JP5210902B2 - Automatic analyzer and analysis method using automatic analyzer - Google Patents

Description

  The present invention relates to an automatic analyzer that automatically executes analysis of components of biological samples such as blood and urine, and more particularly to an automatic analyzer that collects a liquid from the sample container or reagent container and dispenses it into a reaction container. About.

  Automatic analyzers that perform qualitative / quantitative analysis of biological samples such as blood and urine are becoming popular, especially in examination centers and large hospitals, due to high measurement reproducibility and high analysis processing speed. The automatic analyzer is a method that uses a reagent that reacts with the analyte in the sample and changes the color of the reaction solution (colorimetric analysis), and a label that specifically binds directly or indirectly to the analyte. This method is largely classified into a method (immunoassay) for counting the label using a reagent to which is added. In any method, a sample is mixed with a predetermined amount of reagent for analysis, but in recent years, an analysis apparatus capable of reducing the amount of reagent used for analysis has been demanded in accordance with a demand for reducing the analysis cost. Accordingly, it is necessary to reduce the amount of sample used for one analysis. The amount of sample used for one analysis with the current automatic analyzer is on the order of one-digit microliters. Such a small amount of liquid must be transferred from the sample container containing the sample to a reaction container for reacting with the reagent. Control of the surface tension of the liquid is important in the transfer of liquid in the microliter order. That is, even if it is attempted to discharge a liquid in the microliter order from the tip of the nozzle for the injection needle, it only adheres as a liquid ball to the tip of the nozzle and does not fall into the reaction vessel. Therefore, it is common to transfer the liquid to the reaction vessel by bringing the nozzle into contact with the reaction vessel and the surface tension that causes the liquid to wet and spread on the bottom surface of the reaction vessel.

  The above conventional technique is described in Patent Document 1, for example.

Japanese Patent No. 3247471

  However, the conventional technique has the following drawbacks.

  This is a disadvantage of the method of dispensing the sample by bringing the tip of the sample probe into contact with the bottom of the reaction vessel. However, since the tip of the sample probe cut obliquely comes into contact with the bottom of the reaction vessel every time, It can be damaged and requires periodic replacement of the probe. In addition, since the bottom of the reaction vessel may be damaged, it is necessary to periodically exchange the reaction vessel. Especially recently, the sample probe tip diameter is thin and sharp to maintain the dispensing accuracy with a sample dispensing volume of 1 μL or less, and the bottom of the reaction vessel and the sample probe tip are susceptible to damage. I can say that.

  Further, when the sample dispensing operation is performed in a state where the sample probe is pressed against the bottom surface of the reaction vessel (the state of the sample probe) and the sample probe rises after sample dispensing, the sample is attached to the side surface of the sample probe. In addition, when the sample probe is pushed up, it returns to its original state (without bending) when it is lifted, and the vibration of the sample probe may cause the sample on the side of the sample probe and the sample attached to the cutting tip to scatter to the side of the reaction vessel. There is. Or there is a possibility that the sample is taken home with the sample attached to the side of the sample probe.

  In addition, each time the sample probe contacts the bottom surface of the reaction container, the tip of the sample probe slips on the bottom surface of the reaction container, and the bottom surface of the reaction container is damaged. If the reproducibility of the position cannot be obtained, the agitation accuracy reproducibility may be affected and the analysis result may be affected.

  The smaller the amount of dispensing, the higher the above-mentioned influence and the possibility of affecting the reliability of the measurement result.

  An object of the present invention is to provide an automatic analyzer that can maintain dispensing accuracy even with a small amount without being damaged at the tip of a sample probe or the bottom of a reaction vessel.

  The configuration of the present invention for achieving the above object is as follows.

  When a sample is sucked from a test tube or the like, a pressure change is measured by a pressure sensor to obtain information such as sample viscosity. Depending on the viscosity of the sample and the amount of sample dispensed, the sample probe is driven at an optimum speed while dispensing.

  In addition, a small camera is placed at the reaction container position where sample dispensing is performed, and the gap between the reaction container bottom surface and the sample probe of each reaction container is accurately measured with the camera, and the sample is taken from the reaction container bottom surface during dispensing. The distance from the probe tip is accurately controlled.

  By observing the state of dispensing into the reaction vessel, it is possible to monitor the presence or absence of nozzle side surface adhesion (takeaway) and confirm the reliable dispensing operation on the bottom of the reaction vessel.

  According to the present invention, when dispensing a sample into a reaction container, it is possible to eliminate sample adhesion to the side surface of the sample probe and scattering of the sample to the reaction container, and the sample probe tip and the bottom of the reaction container are not brought into contact with each other. So it will not damage the probe or reaction vessel.

  In addition, the gap between the tip of the sample probe and the bottom of the reaction container can be kept constant, and the dispensing accuracy can be improved and maintained without being restricted by the viscosity of the sample.

Schematic diagram of a general automatic analyzer. Dispensing method 1. Dispensing method 2. The layout using a CCD camera. A reaction vessel in the form of a divided block. Minimum gap measurement 1. Minimum gap measurement 2. CCD camera scan by reaction vessel rotation. Sample probe tip shape. Dispensing method 3. Dispensing method 4. Dispensing method 5. Relationship between sampling nozzle rise speed and discharge end. The amount of sample adhering to the side of the sampling nozzle with hydrophobicity.

  Embodiments of the present invention will be described below with reference to the drawings.

  FIG. 1 shows an outline of a general automatic analyzer in which the present invention is implemented.

  Since the function of each part is well-known, detailed description is omitted.

  The sampling arm 2 of the sampling mechanism 1 moves up and down and rotates. Using the sample probe 3 attached to the sampling arm 2, the sample in the sample container 101 arranged on the sample disk 102 rotating left and right is sucked and reacted. It is configured to dispense into the container 5. As can be seen from this figure, the sample container 101 is placed on the sample disk 102 in a universal arrangement in which the sample container 101 can be placed directly on the sample disk 102 or on the test tube (not shown). In general, a structure that can cope with the above is applicable.

  On the rotatable reagent disk 125, reagent bottles 112 corresponding to a plurality of analysis items to be analyzed are arranged. The reagent dispensing probe 110 attached to the movable arm dispenses a predetermined amount of reagent from the reagent bottle 112 to the reaction container 5.

  The sample probe 3 performs a sample suction operation and a dispensing operation in accordance with the operation of the sample syringe pump 107. The reagent dispensing probe 110 performs a reagent aspirating operation and a dispensing operation with the operation of the reagent pump 111. Analysis items to be analyzed for each sample are input from an input device such as the keyboard 121 or the screen of the CRT 118. The operation of each unit in this automatic analyzer is controlled by the computer 103.

  As the sample disk 102 rotates intermittently, the sample container 101 is transferred to the sample suction position, and the sample probe 3 is lowered into the stopped sample container. When the tip of the sample probe 3 comes into contact with the liquid level of the sample in accordance with the lowering operation, a detection signal is output from the liquid level detection circuit 151, and based on this, the computer 103 stops the lowering operation of the driving unit of the sampling arm 2. Control. Next, after a predetermined amount of sample is sucked into the sample probe 3, the sample probe 3 rises to the top dead center. While the sample probe 3 is sucking the sample by a predetermined amount, the pressure detection circuit 153 uses the signal from the pressure sensor 152 to detect the pressure fluctuation in the channel during the suction operation between the sample probe 3 and the sample pump 107 channel. If an abnormality is detected in the pressure fluctuation during the suction, there is a high possibility that the predetermined amount is not sucked, so an alarm is added to the analysis data.

  Next, the sampling arm 2 rotates in the horizontal direction, the sample probe 3 is lowered at the position of the reaction vessel 5 on the reaction disk 4, and the sample held in the reaction vessel 5 is dispensed. When the reaction container 5 containing the sample is moved to the reagent addition position, a reagent corresponding to the corresponding analysis item is added from the reagent dispensing probe 110. As the sample and reagent are dispensed, the liquid level of the sample in the sample container 101 and the reagent in the reagent bottle 112 is detected. The mixture in the reaction vessel to which the sample and the reagent are added is stirred by the stirrer 113. The reaction container containing the mixture is transferred to the photometer 115, and the luminescence value or absorbance of each mixture is measured by a photomultiplier tube or photometer as a measuring means. The light emission signal or light reception signal enters the computer 103 via the interface 104 via the A / D converter 116, and the concentration of the analysis item is calculated. The analysis result is printed out to the printer 117 via the interface 104 or output to the CRT 118 and stored in the memory 122. After completion of photometry, the reaction vessel 5 is washed at the position of the reaction vessel washing mechanism 119. The cleaning pump 120 supplies cleaning water to the reaction container and discharges waste liquid from the reaction container. In the example of FIG. 1, three rows of container holders are formed so that three rows of sample vessels 101 can be set concentrically on the sample disc 102, and one sample suction position by the sample probe 3 is provided in each row. It is set one by one.

  The above is the general operation of the automatic analyzer.

  Next, an embodiment of this patent will be described with reference to FIGS.

  As shown in FIG. 2, the tip of the sample probe 3 is brought into contact with the reaction vessel bottom surface 201. When discharging with the sample pump 107, the sample probe 3 is raised while discharging the sample with the sample probe 3.

  Actually, the sample probe 3 is pressed against the reaction vessel bottom surface 201 with a spring cushion by an operation of pressing the sample probe 3 against the reaction vessel bottom surface 201 after contacting the reaction vessel bottom surface 201 with a spring attached to the upper portion of the sample probe 3. When the sample probe 3 is raised, the sample probe 3 does not move away from the reaction vessel bottom surface 201 and remains in contact with the reaction vessel bottom surface 201, and when the sample probe 3 is removed from the reaction vessel bottom surface 201, the sample probe 3 remains in contact with the reaction vessel bottom surface 201. By starting dispensing while raising the sample probe 3 while discharging at 3, it becomes possible to dispense without attaching the sample to the outer surface of the sample probe 3.

  In addition, as shown in FIG. 3, the post-dispensing sample height 203 of the reaction vessel 5 with respect to the dispensed amount can be easily calculated from the vertical and horizontal dimensions of the reaction vessel. The sample is lowered to the gap 200, and after the dispensed sample comes into contact with the bottom surface 201 of the reaction vessel, the sample probe 3 is dispensed while being raised to the sample height 203, and the discharged sample becomes the sample height 203 after dispensing. By waiting for this to occur, the sample ball remaining at the tip of the sample probe 3 can be reduced, and the sample adhering to the outer surface of the sample probe 3 can be eliminated.

  Here, there are variations in the dimensions of the sample probe 3 and all the reaction vessels 5, and the following methods can be considered as means for correcting the variations.

  As shown in FIG. 4, the CCD camera 202 is disposed at a position where the sample probe 3 dispenses the reaction vessel 5, and the height of the gap 200 between the bottom surface 201 of all the reaction vessels and the tip of the sample probe 3 is measured. The gap 200 between the reaction vessels varies. The reaction container is made of a resin molded product as a cause of the gap 200 variation, and a slight warp occurs due to heat shrink deformation at the time of molding, and the reaction container shape is integrated with the entire reaction disk. Since it is very difficult to mold the resin, a reaction vessel having a divided block shape as shown in FIG. 5 is used. The deformation of the reaction vessel gap 200 is also caused by deformation of the reaction vessel by forming one round with a plurality of blocks and firmly fixing the reaction vessel block 17 to the reaction disk 4 with screws using the screw holes 11.

  As shown in FIG. 6, the gap 200 is measured by bringing the sample probe 3 into contact with the bottom surface 201 of the first reaction vessel with a pulse motor that drives the vertical movement of the sampling mechanism 1 until the sample probe 3 comes into contact. By calculating the height 204 of the tip of the sample probe from the reaction vessel bottom of the reaction vessel bottom surface 201 from the sample probe 3 from the number of pulses used in the above, The clearance 200 of the reaction vessel 5 can be calculated.

  Alternatively, a reference surface 206 is provided as shown in FIG. The height positions of the CCD camera 202 and the reference surface 206 do not depend on the attachment of the sample probe 3 and the reaction vessel 5, that is, do not change. Therefore, the reaction disk 4 to which the reaction vessel 5 is attached is rotated as shown in FIG. Then, the height 207 from the cell bottom with respect to the reference plane 206 and the height 208 from the tip of the sample probe are read by the CCD camera 202, and the necessary movement amount for stopping the sample probe 3 at the gap 200 is calculated.

  Alternatively, a metal reference surface 206 is provided, the sample probe 3 is brought into contact with the reference surface 206, and the movement pulse amount from when the contact is made until the abnormal lowering detection is entered is stored. At the time of sample dispensing, the number of pulses from when the sample probe 3 comes into contact with the reaction vessel bottom surface 201 to when abnormal drop detection is detected is obtained as described above, so after the sample probe 3 comes into contact with the reaction vessel bottom surface 201 and abnormality detection stops. Then, the necessary number of pulses for 200 gaps is added to the stored number of pulses, and the sample probe 3 is raised and stopped at the gap 200.

  As shown in FIG. 4, the gap 200 is measured by lowering the sample probe 3 by a certain amount with respect to each reaction vessel 5 and measuring the height from the reaction vessel bottom surface 201 with the CCD camera 202. Is calculated.

  Alternatively, when the sample probe 3 is lowered by a certain amount and the gap 200 of the first reaction vessel 5 is measured, the remaining gap 200 of the reaction vessel 5 is rotated by rotating the reaction disk 4 with the reaction vessel 5 attached as shown in FIG. Simultaneously, the height of the reaction vessel bottom surface 201 is measured by the CCD camera 202, and the same result is obtained even if the gap 200 of each reaction vessel is calculated based on the difference from the reaction vessel bottom surface 201 measured first. In addition, since the gap 200 can be measured without contacting the sample probe 3, the reaction vessel bottom surface 201 is not damaged.

  The measurement of the gap 200 is performed when the sample probe 3 and the reaction vessel 5 are replaced or when the apparatus is initialized.

  Next, the sample suction operation will be described.

  The sample probe 3 sucks a necessary amount of the sample in the test tube or the like installed on the sample disk 102 by the sample probe 3. Samples have different viscosities.

  When the pressure applied to the suction operation is measured by the pressure sensor 152 for each sample suction and dispensed into the reaction vessel 5 by the sample pump 107, serum, urine, standard solution, etc. are removed from the difference in the pressure applied to the suction operation. When distinguishing and dispensing, the dispensing operation of the sample probe 3 and the sample pump 107 is changed. That is, the dispensing position height of the sample probe 3 and the dispensing operation of the sample pump 107 are changed depending on the viscosity of the sample to improve the dispensing accuracy.

  Here, the shape of the tip of the sample probe 3 is preferably flatter than the conventional oblique processing. For example, when the sample is aspirated, if the tip has an oblique shape, unevenness occurs in the flow rate of the sample aspirating operation. However, if the tip is flat, the flow rate of the sample during aspiration can be aspirated at a constant rate. In addition, after detecting the liquid level, the sample probe 3 is pushed into the sample by a certain amount and stopped.

  After the sample is aspirated, it is confirmed again whether the sample probe 3 is in the sample by detecting the liquid level. This is to prevent empty sucking. If the nozzle tip is slanted, as shown in Fig. 9, even if air is sucked after sample suction, the slanted tip is in contact with the sample and the liquid level is detected. I do not realize that Therefore, the fact that the tip of the sample probe 3 is flat also has an advantage that erroneous suction can be prevented.

  Also in the cleaning operation after sample dispensing, the adhesion of the tip of the sample probe 3 to the cleaning water can be reduced by reducing the cross-sectional area.

  Moreover, if the shape of the tip of the sample probe 3 is flat, the contact area with the sample can be reduced. As shown in FIG. 10, in a minute amount of 1 μL or less, the sample is dispensed onto the bottom surface 201 of the reaction vessel having hydrophilicity. At this time, the sample can be discharged to the tip of the sample probe 3 in advance, and then the sample can be dispensed to the reaction container bottom surface 201 having hydrophilicity by contacting the sample with the reaction container bottom surface 201.

  Further, as shown in FIG. 11, after the sample probe 3 is lowered to the reaction vessel bottom surface 201, the dispensing operation is started. A sample liquid ball 205 made at the tip of the sample probe 3 is brought into contact with the bottom surface 201 of the reaction vessel having hydrophilicity, and dispensed with the sample probe 3 having hydrophobicity as shown in FIG. However, when dispensing, it is possible to eliminate the take-out of the sample by the sample probe 3.

  In addition, as shown in FIG. 12, since the necessary dispensing amount is set in advance, the size of the sample liquid ball 205 made at the tip of the sample probe 3 can be predicted. Therefore, the amount of lowering of the sample probe 3 is changed according to the dispensing amount, and the gap 200 is changed depending on the dispensing amount.

  If the shape of the tip of the sample probe 3 is flat, the reaction vessel bottom surface 201 is not damaged, so that the life of the reaction vessel 5 can be extended, and bubbles and dirt during measurement can be reduced.

  FIG. 11 shows an example of the dispensing operation. In the operation of dispensing the sample to the reaction vessel bottom surface 201, the sample probe 3 is lowered until the gap 200 is reached, and dispensed to the reaction vessel 5 by the sample pump 107. The state of this dispensing is observed with the CCD camera 202, and the dispensing operation is performed while raising the sample probe 3 when the sample comes into contact with the bottom surface 201 of the reaction container and becomes a certain size. By changing the ascending operation of the sample probe 3 and the suction operation of the sample pump 107 in accordance with the viscosity of the sample measured by the pressure sensor 152 in advance, the sample does not adhere to the side surface of the sample probe 3. That is, the dispensing accuracy can be improved.

  FIG. 13 shows a drive parameter diagram for ascending the sample probe 3 during dispensing. In order to improve the dispensing accuracy, it is not desirable that the dispensing of the sample pump 107 is completed at the point B where the acceleration of the sample probe 3 is finished. From the acceleration region of the sample probe 3 to the constant velocity region (FIG. 13A), the speed change from the constant velocity region to the acceleration region (FIG. 13B) occurs, the sample probe 3 vibrates, and the reaction vessel 5 This is because the sample scatters on the side surface or causes the sample to adhere to the side surface of the sample probe 3. In order to improve the dispensing accuracy, it is necessary to finish dispensing in the section A to B.

  Further, as shown by the dotted line in FIG. 13, by changing the ascending speed of the sample probe 3 depending on the viscosity of the sample and raising the sample probe 3 while dispensing, it is possible to perform dispensing with high accuracy without being affected by the viscosity. .

  In general, the sample pump 107 drive motor and the sample probe 200 drive motor use separate controllers, but the dispensing operation of the sample pump 107 and the ascending operation of the sample probe 200 are operated from the same controller. Thus, the time difference from the operation instruction between the drive motors can be filled, and the dispensing accuracy can be improved.

  In the present embodiment, only the sample dispensing has been described, but the reagent is not attached to the side surface of the sample probe 3 only when the reagent is dispensed into the reaction vessel 5 first. The same can be done from the technology (the effect is great when the reagent dispensing amount is very small), and the application range is not limited by the type or use of the liquid to be dispensed.

DESCRIPTION OF SYMBOLS 1 Sampling mechanism 2 Sampling arm 3 Sample probe 4 Reaction disk 5 Reaction container 6 Mechanism base 7 Drive mechanism 8 Drive shaft 9 Reaction tank 10 Reaction tank water 11 Screw hole 12 Center stainless pipe 13 Insulating adhesive 14 Shield stainless pipe 15 Step 16 Reaction Container edge 17 Reaction container block 18, 101 Sample container 102 Sample disk 103 Computer 104 Interface 107 Sample pump 110 Reagent dispensing probe 111 Reagent pump 112 Reagent bottle 113 Stirring mechanism 114 Light source lamp 115 Photometer 116 A / D converter 117 Printer 118 CRT
119 Reaction vessel cleaning mechanism 120 Cleaning pump 121 Keyboard 122 Memory 125 Reagent disk 151 Liquid level detection circuit 152 Pressure sensor 153 Pressure detection circuit 200 Gap 201 Reaction vessel bottom surface 202 CCD camera 203 Sample height after dispensing 204 Sample from reaction vessel bottom Probe tip height 205 Liquid ball 206 Reference surface 207 Height from cell bottom 208 Height from sample probe tip

Claims (7)

A probe for aspirating and discharging a sample;
In an analysis method using an automatic analyzer equipped with a plurality of reaction containers containing samples discharged from the probe,
Generating a sample droplet at the tip of the probe before or during lowering of the probe into the reaction vessel;
Lowering the probe until the droplet contacts the reaction vessel with the droplet attached to the probe tip; and
The state of the droplets was observed with a CCD camera, a sample is brought into contact with the reaction vessel bottom, and upon reaching a certain size, possess the steps of raising the probe while discharging the sample, a,
The step of lowering the probe reads the height from the bottom of the reaction vessel and the height from the tip of the probe with respect to a reference plane that does not depend on the attachment of the probe and the reaction vessel, and reads the probe from the reaction vessel. An analysis method using an automatic analyzer, characterized in that an amount of movement that stops at a certain gap from the bottom is calculated, and the probe is lowered based on the amount of movement calculated in each reaction vessel . In the analysis method using the automatic analyzer according to claim 1,
The automatic analyzer includes a reaction disk on which a plurality of the reaction vessels are attached,
An analysis method using an automatic analyzer, comprising the step of rotating the reaction disk and simultaneously measuring the height of the bottom surface of each of the plurality of reaction vessels with the CCD camera. In the analysis method using the automatic analyzer according to claim 1 or 2,
An analysis method using an automatic analyzer, wherein in the step of raising the probe, the raising speed is changed by the viscosity of the sample. A probe for aspirating and discharging a sample;
A plurality of reaction containers containing samples discharged from the probe;
A CCD camera for observing the state of the sample droplet generated at the tip of the probe;
In an automatic analyzer comprising a computer for controlling the operation of the probe,
The computer
Read from the CCD camera the height from the bottom of the reaction vessel and the height from the tip of the probe relative to the reference plane that does not depend on the attachment of the probe and the reaction vessel, and stop the probe at a certain gap from the bottom of the reaction vessel. Calculate the amount of movement
Before or during lowering of the amount of movement calculated in each reaction vessel into the reaction vessel, a sample droplet is generated at the probe tip,
With the droplet attached to the probe tip, the probe is lowered until the droplet contacts the reaction vessel,
The state of the droplet is observed with the CCD camera, and when the sample comes into contact with the bottom surface of the reaction vessel and becomes a certain size, the probe is raised while discharging the sample,
An automatic analyzer characterized by performing control. The automatic analyzer according to claim 4,
Furthermore, a reaction disk provided with a plurality of the reaction vessels is provided,
An automatic analyzer which measures the height of the bottom surface of each of the plurality of reaction vessels with the CCD camera at the same time as the reaction disk is rotated. The automatic analyzer according to claim 4 or 5,
The CCD camera is disposed at a position where the probe is dispensed into the reaction container. The automatic analyzer according to any one of claims 4 to 6,
The automatic analyzer according to claim 1, wherein the probe is raised by changing a rising speed according to a viscosity of the sample.

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