JP2010175420A - Sample analyzer - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To solve the problems wherein process control is important for analyzers including a dispenser in order to improve reliability of analysis results, and analyzers that are used in fields such as genetic testing and perform an amplification reaction have high risk of contamination and require an adequate recovery process upon occurrence of a failure. <P>SOLUTION: A sample analyzer includes a dispensing means; a conveyance mechanism for moving a vessel transfer means; and a photographing means for monitoring a dispensing step and a vessel transferring step. With this structure, it is possible to surely determine whether each step is performed by monitoring the operations at an operating location. Further, it is possible to prevent a secondary failure. Accordingly, it is possible to construct a highly reliable system. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to an apparatus having a mechanism for dispensing by sucking and discharging a liquid sample and a mechanism for transferring a consumable such as a container and a nozzle chip installed in the apparatus, for example, a nucleic acid analyzer.

  2. Description of the Related Art Conventionally, dispensing apparatuses that perform liquid suction and discharge have been striving to improve the accuracy and reproducibility of dispensing in order to meet the demands for improving the accuracy of analysis and dispensing an extremely small amount of liquid. Specifically, the performance has been improved by improving the precision of related machines and parts, the evolution of materials, the evolution of machine control technology, etc. In recent years, there has been an increasing demand to verify the process of operation. This requirement contributes to ensuring the reliability of the final results by verifying that the necessary processes have been executed reliably, and to continue the process if a problem occurs in the process. The purpose is to minimize problems that may occur. For example, in a dispensing device, the problem is that the nozzle tip that temporarily stores the liquid and the tip fitting that is connected to the syringe unit for sucking the liquid are insufficiently bonded, and the amount of liquid to be dispensed Is inaccurate and correct analysis results cannot be obtained. As a method for detecting such a problem, a mechanism for sucking and discharging a liquid uses a method for monitoring a flow state of the liquid by detecting a pressure fluctuation in the flow path.

  In recent years, automation has progressed, and there are analysis apparatuses and systems that have a function of transporting consumable members such as containers used for analysis. Even in this case, it is often the case that the holding or presence of consumables is determined and the same process is monitored. Specifically, for example, in an apparatus that transports a container using a robot hand, a method of confirming gripping of a container is used by utilizing the fact that the stop position of a gripping member varies depending on whether or not the container is present. Yes.

  Japanese Unexamined Patent Application Publication No. 2007-292606 (Patent Document 1) discloses a semiconductor wafer surface inspection apparatus that acquires a plurality of partial images over the entire surface of a semiconductor wafer by performing a plurality of times of moving imaging with an imaging unit. It is disclosed.

  Japanese Patent Laid-Open No. 2005-164506 (Patent Document 2) detects reflection of emitted light in an automatic analyzer such as blood or urine provided with a dispensing probe for dispensing a reagent into a reaction container. A light reflection detector for detecting the intensity of the reflected light and the distance to the reflecting object is provided in the reagent holding mechanism and the reagent cap opening mechanism that can move in the three-axis directions.

JP 2007-292606 A JP 2005-164506 A

  The inventor of the present application diligently studied a device for dispensing a liquid sample and transferring consumables, and as a result, the following knowledge was obtained.

  In order to further improve the reliability of analysis performance and take appropriate measures in the event of problems, for example, not only the problem of scattering of samples and chemicals, but also secondary problems that occur when they are mixed. It is necessary to take appropriate measures in consideration. For that purpose, it is an important subject to know more accurately the state of the nozzle tip to be monitored and the liquid state in the container.

  On the other hand, in the prior art, the phenomenon that can be detected is limited due to the indirect state detection method. For example, in the method of monitoring the flow state of the liquid by detecting the pressure fluctuation in the flow path, the pressure difference in the flow path generated between the syringe unit operation and the liquid flowed by the operation is detected. Variations in quantity could not be detected directly.

  Similarly, in the method of detecting the holding state of the container by the stop position of the member that holds the container, it is easy to detect the presence or absence of the container, but detection of the amount of liquid in the held container, the holding angle of the container itself, etc. It was limited.

  Furthermore, since the state of the liquid cannot be grasped, there is a risk that contamination will occur due to leakage of the liquid from the nozzle tip, which may occur when the nozzle tip is discarded or when the container is discarded, or a drop of the container. Especially in fields involving amplification reactions of collected samples, such as genetic testing, if the processing steps after the occurrence of a failure are not optimized, amplification reactions occur when the droplets attached to the discarded nozzle tip come into contact with each other. There was a risk of serious impact on the operation of the equipment, such as an increase in recovery work time.

  The present invention relates to disposing means and providing a photographing mechanism for monitoring the dispensing process and the container transfer process in a transport mechanism for moving the container transporting means.

  According to the present invention, it is possible to reliably determine whether or not each step has been performed by monitoring the operation at the operation location. Furthermore, secondary problems can be prevented. Thereby, a highly reliable system can be constructed.

1 is a configuration diagram of an analyzer in Example 1. FIG. FIG. 3 is a functional integration unit configuration diagram according to the first embodiment. FIG. 2 is a system diagram of the analyzer according to the first embodiment. FIG. 3 is a flow chart of liquid amount detection in the first embodiment. FIG. 6 is an operation flow diagram at the time of liquid amount detection NG determination in the first embodiment. The container detection flowchart in Example 1. FIG. The operation | movement flowchart at the time of the container detection NG determination in Example 1. FIG. FIG. 6 is a configuration diagram of a function integration unit in the second embodiment.

  In the embodiment, the mechanism for dispensing the liquid and transferring the consumables and the imaging means are integrated into one unit. By using the imaging means, it is possible to directly detect the amount of fluctuation necessary for calculating the amount of liquid and the presence / absence of the container itself to determine the state. Further, it is possible to determine the state at the place where the liquid is dispensed or the consumable is transferred. Furthermore, by sharing the detection means, the detectors can be shared and integrated, and the analyzer can be downsized. As a result, it is possible to immediately detect the operation at any location in the unit operating range, and it is possible to prevent secondary problems.

  More specifically, the shared and aggregated detection means is integrated with a dispensing mechanism, a robot handling mechanism, or the like to be detected. The integration makes it possible to monitor various processes such as dispensing and container conveyance at every place, increasing the reliability of process management, improving the detection accuracy when a failure occurs, and enabling appropriate processing. Thus, by monitoring the operation at the operation location, it is possible to determine whether or not the process has been executed reliably, and to build a highly reliable system capable of preventing secondary problems. Further, by integrating the functions, it is possible to provide a small apparatus.

  The embodiment includes a unit including a dispensing unit that sucks and discharges a liquid, a transfer unit that holds and moves the container, and a transport mechanism that moves the unit. Disclosed is a sample analyzer including an imaging means for monitoring the means and the transfer means.

  In addition, in the embodiment, a unit including a nozzle chip connecting unit and a container holding unit and a transport mechanism for moving the unit are provided, and the unit accommodates the nozzle chip and the container in the field of view. Disclosed is a sample analyzer including imaging means.

  In addition, in the embodiment, a sample analyzer including a calculation unit that determines success or failure of the dispensing process and the transfer process using image information obtained from the imaging unit is disclosed.

  Also, in this embodiment, a sample analyzer that changes the procedure of the dispensing process and the transfer process using image information obtained from the imaging means is disclosed.

  In addition, this embodiment discloses a sample analyzer that includes a plurality of container disposal locations, and that includes a calculation unit that determines the disposal location of the containers using image information obtained from the imaging unit.

  Further, in this embodiment, a sample analyzer in which the dispensing means includes a nozzle tip is disclosed.

  In addition, this embodiment discloses a sample analyzer that includes a plurality of nozzle tip disposal locations, and includes a calculation unit that determines the disposal location of the nozzle tips using image information obtained from the imaging unit.

  In addition, this embodiment discloses a sample analyzer including a plurality of disposal locations for containers and nozzle tips, and a computing means for determining the disposal locations for containers and nozzle tips using image information obtained from the imaging means. To do.

  In the present embodiment, a sample analyzer including a CCD camera as an imaging unit is disclosed.

  Further, in the present embodiment, a sample analyzer is disclosed in which the imaging unit has the dispensing unit and the transfer unit in the field of view at the same time.

  Further, in this embodiment, a sample analyzer is disclosed in which the imaging means includes a moving mechanism for changing the field of view.

  Hereinafter, the above and other novel features and effects of the present invention will be described with reference to the drawings. It should be noted that the drawings are exclusively used for explanation and do not reduce the scope of rights.

  In the present embodiment, an analysis apparatus will be described in which a mechanism for performing each step and a function by a highly versatile imaging means are integrated into one unit. By using the imaging means, it is possible to detect and determine the state of the fluctuation amount necessary to calculate the amount of liquid and the presence / absence of liquid in the container directly and at the place where the detection target is searched. In addition, it is possible to select highly accurate process management and an appropriate recovery operation that reduces the risk of contamination when a failure occurs.

  FIG. 1 shows an overall view of an analyzer 10 in the present embodiment.

  The analysis device 10 is a device that analyzes a sample containing a nucleic acid for genetic testing. In the analyzer 10, a stirring unit 48 for mixing the sample and the reagent, a closing unit 49 for closing the container 5, and an analyzing unit 15 are arranged as functions necessary for the analysis. The function of the analysis unit 15 is, for example, an optical measurement function equivalent to a spectrophotometer.

  On the left side of the analyzer 10, a nozzle chip rack 11 that holds a plurality of nozzle chips 3 and a container rack 12 that holds a plurality of containers 5 are arranged.

  Further, the analyzer 10 includes a function integrating unit 1 having a dispensing function for dispensing a sample or a reagent using the nozzle chip 3 and a transfer function for grasping and moving the container 5. The function integrating unit 1 is held by the robot arm X axis 44 and the robot arm Y axis 45 and can move two-dimensionally. The partial configuration of the function integrating unit 1 can be moved in the Z-axis direction (vertical direction). However, it is also possible to add the robot arm Z-axis and move the function integrating unit 1 itself in a three-dimensional manner. .

  The analysis apparatus 10 has two disposal boxes 14 and 17 so that a disposal place can be selected according to an object to be discarded. The used nozzle tip 3 and container 5 are dumped in these waste boxes.

  In FIG. 2, the block diagram of the function integration unit 1 in a present Example is shown.

  The function integrating unit 1 is equipped with a dispensing mechanism using the nozzle tip 3 and the syringe unit 2, a gripper 4 that can hold the container 5, and a CCD camera 30 that is an imaging means. The image sensor used for the CCD camera 30 may be other types as long as it can output with electronic data such as CMOS. The syringe unit 2 and the gripper 4 are disposed in front of the CCD camera 30, and both are disposed in the field of view of the CCD camera 30.

  In the dispensing mechanism, a syringe unit 2 for sucking a liquid is disposed. The syringe unit 2 has a plunger 41 driven by a stepping motor, and can suck and discharge a liquid corresponding to a designated liquid amount. A tip fitting 6 (not shown) for holding the nozzle tip 3 is connected to the tip of the syringe unit 2 and can be connected to the nozzle tip 3 by bonding. The nozzle tip 3 used in the present embodiment is made of a transparent or translucent material so that the liquid state can be confirmed from the outside. It is also desirable to use a resin with high chemical resistance such as polypropylene.

  Two gripper arms 46 for gripping the container 5 are attached to the gripper 4, and the container 5 can be held by sandwiching the container 5. The gripper arm 46 is moved in a certain direction by a solenoid (not shown), and can be operated in the opposite direction when the solenoid is not driven by a spring (not shown) installed between the two gripper arms 46.

  Since the CCD camera 30 is installed on the function integrating unit 1 on which the syringe unit 2 and the gripper 4 mechanism are mounted, the positional relationship with these mechanisms is always constant even if the function integrating unit 1 moves. Kept.

  FIG. 3 shows an apparatus system diagram in this embodiment. The control software is stored in the PC 50, and the operation is started by an input from the operator. Syringe unit 22 (plunger 41) for sucking a sample, syringe vertical movement mechanism (syringe Z axis 42), gripper arm 46 for holding container 5, gripper vertical movement mechanism (gripper Z axis 43), and robot for moving these The arm X axis 44 and the robot arm Y axis 45 are connected to the PC 50 via the mechanism control unit 53 and are instructed to operate by software stored in the PC 50. The CCD camera 30 is connected to the PC 50 via the image processing unit 54, and determines the status of the monitoring target by software stored in the PC 50.

  FIG. 4 shows a flow chart for detecting the liquid amount in this embodiment. The function integrating unit 1 moves to the position of the target nozzle tip 3 on the nozzle tip rack 11 by the operation of the robot arm X axis 44 and the robot arm Y axis 45. Thereafter, the syringe unit 2 is lowered by a syringe vertical movement mechanism (not shown) that can move in the vertical direction, and the tip fitting 6 is press-fitted into the nozzle tip 3 to be coupled. After the nozzle chip 3 is coupled, the syringe is raised by the syringe vertical movement mechanism and stopped within the field of view of the CCD camera 30. Thereafter, the nozzle chip 3 is photographed by the CCD camera 30 to determine whether or not the nozzle chip 3 is mounted. When the nozzle tip 3 is not mounted, the remounting process is repeated a specified number of times, and after that, when it is determined that the nozzle tip 3 is not mounted, an alarm is issued and the apparatus is stopped. When it is determined that the nozzle tip 3 is attached, the syringe unit 2 is raised to a height at which the robot arm X axis 44 and the robot arm Y axis 45 can be operated, and moved to the sample container 18 that is a dispensing source. After moving to the sample container 18, the syringe unit 2 is lowered by the syringe up-and-down mechanism, and the tip of the nozzle tip 3 is inserted into a sample in a certain amount of the sample container. Thereafter, the plunger 41 of the syringe unit 2 is operated to suck a specified amount of the sample, and then the nozzle chip 3 is raised into the field of view of the CCD camera 30. Thereafter, the nozzle chip 3 is photographed by the CCD camera 30, and an area filled with the sucked sample is detected according to the difference in the presence or absence of the liquid level. The region detection method is, for example, a method in which detection is performed by software using a difference in contrast caused by the presence or absence of liquid.

  Thereafter, the cross-sectional area is calculated from the detected region, and the liquid amount of the sucked sample is calculated from the shape information of the chip acquired in advance. Thereafter, if the difference between the calculated liquid amount and the liquid amount instructed to suck is within a predetermined range, it is determined to be normal, otherwise it is determined to be abnormal. When it is determined to be normal, the syringe unit 2 is raised to a height at which the robot arm X axis 44 and the robot arm Y axis 45 can be operated, and the operation is continued according to a predetermined process. If it is determined to be abnormal, a warning is issued and the device is stopped. In the procedure in the present embodiment, whether the sample is normal or not is determined on the sample container that is the dispensing source. Therefore, even if the sample leaks due to poor bonding of the nozzle tip 3, the sample remains in the sample container. Fall. For this reason, it is possible to prevent secondary troubles due to scattering of the sample and scattering.

  Note that the CCD camera 30 can be used for monitoring during sample discharge as well as sample suction. Specifically, it is confirmed that there is no sample in the nozzle chip 3 after the sample is discharged.

  FIG. 5 shows an operation flow at the time of determining a liquid amount detection abnormality in the present embodiment. When an abnormality is determined, the next process is first determined depending on whether the liquid such as the sample is sucked or not. If it is before liquid suction, the nozzle tip 3 can be discarded as it is. On the other hand, in the case of the nozzle tip 3 that has been in contact with a liquid that cannot be mixed with the nozzle tip 3 that has already been discarded after the liquid suction, another appropriate disposal destination is selected. Further, when the liquid remains in the nozzle chip 3, for the purpose of preventing the liquid from splashing to the disposal destination, the recovery operation is performed by the operator's work without performing automatic disposal.

  FIG. 6 shows a container detection flow in this embodiment. The function integrating unit 1 moves to the position of the target container 5 on the container rack 12 by the operation of the robot arm X axis 44 and the robot arm Y axis 45. Thereafter, the gripper 4 is lowered by a gripper vertical movement mechanism (not shown) that can move in the vertical direction, and the container 5 is sandwiched and gripped by the gripper arm 46. After gripping the container 5, the gripper 4 is raised by the gripper vertical movement mechanism and stopped within the field of view of the CCD camera 30. Thereafter, the container 5 is photographed by the CCD camera 30 to determine whether or not the container 5 is gripped. When the container 5 is not gripped, the re-grip process is repeated a specified number of times. If it is determined that the container 5 is not gripped after that, an alarm is issued and the apparatus is stopped. When it is determined that the container 5 has been gripped, the gripper 4 is raised to a height at which the robot arm X axis 44 and the robot arm Y axis 45 can be operated, and moved to the installation destination. This operation is applied not only when the container 5 is gripped but also when the container 5 is installed at the installation location. Specifically, after the container 5 is installed, the CCD camera 30 may confirm that there is no container 5 in the gripper 4.

  In FIG. 7, the operation | movement flow at the time of the container detection abnormality determination in a present Example is shown. When an abnormality is determined, the next process is first determined depending on whether the sample or other liquid is discharged into the container. If the liquid is not discharged, no liquid is contained in the container, and the container 5 can be discarded as it is. On the other hand, when the liquid is discharged, the next process is determined before or after the target container 5 is closed. If it is closed, there is no risk of adhering to the discarded nozzle tip 3 or mixing with the liquid in the container 5 that is not closed. 5 can be discarded. If it is before closing, the next step is determined depending on whether or not it reacts with the liquid in the container 5 that is not attached to the nozzle tip 3 that has already been discarded or is not closed.

  In the case of a container 5 in which liquid that cannot be mixed is dispensed, it is not automatically discarded, but a recovery operation is promoted by the operator's work, and the risk of contamination due to scattering of the sample is suppressed. Is possible.

  In an analyzer including a dispensing device, process management is important in order to improve the reliability of analysis results. Furthermore, in the field of genetic testing and the like, an apparatus with an amplification reaction has a high contamination risk, and it is necessary to perform an appropriate recovery process when a failure occurs.

  In the present embodiment, the mechanism for performing each step and the function of the imaging means are integrated into one unit. By using the imaging means, the amount of liquid necessary to calculate the amount of liquid and the presence / absence of the container itself, not the state of the container itself, and the state detection / Judgment can be made. By monitoring the operation at the operation location, it is possible to determine whether or not the process has been executed reliably and to build a highly reliable system capable of preventing secondary problems. Further, by integrating functions, it is possible to provide a small apparatus.

  In this embodiment, the analysis apparatus for nucleic acid-containing samples has been described as an example. However, the present invention can also be applied to analysis apparatuses for other samples, for example, biological samples such as blood and urine.

  In this embodiment, another example of the function aggregation unit 1 is shown. Hereinafter, the difference from the first embodiment will be mainly described.

  In FIG. 7, the block diagram of the function aggregation unit 1 in a present Example is shown. In this embodiment, the CCD camera 30 includes a rotation mechanism 61, and a wider field of view can be monitored than when the CCD camera 30 is fixed around the camera rotation axis 62. As a result, the degree of freedom of the layout to be monitored increases, and the size of the aggregation unit can be further reduced and the arrangement can be optimized. It should be noted that the rotation mechanism of the CCD camera 30 can be combined with a single or a plurality of linear motion axes capable of linear movement. In this case, a wider range can be monitored.

DESCRIPTION OF SYMBOLS 1 Function integration unit 2 Syringe unit 3 Nozzle tip 4 Gripper 5 Container 6 Chip fitting 10 Analyzer 11 Nozzle tip rack 12 Container rack 13 Dispensing station 14 Disposal box 1
15 Analysis unit 16 Loading / unloading port 17 Waste box 2
18 Sample container 30 CCD camera 31 to 35 Stepping motor 36 Solenoid 41 Plunger 42 Syringe Z axis 43 Gripper Z axis 44 Robot arm X axis 45 Robot arm Y axis 46 Gripper arm 47 Disposal port 48 Stirring unit 49 Closing unit 50 PC
51 Keyboard 52 Monitor 53 Mechanism Control Unit 54 Image Processing Unit 61 Camera Rotation Mechanism 62 Camera Rotation Axis

Claims (19)

A unit comprising: dispensing means for sucking and discharging liquid; and transport means for gripping and moving the container;
A transport mechanism for moving the unit;
A sample analyzer comprising:
The apparatus includes an imaging unit for monitoring the dispensing unit and the transfer unit. The sample analyzer according to claim 1.
An apparatus comprising: an arithmetic unit that determines success or failure of a dispensing process and a transfer process using image information obtained from the imaging unit. The sample analyzer according to claim 1.
An apparatus characterized in that the procedure of the dispensing process and the transfer process is changed using image information obtained from the imaging means. The sample analyzer according to claim 1.
With multiple container disposal locations,
An apparatus comprising: arithmetic means for judging a disposal place of a container using image information obtained from the imaging means. The sample analyzer according to claim 1.
The apparatus wherein the dispensing means includes a nozzle tip. The sample analyzer according to claim 5,
A plurality of disposal locations for the nozzle tip;
An apparatus comprising arithmetic means for judging a disposal place of a nozzle chip using image information obtained from the imaging means. The sample analyzer according to claim 5,
A plurality of disposal locations for the container and the nozzle tip;
An apparatus comprising: calculating means for determining the disposal location of the container and the nozzle chip using image information obtained from the imaging means. The sample analyzer according to claim 1.
An apparatus wherein the photographing means includes a CCD camera. The sample analyzer according to claim 1.
The apparatus characterized in that the photographing means has the dispensing means and the transfer means simultaneously in view. The sample analyzer according to claim 1.
The apparatus according to claim 1, wherein the photographing means includes a moving mechanism for changing a visual field. A unit comprising a connection means with a nozzle tip, and a container holding means;
A transport mechanism for moving the unit;
A sample analyzer comprising:
The apparatus is characterized in that the unit includes photographing means for keeping the nozzle chip and the container in a visual field. The sample analyzer according to claim 11,
An apparatus comprising: an arithmetic unit that determines success or failure of a dispensing step and a transfer step using image information obtained from the imaging unit. The sample analyzer according to claim 11,
An apparatus characterized in that the procedure of the dispensing process and the transfer process is changed using image information obtained from the imaging means. The sample analyzer according to claim 11,
With multiple container disposal locations,
An apparatus comprising: arithmetic means for judging a disposal place of a container using image information obtained from the imaging means. The sample analyzer according to claim 11,
A plurality of disposal locations for the nozzle tip;
An apparatus comprising arithmetic means for judging a disposal place of a nozzle chip using image information obtained from the imaging means. The sample analyzer according to claim 11,
A plurality of disposal locations for the container and the nozzle tip;
An apparatus comprising: calculating means for determining the disposal location of the container and the nozzle chip using image information obtained from the imaging means. The sample analyzer according to claim 11,
An apparatus wherein the photographing means includes a CCD camera. The sample analyzer according to claim 11,
The apparatus characterized in that the photographing means has the dispensing means and the transfer means simultaneously in view. The sample analyzer according to claim 11,
The apparatus according to claim 1, wherein the photographing means includes a moving mechanism for changing a visual field.

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