JP5363604B2 - Chemical analyzer - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a chemical analyzer capable of suppressing lowering of analysis and inspection accuracy without complicating a structure by avoiding contamination due to remaining specimen and reagent. <P>SOLUTION: A dispensation unit 2 includes a syringe 2a, a plunger 2b, and a needle part 2c disposed with a nucleic acid capturing carrier 2d, and a detecting container 6 is attached to the needle part 2c. A dispensation driving system 3 is configured to freely attach/detach the dispensation unit 2. After the detecting container 6 is detached from the dispensation unit 2 and fixed to a nucleic acid amplification detecting unit 8, the dispensation unit 2 performs an operation for sucking/discharging the reagent and specimen, and a component subject for measurement is captured by the carrier 2d. The captured component is discharged to the detecting container 6 fixed to the nucleic acid amplification detecting unit 8 to be measured. After that, the detecting container 6 is taken out from the nucleic acid amplification detecting unit 8 with the detecting container 6 attached to the dispensation unit 2, and the whole body of the dispensation unit 2 is removed from the dispensation driving system 3. <P>COPYRIGHT: (C)2012,JPO&amp;INPIT

Description

  The present invention relates to a chemical analyzer that has a function of dispensing a liquid sample and a reagent and that analyzes a chemical substance in a sample solution.

  In systems that dispense, analyze, and inspect different liquid samples and reagents, the flow path during dispensing and the liquid storage part are often shared by different samples and reagents. There was a problem that they became a source of contamination with each other.

  For this reason, in the prior art, it is assumed that the tip of the dispensing means is replaced. However, there is a part that comes into contact with the liquid among the parts that are repeatedly used, and it is possible to avoid contamination by residual samples and reagents in this part. There was a problem that was difficult.

  In order to prevent this, as described in Patent Document 1, a part including a liquid dispensing channel or a reagent container is washed.

  Further, in a genetic test involving nucleic acid amplification, nucleic acid may leak in the amplification process and become a contamination source, and therefore, as described in Patent Document 2, it is sealed in a container for carrying out an amplification reaction.

JP 2000-121650 A JP-T 9-504690

  However, the technique described in Patent Document 1 requires a means for cleaning the portion including the reagent container, and thus there is a problem that the configuration of the analyzer is complicated.

  In addition, the technique described in Patent Document 2 requires a means for sealing a container for performing an amplification reaction, and there is still a problem that the configuration of the analyzer is complicated. In addition, the stirring operation, dispensing, and dropping operation of the solution required during the reaction also cause contamination during repeated analysis.

  The object of the present invention is to avoid contamination by samples and reagents remaining in the chemical analysis device for chemical analysis and genetic testing, and to suppress degradation of analysis accuracy and test accuracy without complicated configuration The realization of a simple chemical analyzer.

  In order to solve the above problems, the present invention is configured as follows.

  In a chemical analyzer, a dispensing unit that sucks and discharges a liquid sample and a liquid reagent, a support unit that removably supports the dispensing unit, and the dispensing unit are driven to drive the liquid sample and the liquid reagent. And a dispensing means moving drive means having a drive part for performing the suction and discharge operations and a moving part for moving the dispensing means.

  Also used in chemical analyzers or genetic testing devices that analyze liquid samples, and in dispensing devices that aspirate and discharge liquid samples and liquid reagents, they have a nucleic acid capture carrier for genetic testing. The needle part for sucking and discharging the liquid sample and the liquid reagent inside, the plunger part for sucking and discharging the liquid sample and the liquid reagent inside the needle part, and the plunger part can be moved through the needle part Since the syringe unit supported by the device, the flange unit removably supported by the chemical analysis device or the genetic testing device, and the plunger unit are driven by the driving means of the chemical analysis device or the genetic testing device, A driving end portion that is detachably supported by the analyzer or the genetic testing device and a needle cover protective cover that is detachably supported by the needle portion. And a detection container analyte is housed.

  In addition, in a genetic test apparatus having a test unit for testing a gene in a liquid sample, a dispensing means that has a nucleic acid capture carrier inside, and sucks and discharges the liquid sample and liquid reagent inside, and the above-described dispensing unit. A dispensing part having a supporting part for detachably supporting the pouring means, a driving part for driving the dispensing means to perform suction and discharge operations of the liquid sample and the liquid reagent, and a moving part for moving the dispensing means. And injection means moving drive means.

  In chemical analysis equipment that performs chemical analysis and genetic testing, a chemical analyzer that avoids contamination by samples and reagents remaining in the equipment and can suppress degradation of analysis accuracy and inspection accuracy without complicated configuration can do.

It is an explanatory view showing the composition of the genetic testing device in a 1st embodiment of the present invention. It is explanatory drawing of attachment / detachment to the dispensing drive system of the dispensing part in the 1st Embodiment of this invention. It is drive mechanism explanatory drawing of the plunger of the dispensing part in the 1st Embodiment of this invention. It is explanatory drawing of the up-down direction moving mechanism of the dispensing part in the 1st Embodiment of this invention. It is an inspection process flowchart in the case of a tubercle bacillus inspection. It is apparatus state explanatory drawing at the time of nucleic acid amplification detection part mounting | wearing of the detection container in 1st Embodiment. It is an apparatus state explanatory view at the time of reagent dispensing in a 1st embodiment. It is apparatus state explanatory drawing of the nucleic acid amplification detection process in 1st Embodiment. It is principal part explanatory drawing of 2nd Embodiment. It is principal part explanatory drawing of 2nd Embodiment. It is principal part explanatory drawing of 3rd Embodiment. It is principal part explanatory drawing of 3rd Embodiment.

  Embodiments of the present invention will be described below with reference to the accompanying drawings. In addition, the following embodiment is an example at the time of applying this invention to a genetic test | inspection apparatus among chemical analyzers.

  1 to 4 are explanatory diagrams of the configuration of the genetic test apparatus according to the first embodiment of the present invention, and FIG. 5 is a test process flowchart in the case of M. tuberculosis test. 6 to 8 are diagrams for explaining the state of the apparatus in each inspection process.

  In FIG. 1, a reagent container 1 is filled with each reagent used for analysis, and this reagent container 1 is covered with a protective film 1a whose surface is coated with aluminum for preventing evaporation based on PET (Polyethylene Terephthalate). Covered. The dispensing part 2 includes a resin syringe 2a, a plunger 2b, and a needle part 2c. The base part of the needle part 2c has a built-in carrier 2d for capturing the nucleic acid, and the single dispensing part 2 is used for both the perforation of the protective film 1a by the needle part 2c, the reagent dispensing and the nucleic acid extraction.

  The aspiration and discharge amount of the reagent and the solution such as the specimen by the dispensing unit 2 and the operation speed thereof are controlled by the pushing distance and the speed of the plunger 2b with respect to the syringe 2a. Insertion and withdrawal of the needle part 2c of the dispensing part 2 with respect to each reagent container and the like are controlled by a dispensing part vertical drive part 3a comprising a pulse motor and a ball screw. The plunger 2b is pushed and pulled, that is, the suction and discharge of the solution are controlled by the plunger drive unit 3b.

  On the other hand, the movement of the dispensing unit 2 in the horizontal direction, that is, the movement between containers is controlled by a dispensing unit horizontal drive unit 3c driven by a pulse motor and a belt. The carrier 2d is made of a material containing silicon oxide, such as glass fibers, glass particles, silica particles, silica wool, or crushed materials thereof.

  A specimen such as blood to be examined is dispensed into the specimen container 4, and the specimen container 4 is attached to the specimen container holding unit 5 after the pretreatment. Similarly, the needle part 2c of the dispensing part 2 is equipped with a detection container 6 that also serves as a protective cover, and is attached to the dispensing part drive system 3 with this detection container 6 attached. The reagent container 1 holds the reagent container. Mounted on the part 7.

  The dispensing unit 2 has a configuration that can be easily attached to and detached from the dispensing drive system 3 by an operator. FIG. 2 is an explanatory view of attaching and detaching the dispensing unit 2 to the dispensing drive system 3. As shown in FIG. 2A, the syringe 2a of the dispensing unit 2 is inserted into the syringe support 3m of the syringe holder 3k, and the drive end 2e of the plunger 2b is supported by the plunger drive ball screw 3f. The plunger holder (plunger support part) is inserted into 3h.

  Then, in order to fix the flange portion 2f, the syringe fixing holder 3e is set at the syringe fixing position, the syringe fixing lock pin 3d is pushed in, the syringe fixing holder 3e is locked, and the state shown in FIG. To.

  When removing the dispensing part 2 from the syringe holder 3k, the syringe fixing lock pin 3d is pulled up to open the syringe fixing holder 3e. And the dispensing part 2 is removed from the syringe holder 3k.

  Further, the plunger 2 b of the dispensing unit 2 is configured to be pushed and pulled by the dispensing drive system 3. FIG. 3 is an explanatory diagram of the drive mechanism of the plunger 2b. As shown in FIG. 3A, the plunger drive ball screw 3f is connected to a plunger drive motor (dispensing part vertical drive part) 3b and is driven to rotate. Then, the plunger drive ball screw 3f is rotationally driven by the plunger drive motor 3b, whereby the plunger 2b is driven to be pushed and pulled ((B) of FIG. 3). Switching between pushing and pulling the plunger 2b (switching in the vertical movement direction) is performed by switching the rotation direction of the plunger drive motor (plunger drive unit) 3b, and switching of the push-pull speed of the plunger 2b is performed by the plunger drive motor 3b. This is done by switching the rotation speed.

  The entire dispensing unit 2 is configured to be moved in the vertical direction by the dispensing drive system 3. FIG. 4 is an explanatory view of the vertical movement mechanism of the dispensing unit 2. As shown in FIG. 4A, the syringe holder 3k is supported by a dispensing unit vertical movement ball screw 3i, and this dispensing unit vertical movement ball screw 3i is connected to a dispensing unit vertical movement motor 3a and is driven to rotate. The Then, the dispensing unit vertical movement motor 3a is rotationally driven by the dispensing unit vertical movement motor 3a, whereby the dispensing unit 2 is moved in the vertical direction ((B) of FIG. 4). Switching of the vertical movement direction of the dispensing unit 2 is performed by switching the rotation direction of the dispensing unit vertical movement motor 3a, and switching of the vertical movement speed is performed by switching the rotation speed of the dispensing unit vertical movement motor 3a. .

  Sample pretreatment is performed (step 100 in FIG. 5), and after the automatic operation of the genetic test apparatus is started (step 101), first, heating for a predetermined time for cell wall lysis of tuberculosis bacteria, and then cooling to return to room temperature. Is performed (step 102). The sample container holding unit 5 includes a Peltier element 5a and a heat radiating fin 5b in order to perform the temperature control described above.

  During the heating operation of the sample solution, the dispensing unit 2 is as shown in FIG. When the detection container 6 is inserted after moving to the nucleic acid amplification detection unit 8, the detection container 6 is separated from the dispensing unit 2 and fixed to the nucleic acid amplification detection unit 8. Although not shown, a means for removing the detection container 6 from the needle portion 2c of the dispensing unit 2 and fixing the nucleic acid amplification detection unit 8 is formed. Further, as will be described later, the detection container 6 fixed to the nucleic acid amplification detection unit 8 inserts the needle 2c of the dispensing unit 2 into the detection container 6, and when it is lifted after certain processing, With the detection container 6 attached, a mechanism is provided that is removed from the nucleic acid amplification detection unit 8.

  Next, the dispensing unit 2 is moved, and as shown in FIG. 7, the nucleic acid binding reagent is sucked from the nucleic acid binding reagent container 1 b into the syringe 2 a of the dispensing unit 2 and then discharged into the sample container 4. Then, aspirate and discharge of the mixed solution of the sample solution and the nucleic acid binding reagent are repeated in the sample container 4 as it is. By this suction and discharge operation, the reagent and the sample solution are mixed and the nucleic acid is bound to the carrier 2d (steps 103 and 104).

  In addition to the nucleic acid, impurities contained in the specimen are also attached to the carrier 2d in the needle portion 2c, and the impurities are removed by a cleaning reagent containing ethanol as a main component in a subsequent cleaning step.

  In the first embodiment of the present invention, four cleaning reagent containers 1c to 1f are provided in the reagent container 1 to form an integral structure. The cleaning reagent is sucked into the syringe 2a from these cleaning reagent containers 1c to 1f, and then the reagent is discharged into the container, whereby the cleaning reagent is replaced and the impurities adhering to the carrier are washed away (step 105).

  Since the cleaning reagent causes reaction inhibition in the subsequent nucleic acid amplification step, the cleaning reagent remaining in the syringe 2a and the carrier 2d is purged (step 106). In the cleaning reagent purge, the needle part 2c is inserted into the reagent waste container 1g, and air is sucked into and discharged from the syringe 2a to absorb the cleaning reagent in the dispensing part 2 in the adsorbent built in the reagent waste container 1g. . The mist containing the cleaning reagent generated at that time is prevented from leaking out of the container by a filter provided in the reagent disposal container 1g.

  Thereafter, the nucleic acid elution reagent is aspirated from the nucleic acid elution reagent container 1h into the syringe 2a, and the nucleic acid captured by the carrier 2d is eluted (step 107). The nucleic acid elution reagent taken into the syringe 2a contains a nucleic acid amplification enzyme, and a specific nucleic acid can be amplified by controlling the nucleic acid elution reagent containing the eluted nucleic acid at an appropriate temperature.

  In order to perform this nucleic acid amplification reaction and detection step, as shown in FIG. 8, the needle part 2c of the dispensing part 2 is moved to the nucleic acid amplification detection part 8 and inserted into the detection container 6, into which it is inserted. The solution in the syringe 2a is discharged. In this case, scattering of the solution can be prevented by performing suction and discharge from the pores on the film.

  The nucleic acid eluent in the detection container 6 is placed in a constant temperature environment by a heater 8a built in the nucleic acid amplification detection unit 8, and the amplification reaction proceeds at a constant temperature. In the first embodiment of the present invention, nucleic acid amplification at a constant temperature such as Nucleic Acid Sequence-Based Amplification (NASBA) method is assumed, but temperature control in the nucleic acid detection amplification unit is cycle control between high temperature and low temperature. Thus, nucleic acid amplification by the PCR method can also be performed. The nucleic acid is fluorescently labeled, and excitation light is incident on the nucleic acid solution in the container and fluorescence is detected through the photometric window 8b provided in the nucleic acid amplification detection unit, and the fluorescence in the solution is measured (step 108).

  If M. tuberculosis having a concentration higher than the lower limit of detection is present in the sample solution, it is determined to be positive when the presence is detected due to an increase in the amount of fluorescent light. On the other hand, when the concentration is lower than the lower limit of detection, it is confirmed that the amount of fluorescent light does not increase during a predetermined measurement time, thereby confirming negative. After the determination of positive or negative, the inspection process ends, and the sample container 4, the dispensing unit 2 with the detection container 6 attached, and the reagent container 1 are removed from the apparatus and discarded (step 109). .

  Thereby, the part which touched the reagent or the sample solution is discarded for each inspection, and cross-contamination of the reagent and the sample between the inspections is prevented. In particular, the detection container 6 is discarded in a state of being capped by the dispensing unit 2, and the amplified nucleic acid does not remain in the apparatus, and contamination due to leakage of the amplified nucleic acid is prevented.

  Therefore, according to the first embodiment of the present invention, a genetic test apparatus capable of avoiding contamination by samples and reagents remaining in the apparatus and suppressing a decrease in analysis accuracy and test accuracy without involving a complicated configuration. Can be realized.

  In addition, when the dispensing unit drive system 3 is provided with a plurality of dispensing unit holding units and is provided with the corresponding reagent container and sample container holding unit, that is, a plurality of the dispensing drive systems 3 shown in FIG. By forming them in parallel, it is possible to perform a plurality of inspection processes at the same time, and it is possible to improve the throughput of inspection processing without adding a new analyzer.

  FIG. 9 is an explanatory view of a main part of the second embodiment of the present invention, and shows a portion corresponding to the sample container holding unit 5 in the first embodiment. Since other configurations are the same as those of the first embodiment, illustration is omitted.

  In FIG. 9, the second embodiment is provided with a sample container rotating unit 9 for mixing the sample solution and the nucleic acid binding reagent. When the sample container is mounted on the genetic testing device, it is connected to the rotation transmission unit 9a. The drive motor 9b rotates the rotation transmitting portion 9a via the belt mechanism 9c, thereby rotating the sample container itself.

  FIG. 10 is a view showing a side cross-section (FIG. 10A) and a cross-section (FIG. 10B) of the specimen container. As shown in the cross section shown in FIG. 10B, a convex portion is provided on the inner wall of the container, so that the solution can be stirred when the specimen container rotates.

  According to the second embodiment of the present invention, the same effects as those of the first embodiment can be obtained. In addition, the sample container rotating unit 9 performs mixing and stirring so that the dispensing unit 2 performs suction and discharge. Compared with the mixing and stirring operations in, the processing time can be shortened.

  In addition, according to the mechanical mixing method using a stirring spatula or the like, the processing time can be shortened compared to mixing and stirring by suction and discharge, but since the stirring means and the solution are brought into contact, there is a possibility of contamination. is there.

  On the other hand, if mixing and stirring are performed by rotating the detection container as in the second embodiment of the present invention, the possibility of contamination can be reduced.

  FIG. 11 and FIG. 12 are explanatory views of the main part of the third embodiment of the present invention. The third embodiment is an example in which a needle is not used for the dispensing unit 2. Since configurations other than those shown in FIGS. 11 and 12 are the same as those in the first embodiment, illustration is omitted.

  In the third embodiment, the dispensing unit 2 uses two types of chips, a nucleic acid extraction chip 10 and a solution dispensing chip 11, which are attached to and detached from each other. Initially, the dispensing unit 2 includes a syringe 2a and a plunger 2b, and the nucleic acid extraction chip 10 and the solution dispensing chip 11 are mounted on the reagent container 1, respectively.

  The nucleic acid extraction chip 10 contains a single unit for capturing a nucleic acid, and the reagent container 1 is covered with a protective film as in the first embodiment, but a septa 12 is mounted inside the container. The septa 12 is formed of a material having resistance to a reagent enclosed in a container, such as chloroprene rubber, and rich in elasticity. The protective film is peeled off by the operator's manual operation immediately before or immediately after the reagent container 1 is mounted on the genetic testing device, and before the automatic operation is started.

  The dispensing unit 2 moves to the nucleic acid amplification detection unit 8 (not shown in FIGS. 11 and 12), and fixes the detection container 6 to the nucleic acid amplification detection unit 8. And the solution dispensing chip | tip 11 is attached to the dispensing part 2, and dispensing of a solution is performed. When performing the nucleic acid extraction operation, the solution dispensing chip 11 is removed from the dispensing unit 2, mounted in the reagent container 1, and the nucleic acid extraction chip 10 is attached to the dispensing unit 2 to perform the nucleic acid extraction operation.

  Thereafter, the dispensing unit 2 with the nucleic acid extraction chip 10 attached is moved to the nucleic acid amplification detection unit 8 and inserted into the detection container 6. Subsequent operations are the same as those in the first embodiment.

  In the third embodiment, the suction and discharge of the solution is performed by inserting the nucleic acid extraction chip 10 or the solution dispensing chip 11 into the container through the septa 12, and when both the chips 10 and 11 are not inserted. The mouth of the septa 12 is closed, and leakage and scattering of internal reagents and sample solutions can be prevented.

  The nucleic acid extraction chip 10 is mounted and used in the dispensing unit 2 during a nucleic acid binding step, a washing step, and a nucleic acid elution step. On the other hand, the solution dispensing chip 11 is used for adding the nucleic acid binding reagent to the sample solution, and mixing the sample solution and the nucleic acid binding reagent by repeated suction and discharge.

  In the first embodiment, the case where the nucleic acid amplification enzyme and the nucleic acid elution reagent are preliminarily mixed is illustrated. However, in order to improve the storage stability, both are separated and the nucleic acid amplification enzyme is dried. When separating and mixing both after the start of the test process, the nucleic acid elution reagent requires high-precision dispensing at about ± 5 μL in the use range of 20 μL to 100 μL.

  In the third embodiment, the use of the solution dispensing tip 11 corresponding to high-precision dispensing enables the dispensing accuracy to be improved as compared with the case where both the nucleic acid extraction and the solution dispensing are supported. There is.

  As described above, according to the present invention, it is possible to discard a portion that touches a specimen or a reagent in the apparatus during analysis or inspection, thereby preventing contamination due to these remaining in the apparatus. .

  In addition, when dispensing a reagent container covered with a protective film, the needle is attached to the dispensing part, and the solution is prevented from being scattered by sucking and discharging from the pores on the film. it can. By using the protective cover at the tip of the dispensing part as a detection container in the nucleic acid amplification reaction and allowing the amplified nucleic acid to be discarded together with the dispensing means, contamination inside and outside the apparatus due to leakage of the amplified nucleic acid can be prevented.

  By incorporating a nucleic acid extraction carrier in the dispensing unit, operations such as dispensing and nucleic acid extraction can be carried out with a single device, and solution scattering accompanying chip replacement and the like can also be prevented.

  Further, by providing a reagent waste container provided with a filter and an adsorbent in the reagent container for the cleaning liquid purging process required in the process, contamination due to mist scattering of the solution can be prevented.

  Furthermore, by providing a rotation transmission unit for mixing the reagent and the specimen, it is possible to obtain both effects of reducing processing time and preventing contamination during mixing.

  In addition, although the example mentioned above is an example at the time of applying this invention to a genetic testing apparatus, this invention is applicable not only to a genetic testing apparatus but another chemical analyzer.

  DESCRIPTION OF SYMBOLS 1 ... Reagent container, 1a ... Protective film, 1b ... Nucleic acid binding reagent container, 1c-1f ... Washing reagent container, 1g ... Reagent disposal container, 1h ... Nucleic acid elution reagent container, 2 ... dispensing part, 2a ... syringe, 2b ... plunger, 2c ... needle part, 2d ... carrier, 2e ... end for plunger drive, 2f ... flange part, 3 ... Dispensing part drive part, 3a ... Dispensing part vertical drive part, 3b ... Plunger drive part, 3c ... Dispensing part horizontal drive part, 3d ... Syringe fixing lock pin, 3e ... Syringe fixing holder, 3f ... Plunger drive ball screw, 3h ... Plunger holder, 3i ... Dispensing part vertical movement ball screw, 3k ... Syringe holder, 3m ... 4 ... Sample container 5 ... Sample container holder, 5a ... Peltier Element, 5b ... radiating fin, 6 ... detection container, 7 ... reagent container holding part, 8 ... nucleic acid amplification detection part, 8a ... heater, 8b ... photometric window, 9. ..Sample container rotating unit, 9a ... rotation transmitting unit, 9b ... drive motor, 9c ... belt mechanism, 10 ... nucleic acid extraction chip, 11 ... solution dispensing chip

Claims (4)

In a chemical analyzer having a liquid sample analyzer,
Dispensing means having a nucleic acid capture carrier inside, aspirating and discharging a liquid sample and a liquid reagent inside,
A support unit that removably supports the dispensing unit; a driving unit that drives the dispensing unit to perform suction and discharge operations of a liquid sample and a liquid reagent; and a moving unit that moves the dispensing unit. Dispensing means movement drive means having,
A plurality of reagent containers in an integrated structure;
With
The dispensing means has a needle part for aspirating and discharging a liquid sample and a liquid reagent inside, and is equipped with a removable detection container on the needle part,
A nucleic acid amplification reaction is performed in the detection container, and excitation light is incident on the nucleic acid amplification reaction to detect fluorescence,
The chemical analysis apparatus according to claim 1, wherein the detection container is removed from the dispensing means movement driving means with the needle portion attached to the detection container and discarded.   2. The chemical analyzer according to claim 1, further comprising: a sample storage container that stores the liquid sample and the liquid reagent; and a rotation driving unit that rotates the sample storage container.   2. The chemical analyzer according to claim 1, wherein the reagent container protects an internal reagent and the surface thereof is covered with a protective film in order to prevent scattering, and the needle portion perforates the protective film. Chemical analysis equipment.   2. The chemical analyzer according to claim 1, wherein a part of the plurality of reagent containers is a reagent waste container having a reagent adsorbent and a mist scattering prevention filter, and discharges a used reagent remaining in the dispensing means. And a chemical analysis device characterized by having a function of capturing the same.

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