Automatic dispensation device

Abstract

To allow appropriate dispensation to be stably conducted in an automatic dispensation device.SOLUTION: An automatic dispensation device includes: a sample container holding unit 200 that includes a plurality of recesses 204 accommodating sample containers 300 and 400; an urging member 205 that abuts on the sample container accommodated in each of the plurality of recesses from below to upwardly urge the sample container; and a fluid dispensation mechanism that includes a discharge pipe 171 that discharges a liquid from a tip end and discharges the liquid while the tip end of the discharge pipe is being pressed from above against at a predetermined dispensation object position within the sample container.SELECTED DRAWING: Figure 3

Description

[Technical field]

[0001] The present invention relates to an automated dispensing device. [Background technology]

[0002] In the analysis of a sample using an analytical instrument such as a liquid chromatograph, a gas chromatograph, or a mass spectrometer, a pretreatment such as extraction, purification, concentration, dilution, labeling, or staining of a detection target contained in the sample may be required prior to the analysis. Conventionally, in order to efficiently perform such sample pretreatment, an automatic dispensing device that automatically dispenses liquid such as a liquid sample or a reagent into a plurality of sample containers has been used. Such an automatic dispensing device includes, for example, a dispensing pipette and a robot arm that can hold the dispensing pipette, and the robot arm holds and moves the dispensing pipette while operating the dispensing pipette to collect a predetermined amount of liquid such as a reagent, and then dispenses the liquid into a predetermined sample container (see, for example, Patent Document 1). [Prior art documents] [Patent documents]

[0003] [Patent Document 1] JP 2019-174369 A Summary of the Invention [Problem to be solved by the invention]

[0004] In the above-mentioned automatic dispensing device, in order to stably dispense a minute amount of liquid, a so-called contact dispensing may be performed in which the tip of the pipette tip attached to the dispensing pipette is in contact with a position to be discharged, such as the inner bottom surface of a sample container, and the liquid is discharged in that state. In order to properly perform such contact dispensing, it is necessary to move the dispensing pipette directly above the sample container by the robot arm, and then lower the dispensing pipette until the tip of the pipette tip contacts the position to be discharged, and then discharge the liquid. However, the distance from the tip position of the pipette tip to the position to be discharged when the dispensing pipette starts to lower varies depending on factors such as the variation in the fitting depth of the pipette tip to the dispensing pipette, the limit of the position reproducibility of the robot arm, and the variation in the dimensions of the sample container or the container rack that holds the sample container. Therefore, even if the robot arm is controlled to lower the dispensing pipette by a distance predetermined as the distance required to bring the tip of the pipette tip into contact with the position to be discharged, there are cases in which the pipette tip does not contact the position to be discharged or contacts the position to be discharged excessively, and appropriate contact dispensing is not performed.

[0005] The present invention has been made in view of the above-mentioned points, and an object of the present invention is to enable appropriate contact dispensing to be performed stably in an automatic dispensing device. [Means for solving the problem]

[0006] The automatic dispensing device according to the present invention, which has been made to solve the above problems, is: a sample container holder having a plurality of recesses for receiving sample containers; a biasing member provided in each of the plurality of recesses and biasing the sample container accommodated in the recess upward; a liquid dispensing mechanism having a discharge tube from a tip thereof, the liquid being discharged while the tip of the discharge tube is pressed against a predetermined dispensing target position in the sample container from above; It has the following.

[0007] In addition, the automatic dispensing device according to the present invention, which has been made to solve the above problems, a sample plate holder for holding a sample plate having a plurality of sample holding regions formed thereon; a biasing member provided on a lower surface of the sample plate at a position corresponding to each of the plurality of sample holding regions, the biasing member biasing the sample plate upward; a liquid dispensing mechanism having a discharge tube that discharges liquid from a tip thereof, the liquid being discharged while the tip of the discharge tube is pressed against each of the plurality of sample holding regions from above; The present invention may also have the following structure. Effect of the Invention

[0008] According to the automatic dispensing device of the present invention having the above-mentioned configuration, appropriate contact dispensing can be stably performed. [Brief description of the drawings]

[0009] [Figure 1] FIG. 1 is a plan view showing a schematic configuration of a sample pretreatment device according to an embodiment of the present invention. [Diagram 2] FIG. 2 is a longitudinal sectional view of a spin column and a collection tube used in the sample pretreatment device. [Diagram 3] FIG. 2 is a longitudinal cross-sectional view showing a state in which the spin column and the collection tube are held in a temperature controller provided in the sample pretreatment device. [Figure 4] FIG. 11 is a vertical cross-sectional view showing contact dispensing onto a flat plate on a plate holder in a sample pretreatment device according to another embodiment of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] A sample pretreatment device, which is an embodiment of an automatic dispensing device according to the present invention, will be described below with reference to the drawings. Fig. 1 is a top view showing a schematic configuration of the sample pretreatment device according to this embodiment. This sample pretreatment device includes a housing 100, a temperature regulator 200 (corresponding to a sample container holder in the present invention) arranged in the housing 100, a centrifuge 110, a dispenser 161, a robot arm 120, and a control unit 130. In this embodiment, the dispenser 161, the robot arm 120, and the control unit 130 work together to function as a liquid dispensing mechanism in the present invention. Further provided within the housing 100 are a column rack arrangement section 140 in which a column rack 141 containing a plurality of spin columns 300 is arranged, a tube rack arrangement section 150 in which a tube rack 151 containing a plurality of collection tubes 400 is arranged, a dispenser accommodating section 160 in which one or more dispensers 161 are accommodated, a tip rack arrangement section 170 in which a tip rack 172 containing a plurality of pipette tips 171 is arranged, a reagent rack arrangement section 180 in which a reagent rack 182 containing one or more reagent containers 181 is arranged, a consumable disposal section 191 in which used spin columns 300 and pipette tips 171 are disposed, and a pretreated sample accommodation section 192 in which collection tubes 400 containing pretreated samples are accommodated.

[0011] As the dispenser 161 in this embodiment, for example, a micropipette is used. A micropipette generally includes a cylinder, a plunger (or piston), and a tubular nozzle connected to the lower end of the cylinder. With a disposable pipette tip (corresponding to the discharge tube in the present invention) attached to the lower end of the nozzle, the plunger is moved up and down within the cylinder to aspirate liquid into the pipette tip and discharge liquid from the pipette tip. As the micropipette, for example, an electric micropipette having a built-in motor for driving the plunger and an operation button for instructing the execution of the aspirating operation and the discharge operation by driving the motor can be used. However, the present invention is not limited to this, and a so-called manual micropipette may be used, which has a push rod connected to the upper end of the plunger and a spring for biasing the push rod upward, and which moves the plunger up and down by pressing or releasing a push button provided at the upper end of the push rod.

[0012] The robot arm 120 includes a hand unit 121 capable of holding the spin column 300, the collection tube 400, and the dispenser 161 and of operating the operation button or the push button provided on the dispenser 161.

[0013] The temperature regulator 200, the centrifuge 110, and the robot arm 120 described above are controlled by a control unit 130. The actual entity of the control unit 130 is a dedicated computer or a general-purpose computer such as a personal computer, and the functions of the control unit 130 in this embodiment are realized by executing a predetermined program installed in the computer. In FIG. 1, the control unit 130 is disposed outside the housing 100, but the control unit 130 may be disposed inside the housing. Note that an input unit consisting of a keyboard or operation buttons, etc., and a display unit consisting of a liquid crystal display, etc., are connected to the control unit 130, but are omitted from the illustration for simplification.

[0014] The column rack 141 holds a number of spin columns 300 as shown in FIG. 2, and the tube rack 151 holds a number of collection tubes 400 as shown in the same figure.

[0015] The collection tube 400 may be a so-called microtube, which includes a cylindrical or substantially conical body with a diameter decreasing downward, closed at the bottom and open at the top, and a lid connected to the periphery of the top end of the body via a hinge and capable of closing the top opening of the body (for simplicity, the lid is not shown in Figs. 2 and 3). However, the collection tube 400 in this embodiment is not limited to such a microtube, and may be any tube that can hold liquid and can accommodate a spin column 300 described below.

[0016] On the other hand, the spin column 300 has a cylindrical portion 301 with a circular upper opening and a lower opening with a smaller diameter than the upper opening, and a filter 302 held inside the cylindrical portion 301, and can be inserted into the upper portion of a collection tube 400, as shown on the right side of Fig. 2. The filter 302 may be any filter that is used for solid-phase extraction, and examples of the filter that can be used include a silica monolith, a silica membrane, a cellulose membrane, or a filter made of a resinous carrier such as an ion exchange resin.

[0017] As described above, the spin column 300 and the collection tube 400 in the state where the spin column 300 is attached to the collection tube 400 correspond to the sample container according to the present invention. In the above state, the region above the filter 302 in the internal space of the tubular part 301 of the spin column 300 corresponds to the upper space in the present invention, and in the same state, the region below the region where the spin column 300 is attached in the internal space of the collection tube 400 corresponds to the lower space in the present invention.

[0018] The temperature regulator 200 includes a base 201 and a heat transfer block 203 placed on the base 201. The base 201 has a recess in its upper portion for accommodating the heat transfer block 203, and a heater 202 for heating the heat transfer block 203 and a temperature sensor (not shown) for measuring the temperature of the heat transfer block 203 are provided below the inner bottom surface of the recess. The temperature regulator 200 may have a cooling function, for example, a fan or a Peltier element, in addition to the heating function by the heater 202 as described above. The heat transfer block 203 is made of a material with high thermal conductivity, such as aluminum, and its upper surface is provided with a tube accommodating section 204 (corresponding to the recess in the present invention) which is a recess for accommodating the collection tube 400. A cylindrical cavity is provided below each tube accommodating section 204, and a spring plunger 205 (corresponding to the biasing member in the present invention) is fitted into the cavity. The cavity may be a through hole whose upper end opens to the inner bottom surface of tube accommodating section 204 and whose lower end opens to the lower surface of heat transfer block 203, or may be a concave shape whose only the upper end is open.

[0019] The spring plunger 205 includes a hollow cylindrical holder 206, a compression coil spring 210 housed in the holder 206, and a pin member 207, a part of which can be freely projected and retracted from the holder 206. The pin member 207 includes a protruding portion 208 protruding from the holder 206 to the outside through a through hole (not shown) provided on the upper surface of the holder 206, and a flange-shaped retaining portion 209 provided at the base end of the protruding portion 208 and capable of sliding up and down within the holder 206. The lower surface of the retaining portion 209 abuts against the upper end of the compression coil spring 210, and the pin member 207 is always biased upward by the biasing force of the compression coil spring 210. Instead of the spring plunger 205 including the pin member 207 as described above, a so-called ball plunger including a ball, a part of which can be freely projected and retracted from the holder 206, and a spring for biasing the ball may be used.

[0020] The flow of pretreatment by the pretreatment device according to this embodiment will be described below. At the start of pretreatment, the column rack 141 and the tube rack 151 hold a plurality of spin columns 300 and a plurality of collection tubes 400, respectively. At this time, a predetermined amount of liquid sample has been added to each spin column 300 in advance, and the target component in the sample is adsorbed to the filter 302.

[0021] First, under the control of the control unit 130, the robot arm 120 grasps the collection tube 400 held in the tube rack 151 and stores it in the tube storage unit 204 of the temperature regulator 200, and then grasps the spin column 300 held in the column rack 141 and attaches it to the collection tube 400 on the temperature regulator 200. At this time, inside each tube storage unit 204, the bottom of the collection tube 400 is in contact with the tip of the pin member 207 of the spring plunger 205. However, since the spin column 300 and the collection tube 400 are relatively lightweight, the pin member 207 is hardly pushed down due to contact with the collection tube 400.

[0022] Next, the robot arm 120 grasps the dispenser 161 housed in the dispenser housing section 160 and moves the dispenser 161 above the tip rack arrangement section 170, and lowers the dispenser 161 toward one of the pipette tips 171 housed in the tip rack 172, thereby attaching the pipette tip 171 to the tip of the nozzle of the dispenser 161.

[0023] Next, the robot arm 120 moves the dispenser 161 to insert the tip of the pipette tip 171 into one of the reagent containers 181 on the reagent rack 182, and collects a predetermined amount of reagent by operating an operation button or the like provided on the dispenser 161.

[0024] Thereafter, the robot arm 120 moves the dispenser 161 to a position directly above the collection tube 400 and the spin column 300 housed in one of the tube housing parts 204 on the temperature regulator 200. Then, the dispenser 161 is lowered a predetermined distance from that position (hereinafter referred to as the initial position) to bring the tip of the pipette tip 171 into contact with the center of the upper surface of the filter 302 in the spin column 300 (corresponding to the dispensing target position in the present invention) (see FIG. 3). Then, in this state, the robot arm 120 operates an operation button or the like provided on the dispenser 161 to eject the reagent from the pipette tip 171.

[0025] However, the distance from the height of the initial position to the upper surface of filter 302 (hereinafter referred to as the initial position-filter distance) varies due to factors such as variations in the fitting depth of pipette tip 171 relative to the nozzle of dispenser 161, limitations in the position repeatability of robot arm 120, and variations in dimensions of collection tube 400, spin column 300, and tube storage section 204. In order to absorb such variations in the initial position-filter distance, the stroke of pin member 207 of spring plunger 205 is set to be equal to or greater than the difference between the maximum and minimum values ​​of the initial position-filter distance when considering the variations due to the above factors, and the descending distance from the initial position is set to a predetermined distance greater than the initial position-filter distance when it is assumed that there is no such distance variation (the predetermined distance corresponds to the amount of displacement in the present invention). As a result, regardless of the above-mentioned fluctuation in the distance between the initial position and the filter, the reagent can be discharged with the tip of the pipette tip 171 always in contact with the upper part of the filter 302, and stable dispensing can be performed even when the amount of reagent dispensed is very small. Furthermore, when the tip of the pipette tip 171 is pressed against the upper surface of the filter 302 by the downward movement of the dispenser 161, the compression coil spring 210 of the spring plunger 205 is compressed by the pressing force, and the collection tube 400 and the spin column 300 are slightly lowered. Therefore, the pipette tip 171 is prevented from being strongly pressed against the upper surface of the filter 302, and damage to the filter 302 can be prevented.

[0026] For example, a spring constant of 0.10 N / mm to 1.02 N / mm (preferably 0.2 N / mm to 0.5 N / mm) can be used as the compression coil spring 210. The control unit 130 controls the robot arm 120 so that the amount of displacement of the collection tube 400 and the spin column 300 caused by the pressing of the pipette tip 171 is 0.5 mm to 5.0 mm (preferably 0.25 mm to 1 mm). However, appropriate values ​​of the spring constant and the amount of displacement in this embodiment vary depending on the type (hardness, material, or dryness) of the filter 302 and the type (hardness, material, or tip shape) of the pipette tip 171, etc. Therefore, it is desirable to conduct trials using the types of filter 302 and pipette tip 171 that will actually be used to identify an appropriate spring constant and displacement amount that will ensure that the tip of the pipette tip 171 abuts the filter 302 without damaging the filter 302, and then use a compression coil spring 210 with the appropriate spring constant and adjust the control amount of the robot arm 120 by the control unit 130 so that the displacement amount becomes an appropriate value.

[0027] After dispensing the reagent into each of the spin columns 300 accommodated in all the collection tubes 400 on the temperature regulator 200 according to the above procedure, the collection tubes 400 and the spin columns 300 are incubated on the temperature regulator 200 for a predetermined time. Then, each collection tube 400 and each spin column 300 attached to the collection tube 400 are transferred to the centrifuge 110 by the robot arm 120 and centrifuged to recover the target component in the sample into each collection tube 400. Then, each spin column 300 is removed from each collection tube 400 by the robot arm 120 and disposed in the consumable disposal section 191, and the lid of the collection tube 400 is closed and transferred to the pretreated sample storage section 192. Note that, in this embodiment, for the sake of simplicity, only one type of reagent is dispensed into each spin column 300, but multiple types of reagents may be dispensed into each spin column 300.

[0028] Although specific examples of the embodiment of the present invention have been described above, the present invention is not limited to the above configurations and suitable modifications are permitted.

[0029] For example, the biasing member in the present invention is not limited to one using a compression coil spring like the spring plunger described above, but may be one that biases the sample container upward using other elastic bodies, such as a leaf spring or a block made of elastomer, or one that biases the sample container upward using the repulsive force of a magnet.

[0030] Furthermore, the sample dispensing device according to the present invention may be a pretreatment device as in the above embodiment, or may be a device that only performs dispensing without performing pretreatment.

[0031] In the above embodiment, the biasing member of the present invention is provided in the temperature regulator 200, but the present invention is not limited to this. A biasing member of the present invention may be provided in a tube rack that does not have a temperature regulation function, and the above-mentioned contact dispensing may be performed with the sample container held in the tube rack. In this case, the tube rack corresponds to the sample container holder of the present invention.

[0032] In the above embodiment, the tip of the pipette tip 171 is brought into contact with the filter 302 provided on the spin column 300 to dispense the reagent, but the present invention is not limited to this. For example, the tip of the pipette tip may be brought into contact with the inner bottom surface of a microtube to which the spin column 300 is not attached to dispense the reagent. Alternatively, the tip of the pipette tip 171 may be brought into contact with the bottom surface of each of a plurality of wells provided in a microtiter plate, or each of a plurality of sample holding areas formed on a flat plate to dispense the reagent. In this case, a biasing member made of a spring plunger or the like as described above is provided at each of the positions where the bottom surface of the plurality of wells or the bottom surface of the positions abuts on a temperature regulator or a holder (plate holder) without a temperature regulation function on which the microtiter plate or flat plate is placed. An example of the configuration in such a case is shown in FIG. 4. This figure shows an automatic dispensing device configured to press the tip of the pipette tip 171 against each of a plurality of sample holding areas 602 formed on the upper surface of a flat plate 600 to dispense the reagent by contact. Here, the flat plate 600 is placed on a plate holder 500 , and the plate holder 500 has spring plungers 505 disposed at positions directly below each sample holding region 602 .

[0033] Further, the dispenser 161 is not limited to a single-channel micropipette, but may be a multi-channel micropipette. In the above embodiment, the dispenser 161 is moved and operated by the robot arm 120 to dispense the reagent, but the present invention is not limited to this. A pipe having one end inserted into a reagent container and a nozzle (corresponding to a discharge tube in the present invention) for discharging liquid attached to the other end, a pump for sucking the reagent from the one end of the pipe and discharging the reagent from the other end of the pipe, and a moving mechanism for moving the nozzle up and down, back and forth, and left and right may be provided, and the reagent may be discharged with the tip of the nozzle in contact with the discharge target position in the sample container.

[0034] [Aspects] It will be apparent to those skilled in the art that the above-described exemplary embodiments are illustrative of the following aspects.

[0035] (Item 1) An automatic dispensing device according to one aspect of the present invention comprises: a sample container holder having a plurality of recesses for receiving sample containers; a biasing member provided in each of the plurality of recesses and biasing the sample container accommodated in the recess upward; a liquid dispensing mechanism having a discharge tube from a tip thereof, the liquid being discharged while the tip of the discharge tube is pressed against a predetermined dispensing target position in the sample container from above; It has the following.

[0036] According to the automatic dispensing device of paragraph 1, the fluctuation in the vertical distance from the tip of the discharge tube in the reference position to the dispensing target position can be absorbed by the biasing member, making it possible to always perform stable contact dispensing.

[0037] (2) The automatic dispensing device according to the second paragraph is the automatic dispensing device according to the first paragraph, The liquid dispensing mechanism is configured to discharge the liquid after lowering the tip of the discharge tube by a predetermined distance from a predetermined initial position above the sample container.

[0038] (3) The automatic dispensing device according to the third paragraph is an automatic dispensing device according to the first or second paragraph, The biasing member is adapted to come into contact with the sample container from below.

[0039] (4) The automatic dispensing device according to the 4th aspect is an automatic dispensing device according to any one of the 1st to 3rd aspects, the sample container holder holds, as the sample container, a container having a filter and an upper space and a lower space partitioned by the filter, The dispensing target position is the position of the upper surface of the filter provided in the sample container accommodated in each of the plurality of recesses.

[0040] According to the automatic dispensing device of the fourth aspect, the tip of the discharge tube can be prevented from being pressed strongly against the upper surface of the filter, and damage to the filter caused by the pressure of the discharge tube can be suppressed.

[0041] (Item 5) The automatic dispensing device according to item 5 is an automatic dispensing device according to any one of items 1 to 4, The sample container holder is a temperature regulator including a heat transfer block and a heater for heating the heat transfer block, and the plurality of recesses are provided on an upper surface of the heat transfer block.

[0042] According to the automatic dispensing device according to the fifth aspect, stable contact dispensing can be performed on a sample container held on a temperature regulator.

[0043] (6) The automatic dispensing device according to 6 is a sample plate holder for holding a sample plate having a plurality of sample holding regions formed thereon; a biasing member provided on a lower surface of the sample plate at a position corresponding to each of the plurality of sample holding regions, the biasing member biasing the sample plate upward; a liquid dispensing mechanism having a discharge tube that discharges liquid from a tip thereof, the liquid being discharged while the tip of the discharge tube is pressed against each of the plurality of sample holding regions from above; It has the following.

[0044] According to the automatic dispensing device of item 6, the fluctuation in the vertical distance from the tip of the discharge tube in the reference position to the sample holding area can be absorbed by the biasing member, making it possible to always perform stable contact dispensing. [Explanation of symbols]

[0045] 100…Housing 110...Centrifuge 120…Robot arm 130...Control unit 161...Dispenser 171...Pipette tip 181...Reagent container 200…Temperature controller 201…Base section 202…Heater 203…Heat transfer block 204...Tube storage section 205...Spring plunger 206…Holder 207...Pin member 300…Spin column 302...Filter 400…Collection tube

Claims

1. A sample container holding part having a plurality of recesses for accommodating sample containers; A biasing member provided in each of the plurality of recesses for biasing the sample container accommodated in the recess upward; A liquid dispensing mechanism having a discharge tube for discharging liquid from its tip, and discharging the liquid with the tip of the discharge tube pressed against a predetermined dispensing target position in the sample container from above; An automatic pipetting device having the above.

2. The automatic pipetting device according to claim 1, wherein the liquid dispensing mechanism discharges the liquid after lowering the tip of the discharge tube by a predetermined distance from a predetermined initial position above the sample container.

3. The automatic pipetting device according to claim 1, wherein the biasing member abuts against the sample container from below.

4. The sample container holding part holds, as the sample container, a container having a filter and an upper space and a lower space partitioned by the filter, and the dispensing target position is the position of the upper surface of the filter provided in the sample container accommodated in each of the plurality of recesses. The automatic pipetting device according to claim 1.

5. The sample container holding part is a temperature control device including a heat transfer block and a heater for heating the heat transfer block, and the plurality of recesses are provided on the upper surface of the heat transfer block. The automatic pipetting device according to claim 1.

6. A sample plate holding part for holding a sample plate in which a plurality of sample holding areas are formed; A biasing member provided at a position corresponding to each of the plurality of sample holding areas of the sample plate holding part for biasing the sample plate upward; A liquid dispensing mechanism having a discharge tube for discharging liquid from its tip, and discharging the liquid with the tip of the discharge tube pressed against each of the plurality of sample holding areas from above; An automatic pipetting device having the above.

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