JP7147564B2 - Magnetic particle manipulator - Google Patents

Description

The present invention provides a magnetic particle for manipulating a magnetic particle that captures a target substance in a tubular device in which layers of a treatment liquid for performing a treatment such as separation and purification of the target substance are stacked with a gel layer interposed therebetween. It relates to an operating device.

It is proposed to separate and purify target substances such as nucleic acids using a tubular device in which multiple treatment liquid layers, such as a lysis/fixation liquid, a washing liquid, and an elution liquid, are stacked with a gel layer sandwiched between them. and has been implemented (see Patent Literature 1).

Separation and purification of a target substance using such a tubular device is performed by introducing magnetic particles that capture the target substance into the tubular device and manipulating the magnetic particles inside the tubular device with a magnet outside the tubular device. . When the treatment liquid layer is a cleaning liquid, a magnet is reciprocated at high speed along the longitudinal direction of the tubular device such that a high speed agitating motion is produced by the magnetic particles within the treatment liquid layer.

Magnetic particles that automatically move the magnetic force source for manipulating the magnetic particles in the tubular device in the longitudinal direction of the tubular device in order to automatically separate and purify the target substance using the magnetic particles as described above. An operating device has been proposed (see Patent Document 2).

WO2015/177933A1 JP 2016-117032 A

In the magnetic particle manipulator as described above, it is necessary to move the magnetic force source in the longitudinal direction of the tubular device while maintaining a constant distance between the tubular device and the magnetic force source. 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 weaker, making it difficult for the magnetic particles 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 of the target substance is not sufficiently performed, and it is necessary to restart the treatment from the beginning using a new tubular device, and the tubular device is wasted. I had a problem.

SUMMARY OF THE INVENTION It is therefore an object of the present invention to enable continued use of a tubular device even if an error occurs during operation of the magnetic force source that affects the magnetic force acting on the magnetic particles.

A magnetic particle manipulating device according to the present invention includes a plurality of processing liquid layers each containing a processing liquid for processing a target substance, which are stacked in the longitudinal direction with a gel layer interposed therebetween. This is an apparatus for processing a target substance using a tubular device in which magnetic particles that capture the substance are loaded. The magnetic particle manipulation apparatus includes a device holding portion for holding 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; The magnetic particles in the tubular device are sequentially moved to the treatment liquid layers by controlling the operation of the magnetic force source moving mechanism so that the target substance thus obtained is processed in the treatment liquid layers in the tubular device. an operation control unit configured to execute a processing operation for moving; A position detection unit configured to perform detection based on a drive amount, and an error detection unit configured to detect an error during execution of the processing operation. The operation control unit suspends the processing operation by stopping the movement of the magnetic force source by the magnetic force source moving mechanism when the error detection unit detects the error, and interrupts the processing operation when the error is canceled. When the interrupted processing operation is restarted and the position of the magnetic force source when the processing operation is interrupted is a position corresponding to the processing liquid layer of the tubular device, the error is canceled. moving the magnetic force source such that the magnetic particles between one end and the other end of the treatment liquid layer in the longitudinal direction are collected by the magnetic force source before resuming the treatment operation interrupted after the configured to perform a recovery operation;

That is, in the magnetic particle manipulation device according to the present invention, first, when an error occurs during the processing operation of moving the magnetic force source, the processing operation is interrupted, and after the error is cleared, the processing operation is resumed. However, if the magnetic force source is suddenly stopped while the magnetic force source is operating at high speed on the side of the treatment liquid layer of the tubular device, the magnetic particles will leave the magnetic force source and diffuse into the treatment liquid layer. After that, even if the error is canceled and the processing operation is continued, some magnetic particles may not follow the magnetic force source. Therefore, when the processing operation is interrupted due to the occurrence of an error, all the magnetic particles diffused in the processing liquid layer are collected by the magnetic force source after the error is cleared. The magnetic force source is moved across the treatment liquid layer such that all magnetic particles diffusing therein follow the magnetic force source. By resuming the processing operation after executing this collection operation, the tubular device can be maintained even after an error occurs while preventing the processing operation from continuing in a state where the magnetic particles do not follow the magnetic force source. Can continue to be used.

By the way, tubular devices are generally composed of resin tubes, and some of them are not perfectly straight. When the tubular device is warped, when the magnetic force source is moved uniaxially along the longitudinal direction of the tubular device, the distance between the magnetic force source and the tubular device between the warped portion and the non-warped portion of the tubular device may change, resulting in inaccurate manipulation of the magnetic particles in the tubular device.

Therefore, in the magnetic particle manipulation device according to the present invention, an opening/closing type cover that covers the device holding portion, and the tubular shape provided on the cover and held by the device holding portion when the cover is closed. It is conceivable to further include a pressing mechanism that presses the device toward the magnetic force source to correct warping of the tubular device. In this case, if the cover is opened during execution of the processing operation, the warp of the tubular device cannot be corrected. It is preferably configured to detect.

In a further preferred embodiment, the device further comprises a position information holding section that holds position information of each of the treatment liquid layers of the tubular device held in the device holding section, wherein the position detection section holds the position information in the position information holding section. It is configured to detect the position of the magnetic force source in the longitudinal direction of the tubular device based on the received positional information.

In addition, since the tubular device used in the magnetic particle manipulation apparatus of the present invention usually ensures the accuracy of the position of each treatment liquid layer, the design value of the position of each treatment liquid layer in the tubular device is set to the position. If the information is stored in the positional 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 positional information. However, it is conceivable that the position of each treatment liquid layer deviates from the designed value due to some factors such as warping of the tubular device and temperature. Therefore, a boundary detection section 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 section may be further provided. In that case, the position information held in the position information holding section can be the position of the boundary detected by the boundary detection section.

In the magnetic particle manipulator according to the present invention, when an error occurs during the processing operation for moving the magnetic force source, the processing operation is interrupted, and after the error is cleared, all the particles diffused in the processing liquid layer are removed. Since it is configured to perform a recovery operation for recovering the magnetic particles by the magnetic force source and then restart the processing operation, it is possible to prevent the processing operation from being continued in a state in which the magnetic particles do not follow the magnetic force source. However, the tubular device can continue to be used after an error has occurred.

1 is a schematic configuration diagram showing an example of a magnetic particle manipulation device; FIG. It is a figure which shows an example of the tubular device used with the same Example. FIG. 4 is a schematic configuration diagram showing a state in which a tubular device is held by a device holding portion of the same magnetic particle manipulation device; 4 is a flow chart for explaining error detection during processing operation of the same embodiment, and operations for interrupting and resuming the processing operation at that time; It is an image figure which shows the collection|recovery operation|movement of the same Example in process order. FIG. 10 is an image diagram showing a processing operation resumed after the recovery operation of the same embodiment; 1 is a schematic configuration diagram showing an embodiment of a magnetic particle manipulation device having a function of detecting boundaries between layers of a tubular device; FIG.

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

First, with reference to FIG. 2, an example of a tubular device used in the magnetic particle manipulator will be described.

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 eluate layer 106 are laminated in the longitudinal direction from one end side of the tube. It is.

A sample constituting the sample layer 102 contains magnetic particles that capture 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 washing liquid for removing contaminants from the target substance captured by the magnetic particles. The eluate that constitutes the eluate layer 106 is for dissolving the target substance that has been subjected to separation, purification, or other treatment through the treatment liquid layer 104, and pure water, for example, can be used.

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

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

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

Here, the front panel 2 constitutes a device holding portion for holding the tubular device 100, and the holding block 10, the ball screw 12 and the stepping motor 14 are the magnetic force source moving mechanism for moving the magnetic force source 8 in the longitudinal direction of the tubular device 100. configure.

An opening is provided in the bottom surface of the recess 4 in the front panel 2 to expose the magnetic force source 8 to the tubular device 100 fitted in the recess 4 . The magnetic force source 8 is held by a holding block 10 in the vicinity of the tubular device 100 fitted in the recess, 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. Magnetic particles within the tubular device 100 follow the movement of the magnetic force source 8 and move longitudinally within the tubular device 100 under the action of the magnetic force from the magnetic force source 8 .

An openable cover 16 is provided to cover the front panel 2 . Inside the cover 16, a pressing plate 18 is attached via an elastic member 20 to press the tubular device 100 fitted in the recess 4 toward the magnetic force source 8 when the cover 16 is closed. When the cover 16 is closed, the pressure plate 18 contacts the tubular device 100 and is urged toward the tubular device 100 by the elastic member 20, thereby correcting the warpage of the tubular device 100. FIG. The pressing plate 18 and the elastic member 20 constitute a pressing mechanism for pressing the tubular device 100 to correct the warp.

A microsensor 22 and a pin 24 for detecting the open/closed state of the cover 16 are provided on the inner surfaces of the front panel 2 and the cover 16 . In FIGS. 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. may be

The magnetic particle manipulator includes a controller 26 for controlling the operation of the stepper motor 14 . The control device 26 can be realized by an electronic circuit having arithmetic elements and storage media. The control device 26 includes an operation control section 28 , a position detection section 30 , an error detection section 32 and a position information holding section 34 . The operation control unit 28, the position detection unit 30, and the error detection unit 32 are functions realized by executing the program by the arithmetic element, and the position information holding unit 34 is realized by a part of the storage area of the 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 each treatment liquid layer 104 and the eluate layer 106, and performs a predetermined processing operation on the target substance captured by the magnetic particles. , 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. As shown in FIG. The target substance is purified by reciprocating the magnetic particles in the treatment liquid layer 104 in the longitudinal direction of the tubular device 100 at high speed.

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 driving pulses given to the stepping motor 14 . The position information holding unit 34 holds information on the position of each treatment liquid layer 104 within the tubular device 100 . Therefore, based on information on the position of the magnetic force source 8 detected by the position detection unit 30 and the position of each treatment liquid layer 104 held in the position information holding unit 34, which layer of the tubular device 100 is the magnetic force source 8 attached to? It is possible to recognize the corresponding position, ie in which layer the magnetic particles are currently located.

The error detection unit 32 detects the open/closed state of the cover 16 during execution of the processing operation for the target substance in the tubular device 100 based on the signal from the microsensor 22, and the cover 16 is opened during execution of the processing operation. It is configured to detect this as an error. The error detector 32 is configured to cancel the error when the cover 16 is closed after detecting the error.

The operation control unit 28 interrupts the processing operation being executed when an error is detected by the error detection unit 32 during execution of the processing operation, and resumes the interrupted processing operation when the error is cleared. It is configured. Interrupting the processing operation means stopping the operation of the magnetic force source 8 by stopping the driving of the stepping motor 14 .

When restarting 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 treatment liquid layer 104 held in the position information holding unit 34. based on which layer of the tubular device 100 the magnetic force source 8 is located. The operation control unit 28 is configured to perform the recovery operation before restarting the treatment operation when the magnetic force source 8 is at a position corresponding to the treatment liquid layer 104 .

The recovering operation is performed between one end and the other end (upper end and lower end in the drawing) 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 to move the magnetic force source 8 . When the operation of the magnetic force source 8 is stopped while the magnetic particles are moving at a high speed in the treatment liquid layer 104, some of the magnetic particles 110 move away from the magnetic force source 8 as shown in FIG. There is a case where they are separated from the magnetic field and diffuse into the treatment liquid layer 104 . Therefore, as shown in FIGS. 5B and 5C, the magnetic force source 8 is moved at a low speed between one end and the other end of the treatment liquid layer 104 before restarting the treatment operation. 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 . The operation control unit 28 is configured to restart the processing operation within the processing liquid layer 104 as shown in FIG. 6 after performing such a recovery operation.

Error detection during the processing operation in this embodiment and operations for interrupting and resuming the processing operation at that time will be described with reference to FIG. 3 and the flow chart of FIG.

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

If the cover 16 is open (step S2), the error detector 32 detects an error (step S3). When an error is detected by the error detection unit 32, the operation control unit 28 stops driving 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 detection unit 32 cancels the error.

If the cover 16 is closed after the processing operation is interrupted (steps S2, S5), the error detector 32 cancels the error (step S6). When the error is cleared, the operation control unit 28 detects which layer of the tubular device 100 corresponds to the stop position of the magnetic force source 8 (step S7). If the stop position of the magnetic force source 8 is the position corresponding to the treatment liquid layer 104 of the tubular device 100, the treatment operation is restarted after the recovery operation is performed (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 above recovery operation (steps S8 and S10).

As noted above, the same tubular device 100 can be used to continue processing operations even if the cover 16 is opened during a processing operation. Conversely, the tubular device 100 is not wasted when the cover 16 is opened during the processing operation, so the cover 16 can be opened to check the progress during the processing operation.

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

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

The embodiment of FIG. 7 is similar to that of FIGS. 1 and 3 in that the holding block 10 is fitted with an optical sensor 40 for detecting the reflectance of the material, and the controller 26 is provided with a boundary detector 36. It differs from the embodiment. The boundary detection unit 36 is a function obtained by executing the program by the arithmetic element.

The boundary detector 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 tubular device 100 in the longitudinal direction with the optical sensor 40 and detects the position where the reflectance of light changes as the position of the boundary between the layers of the tubular device 100 . The position of the boundary between layers detected by the boundary detection unit 36 is held in the position information holding unit 34 as information on the position of the treatment liquid layer 104 of the tubular device 100 .

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

2 Front Panel 4 Recess 6 Opening 8 Magnetic Force Source 10 Holding Block 12 Ball Screw 14 Stepping Motor 16 Cover 18 Pressing Plate 20 Elastic Member 22 Microsensor 24 Pin 26 Controller 28 Operation Control Section 30 Position Detection Section 32 Error Detection Section 34 Position Information Holding Section 36 Boundary Detection Section 40 Optical Sensor 100 Tubular Device 102 Sample Layer 104 Treatment Liquid Layer 106 Elution Liquid Layer 108 Gel Layer

Claims (4)

A plurality of treatment liquid layers made of a treatment liquid for processing a target substance are stacked in the longitudinal direction with a gel layer sandwiched between each other, and magnetic particles for capturing the target substance are loaded inside. a device holding portion for holding a tubular device that is held in place;
a magnetic force source for exerting a magnetic force on the magnetic particles in the tubular device held by the device holding portion to cause the magnetic particles to follow, thereby manipulating the magnetic particles from outside the tubular device;
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;
The magnetic particles in the tubular device are moved to the respective treatment liquid layers in the tubular device by controlling the operation of the magnetic force source moving mechanism so that the target substance captured by the magnetic particles is processed in the treatment liquid layers in the tubular device. an operation controller configured to execute a treatment operation for sequentially moving the treatment 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 a driving amount of the magnetic force source by the magnetic force source moving mechanism;
an error detection unit that detects an error in which the magnetic particles do not follow the magnetic force source during execution of the processing operation;
The operation control unit interrupts the processing operation by stopping movement of the magnetic force source by the magnetic force source moving mechanism when the error detection unit detects the error, and interrupts the processing operation when the error is canceled. The error is cleared when the position of the magnetic force source when the treatment operation is interrupted is a position corresponding to the treatment liquid layer of the tubular device. a recovery operation of moving the magnetic force source such that the magnetic particles between one end and the other end of the treatment liquid layer in the longitudinal direction are recovered by the magnetic force source before resuming the interrupted treatment operation later; A magnetic particle manipulation device configured to perform an openable cover that covers the device holding portion;
a pressing mechanism that is provided on the cover and presses the tubular device held by the device holding portion toward the magnetic force source to correct warping of the tubular device when the cover is closed; prepared,
2. The magnetic particle manipulation device according to claim 1, wherein said error detection unit is configured to detect that said cover has been opened during execution of said processing operation as said error. further comprising a position information holding unit that holds position information of each of the treatment liquid layers of the tubular device held by the device holding unit;
3. 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 manipulation device according to 1. further comprising a boundary detection unit configured to optically detect a position of a boundary between the treatment liquid layer and the gel layer of the tubular device held by the device holding unit;
4. The magnetic particle manipulation device according to claim 3, wherein said position information held in said position information holding section is the position of said boundary detected by said boundary detection section.

Images