JP2020110741A - Magnetic particle operation device - Google Patents

Abstract

PROBLEM TO BE SOLVED: To enable a tubular device to be continuously used even when an error affecting a magnetic force acting on magnetic particles occurs during the operation of a magnetic force source.
A processing operation is interrupted when an error occurs during a processing operation of moving a magnetic force source, and the processing operation is restarted after the error is released. When the processing operation is interrupted due to the occurrence of an error, after the error is released, the magnetic force source is used to collect all the magnetic particles diffused in the processing liquid layer by the magnetic force source. Move between both ends in.
[Selection diagram]

Description

The present invention relates to magnetic particles for operating magnetic particles supplemented with a target substance in a tubular device in which layers of a treatment liquid for performing a process such as separation and purification of the target substance are stacked inside with a gel layer sandwiched therebetween. The present invention relates to an operating device.

Proposed to perform separation/purification of target substances such as nucleic acids by using a tubular device in which multiple processing solution layers consisting of processing solutions such as lysing/fixing solution, washing solution, and eluate are stacked with a gel layer in between. It has been implemented and implemented (see Patent Document 1).

Separation and purification of a target substance using such a tubular device is carried out by introducing magnetic particles trapping the target substance into the tubular device and manipulating the magnetic particles in the tubular device with a magnet outside the tubular device. .. When the treatment liquid layer is a cleaning liquid, the magnet is reciprocated at a high speed along the longitudinal direction of the tubular device so that the magnetic particles cause a high-speed stirring motion in the treatment liquid layer.

In order to automatically perform separation/purification of a target substance using magnetic particles as described above, magnetic particles that automatically move a magnetic force source for manipulating the magnetic particles in the tubular device in the longitudinal direction of the tubular device. An operating device has been proposed (see Patent Document 2).

WO2015/177933A1 JP, 2016-117032, A

In the above magnetic particle manipulation device, it is necessary to move the magnetic force source in the longitudinal direction of the tubular device while keeping the distance between the tubular device and the magnetic force source constant. If the distance between the tubular device and the magnetic force source increases due to some error during the operation of the magnetic force source, the magnetic force acting on the magnetic particles in the tubular device becomes weak, and the magnetic particles are less likely to follow the operation of the magnetic force source. Even if the operation of the magnetic force source is continued in such a state, the desired treatment for the target substance is not sufficiently performed, and the treatment needs to be restarted from the beginning using a new tubular device, which is a waste of the tubular device. There was a problem.

Therefore, it is an object of the present invention to allow the tubular device to continue to be used even when an error affecting the magnetic force acting on the magnetic particles occurs during the operation of the magnetic force source.

The magnetic particle operating apparatus according to the present invention is such that a plurality of processing liquid layers each containing a processing liquid for performing a treatment on a target substance inside are laminated in the longitudinal direction with a gel layer interposed therebetween. This is an apparatus for treating a target substance by using a tubular device in which magnetic particles for trapping the substance are loaded. The magnetic particle manipulation apparatus is a device holding unit for holding the tubular device, and a magnetic force is applied to the magnetic particles in the tubular device held by the device holding unit to cause the magnetic particles to move in the tubular device. A magnetic force source for operating from the outside, a magnetic force source moving mechanism for moving the magnetic force source in the longitudinal direction of the tubular device at a position close to the tubular device held by the device holding portion, and trapped by the magnetic particles The operation of the magnetic force source moving mechanism is controlled to sequentially process the magnetic particles in the tubular device into each of the treatment liquid layers so that the treated target substance is treated in each of the treatment liquid layers of the tubular device. An operation control unit configured to execute a processing operation for moving the position of the magnetic force source in the longitudinal direction of the tubular device held by the device holding unit, and a position of the magnetic force source by the magnetic force source moving mechanism. A position detector configured to detect based on the drive amount, and an error detector that detects an error during execution of the processing operation are provided. When the error detection unit detects the error, the operation control unit stops the movement of the magnetic force source by the magnetic force source movement mechanism to interrupt the processing operation, and when the error is released. When the interrupted processing operation is restarted, and the position of the magnetic force source when the processing operation is interrupted is the position corresponding to the processing liquid layer of the tubular device, the error is cleared. The magnetic force source is moved so as to collect the magnetic particles between one end and the other end of the treatment liquid layer in the longitudinal direction by the magnetic force source before restarting the treatment operation that has been interrupted after being processed. It is configured to perform a retrieval operation.

That is, in the magnetic particle operating apparatus according to the present invention, first, the processing operation is interrupted when an error occurs during the processing operation of moving the magnetic force source, and the processing operation is restarted after the error is released. However, when the magnetic force source is suddenly stopped while operating the magnetic force source at the side of the treatment liquid layer of the tubular device at a high speed, the magnetic particles separate from the magnetic force source and diffuse into the treatment liquid layer. After that, even if the error is released and the processing operation is continued, it is conceivable that some magnetic particles do not follow the magnetic force source. Therefore, when the processing operation is interrupted due to the occurrence of an error, after the error is released, all magnetic particles diffused in the processing liquid layer should be collected by the magnetic force source, that is, the processing liquid layer. The magnetic force source is moved between both ends in the processing liquid layer so that all the magnetic particles diffused therein follow the magnetic force source. By restarting the processing operation after performing this recovery operation, it is possible to prevent the processing operation from continuing in a state where the magnetic particles do not follow the magnetic force source, and to prevent the tubular device from operating even after an error occurs. It can be used continuously.

By the way, the tubular device is generally composed of a resin tube, and there are some that are not completely straight. When the tubular device has a warp, the distance between the magnetic source and the tubular device between the warped portion and the non-warped portion of the tubular device when the magnetic force source is moved uniaxially along the longitudinal direction of the tubular device. May change, and the magnetic particles in the tubular device may not be manipulated accurately.

Therefore, in the magnetic particle operating device according to the present invention, an openable cover that covers the device holding portion, and the tubular shape that is provided in the cover and is held in the device holding portion when the cover is closed It is possible to further include a pressing mechanism that presses the device toward the magnetic force source to correct the warp of the tubular device. In this case, if the cover is emptied during the execution of the processing operation, the warp of the tubular device cannot be corrected, so the error detection unit determines that the cover was opened during the execution of the processing operation as the error. It is preferably configured to detect.

In a further preferred embodiment, the device holding unit further comprises a position information holding unit that holds the position information of each processing liquid layer of the tubular device, and the position detection unit holds the position information holding unit. The position of the magnetic force source in the longitudinal direction of the tubular device is detected based on the position information.

In addition, since the tubular device used in the magnetic particle operating apparatus of the present invention is generally one in which the accuracy of the position of each treatment liquid layer is ensured, the design value of the position of each treatment liquid layer in the tubular device is set to the position. If the information is also stored in the position information holding unit, the magnetic force source can be accurately moved to a desired layer or the current position of the magnetic force source can be accurately grasped based on the position information. However, the position of each processing liquid layer may deviate from the design value due to some factors such as the warp and temperature of the tubular device. Therefore, a boundary detection unit configured to optically detect the position of the boundary between the treatment liquid layer and the gel layer of the tubular device held by the device holding unit may be further provided. In that case, the position information held in the position information holding unit can be the position of the boundary detected by the boundary detection unit.

In the magnetic particle manipulation device according to the present invention, when an error occurs during the processing operation of moving the magnetic force source, the processing operation is interrupted, and after the error is released, all the particles diffused in the processing liquid layer Prevents the processing operation from continuing in a state where the magnetic particles do not follow the magnetic source because it is configured to restart the processing operation after performing the recovery operation to recover the magnetic particles with the magnetic source. However, the tubular device can continue to be used after the error occurs.

It is a schematic block diagram which shows one Example of a magnetic particle operating device. It is a figure which shows an example of the tubular device used in the same Example. It is a schematic block diagram which shows the state by which the tubular device was hold|maintained at the device holding part of the same magnetic particle operating apparatus. 6 is a flowchart for explaining an error detection during the processing operation of the embodiment and the operation of interrupting and resuming the processing operation at that time. It is an image figure which shows the collection|recovery operation|movement of the Example in a process order. It is an image figure which shows the processing operation restarted after the collection|recovery operation of the Example. It is a schematic block diagram which shows one Example of the magnetic particle operation apparatus provided with the function which detects the boundary of each layer of a tubular device.

Hereinafter, an embodiment of a magnetic particle manipulation device will be described with reference to the drawings.

First, an example of a tubular device used in a magnetic particle manipulation apparatus will be described with reference to FIG.

In the tubular device 100, a sample layer 102, a gel layer 108, a treatment liquid layer 104, a gel layer 108, a treatment liquid layer 104, a gel layer 108, and an elution liquid layer 106 are laminated in the longitudinal direction from one end side inside the pipe. It is a thing.

The sample forming the sample layer 102 contains magnetic particles trapping a target substance such as nucleic acid. The treatment liquid layer 104 is composed of a treatment liquid for treating the target substance captured by the magnetic particles. Examples of the treatment liquid include a cleaning liquid for removing contaminants from the target substance captured by the magnetic particles. The eluent that constitutes the eluate layer 106 is for dissolving the target substance that has been subjected to the processes such as separation and purification via the process liquid layer 104, and pure water can be used, for example.

Next, an embodiment of the magnetic particle operating device will be described.

As shown in FIGS. 1 and 3, the magnetic particle manipulating device includes a front panel 2 having a recess 4 for fitting a tubular device 100 therein, and a magnetic force source 8 is provided behind the front panel 2. The holding block 10, the ball screw 12, and the stepping motor 14 are provided.

The magnetic force source 8 generates a magnetic force for manipulating the magnetic particles in the tubular device 100, and is realized by, for example, a permanent magnet. The ball screw 12 is provided parallel to the longitudinal direction of the tubular device 100 fitted in the recess 4 of the front panel 2, and is rotated by the stepping motor 14. The holding block 10 is screwed into the ball screw 12, and is configured to move in the axial direction of the ball screw 12 when the ball screw 12 rotates.

Here, the front panel 2 constitutes a device holding portion which holds the tubular device 100, and the holding block 10, the ball screw 12 and the stepping motor 14 move the magnetic force source 8 in the longitudinal direction of the tubular device 100. Make up.

An opening for exposing the magnetic force source 8 to the tubular device 100 fitted in the depression 4 is provided on the bottom surface of the depression 4 of the front panel 2. The magnetic force source 8 is held in the vicinity of the tubular device 100 fitted in the recess by the holding block 10, and the holding block 10 moves in the longitudinal direction of the tubular device 100 as the ball screw 12 moves in the axial direction. The magnetic particles in the tubular device 100 follow the operation of the magnetic force source 8 by the action of the magnetic force from the magnetic force source 8 and move in the tubular device 100 in the longitudinal direction.

An openable cover 16 that covers the front panel 2 is provided. A pressing plate 18 for pressing the tubular device 100 fitted in the recess 4 toward the magnetic source 8 when the cover 16 is closed is attached to the inside of the cover 16 via an elastic member 20. When the cover 16 is closed, the pressing plate 18 comes into contact with the tubular device 100 and is urged toward the tubular device 100 by the elastic member 20, whereby the warpage of the tubular device 100 is corrected. The pressing plate 18 and the elastic member 20 constitute a pressing mechanism for pressing the tubular device 100 to correct the warp.

A micro sensor 22 and a pin 24 for detecting the open/closed state of the cover 16 are provided on the inner side surfaces of the front panel 2 and the cover 16. 1 and 3, the microsensor 22 is provided on the front panel 2 side and the pin 24 is provided on the cover 16 side, but conversely, the pin 24 is provided on the front panel 2 side and the microsensor 22 is provided on the cover 16 side. May be.

The magnetic particle operating device includes a control device 26 for controlling the operation of the stepping motor 14. The control device 26 can be realized by an electronic circuit including a computing element and a storage medium. The control device 26 includes an operation control unit 28, a position detection unit 30, an error detection unit 32, and a position information holding unit 34. The operation control unit 28, the position detection unit 30, and the error detection unit 32 are functions realized by the arithmetic element executing a program, and the position information holding unit 34 is realized by a partial storage area of a storage medium. It is a function.

The operation control unit 28 sequentially transfers the magnetic particles in the tubular device 100 from the sample layer 102 to the processing liquid layers 104 and the elution liquid layer 106, and executes a predetermined processing operation for the target substance captured by the magnetic particles. Thus, the operation of the stepping motor 14 is controlled to move the magnetic force source 8 in the longitudinal direction of the tubular device 100. The purification treatment of the target substance is performed by reciprocating the magnetic particles in the treatment liquid layer 104 at high speed in the longitudinal direction of the tubular device 100.

The position detector 30 is configured to detect the position of the magnetic force source 8 in the longitudinal direction of the tubular device 100 based on the number of drive pulses given to the stepping motor 14. The position information holding unit 34 holds information regarding the position of each processing liquid layer 104 in the tubular device 100. Therefore, based on the information on the position of the magnetic force source 8 detected by the position detection unit 30 and the position of each processing liquid layer 104 held in the position information holding unit 34, which layer of the tubular device 100 the magnetic force source 8 is placed on. It is possible to recognize whether they are at the corresponding positions, that is, in which layer the magnetic particles are presently present.

The error detection unit 32 detects the open/closed state of the cover 16 during the processing operation on the target substance in the tubular device 100 based on the signal from the microsensor 22, and the cover 16 is opened during the processing operation. Is configured to be detected as an error. When the cover 16 is closed after detecting the error, the error detection unit 32 is configured to cancel the error.

The operation control unit 28 interrupts the processing operation in progress when an error is detected by the error detection unit 32 during execution of the processing operation, and restarts the interrupted processing operation when the error is released. It is configured. Discontinuing the processing operation means stopping the driving of the stepping motor 14 and stopping the operation of the magnetic force source 8.

When resuming the interrupted processing operation, the operation control unit 28 detects the stop position of the magnetic force source 8 detected by the position detection unit 30 and the position information of each processing liquid layer 104 held in the position information holding unit 34. It is detected based on which layer of the magnetic force source 8 the tubular device 100 is located. Then, the operation control unit 28 is configured to execute the collecting operation before restarting the processing operation when the magnetic force source 8 is at the position corresponding to the processing liquid layer 104.

The recovery operation is performed between one end and the other end (the upper end and the lower end in the figure) of the treatment liquid layer 104 so that all the magnetic particles diffused in the treatment liquid layer 104 follow the magnetic force source 8. This is an operation of moving the magnetic force source 8. When the operation of the magnetic force source 8 is stopped while the magnetic particles are operating at high speed in the treatment liquid layer 104, as shown in FIG. There is a case where it is separated from the magnetic field and diffuses into the processing liquid layer 104. Therefore, as shown in FIGS. 5B and 5C, before restarting the processing operation, the magnetic force source 8 is moved at a low speed between one end and the other end of the processing liquid layer 104 to perform the processing. The magnetic particles 110 diffused in the liquid layer 104 are collected by the magnetic force source 8 so that all the magnetic particles 110 follow the operation of the magnetic force source 8. After performing such a collecting operation, the operation control unit 28 is configured to restart the processing operation in the processing liquid layer 104, as shown in FIG.

The error detection during the processing operation in this embodiment and the interruption and resumption of the processing operation at that time will be described with reference to the flowchart of FIG. 4 together with FIG.

When the tubular device 100 is fitted into the recess 4 and the cover 16 is closed and the start of the processing operation is input, the operation control unit 28 starts a predetermined processing operation. During execution of the processing operation, a signal from the microsensor 22 is periodically fetched by the control device 26 (step S1). The error detection unit 32 determines whether the cover 16 is empty based on the signal from the micro sensor 22 (step S2). If the cover is not empty, the processing operation is continued (steps S2 and S5).

When the cover 16 is empty (step S2), the error detection unit 32 detects an error (step S3). When the error detection unit 32 detects an error, the operation control unit 28 stops the driving of the stepping motor 14 and interrupts the processing operation (step S4). When the processing operation is interrupted, the interrupted state of the processing operation is maintained until the error is canceled by the error detection unit 32 thereafter.

When the cover 16 is closed after the processing operation is interrupted (steps S2 and S5), the error detection unit 32 cancels the error (step S6). When the error is released, the operation control unit 28 detects which layer of the tubular device 100 the stop position of the magnetic force source 8 corresponds to (step S7). When the stop position of the magnetic force source 8 is a position corresponding to the processing liquid layer 104 of the tubular device 100, the processing operation is restarted after the recovery operation is executed (steps S8 to S10). On the other hand, when the stop position of the magnetic force source 8 is the position corresponding to the gel layer 108 of the tubular device 100, the processing operation is restarted without performing the recovery operation (steps S8 and S10).

As described above, even if the cover 16 is opened during execution of the processing operation, the same tubular device 100 can be used to continue the processing operation. Conversely, even if the cover 16 is opened during the execution of the processing operation, the tubular device 100 is not wasted, so that the cover 16 can be opened to check the progress status during the processing operation.

As the position information of each processing liquid layer 104 held in the position information holding unit 34, for example, the design value of each layer of the tubular device 100 can be used. However, it is possible that the actual position of each treatment liquid layer 104 differs from the design value due to individual differences in the tubular device 100 and the like.

Therefore, the magnetic particle operating device may be provided with a function of acquiring the actual position of each processing liquid layer 104 of the tubular device 100. FIG. 7 shows an embodiment of the magnetic particle manipulation device having a function of acquiring the actual position of each treatment liquid layer 104 of the tubular device 100.

The embodiment of FIG. 7 is shown in FIGS. 1 and 3 in that an optical sensor 40 for detecting the reflectance of a substance is attached to the holding block 10 and a boundary detection unit 36 is provided in the control device 26. Different from the embodiment. The boundary detection unit 36 is a function obtained by the arithmetic element executing a program.

The boundary detection unit 36 is configured to detect the position of the boundary of each layer of the tubular device 100 based on the signal obtained by the optical sensor 40. Specifically, the boundary detection unit 36 scans the optical sensor 40 in the longitudinal direction of the tubular device 100, and detects the position where the light reflectance changes as the position of the boundary of each layer of the tubular device 100. The position of the boundary of each layer detected by the boundary detection unit 36 is held in the position information holding unit 34 as information regarding the position of the treatment liquid layer 104 of the tubular device 100.

In the embodiment described above, only the opening of the cover 16 during the processing operation is detected as the error that causes the interruption of the processing operation, but the present invention is not limited to this. If the magnetic particles in the tubular device 100 do not normally follow the magnetic force source 8, an error can be detected in addition to the open/close state of the cover 16 or together with the open/close state of the cover. Items detected as an error include, for example, detachment of the tubular device 100 from the recess 4.

2 Front Panel 4 Depression 6 Opening 8 Magnetic Source 10 Holding Block 12 Ball Screw 14 Stepping Motor 16 Cover 18 Pressing Plate 20 Elastic Member 22 Micro Sensor 24 Pins 26 Control Device 28 Operation Control Section 30 Position Detection Section 32 Error Detection Section 34 Position Information Retention Part 36 Boundary detecting part 40 Optical sensor 100 Tubular device 102 Sample layer 104 Processing liquid layer 106 Eluent layer 108 Gel layer

Claims (4)

A plurality of treatment liquid layers composed of a treatment liquid for treating the target substance are stacked in the longitudinal direction with a gel layer sandwiched between each other, and magnetic particles for trapping the target substance are loaded inside. A device holding part for holding the tubular device
A magnetic force source for operating the magnetic particles from the outside of the tubular device by applying a magnetic force to the magnetic particles in the tubular device held by the device holding unit.
A magnetic force source moving mechanism that moves the magnetic force source in the longitudinal direction of the tubular device at a position close to the tubular device held by the device holding unit;
The operation of the magnetic force source moving mechanism is controlled so that the treatment of the target substance captured by the magnetic particles is performed in each treatment liquid layer in the tubular device, and the magnetic particles in the tubular device are treated by An operation control unit configured to perform a processing operation of sequentially moving to a processing liquid layer,
A position detection unit configured to detect the position of the magnetic force source in the longitudinal direction of the tubular device held by the device holding unit based on the drive amount of the magnetic force source by the magnetic force source moving mechanism,
An error detection unit that detects an error during execution of the processing operation,
The operation control unit suspends the movement of the magnetic force source by the magnetic force source moving mechanism when the error detection unit detects the error to suspend the processing operation, and suspends when the error is released. The error is released when the processing operation is restarted and the position of the magnetic force source when the processing operation is interrupted is the position corresponding to the processing liquid layer of the tubular device. Before resuming the processing operation that was interrupted later, a recovery operation of moving the magnetic source so that the magnetic particles between the one end and the other end of the processing liquid layer in the longitudinal direction are recovered by the magnetic source. A magnetic particle manipulation device configured to perform. An openable cover that covers the device holding unit,
A pressing mechanism provided on the cover, for pressing the tubular device held by the device holding portion toward the magnetic force source when the cover is closed, and correcting the warpage of the tubular device. Prepare,
The magnetic particle manipulation device according to claim 1, wherein the error detection unit is configured to detect that the cover is opened during the execution of the processing operation as the error. Further comprising a position information holding unit for holding the position information of each processing liquid layer of the tubular device held in the device holding unit,
The position detection unit is configured to detect the position of the magnetic force source in the longitudinal direction of the tubular device based on the position information held in the position information holding unit. The magnetic particle operating device according to item 1. Further comprising a boundary detection unit configured to optically detect the position of the boundary between the treatment liquid layer and the gel layer of the tubular device held in the device holding unit,
The magnetic particle manipulation device according to claim 3, wherein the position information held in the position information holding unit is a position of the boundary detected by the boundary detection unit.

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