Biological sample processing device

Abstract

The purpose of present invention is to provide a biological sample processing device capable of recovering an eluent as a final product at a high recovery rate. This biological sample processing device has a feature in which a pipette performs an aspiration operation in a state where the tip of the pipette is in contact with magnetic beads, and after the biological sample is aspirated, the pipette waits for an amount of time sufficient for the magnetic beads in the pipette to be discharged to the outside of the pipette by the magnet.

Description

Biological sample processing device

[0001] The present invention relates to a technique for processing a biological sample containing nucleic acids and magnetic particles.

[0002] In recent years, information obtained through nucleic acid analysis, such as cancer genome testing using next-generation sequencing (NGS) systems, has been utilized in various fields, including medicine, clinical testing, the pharmaceutical industry, and the food industry. In this nucleic acid analysis, nucleic acid extraction from various biological samples, such as blood, tissue, and cultured cells, is an essential pretreatment step.

[0003] Nucleic acid extraction methods generally do not use harmful organic solvents such as phenol or chloroform, but rather rely on the property of nucleic acids to bind to silica in the presence of chaotropic agents or on the property of nucleic acids to bind to silica in the presence of organic solvents. Using these methods, nucleic acid extraction methods using nucleic acid capture chips incorporating a silica-containing solid phase as a nucleic acid capture carrier, and methods using magnetic beads (nucleic acid capture carriers) with silica-coated surfaces have been reported. These methods include a step of binding nucleic acids to the nucleic acid capture carrier and an elution step of eluting the nucleic acids from the nucleic acid capture carrier using an eluent.

[0004] In the method using magnetic beads, after the elution step, the magnetic beads are recovered from the eluent using a magnet. One example is a method in which the eluent containing the magnetic beads is drawn into a dispensing tip, the magnetic beads are retained in the dispensing tip using a magnet, and only the eluent is discharged from the dispensing tip. Another example is a method in which a rod-shaped magnet covered with a cover is inserted into the eluent containing the magnetic beads to recover the magnetic beads from the eluent.

[0005] Patent Document 1 describes a method for efficiently collecting magnetic beads, in which the magnetic beads are first collected on the wall of a container and then recovered using a magnetic rod. Patent Document 2 describes an example of extracting nucleic acids from a large volume (2 mL) of sample using a thick magnetic comb and a thin magnetic comb according to the procedure shown in FIG. 23. Patent Document 3 describes a technology in which magnetic material is collected from a magnetic material-containing liquid not in the container containing the sample, but by a dispenser that aspirates and dispenses the magnetic material-containing liquid.

[0006] US6020211US2022 / 0176369A1 Patent No. 3115501

[0007] Consider a nucleic acid extraction device as an example of a biological sample processing device. This device is particularly suitable for testing liquid biological samples, where gene extraction is required from a large volume of specimen (several mL to several tens of mL). Furthermore, it is desirable for the volume of sample liquid after extraction to be concentrated to a small volume (several tens of μL) in consideration of the subsequent testing process.

[0008] When the sample volume is large, the volume of reagents used, including magnetic beads, also increases accordingly. After capturing nucleic acids from the sample, the magnetic beads undergo a washing process and are then introduced into the eluent, where they are removed after eluting the nucleic acids. When using a device that uses a magnetic rod to remove the magnetic beads from the eluent, the magnetic rod is introduced into the eluent, the magnetic beads are attracted by the magnet at the tip of the rod, and the magnetic rod is then withdrawn in this state. At this time, the eluent is recovered while still adsorbed to the magnetic beads, resulting in a large loss of the recovered eluent.

[0009] To address this issue, there is a method for performing the elution process for nucleic acid extraction twice, as shown in FIG. 23 of Patent Document 2. In this method, the nucleic acid is eluted once in a medium volume (several hundred μL) of eluent, then bound to a small amount of magnetic beads again, and the nucleic acid is then eluted in a small volume (several hundred μL) of eluent. This method involves two processes of adsorption (collection) and elution of the nucleic acid and magnetic particles, which may result in losses during the process and a reduced nucleic acid recovery rate. Furthermore, the processing time is also increased.

[0010] The present invention has been made in view of the above problems, and has as its object to provide a biological sample processing apparatus that is capable of recovering the eluent, which is the final product, at a high recovery rate.

[0011] In the biological sample processing device of the present invention, the pipette performs an aspirating operation with the tip of the pipette in contact with the magnetic beads, and after aspirating the biological sample, the pipette waits for a time sufficient for the magnetic beads in the pipette to be expelled from the pipette by the magnet.

[0012] The biological sample processing device according to the present invention can provide a biological sample processing device that can recover the eluate, which is the final product, with a high yield. This improves the recovery rate of the eluted final product (such as nucleic acid), and is expected to improve the accuracy of testing after processing, for example.

[0013] FIG. 1 is a perspective view of a biological sample processing apparatus 1 according to embodiment 1. FIG. 2 is a diagram illustrating details of each element of the biological sample processing apparatus 1. FIG. 3 is a diagram illustrating a stirring operation. FIG. 4 is a diagram illustrating a magnetic collection operation. FIG. 5 is a flowchart of an eluent recovery operation after an elution step. FIG. 6 is a diagram illustrating an eluent aspirating operation in an eluent recovery operation. FIG. 7 is a diagram illustrating the transition of pressure measured by a pressure sensor provided in a pipette when recovering an eluent. FIG. 8 is a diagram illustrating how loss of recovered eluent occurs in a conventional biological sample processing apparatus. FIG. 9 is a side view illustrating setting positions used in an eluent recovery operation in embodiment 2. FIG. 10 is a flowchart of an eluent recovery operation after an elution step in embodiment 2. FIG. 11 is a diagram illustrating an eluent aspirating operation in an eluent recovery operation. FIG. 12 is a diagram illustrating a pipette unit 200 of a biological sample processing apparatus 1 according to embodiment 3.

[0014] <Embodiment 1> Figure 1 is a perspective view of a biological sample processing apparatus 1 according to embodiment 1 of the present invention. In embodiment 1, the present invention is applied to a nucleic acid extraction apparatus, which is a biological sample processing apparatus. The biological sample processing apparatus 1 is an apparatus that extracts nucleic acids from a sample containing nucleic acids and magnetic particles. The biological sample processing apparatus 1 is composed of a magnetic rod unit 100, a pipette unit 200, a container transport unit 300, and a bottom magnet unit 400. A horizontal movement motor 206, a pipette up and down movement motor 204, and a container movement motor 305 will be described later.

[0015] FIG. 2 shows the details of each element of the biological sample processing apparatus 1. The magnetic rod unit 100 is a unit that moves the magnetic rod 101 and magnetic rod cover 102 up and down in the vertical direction (Z-axis direction in the figure) to stir the sample in a container and collect the magnetic beads contained in the sample. The tip or the entire magnetic rod 101 is made of a neodymium magnet, and a magnetic force acts in the vertical direction (Z-axis direction in the figure), allowing the magnetic beads in the liquid to be collected. The magnetic rod cover 102 is hollow so that the magnetic rod 101 can be inserted inside, and is made of resin (such as polypropylene). The inner diameter of the magnetic rod cover 102 is approximately the same as the outer diameter of the magnetic rod 101.

[0016] The magnetic bar unit 100 comprises a magnetic bar 101, a magnetic bar cover 102, and for driving them, a magnetic bar drive motor 103 and a magnetic bar cover drive motor 104. By providing a drive motor for each of the magnetic bar 101 and the magnetic bar cover 102, the magnetic bar 101 and the magnetic bar cover 102 can be driven independently.

[0017] The pipette unit 200 is a unit equipped with a pipette for aspirating and dispensing a sample. This unit is equipped with a plunger 201 for generating suction pressure and a plunger drive motor 202 for operating the plunger 201. The plunger drive motor 202 is controlled by a controller (not shown), and its speed can be set and changed as desired, making it possible to change the aspirating speed of the pipette depending on the situation.

[0018] The pipette unit 200 also includes a pressure sensor 203 for measuring the suction pressure of the pipette. The pressure sensor 203 can measure the pressure inside the pipette, and can measure the suction pressure of the pipette in real time during the suction operation. The measured pressure data is sent to a calculation means (not shown) and can be used to control each motor. The pipette unit 200 also includes a pipette up / down motor 204 for moving the pipette up and down in the Z direction in the figure.

[0019] In this embodiment, the pipette unit 200 has one pipette, which can be moved in the Y direction by the horizontal movement motor 206 and can access all containers, but the number of pipettes is arbitrary and multiple pipettes may be provided.

[0020] The container transport unit 300 is a unit for moving containers containing samples in the horizontal direction (X-axis direction) according to each process. The container transport unit 300 includes a container holder 304 for supporting the containers, and a container transport motor 305 for moving the container holder 304 and each container.

[0021] The biological sample processing apparatus 1 is equipped with three types of containers used for processing: a large container 301, a medium container 302, and a small container 303, and these containers are placed at regular intervals in the X and Y directions in the figure.

[0022] The bottom magnet unit 400 is a unit for bringing a magnet into contact with and away from the bottom of a container containing a sample. In this embodiment, the bottom magnet units 400 are installed in two locations. Each bottom magnet unit 400 is composed of a bottom magnet 401, for example, a neodymium magnet, and an actuator 402 for moving it up and down in the vertical direction (Z-axis direction in the figure). When the bottom magnet 401 approaches the bottom surface of the container, it can attract magnetic beads to the bottom surface of the container.

[0023] Of the two bottom magnet units 400, one is located directly below the magnetic rod 101 and magnetic rod cover 102 of the magnetic rod unit 100 and can be used when the magnetic rod unit 100 processes a sample. The other is located directly below the pipette tip 205 of the pipette unit 200 and can be used when the pipette unit 200 processes a sample.

[0024] In the biological sample processing device 1, the stirring operation for stirring the liquid in the container, the magnetic collection operation for collecting and recovering magnetic beads present in the liquid using the magnetic rod 101, and the release operation for releasing the recovered magnetic beads back into the liquid are performed by the up and down movement of the magnetic rod unit 100.

[0025] Processing using the magnetic bar unit 100 is performed by moving the container to be processed horizontally (in the X direction in the figure) to directly below the magnetic bar 101 and magnetic bar cover 102, and then moving the magnetic bar 101 or the magnetic bar cover 102 up and down.

[0026] 3 is a diagram illustrating the stirring operation. The stirring operation is an operation for stirring a solution in a container to be stirred, and is performed by inserting only the magnetic bar cover 102 into the container and moving it up and down, as shown in FIG.

[0027] FIG. 4 is a diagram illustrating the magnetic collection operation. The magnetic collection operation is an operation in which magnetic beads are collected and recovered by the magnetic bar 101. At this time, as shown in FIG. 4, the magnetic bar 101 is inserted into the magnetic bar cover 102 so that the solution and magnetic beads do not come into direct contact with the magnetic bar 101. The magnetic bar cover 102 and the magnetic bar 101 are simultaneously moved up and down in the container liquid to stir the sample solution and capture the magnetic beads. More preferably, by moving the magnetic bar 101 up and down while bringing the bottom magnet 401 toward the wall (bottom) of the container, the magnetic beads can be captured at two locations: the wall (bottom) of the container and the magnetic bar 101, thereby increasing capture efficiency.

[0028] The release operation is an operation of releasing magnetic beads captured by the magnetic rod 101 into a solution. This operation is performed when transferring magnetic beads between containers, when magnetic beads collected in a source container are poured into a destination container. When magnetic beads are collected on the magnetic rod 101, the magnetic rod 101 and magnetic rod cover 102 are poured into the solution. Then, by pulling out only the magnetic rod 101, the magnetic force no longer acts on the tip of the magnetic rod cover 102, and the collected magnetic beads are released into the solution. In this state, the magnetic rod cover 102 may be moved up and down in the solution to shake off the magnetic beads attached to its tip. Alternatively, the magnetic beads may be detached from the magnetic rod cover 102 by attracting them to the bottom of the container using the bottom magnet 401.

[0029] The biological sample processing device 1 performs the following three steps (1) to (3) in order to extract nucleic acids from a sample.

[0030] (1) Binding process: This is a process for binding nucleic acids present in a sample to magnetic beads. Magnetic beads are added to a large amount of liquid sample (whole blood, plasma, serum, etc.) in a large container 301. The amount of magnetic beads added is determined based on the volume of the liquid sample. Generally, the larger the volume of the sample, the larger the amount of magnetic beads added. Furthermore, a reagent that promotes binding between the nucleic acid to be captured and the magnetic beads is added as needed. Then, the magnetic bar cover 102 is used to stir the sample solution so that the magnetic beads bind to the biological material. Once the magnetic beads and nucleic acids have sufficiently bound, the magnetic beads in the liquid are magnetically attracted and recovered.

[0031] (2) Washing Step: This step involves washing the nucleic acid-bound magnetic beads and removing nonspecifically bound substances from the magnetic beads. This step is carried out by placing the nucleic acid-bound magnetic beads into the inner container 302 containing a washing reagent and stirring. The washing reagent is not particularly limited, but any reagent capable of removing the reagent added in step 1 and impurities from the nucleic acid capture carrier while maintaining the binding of the nucleic acid to the nucleic acid capture carrier can be used. For example, organic compounds such as lower alcohols and low-molecular-weight ketones can be used. Alternatively, ethanol or isopropanol can be used as the washing reagent, with ethanol at a concentration of 70% or higher being particularly preferred. After washing the magnetic bar cover 102 and the magnetic beads, the alcohol components are dried to prevent the washing solution from contaminating the nucleic acid elution solution in the next step. While any drying method is used, the alcohol components can be evaporated by allowing the magnetic bar cover 102 with the magnetic bar 101 inserted therein to stand over the washing container.

[0032] (3) Elution step: This is the step of eluting the nucleic acid that has been bound to and captured by the magnetic beads and washed from the specimen into an eluent. Since the eluent is sent to the subsequent testing step, a small amount is generally desired; here, a volume of approximately 30 to 50 μL is assumed. After the washing step is completed, the magnetically collected magnetic beads are released into a small container 303, immersed in a container containing a nucleic acid eluent, and stirred in that state. This elutes the nucleic acid into the nucleic acid eluent.

[0033] After elution, the sample contains the nucleic acid to be tested, and this eluate is recovered. At this time, unnecessary magnetic beads remain immersed in the eluate, and these magnetic beads must be removed. The magnetic beads contained in the solution are numerous, having been bound in a large volume of liquid. The operation for recovering a small amount of eluate containing a large amount of magnetic beads is described below. The recovery of the eluate is performed using a pipette unit 200.

[0034] Fig. 5 is a flowchart of the eluate recovery operation after the elution step. Fig. 6 is a diagram explaining the eluate aspirating operation during the eluate recovery operation. In order to recover the eluate adsorbed to the magnetic beads, the biological sample processing apparatus 1 performs the aspirating operation while the tip of the pipette tip 205 is in contact with the surface of the magnetic beads 303B that have been collected and deposited at the bottom of the small container 303 by the bottom magnet 401. The eluate recovery operation will be explained below with reference to these drawings.

[0035] 6(1): Immediately after the elution step is completed, the magnetic beads are suspended and scattered in the eluent, so before starting to draw the eluent, the bottom magnet 401 is brought into contact with the bottom of the small container 303 and the process waits for a predetermined time. This causes the magnetic beads 303B to be attracted to the bottom of the small container 303 (setting the bottom magnet and waiting for a predetermined time).

[0036] FIG. 6(2): The pipette is lowered, and it is detected that the eluent 303L at the tip of the pipette tip 205 has come into contact with the liquid surface (pipette lowered to liquid level detection). After detection, suction of the eluent begins (suction start (suction speed v1)). The amount of liquid to be collected is set in advance, but counting the amount of eluent suctioned begins when suction begins (suction amount count start). This suction amount count may be determined, for example, by the amount of plunger movement. In this case, the plunger is generally driven by a stepping motor, and the drive pulse of the stepping motor may be set in advance according to the amount of suction.

[0037] While continuing to aspirate the eluent, the pipette tip 205 is continuously lowered. The speed of descent is determined by the aspirating speed and the shape of the container, and is set to be equal to or greater than the rate at which the liquid level drops due to aspirating. By lowering the pipette tip 205 in this way in accordance with the drop in the liquid level due to aspirating, it is possible to prevent the tip from being exposed to air due to the drop in the liquid level, and thus prevent air from being accidentally aspirated.

[0038] 6(3): After that, it is detected that the tip of the pipette tip 205 has come into contact with the upper surface of the magnetic beads 303B that have been attracted and accumulated at the bottom of the small container 303 by the bottom magnet 401. At the timing of detection, the descent of the pipette is stopped (bead detection - pipette descent stopped).

[0039] At this point, the tip of the pipette tip 205 is in contact with the upper surface of the magnetic beads 303B. At this point, the plunger movement speed is reduced, and the suction speed is slowed (here, the suction speed is set to v2 (v1 > v2)). The suction operation continues until the entire preset recovery volume of eluent is aspirated. The suction speed at this time is set so that the suction force is lower than the magnetic force of the bottom magnet. In other words, the suction force is set so that the suction force expected from the material, shape, plunger diameter, etc. of the pipette tip 205 is lower than the magnetic force expected from the type and size of the bottom magnet and the physical properties of the magnetic beads (magnetic permeability, particle size, etc.). By continuing suction under these suction conditions, it is possible to recover the eluent contained between the magnetic beads with a high recovery rate without aspirating the magnetic beads themselves.

[0040] Figure 6 (4): Once a predetermined amount has been aspirated, the plunger stops moving and the aspirator stops ( ). Then, the pipette is moved and the collected eluent is dispensed into another container. When the pipette is moved, a small amount of magnetic beads may have been aspirated to the tip of the pipette tip 205. Therefore, it is preferable to use the magnetic force of the bottom magnet 401 to attract the magnetic beads in the pipette tip 205 and remove them from the pipette tip 205. Taking into account the time it takes for the magnetic beads to move, it is preferable to wait a predetermined time after aspirating (wait for a predetermined time) and then move the pipette (raise the pipette). It should be noted that in this step, the liquid near the bottom of the container is aspirated into the pipette along the surface of the beads.

[0041] In the above-described process, contact detection between the tip of the pipette tip 205 and the eluent surface and contact detection with the upper surface of the magnetic beads 303B can be performed by detecting changes in the suction pressure of the pipette using a pressure sensor provided in the pipette.

[0042] Figure 7 shows the transition of pressure measured by a pressure sensor attached to the pipette during eluent recovery. When the pipette tip 205 descends from its initial position and its tip contacts the surface of the eluent 303L (the tip movement amount at this time is z1), the eluent 303L is aspirated, and the pressure changes (point A in Figure 7). Also, when the tip of the pipette tip 205 contacts the top surface of the magnetically collected and accumulated magnetic beads 303B (the descending amount at this time is z2), the magnetic beads 303B are aspirated, and the pressure changes (point B in Figure 7). By detecting these pressure changes, contact between the pipette tip 205 and the surface of the eluent 303L and between the pipette tip 205 and the top surface of the magnetic beads 303B can be detected.

[0043] When a small amount of magnetic beads 303B enters the pipette tip 205 during pressure detection in FIG. 7, the beads may be attracted to the bottom of the container again by the bottom magnet 401 and expelled from the pipette tip 205.

[0044] Figure 8 is a diagram illustrating the loss of eluent recovered in a conventional biological sample processing device. When removing magnetic beads from the eluent, as shown in Figure 8, the magnetic rod 101 is immersed in the eluent, the magnetic beads 303B are attracted by the magnet at the tip of the magnetic rod 101, and the magnetic rod 101 is then pulled out. At this time, the eluent is recovered in a state where it is still attracted to the magnetic beads, resulting in a large loss of the recovered eluent. This embodiment can suppress such loss.

[0045] Summary of First Embodiment The biological sample processing apparatus 1 according to the first embodiment aspirates the eluent 303L with the pipette while aspirating the magnetic beads 303B with the bottom magnet 401, and when the end of the pipette tip 205 comes into contact with the magnetic beads 303B, the pipette stops descending and the suction force is weakened. This makes it possible to recover the liquid adsorbed to the magnetic beads 303B when recovering the eluent, thereby achieving a high recovery rate of the final product, nucleic acid eluent.

[0046] <Embodiment 2> The biological sample processing apparatus 1 according to embodiment 2 of the present invention has a configuration that is almost the same as that of embodiment 1 and performs the same operations. Therefore, in the following explanation, the explanation of the configuration that is common to both embodiments will be omitted, and the explanation will focus on the differences between the two.

[0047] In the second embodiment, as in the first embodiment, the surfaces of the magnetic beads 303B are brought into contact with the tip of the pipette tip 205 during eluent collection, and aspirated. However, unlike the first embodiment, the surface position of the magnetic beads 303B at this time uses a preset value. However, variations in the amount of beads and variations in the placement position of the container can cause an error between the preset value and the actual top surface position of the magnetic beads. This error can lead to erroneous aspirating of beads or clogging of the tip. The second embodiment aims to solve this problem.

[0048] 9 is a side view illustrating the set positions used in the eluent recovery operation in embodiment 2. In embodiment 2, two values, a first set position (Za) and a second set position (Zb) shown in FIG. 9 are set. The first set position (Za) is a position where the tip does not contact the surface of the magnetic beads 303B even if there is variation, and is a position between the liquid surface of the eluent and the upper surface of the magnetic beads 303B that have been magnetically collected and accumulated. The second set position (Zb) is a position where the magnetic beads 303B come into contact with the pipette tip 205.

[0049] Fig. 10 is a flowchart of the eluent recovery operation after the elution step in embodiment 2. Fig. 11 is a diagram illustrating the eluent suction operation in the eluent recovery operation. The eluent recovery operation in embodiment 2 will be described below with reference to these drawings.

[0050] Immediately after the elution step is completed, the magnetic beads are suspended and scattered in the eluent, so before starting to draw in the eluent, the bottom magnet 401 is brought into contact with the bottom of the small container 303 and left standing for a predetermined time, thereby attracting the magnetic beads 303B to the bottom of the small container 303 (setting the bottom magnet and waiting for a predetermined time).

[0051] FIG. 11(1): The pipette is then lowered, and suction by the pipette begins (pipette lowering to suction start (aspiration speed v1)), and aspirates to the first set position (Za) (start of movement amount counting to whether it has moved to the first set position (Za)). The descent speed and aspiration speed at this time are determined by the shape of the container and are set so that the pipette descent speed is equal to or greater than the rate at which the liquid level drops due to aspiration. By lowering the pipette tip 205 in this way in accordance with the drop in the liquid level due to aspiration, the tip is exposed to air due to the drop in the liquid level, preventing the air from being accidentally aspirated.

[0052] 11 (2) to (5): After descending to the first set position (Za), stepwise suction and movement are performed (low-speed stepwise suction (suction speed v2) to the second set position (Zb)). That is, the pipette's suction speed is reduced (here, the suction speed is v2), a predetermined amount is aspirated, the pipette tip 205 is lowered, and a predetermined waiting time is repeated until the pipette tip 205 reaches the second set position (Zb). The waiting time is set to be sufficient for magnetic beads to return to their original position due to magnetic force when they are mixed into the pipette.

[0053] 11(6): After the pipette tip 205 comes into contact with the magnetic beads 303B, when a predetermined amount of eluent is aspirated, some of the magnetic beads are mixed in. During the waiting time, the magnetic beads in the pipette tip 205 are attracted to the bottom magnet 401 and are discharged from the pipette tip 205 (wait for a predetermined time). After the magnetic beads are discharged, the pipette is raised (pipette raised).

[0054] In this way, when recovering the eluate, the surface of the magnetic beads is brought into contact with the tip of the pipette tip and sucked in, but any magnetic beads mixed in the pipette tip 205 are expelled from the pipette by the bottom magnet 401. As in the first embodiment, this makes it possible to recover the liquid adsorbed to the magnetic beads 303B when recovering the eluate, thereby achieving a high recovery rate of the final product, the nucleic acid eluate.

[0055] In the second embodiment, the information from the pressure sensor is not used, and instead the first set position Za and the second set position Zb are used, but the pressure sensor described in the first embodiment may also be used in combination.

[0056] <Embodiment 3> The biological sample processing apparatus 1 according to embodiment 3 of the present invention has a configuration that is almost the same as that of embodiment 1 and performs the same operations. Therefore, in the following explanation, the explanation of the configuration that is common to both embodiments will be omitted, and the explanation will focus on the differences between the two.

[0057] 12 is a diagram showing the pipette unit 200 of the biological sample processing apparatus 1 according to embodiment 3. In embodiment 3, an image capturer 500 is used that captures images of the liquid surface of the eluent and the interface between the magnetic beads and the eluent after magnetic collection.

[0058] The calculator 501 acquires in advance a threshold value for the color difference between the color of the eluent 303L and the color of the magnetic beads 303B (RGB data or a binarized version of the RGB data). The calculator 501 uses this threshold value to calculate the Z-direction position of the interface between the two from the image data acquired by the image capturer 500. The calculator 501 then lowers the pipette toward the interface position. Alternatively, the calculator 501 may measure the Z-direction tip position of the pipette tip 205 from the color information or the like of the image data acquired by the image capturer 500. The calculator 501 may determine the state of contact between the tip of the pipette tip 205 and the magnetic bead interface based on the measured value.

[0059] The calculator 501 may detect the liquid level of the eluent 303L using image data acquired by the image capturer 500. The calculator 501 lowers the pipette tip 205 according to this height and starts aspirating from that liquid level position. The calculator 501 then lowers the pipette tip 205 at a predetermined speed to the calculated height of the magnetic bead 303B interface, and aspirates (aspiration speed v1). The pipette tip 205 is lowered, and when the tip of the pipette tip 205 comes into contact with the magnetic bead 303B interface, the pipette is stopped. At this position, the aspiration speed is reduced (the aspiration speed is now v2, where v1 > v2), and a predetermined amount is aspirated.

[0060] In the third embodiment, the control of moving the pipette stepwise as in the second embodiment may be used in combination. The pressure sensor in the first embodiment may also be used in combination.

[0061] <Regarding Modifications of the Present Invention> In the above embodiments, the means for detecting the pressure change described in FIG. 7 can be, for example, the calculator 501 described in embodiment 3. The calculator 501 can determine contact by comparing the pressure value or the pressure change rate (time differential value) with a preset threshold value. Alternatively, the calculator 501 can determine contact by matching with a standard pressure change pattern. Any other method or a combination of these may also be employed.

[0062] In the above embodiment, the operations described with reference to FIGS. 5 and 6 and the operations described with reference to FIGS.

[0063] The arithmetic unit 501 can be configured by hardware such as a circuit device that implements its functions, or by software that implements its functions being executed by an arithmetic device such as a CPU (Central Processing Unit).

[0064] In the above embodiment, v1 is, for example, 5 times, 10 times, or more times larger than v2, but this is not limiting, and the effects of the present invention can be achieved as long as v1 > v2. However, the larger v1 is, the faster the liquid is sucked.

[0065] In the above embodiment, the attractive force of v1 to attract the magnetic beads may be weaker than the attractive force of the bottom magnet 401 to attract the magnetic beads. If the attractive force of v1 is weak, there is an advantage in that it reduces the possibility of attracting the magnetic beads into the pipette while the pipette is descending. However, since the speed at which the liquid is aspirated also decreases, if the efficiency of liquid aspirating is important, it can be said that the larger v1 is, the better.

[0066] 1 Biological sample processing apparatus 100 Magnetic rod unit 101 Magnetic rod 102 Magnetic rod cover 103 Magnetic rod drive motor 104 Magnetic rod cover drive motor 200 Pipette unit 201 Plunger 202 Plunger drive motor 203 Pressure sensor 204 Pipette up and down movement motor 205 Pipette tip 206 Horizontal movement motor 300 Container transport unit 301 Large container 302 Medium container 303 Small container 304 Container holder 305 Container movement motor 400 Bottom magnet unit 401 Bottom magnet 500 Image capture device

Claims

1. A biological sample processing apparatus for processing a biological sample containing magnetic beads, comprising a magnet that can be arranged to contact the bottom surface of a container for accommodating the biological sample, and a pipette for sucking the biological sample in the container or discharging the biological sample to the container, wherein the pipette performs a suction operation with the tip of the pipette in contact with the magnetic beads, and after sucking the biological sample, the pipette waits for a time sufficient for the magnetic beads in the pipette to be discharged outside the pipette by the magnet. A biological sample processing apparatus characterized by this.

2. The pipette performs a suction operation at a first suction rate while descending with the tip of the pipette immersed in the biological sample, the pipette performs a suction operation at a second suction rate smaller than the first suction rate with the tip of the pipette in contact with the magnetic beads, and after performing the suction operation at the second suction rate, the pipette waits for a time sufficient for the magnetic beads in the pipette to be discharged outside the pipette by the magnet. The biological sample processing apparatus according to claim 1, characterized by this.

3. The biological sample processing apparatus further includes an arithmetic unit for detecting that the tip of the pipette is in contact with the magnetic beads, and when the tip of the pipette is in contact with the magnetic beads, the pipette stops the suction operation at the first suction rate and also stops descending. The biological sample processing apparatus according to claim 2, characterized by this.

4. The suction force for sucking the magnetic beads by the second suction rate is smaller than the suction force by which the magnet sucks the magnetic beads. The biological sample processing apparatus according to claim 3, characterized by this.

5. The suction force by which the pipette sucks the magnetic beads is smaller than the suction force by which the magnet sucks the magnetic beads. The biological sample processing apparatus according to claim 1, characterized by this.

6. The biological sample processing apparatus further includes a pressure sensor that measures the pressure inside the pipette, and the arithmetic unit detects that the tip of the pipette has come into contact with the magnetic beads by comparing the pressure measured by the pressure sensor with a threshold value. The biological sample processing apparatus according to claim 3, characterized in that.

7. The pipette descends while performing a suction operation at the first suction rate to a first set position below the liquid level of the biological sample and above the upper surface of the magnetic beads. After descending to the first set position, the pipette repeats a predetermined amount of descent, a suction operation at the second suction rate, and a standby for a predetermined time to a second set position below the upper surface of the magnetic beads. The biological sample processing apparatus according to claim 2, characterized in that.

8. After descending to the second set position, the pipette performs an operation of waiting for a time sufficient for the magnetic beads inside the pipette to be discharged outside the pipette by the magnet. The biological sample processing apparatus according to claim 7, characterized in that.

9. The biological sample processing apparatus further includes an imager that images the side surface of the container, and the arithmetic unit detects that the tip of the pipette has come into contact with the magnetic beads by specifying the positions of the tip of the pipette and the magnetic beads based on the image captured by the imager. The biological sample processing apparatus according to claim 3, characterized in that.

10. The biological sample processing apparatus further includes an imager that images the side surface of the container, and the arithmetic unit specifies the liquid level height of the biological sample based on the image captured by the imager. After descending to the liquid level height of the biological sample, the pipette starts a suction operation at the first suction rate. The biological sample processing apparatus according to claim 3, characterized in that.

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