1 is an example, and other mechanisms may be employed as the sample dispensing mechanism 28. For example, a sample dispensing mechanism 28 that does not have the rail mechanism 46 may be employed, or a sample dispensing mechanism that includes an X rail and a Y rail may be employed.

The chip rack 54 is a member that holds a plurality of nozzle chips. When replacing a nozzle tip, the used nozzle tip is removed from the nozzle body and discarded. Thereafter, the tip of the nozzle body is inserted into the upper opening of the nozzle tip selected from the tip rack 54. This attaches a new nozzle tip to the nozzle body. The chip rack is replaced by a chip rack replacement mechanism (not shown).

Suction and discharge control will be explained using FIG. 2. The sample dispensing mechanism has a nozzle transport mechanism 28A. The nozzle conveyance mechanism 28A is composed of the already explained rail mechanism, slide base, arm, etc. A syringe pump 76 is fixed to the arm. The syringe pump 76 has a syringe and a piston, and generates suction pressure and discharge pressure. Other types of pumps may be utilized.

Nozzle 52 is held by nozzle transport mechanism 28A. The nozzle 52 can be freely moved in the vertical and horizontal directions by the nozzle transport mechanism 28A. The nozzle 52 is composed of the nozzle body 70 and the nozzle tip 72, as described above. The nozzle body 70 can also be called a sample rod. FIG. 2 shows the sample container 66 that has been transferred to the aspiration position in the sample supply section 12 and is stopped at the aspiration position. A specimen (whole blood) 68 is stored inside.

A tube 74 is provided between the nozzle body 70 and the syringe pump 76, and suction pressure and discharge pressure are transmitted via air within the tube 74. A pressure sensor 78 is provided in the middle of the tube 74. The pressure of the air inside the tube 74 is detected by a pressure sensor 78 . The pressure is indicative of the pressure within the nozzle 52. A detection signal from the pressure sensor 78 is output to the information processing section 80.

The information processing unit 80 is configured by, for example, a computer including a processor. The information processing section 80 functions as a control section, a calculation section, etc. In the illustrated configuration example, a timer 82, an input device 84, a display device 86, and a communication device 88 are connected to the information processing section 80. Although the information processing section 80 has a storage section, its illustration is omitted in FIG.

The timer 82 measures the elapsed time from the reference time to the determination time for each sample container. The information processing unit 80 itself may have a timekeeping function. The reference time is, for example, the time when the sample container is installed in the sample supply section and the barcode label of the sample container is read to identify the sample ID. The time point when the sample container is erected may be set as the reference time, or another timing related to the erecting of the sample may be set as the reference time. The determination time is, for example, the start of a specific cycle time assigned to the dispensing process. Other timing related to sample aspiration may be used as the determination time. The elapsed time is used as one guideline for estimating the sedimentation rate of blood cell components within the sample container 66. That is, the elapsed time is used as information for determining that the sample state is suitable for sample agitation by the nozzle 52.

The input device 84 may include a button, a switch, a touch panel, a pointing device, a keyboard, or the like. The display 86 may be configured with a liquid crystal display, an organic EL display device, or the like. The communication device 88 functions when the information processing unit 80 exchanges data with the host computer via the network.

In the embodiment, if the stirring execution conditions are satisfied, sample stirring is performed immediately before sample dispensing. Specifically, the nozzle is transferred above the sample container 66 in the suction position, and then the nozzle 52 is lowered downward. In the descending state, air is continuously fed into the nozzle 52 by the action of the syringe pump 76. The pressure sensor 78 detects the increase in air pressure at the time when the tip of the nozzle 52 comes into contact with the liquid surface of the sample 68 and the tip opening is closed. Based on the output signal from the pressure sensor 78, the information processing section 80 specifies the height of the liquid level, and calculates the liquid amount from the height. Incidentally, the type of the sample container 66 can be specified based on the sample ID, and the type of the sample container 66 is referred to when calculating the liquid amount.

After the liquid level is detected, the sample is sucked into the nozzle tip 72 by the action of the syringe pump 76 . During the suction process, the nozzle 52 is transported downward as the liquid level falls. Thereby, the amount of entry of the nozzle tip 72 into the sample 68 is maintained constant. When a predetermined amount of suction is completed, the nozzle 52 is stopped lowering and the sample suction is stopped. Immediately after that, or after a certain temporary standby time, the nozzle 52 is pulled upward and the syringe pump 76 acts to discharge the sample. During the discharge process, the nozzle 52 is transported upward as the liquid level rises. Thereby, the amount of entry of the nozzle tip 72 into the sample 68 is maintained constant.

For example, a value within the range of 0.5-15 mm is selected as the amount of penetration of the nozzle tip 72. The lower limit of the range is determined from the viewpoint of avoiding air suction by the nozzle tip 72. The upper limit of the range is determined from the viewpoint of avoiding contact of the tip of the nozzle tip 72 with the inner bottom surface of the specimen container 66, and from the viewpoint of suppressing the amount of specimen adhering to the outer surface of the nozzle tip 72. Preferably, the amount of penetration of the nozzle tip 72 is selected to be within the range of 1-4 mm. All numerical values listed in this specification are merely examples. After the ejection is completed, the nozzle 52 is lifted and the sample ejected is stopped while the above-mentioned inflow amount is maintained.

The above suction operation and discharge operation are repeatedly performed. Specimen stirring consists of n times of suction and discharge operations. Any value can be specified in advance as the number of repetitions n. For example, n is an integer of 1 or more, and a numerical value such as 5, 6, or 7 may be specified as n. The maximum number of repetitions that can be executed within one cycle time may be specified as n. n may be adaptively varied according to various conditions. This will be discussed later. As described above, during sample agitation, the nozzle is conveyed up and down in accordance with the vertical movement of the liquid level of the sample. In other words, the nozzle moves up and down in accordance with and synchronizes with the up and down movement of the liquid level of the sample. In this process, the amount of entry of the nozzle into the sample is set to be relatively small, and this amount of entry is maintained. This makes it possible to reduce adhesion of the sample to the outer surface of the nozzle, and to perform stable and reliable sample agitation.

After the sample stirring is completed, the nozzle tip is replaced, and then the suction operation is performed. As a result, a predetermined amount of sample is accommodated within the nozzle tip 72. While maintaining the accommodated state, the nozzle 52 is pulled upward and transported to the cuvette, which is the discharge destination. By replacing the nozzle tip, it is possible to avoid the problem of reduced measurement accuracy due to residual specimen adhering to the inner and outer surfaces of the nozzle tip 72. If such a problem does not occur or can be ignored, nozzle tip replacement may be omitted. The sample container 66 shown in FIG. 2 is an example, and various containers can be used as the sample container.

By continuously performing specimen stirring and specimen suction at the same suction position, it becomes possible to quickly accommodate the specimen in the nozzle tip after the specimen is stirred. Even when blood cell components are precipitated in whole blood, specimen agitation is applied to the whole blood, and whole blood with a uniform blood cell component concentration can be sampled.

FIG. 3 shows an example of the configuration of the information processing section 80. In FIG. 3, elements similar to those shown in FIG. 2 are denoted by the same reference numerals, and their explanations will be omitted. The information processing section 80 includes a processor 90. The processor 90 is composed of, for example, a CPU that executes a program.

In FIG. 3, a plurality of functions performed by the processor 90 are expressed by a plurality of blocks. The processor 90 functions as an operation control section (error processing section) 94, an excess determination section 96, a bubble suction determination section 98, a clogging determination section 100, and the like. The processor 90 determines whether the stirring execution conditions are satisfied. Stirring execution conditions include, for example, conditions that require the elapsed time not to exceed a predetermined time, conditions that require the sample amount to be within a predetermined range, conditions that require that the sample container is not in a shape unsuitable for stirring, and conditions that require that the sample container is not in a shape unsuitable for stirring. Examples include conditions requiring the degree of hemocyte sedimentation to be lower than a predetermined level, and conditions requiring the degree of hemocyte sedimentation to be lower than a predetermined level. In FIG. 3, the function of making a determination regarding elapsed time is clearly shown as an excess determination section 96. A storage section 92 is connected to the processor 90. A management table 102 is stored in the storage unit 92. The processor 90 performs control, calculation, etc. based on the management table 102.

The excess determination unit 96 determines whether the elapsed time exceeds a predetermined time (reference time) for each sample. If it is determined that the amount exceeds the limit, the operation control unit 94 executes error processing. For example, an excess is reported to the tester and prompting manual agitation of the sample container. After manual stirring, the sample container is returned to the sample supply section. Thereafter, that sample container may be processed preferentially. Note that a plurality of reference times may be set to be compared with the elapsed time. For example, if the elapsed time does not exceed the first reference time, stirring is postponed and sampling is performed, and if the elapsed time exceeds the first reference time and does not exceed the second reference time, Sampling may be performed after stirring is performed, and error processing may be performed if the elapsed time exceeds the second reference time.

The bubble suction determining section 98 determines whether bubbles are suctioned based on the detection signal from the pressure sensor. For example, if bubbles are present on the liquid surface of the sample and the surface of the bubbles is mistakenly recognized as the liquid surface, only the bubbles will be sucked into the nozzle tip. This is determined by the bubble suction determining section 98. If bubble suction is determined, error processing is executed and the user is notified of this.

The clogging determination unit 100 determines clogging based on a detection signal from a pressure sensor. For example, if a blockage occurs within the nozzle tip during suction, the pressure inside the nozzle tip will rise rapidly. A blockage is determined based on the pressure change. If a blockage is determined, error handling is performed and the user is notified.

In addition to the above, other monitoring and other determinations may be performed in order to properly perform sample stirring and sample dispensing. The processor 90 according to the embodiment executes various determinations and various error processes. For example, entry of air (ie, leak) into the suction path including the interior of the nozzle tip may be determined. A leak may be determined based on a detection signal from the pressure sensor. Bubble suction, clogging, and leaks can all be considered suction abnormalities. Other suction abnormalities may also be determined. A camera may also be connected to processor 90. The state of the sample before or during sample agitation may be photographed by a camera, and the resulting image may be analyzed to determine an error or to change the sample agitation execution conditions. As will be explained later, prior to stirring the sample, it is determined whether the liquid level of the sample is within a predetermined height range. If the liquid level height of the sample is outside the predetermined height range, error processing is executed.

FIG. 4 shows a first example of the stirring and dispensing operation as a timing chart. (A) shows the i-th cycle time, the i+1-th cycle time, and the i+2-th cycle time. i is an integer of 1 or more. (B) shows processing for the j-th specimen and processing for the j+1-th specimen. j is an integer of 1 or more. For the j-th sample, a stirring operation is performed within the i-th cycle time, and a dispensing operation is performed within the subsequent i+1-th cycle time. On the other hand, for the j+1-th sample, the stirring operation is performed within the i+2-th cycle time, and the dispensing operation is performed within the subsequent i+3-th cycle time. In this first example, a stirring operation and a dispensing operation are performed for each cycle time unit 200 consisting of two consecutive cycle times.

In FIG. 4, Tx indicates the elapsed time for the j-th sample. The elapsed time Tx is the time between the reference time T1 and the determination time T2. If the elapsed time Tx exceeds a predetermined time, error processing is executed. The elapsed time for each sample is compared with a predetermined time.

FIG. 5 shows a second example of the stirring and dispensing operation as a timing chart. (A) shows the i-th cycle time and the i+1-th cycle time. (B) shows processing for the j-th specimen and processing for the j+1-th specimen. Regarding the j-th sample, the stirring operation and the dispensing operation are performed sequentially within the i-th cycle time. On the other hand, for the j+1th sample, the stirring operation and the dispensing operation are performed sequentially within the i+1th cycle time. In this way, in the second stirring and dispensing operation, the stirring operation and the dispensing operation are performed at each cycle time. Stirring and dispensing operations other than the first and second examples shown in FIGS. 4 and 5 may be employed.

FIG. 6 shows an example of the configuration of the management table. The illustrated management table 102 has a plurality of records 104 corresponding to a plurality of specimens. Each record 104 includes information 106 specifying the position of the sample container, information 108 specifying the sample ID, information 110 indicating the sample type, and information 112 indicating the analysis item. It includes information 114 representing the beginning of the time. The elapsed time is calculated based on the information 114.

The appropriate range of sample amount will be explained using FIG. 7. (A) shows an appropriate range 122 determined for the sample container 116. Specifically, an upper limit 118 and a lower limit 120 are determined for the sample container 116, and an appropriate range 122 is between them. When the liquid level is within the appropriate range 122, that is, when the amount of the sample is within a certain range, execution of sample stirring is permitted. If the liquid level does not exist within the appropriate range 122, especially if the liquid level is at a position exceeding the upper limit 118, sample stirring is not performed and error processing is performed. In that case, manual specimen stirring is encouraged. Error processing is also executed when the sample amount is below the lower limit 120. In that case, the user is notified of the insufficient amount of sample.

In FIG. 7, (B) shows an appropriate range 132 determined for the sample container 124. In FIG. Specifically, the sample container 124 is held by an adapter 126. An upper limit 128 and a lower limit 130 are defined for the sample container 124, with an appropriate range 132 between them. Similarly to the above, when the liquid level is within the appropriate range 132, execution of sample stirring is permitted. If the liquid level does not exist within the appropriate range 132, sample stirring is not performed and error processing is performed.

FIG. 8 shows the entire sample analysis process as a flowchart. The flowchart assumes a two-step method including two immunoreaction steps.

In S10, a sample container is installed on the sample supply section. In S12, the barcode affixed to the sample container is read by the barcode reader. As a result, the specimen ID is specified, and an inquiry to the host computer is executed using the specimen ID. Note that the specimen ID may be specified using the specimen installation position information without using the barcode. S14 is a standby step, and in S14, the specimen is in a waiting state.

If the stirring execution conditions are satisfied, sample stirring is performed in S16. That is, n suction and discharge operations are repeatedly performed. In S18, sample dispensing is performed. Specifically, a sample in a sample container is aspirated by a nozzle, and the aspirated sample is discharged from the nozzle into a cuvette.

S20 is normally executed before sample dispensing. In S20, the first reagent is sucked by the reagent dispensing nozzle, and the sucked first reagent is discharged into the cuvette. In S18, when the sample is discharged from the nozzle into the cuvette, a mixed state of the first reagent and the sample occurs in the cuvette.

In S22, the liquid mixture in the cuvette is stirred. S24 indicates the primary immune reaction step. After S24, B/F cleaning is performed in S26. Thereafter, in S28, the second reagent is dispensed into the cuvette using the reagent dispensing nozzle. In S30, the liquid in the cuvette is stirred. S32 indicates the secondary immune reaction step. B/F cleaning is performed in S34.

In S38, the substrate is dispensed into the cuvette. In that case, a substrate dispensing nozzle is utilized. In S40, the liquid in the cuvette is stirred. S42 indicates an enzyme reaction step. At S44, the luminescence generated within the cuvette is measured. In S46, the concentration of the substance to be analyzed is calculated based on the amount of luminescence. Further, in S46, the measurement results are output.

The stirring and dispensing process A1 in FIG. 8 will be described in detail with reference to FIGS. 9 and 10. FIG. 9 is a flowchart (part 1) showing the stirring and dispensing process, and FIG. 10 is a flowchart (part 2) showing the stirring and dispensing process. They also indicate the details of control by the processor.

In FIG. 9, in S50, a barcode affixed to a sample container installed in the sample supply section is read by a barcode reader. As a result, the sample ID is specified, and the sample type and container type are specified based on the sample ID. In S50, measurement of elapsed time from the reference time is started.

In S52, it is determined whether the sample in the sample container is a sample to be stirred, based on the specified sample type. If the sample is not to be stirred, another process for sample analysis is applied in S54. If the specified specimen type is whole blood, the state of the specimen in the specimen container is determined in S55. For example, it is determined whether the specimen is in a hemolytic state based on the hemoglobin value and color tone of the supernatant portion of the specimen. Specifically, the hemoglobin value of the supernatant is measured and compared with a threshold value (predetermined value), and if the hemoglobin value exceeds the threshold value, it is determined that the sample is in a hemolytic state. It will be judged. The hemolyzed state may be determined based on the color tone of the supernatant portion. If a hemolyzed state is determined, other processes for sample analysis are applied at S54. Note that the condition of the specimen may be determined from the degree (degree or speed) of hemocyte sedimentation.

In S56, it is determined whether the sample container is suitable for stirring based on the container type. For example, if the sample container is a large container, it is determined that the sample container is not suitable for stirring. In that case, error processing is executed in S58, and the user who is the inspector is notified of the error.

If it is determined in S56 that the sample container is suitable for stirring, stirring execution conditions and the like are set in S60. For example, the suction/discharge repetition number n, suction amount, suction speed, temporary standby time after suction, discharge amount, discharge speed, temporary standby time after discharge, nozzle descending speed, nozzle rising speed, etc. are set. S62 indicates a standby step. This corresponds to S14 shown in FIG.

In S64, it is determined whether the elapsed time from the reference time to the determination time has exceeded a predetermined time. If the elapsed time exceeds the predetermined time, error processing is executed in S66. In this case, the user is notified of the error and prompted to manually mix the sample. If it is determined in S64 that the elapsed time has not exceeded the predetermined time, the nozzle tip is attached to the nozzle body in S68, and the nozzle is positioned above the suction position in S70.

In FIG. 10, in S72, the nozzle begins to descend. In S74, it is determined whether the tip of the nozzle tip has reached the liquid level. In S76, the sample amount is calculated from the liquid level, and it is determined whether the sample amount is within an appropriate range. However, it may be determined directly from the liquid level whether the sample amount is within an appropriate range. If the sample amount is outside the appropriate range, that is, if the sample amount is inappropriate, error processing is executed in S78, and the user is notified of the error. In that case, as a result, the stirring execution conditions are not satisfied. If it is determined in S76 that the sample amount is appropriate, steps from S80 onwards are executed. In the embodiment, the nozzle's descent is temporarily stopped when the liquid level is detected, but it is also possible to start suction without stopping the nozzle's descent.

In S80, suction by the nozzle is started, and at the same time, the nozzle starts to descend. In S82, the nozzle is lowered to follow the lowering of the liquid level. When a predetermined amount of the specimen has been aspirated, in S84, the suction of the specimen is stopped, and the nozzle is stopped from descending. Thereafter, after a temporary standby time, in S86, the ejection of the sample is started and the nozzle is started to rise. In S88, the nozzle is raised to follow the rise in the liquid level. In S90, the ejection of the sample is finished, and the nozzle is finished rising.

In S92, it is determined whether or not the number of suction/discharge repetitions nx has reached the set value n. If it has not reached the set value n, nx is incremented by one, and the steps after S80 are executed again. A temporary standby time is provided before executing S80. The initial value of nx is 1, and n is given an integer of 1 or more.

If it is determined in S92 that n suction and discharge operations have been completed, the nozzle is transported to a tip disposal site in S100, where the nozzle tip is removed from the nozzle body. In S102, a new nozzle tip is attached to the nozzle body. In S104, the nozzle is transported above the suction position.

In S106, nozzle descent is started, and in S108, it is determined whether the tip of the nozzle tip has reached the liquid level. In the embodiment, the nozzle is stopped from descending at that point, but the nozzle may be allowed to descend as it is. At S110, suction of the sample and lowering of the nozzle are started, and at S112, the nozzle is lowered to follow the drop in the liquid level. When a predetermined amount of the specimen has been aspirated, in S114, the suction of the specimen is stopped, and the nozzle is stopped from descending. Thereafter, after a temporary standby time, the nozzle is pulled upward in S116. Thereafter, the nozzle is transported to the cuvette at the discharge destination. In S118, the sample is discharged from the nozzle into the cuvette. In S120, the used nozzle tip is removed and discarded.

S96 indicates a step of monitoring abnormal suction during the suction process. That is, in S96, bubble suction and clogging are determined. S98 indicates a step of monitoring abnormal discharge during the discharge process. That is, in S98, clogging is determined. S122 indicates a step of monitoring abnormal suction during the suction process. That is, in S122, as in S96, bubble suction and clogging are determined.

FIG. 11 shows a sample analyzer according to a modified example. In FIG. 11, elements similar to those shown in FIG. 1 are given the same reference numerals. The sample analyzer 10A consists of an apparatus main body 134 and a rack carrier 136 attached thereto. The main body 134 of the apparatus is provided with a sample dispensing mechanism 28 . The sample dispensing mechanism 28 includes a rail mechanism 46, a slide base 48, an arm 50, and a nozzle 52.

Individual racks are transported on the rack transport platform 136. Reference numeral 140 indicates a row of sample container racks set by the user (hereinafter, the sample container racks will be simply referred to as racks). Reference numeral 142 indicates a rack to be processed. Reference numeral 144 indicates a reprocessable rack row 144 within the buffer area. Reference numeral 146 indicates the ejected rack row 146. Each rack holds a plurality of sample containers.

The samples in the individual sample containers held in the rack 142 are to be dispensed. In other words, the position of each sample container corresponds to the suction position where the stirring operation and the suction operation for dispensing are performed. The nozzle transport mechanism in the sample dispensing mechanism 28 sequentially positions the nozzles 52 at each suction position.

In the sample analyzer 10A according to the modified example, for example, the samples in the sample supply section 12 are processed preferentially, and then each sample in each rack is processed. However, control may be performed so that each sample in each rack is processed preferentially.

As shown in FIG. 12, the stirring execution conditions may be changed based on the elapsed time 148. For example, the number of times of suction and discharge (n) 150 may be set based on the elapsed time 148. In that case, the longer the elapsed time 148 is, the more the number of times of suction and discharge (n) may be increased. The suction and discharge speed 152 may be set based on the elapsed time 148.

As shown in FIG. 13, the number of times of suction and discharge (n) 156 may be changed based on the sample amount/sample state/container type 154 (here, "/" means "or"). For example, the number of times of suction and discharge (n) 156 may be increased as the amount of specimen increases or as the container becomes larger. Based on the sample amount/sample status/container type 154, the suction/discharge speed 158, the suction/discharge amount 160, the amount of ingress into the liquid surface 162, the waiting time from the end of suction to the start of dispensing (or the waiting time from the end of dispensing to the start of suction) time) 164, the horizontal position 166 of the nozzle within the sample container, etc. may be changed. Similarly, based on the capacity of the nozzle tip and the type of specimen, the suction discharge speed 158, the suction discharge amount 160, the amount of penetration into the liquid surface 162, the waiting time from the end of suction to the start of discharge (or from the end of discharge to the start of suction) (waiting time) 164, the horizontal position 166 of the nozzle within the sample container, etc. may be changed.

According to the above embodiment, when the stirring execution conditions are satisfied, sample stirring is performed prior to sample dispensing, and a mixed state of the specimen is formed in the original container. Since the specimen can be sampled after that, the accuracy of analysis of the substance to be analyzed can be improved. There is no need to provide special equipment for stirring the specimen, and existing equipment can be used to stir the specimen. In the embodiment, since the stirring position and the aspiration position for dispensing are the same, the sample can be aspirated immediately after stirring the sample.

10 sample analyzer, 12 sample supply unit, 14 reaction unit, 16 reagent supply unit, 18 light detection unit, 28 sample dispensing mechanism, 30, 32 reagent dispensing mechanism, 46 rail mechanism, 48 slide base, 50 arm, 52 Nozzle, 70 nozzle body, 72 nozzle chip, 78 pressure sensor, 80 information processing section, 82 timer, 90 processor.

Claims (15)

a nozzle and
a control unit that controls sample dispensing using the nozzle, the control unit controlling sample agitation using the nozzle prior to controlling the sample dispensing when a stirring execution condition is satisfied;
including;
In the sample dispensing, the sample in the original container transferred to the suction position is sucked into the nozzle, the sucked sample is discharged from the nozzle into the reaction container,
The sample stirring includes n (where n is an integer of 1 or more) suction and discharge operations performed at the suction position,
In each of the suction and discharge operations, the sample in the source container is sucked into the nozzle, and the sucked sample is discharged from the nozzle into the source container.
A sample analyzer characterized by: The sample analyzer according to claim 1,
The analyte analyzer operates according to the cycle time;
The sample stirring and the sample dispensing are performed for each cycle time unit consisting of a plurality of cycle times or for each cycle time.
A sample analyzer characterized by: The sample analyzer according to claim 1,
The control unit includes:
Measuring the elapsed time from a reference time determined based on the erection of the original container to a determination time before starting the sample stirring,
controlling the operation of the nozzle based on the elapsed time;
A sample analyzer characterized by: The sample analyzer according to claim 3,
The control unit determines an error without causing the nozzle to stir the sample when the elapsed time exceeds a predetermined time.
A sample analyzer characterized by: The sample analyzer according to claim 3,
The control unit changes conditions for the sample stirring according to the elapsed time.
A sample analyzer characterized by: The sample analyzer according to claim 5,
The control unit changes the n according to the elapsed time.
A sample analyzer characterized by: The sample analyzer according to claim 1,
The nozzle is composed of a nozzle body and a nozzle tip attached to the nozzle body,
a nozzle tip exchange is performed between the sample stirring and the sample dispensing;
A sample analyzer characterized by: The sample analyzer according to claim 1,
The stirring execution conditions include liquid volume conditions,
The liquid volume condition is a condition that the amount of the sample in the original container should satisfy.
A sample analyzer characterized by: The sample analyzer according to claim 1,
The stirring execution conditions include container conditions,
The container condition is a condition that the original container should satisfy;
A sample analyzer characterized by: The sample analyzer according to claim 1,
The stirring execution conditions include a specimen state condition,
The specimen state condition is a condition that the state of the specimen in the original container should satisfy;
A sample analyzer characterized by: The sample analyzer according to claim 1,
During the sample stirring, the nozzle is conveyed up and down in accordance with the vertical movement of the liquid level of the sample in the original container.
A sample analyzer characterized by: The sample analyzer according to claim 1,
The amount of penetration of the nozzle into the sample in the original container in each of the suction and discharge operations is within the range of 0.5-15 mm.
A sample analyzer characterized by: The sample analyzer according to claim 1,
a pressure sensor that detects the pressure within the nozzle;
In the sample stirring, means for determining at least one of bubble suction, clogging, and leak as an abnormal suction based on the output signal of the pressure sensor;
means for executing error processing when the suction abnormality is determined;
A sample analyzer characterized by comprising: The sample analyzer according to claim 1,
means for determining the height of the liquid level of the sample in the original container prior to stirring the sample;
means for executing error processing when the height of the liquid level is outside a predetermined height range;
A sample analyzer characterized by comprising: A step of dispensing the sample using a nozzle;
a step of stirring the sample using the nozzle before the sample dispensing;
performing a sample analysis after the sample dispensing;
including;
In the sample dispensing, the sample in the original container transferred to the suction position is sucked into the nozzle, the sucked sample is discharged from the nozzle into the reaction container,
The sample stirring includes n (where n is an integer of 1 or more) suction and discharge operations performed at the suction position,
In each of the suction and discharge operations, the sample in the source container is sucked into the nozzle, and the sucked sample is discharged from the nozzle into the source container.
A sample analysis method characterized by:

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