Magnetic collecting device and magnetic collecting method

Abstract

This improves the magnetic collection and tracking ability of magnetic particles within a well using magnets. [Solution] The magnetizing device 1 comprises a holding part configured to hold a multiwell plate, a magnet unit having a plurality of vertically arranged bar-shaped magnets, and a vertical movement mechanism configured to move the magnet unit up and down. The vertical movement mechanism is configured to generate a magnetizing state in which the plurality of bar-shaped magnets are positioned next to the corresponding plurality of wells of the multiwell plate held by the holding part, thereby magnetizing the magnetic particles in each of the plurality of wells, and a non-magnetizing state in which the plurality of bar-shaped magnets are positioned below the multiwell plate, so as not to magnetize the magnetic particles in each of the wells. In a plan view, the plurality of bar-shaped magnets are positioned at two locations on both sides of each well.

Description

Technical Field

[0006] , ,

[0005] ,

[0001] The present invention relates to a magnetic field collecting device and a magnetic field collecting method.

Background Art

[0002] By analyzing the sugar chain structures of glycoproteins and glycopeptides contained in biological samples, there have been attempts to clarify the mechanisms of diseases such as infectious diseases, immune diseases, and the occurrence and metastasis of cancer, and to develop treatment and diagnostic methods. In such cases, a pretreatment is required to extract target substances such as proteins and peptides to be analyzed from biological samples such as blood. In such a pretreatment, a magnetic separation technique is used in which a target substance is bound to magnetic particles, and the magnetic particles to which the target substance is bound are attracted (magnetic field collected) by a magnet to separate the target substance from other coexisting substances.

[0003] As a magnetic separation device, a device in which a magnet is inserted beside a plurality of wells containing a sample containing magnetic particles is known (see Patent Document 1).

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0005] By the way, in magnetic separation such as the above-described pretreatment, it is preferable to be able to simultaneously perform magnetic separation of samples contained in a plurality of wells at high speed. Further, in the pretreatment, since magnetic separation may be performed a plurality of times on the sample in the well, if the time required for one magnetic separation can be shortened, the total time required for the pretreatment can be shortened. From these viewpoints, in magnetic separation, the magnetic field collecting property for quickly collecting magnetic particles in a well by a magnet is important.

[0006] Furthermore, in magnetic separation as described above, it is desirable to be able to perform as diverse and complex magnetic separation as possible. To achieve this, it is important not only to collect magnetic particles in the well using a magnet, but also to ensure that the magnetic particles collected in the well follow the magnet and move accordingly.

[0007] However, conventional magnetic separation devices as described above do not have sufficient magnetic collection and tracking capabilities for magnetic particles using magnets.

[0008] The present invention has been made in view of the above, and aims to provide a magnetizing device and magnetizing method that can improve the magnetization and tracking ability of magnetic particles in a well by a magnet. [Means for solving the problem]

[0009] As shown in Figures 1, 2, 4 to 6, the magnetizing device (1) of the present invention is a magnetizing device (1) for collecting magnetic particles in a liquid, comprising: a holding part (12) configured to hold a multiwell plate (200) in which a plurality of wells (210) for containing liquid are arranged in a plurality of rows and a plurality of columns; a magnet unit (13) having a plurality of bar-shaped magnets (50) arranged upright below the multiwell plate (200) held by the holding part (12) so as to correspond to the spaces between the plurality of wells (210); and a vertical movement mechanism (14) configured to move the magnet unit (13) up and down. 4) is configured to generate a magnetizing state in which multiple bar magnets (50) are positioned next to the corresponding multiple wells (210) of the multiwell plate (200) held by the holding part (12) by moving the magnet unit (13) up and down, thereby magnetizing the magnetic particles in each of the multiple wells (210), and a non-magnetizing state in which multiple bar magnets (50) are positioned below the multiwell plate (200) and the magnetic particles in each of the multiple wells (210) are not magnetized. In a plan view, the multiple bar magnets (50) are positioned at two locations on both sides of each well (210).

[0010] According to the magnetic collecting device (1) of the present invention, the magnetic particles in the well (210) are divided into two opposing locations within the well (210) and then magnetized. This improves the magnetization and tracking ability of the rod magnet (50) for the magnetic particles in the well (210). [Effects of the Invention]

[0011] According to the present invention, it is possible to improve the magnetic collection and tracking ability of magnetic particles in a well using a magnet. [Brief explanation of the drawing]

[0012] [Figure 1] Figure 1 is a diagram illustrating an example of the configuration of a magnetic collector according to this embodiment. [Figure 2] Figure 2 is a diagram illustrating an example of the configuration of a magnetic collector with multiple plates arranged. [Figure 3] Figure 3 is a diagram illustrating an example of the configuration of a bar magnet. [Figure 4] Figure 4 is a diagram illustrating an example of the arrangement of a bar magnet and a well. [Figure 5] Figure 5 is a diagram illustrating the magnetic particles collected in each well. [Figure 6] Figure 6 is a diagram illustrating an example of the orientation of the two magnetic poles of a bar magnet. [Figure 7] Figure 7 is a diagram illustrating an example of the configuration of the first component. [Figure 8] Figure 8 is a diagram illustrating an example of the configuration of the first and second members. [Figure 9] Figure 9 is a diagram illustrating an example of the configuration of the first component. [Figure 10] Figure 10 is a diagram illustrating an example of the arrangement of the first component. [Figure 11] Figure 11 is a diagram illustrating an example of the configuration of the vertical drive mechanism of a magnetic collector. [Figure 12] Figure 12 is a diagram illustrating the non-magnetic state of a bar magnet. [Figure 13]FIG. 13 is a diagram for explaining the magnetic flux concentration state of the bar magnet. [Figure 14] FIG. 14 is a diagram for explaining a configuration example of the control unit. [Figure 15] FIG. 15 is a diagram for explaining an example of the steps (a) to (c) of the magnetic flux concentration method. [Figure 16] FIG. 16 is a diagram for explaining an example of the steps (d) to (f) of the magnetic flux concentration method. [Figure 17] FIG. 17 is a diagram for explaining an example of the steps (g) to (i) of the magnetic flux concentration method. [Figure 18] FIG. 18 is a diagram for explaining an example of the descent while repeating the vertical movement of the bar magnet in the magnetic flux concentration method. [Figure 19] FIG. 19 is a diagram for explaining an example of the steps (j) to (l) of the magnetic flux concentration method. [Figure 20] FIG. 20 is a diagram for explaining an example of the step (m) of the magnetic flux concentration method. [Figure 21] FIG. 21 is a diagram for explaining another example of the directions of the two magnetic poles of the bar magnet.

Mode for Carrying Out the Invention

[0013] Hereinafter, an example of an embodiment of the magnetic flux concentration device and the magnetic flux concentration method according to the present invention will be described in detail with reference to the drawings.

[0014] <Configuration Example of Magnetic Flux Concentration Device> FIG. 1 is a diagram for explaining a configuration example of the magnetic flux concentration device 1 according to the present embodiment. FIG. 2 is a diagram for explaining a configuration example of the magnetic flux concentration device 1 holding the multi-well plate 200. The magnetic flux concentration device 1 is a device that concentrates magnetic particles in a liquid (collects them by magnetic force). The magnetic flux concentration device 1 may be included in a magnetic separation device.

[0015] As shown in FIGS. 1 and 2, the magnetic flux concentration device 1 in one embodiment includes a base 10, a support portion 11, a holding portion 12, a magnet unit 13, a vertical movement mechanism 14, and a control unit 15.

[0016] The base 10 has a rectangular plate shape. The base 10 is positioned horizontally with its plate surface facing upward. The support portion 11 has a first support member 20 extending in the vertical direction and a second support member 21 positioned at the upper end of the first support member 20 and extending in the horizontal direction. The first support member 20 has a rectangular plate shape. The first support member 20 is erected on the base 10 with its plate surface facing a second horizontal direction (direction X shown in Figures 1 and 2). The second support member 21 has a rectangular plate shape. The second support member 21 extends from the upper end of the first support member 20 in one direction of the second horizontal direction X.

[0017] The holding portion 12 is configured to hold the multiwell plate 200, as shown in Figure 2. The multiwell plate 200 has a roughly rectangular parallelepiped shape. In plan view, the multiwell plate 200 has a plurality of wells 210 arranged in two mutually orthogonal horizontal directions. In plan view, the plurality of wells 210 are arranged in multiple columns and multiple rows. Each well 210 has a cylindrical shape with an open top and is capable of containing liquid.

[0018] As shown in Figures 1 and 2, the holding portion 12 has a rectangular frame shape. A rectangular opening 12a is formed in the center of the holding portion 12. The size of the opening 12a is slightly smaller than the outer dimensions of the multiwell plate 200. This allows the holding portion 12 to support the multiwell plate 200 at the outer periphery of the opening 12a. The holding portion 12 has retaining members 30 positioned outside the four corners of the opening 12a. The retaining members 30 press the multiwell plate 200 from the outside, positioning the multiwell plate 200 in a predetermined position on the opening 12a.

[0019] The magnet unit 13 is positioned below the multiwell plate 200 which is held by the holding part 12. The magnet unit 13 has a plurality of bar-shaped magnets 50, a plurality of first members 51, and a second member 52.

[0020] Each of the multiple bar-shaped magnets 50 has a substantially cylindrical shape and is arranged upright. The length of the bar-shaped magnets 50 is more than half the length of the well 210. The bar-shaped magnets 50 are, for example, neodymium magnets. The N grade indicating the magnetic strength of the neodymium magnets of the bar-shaped magnets 50 may be N40 to N55. The N grade value is the maximum energy product ((BH)max), for example, N40 is a magnet with a maximum energy product of 40 MGOe. The bar-shaped magnets 50 have a plated surface. The plating is, for example, nickel plating. The plating improves the smoothness of the surface compared to before plating. The plating may be carried out using corrosion-resistant materials.

[0021] As shown in Figure 3, each of the multiple bar-shaped magnets 50 has a tapered tip 50a. The tip 50a is formed to gradually become thinner as it approaches the end. The tip of the tip 50a may have an upwardly convex curved shape.

[0022] As shown in Figure 2, the multiple bar magnets 50 are arranged in two mutually orthogonal horizontal directions to correspond to the multiple wells 210 of the multiwell plate 200. The multiple bar magnets 50 are arranged in multiple rows and multiple columns. In this embodiment, the row direction in which the multiple rows are arranged is the second horizontal direction X, and the column direction in which the multiple columns are arranged is the first horizontal direction (the Y direction shown in Figure 2) that is orthogonal to the second horizontal direction X.

[0023] As shown in Figures 4 and 5, the multiple bar-shaped magnets 50 are arranged in two locations on either side of each well 210 in a plan view. As a result, the magnetic particles T1 in each well 210 are divided into two opposing locations within the well 210 and magnetized therein when magnetized.

[0024] As shown in Figure 4, for example, in a virtual planar grid D1 having grid points at planar coordinates (x,y) (where x is an integer from 1 to n (n is 2 or greater), and y is an integer from 1 to m (m is 2 or greater)), multiple wells 210 are arranged between the grid points. Multiple bar magnets 50 are placed at grid points where both x and y are odd, and at grid points where both x and y are even, and no bar magnets 50 are placed at grid points where x is odd and y is even, and at grid points where x is even and y is odd. For example, if there are 13 grid points in the row direction (second horizontal direction X) (n=13) and 9 grid points in the column direction (first horizontal direction Y) (m=9), a total of 96 wells 210 are placed between grids arranged in rows of 12 in the row direction X and in columns of 8 in the column direction Y. Multiple wells 210 are arranged at equal intervals along the row direction X and column direction Y. Multiple wells 210 are arranged so that the outer surfaces of adjacent wells 210 are in contact with each other. Multiple bar magnets 50 are placed only at grid points where both x and y coordinates are odd, and where both x and y coordinates are even, for example, at grid points such as (1,1), (1,3)..., (2,2), (2,4)..., (3,1), (3,3)..., (4,2), (4,4)..., etc., for a total of 59 magnets. As a result, for each well 210, bar magnets 50 are placed only on both sides of each well 210. The two bar magnets 50 flanking each well 210 are positioned at a 45-degree angle to each well 210 with respect to the row direction X and the column direction Y.

[0025] From another perspective, the multiple bar magnets 50 are arranged in a portion of the multiple gaps Q1 formed by four rectangularly adjacent wells 210. The multiple bar magnets 50 are arranged alternately in the multiple gaps Q1 that are aligned along the row direction X and the column direction Y. The multiple bar magnets 50 are arranged in each of the row direction X and column direction Y at a pitch P1 that is twice the outer diameter R1 of one well 210 (the distance between the centers of two adjacent bar magnets 50 in each of the row direction X and column direction Y).

[0026] Each of the multiple bar magnets 50 has two magnetic poles S and N aligned horizontally. Half of the cylindrical bar magnet 50 has magnetic pole S, and the other half has magnetic pole N. The multiple bar magnets 50 are arranged such that the direction in which the two magnetic poles N and S are aligned is constant. That is, the orientation of the magnetic poles of all the bar magnets 50 is aligned. For example, as shown in Figure 6, the multiple bar magnets 50 are arranged such that, in a plan view, the direction in which two bar magnets 50 placed on opposite sides of the corresponding well 210 are aligned A1 and the direction in which the two magnetic poles S and N of the bar magnets 50 are aligned A2 have an angle α1 of 45 degrees. The direction A2 in which the two magnetic poles S and N of the bar magnets 50 are aligned is the first horizontal direction Y, and the direction A1 in which two bar magnets 50 placed on opposite sides of the corresponding well 210 are aligned is a direction that is 45 degrees to the horizontal directions X and Y.

[0027] The ratio of the inner diameter of the well 210 to the outer diameter of the bar magnet 50 (inner diameter of well 210 / outer diameter of bar magnet 50) is preferably between 1.5 and 3.2. Generally, the smaller the inner diameter of each well in a well plate, the narrower the space between each well. By setting the ratio to 1.5 or higher, it becomes easier to position the bar magnet 50 between each well 210 in the magnetizing state. By setting the ratio to 3.2 or lower, it becomes possible to apply a larger magnetic force within the well 210.

[0028] As shown in Figures 1 and 2, each of the multiple first members 51 is configured to hold multiple bar magnets 50 arranged in a row in the first horizontal direction Y. As shown in Figure 7, the first member 51 has a substantially rectangular parallelepiped shape. The first member 51 has a top surface 70, a bottom surface 71, a first side surface 72, a second side surface 73, a third side surface 74, and a fourth side surface 75. The first side surface 72 and the second side surface 73 are of the same size and face each other, and the third side surface 74 and the fourth side surface 75 are of the same size and face each other. The first side surface 72 and the second side surface 73 are connected to the top surface 70, the bottom surface 71, the third side surface 74, and the fourth side surface 75, respectively.

[0029] The upper surface 70 of the first member 51 has a rectangular shape that is elongated in one direction. Multiple insertion holes 80 into which multiple bar-shaped magnets 50 are inserted are formed on the upper surface 70. The insertion holes 80 are arranged in a row at equal intervals along the longitudinal direction of the upper surface 70. As shown in Figure 8, the insertion holes 80 are bottomed and are formed so that the lower part of the bar-shaped magnet 50 is inserted. The insertion holes 80 have the same shape as the lower part of the bar-shaped magnet 50 and have an inner diameter that is slightly larger than the lower part of the bar-shaped magnet 50. As a result, the bar-shaped magnet 50 inserted into the insertion hole 80 can be rotated by an external magnetic force.

[0030] As shown in Figures 7 and 9, the first member 51 has a fixing mechanism 81 configured to fix the bar magnets 50 inserted into each of the multiple insertion holes 80. For example, as shown in Figure 9, the fixing mechanism 81 has fixing holes 90 that lead from the first side surface 72 to each insertion hole 80, and bolts 91 that are fitted into the fixing holes 90 to fix the bar magnets 50 inserted into the insertion holes 80 to the first member 51.

[0031] As shown in Figures 1 and 2, the second member 52 is configured to hold multiple first members 51, each oriented in a first horizontal direction Y, with multiple bar-shaped magnets 50 facing in a first horizontal direction Y, arranged in a second horizontal direction X perpendicular to the first horizontal direction Y. The second member 52 has a rectangular plate shape. The second member 52 is positioned horizontally with its plate surface facing upward. As shown in Figure 8, the second member 52 has multiple fixing holes 110 for fixing each of the multiple first members 51. The bottom surface 71 of each first member 51 has multiple fixing holes 100 corresponding to the multiple fixing holes 110. The first member 51 can be fixed onto the second member 52 by placing the first member 51 on the second member 52 and fitting bolts 111 into the fixing holes 100, 110.

[0032] The positions of the insertion holes 80 of the multiple first members 51 arranged on the second member 52 coincide with the grid points of the virtual planar grid D1 shown in Figure 4. For example, as shown in Figure 10, each first member 51 has nine insertion holes 80. In the first members 51 located in odd-numbered rows in the second horizontal direction X, bar magnets 50 are inserted into five alternating insertion holes 80. The positions of the five insertion holes 80 into which the bar magnets 50 are inserted in the first members 51 in odd-numbered rows in the second horizontal direction X correspond to grid points in the virtual planar grid D1 where both x and y coordinates are odd. In the first members 51 located in even-numbered rows in the second horizontal direction X, bar magnets 50 are inserted into four alternating insertion holes 80. In the first member 51 of the second horizontal X-row, the positions of the four insertion holes 80 into which the bar magnets 50 are inserted correspond to grid points in the virtual planar grid D1 where both x and y coordinates are even. Thus, the bar magnets 50 may be inserted into some of the multiple insertion holes 80.

[0033] As shown in Figures 1 and 11, the vertical movement mechanism 14 is configured to move the magnet unit 13 up and down. The vertical movement mechanism 14 includes a slider 131 configured to hold the magnet unit 13 and move up and down along a rail 130, and a drive source 133 configured to drive the slider 131 via a drive belt 132. The vertical movement mechanism 14 is located, for example, on a support 11. The rail 130 is located on the front of the first support member 20 in the second horizontal direction X and extends in the vertical direction Z. The drive belt 132 and the drive source 133 are located on the back of the first support member 20 in the second horizontal direction X. The slider 131 is connected to the drive belt 132 through an elongated hole 140 formed in the first support member 20. The drive source 133 is, for example, a motor. By driving the drive belt 132 with the drive source 133, the slider 131 can be moved up and down along the rail 130.

[0034] The vertical movement mechanism 14 can generate two states: a non-magnetizing state in which the multiple bar magnets 50 of the magnet unit 13 are positioned below the multiwell plate 200 of the holding unit 12, as shown in Figure 12, and the magnetic particles in each of the multiple wells 210 are not magnetized; and a magnetizing state in which the multiple bar magnets 50 are positioned next to the corresponding multiple wells 210 of the multiwell plate 200 of the holding unit 12, as shown in Figure 13, and the magnetic particles in each of the multiple wells 210 are magnetized.

[0035] As shown in Figure 14, the control unit 15 includes an arithmetic unit 150, a communication unit 151, and a storage unit 152. The arithmetic unit 150 includes a processor composed of a CPU or FPGA and memory, and can control the operation of the vertical movement mechanism 14 by executing a program stored in the storage unit 152. The storage unit 152 consists of semiconductor memory elements and can store programs executed by the arithmetic unit 150, etc. The communication unit 151 has an I / O interface and a communication interface for communicating with external devices.

[0036] <Magnetic collection method> An example of a magnetic collection method using the magnetic collection device 1 will be described. This magnetic collection method will be explained using the case where a target substance is separated from a sample and concentrated using magnetism as an example. In this magnetic collection method, the operation of the magnetic collection device 1 is controlled by the control unit 15.

[0037] First, as shown in Figure 2, the multiwell plate 200 is provided to the holding unit 12 and held by the holding unit 12. The multiple wells 210 of the multiwell plate 200 contain liquids containing a sample, magnetic particles, and a dispersion. The sample may contain biological materials such as blood or plasma. The multiwell plate 200 is placed on the opening 12a of the holding unit 12. The multiwell plate 200 is positioned by the retaining member 30. At this time, as shown in step (a) of Figures 12 and 15, the multiple bar magnets 50 of the magnet unit 13 are positioned below the multiwell plate 200, and are in a non-magnetizing state, not magnetizing the magnetic particles T1 in the liquid L1 (containing the sample, magnetic particles T1, and dispersion W1) in each well 210.

[0038] Next, the magnet unit 13 is moved upward by the vertical movement mechanism 14. As shown in step (b) of Figures 13 and 15, the multiple bar-shaped magnets 50 rise to a first height position next to the corresponding multiple wells 210 of the multiwell plate 200 held by the holding part 12, and enter a magnetizing state in which they magnetize the magnetic particles T1 in the liquid L1 in each well 210. The first height position is a position where the tip of the bar-shaped magnet 50 is lower than the liquid surface of the liquid L1 in the well 210. If the tip of the bar-shaped magnet 50 is higher than the liquid surface of the liquid L1 in the well 210, some of the magnetic particles T1 will be magnetized outside the liquid L1, and in the step of lowering the bar-shaped magnet 50 described later (step (i) in Figure 17), the magnetic particles T1 magnetized outside the liquid L1 will have difficulty following the bar-shaped magnet 50. For example, the first height position may be such that the tip of the bar magnet 50 is lower than the liquid surface and higher than a position 5 mm below the liquid surface. More preferably, the first height position may be such that the tip of the bar magnet 50 is lower than the liquid surface and higher than a position 3 mm below the liquid surface. By maintaining this magnetization state for a predetermined time, as shown in step (c) of Figure 15, the magnetic particles T1 in each well 210 are magnetized by the two bar magnets 50 positioned on both sides of the well 210. As shown in Figure 5, the magnetic particles T1 in each well 210 are divided and magnetized at two opposing locations within the well 210. The magnetic particles T1 are magnetized at two opposing locations on the inner surface of the well 210, and the magnetic elements T1 are not magnetized at other locations on the inner surface of the well 210. In this case, for example, the magnetic particle T1 has the target substance and some of the impurities in the sample bound to it, and the target substance and some of the impurities are magnetized together with the magnetic particle T1. The remaining impurities are left in the dispersion W1.

[0039] Next, as shown in step (d) of Figure 16, with the magnetic particles T1 magnetized, some or all of the liquid (dispersion W1 (supernatant)) in the well 210 is removed. This removes impurities from the dispersion W1 in the well 210. Next, as shown in step (e) of Figure 16, the multiple bar magnets 50 are moved to the bottom of the multiwell plate 200, resulting in a non-magnetized state where the magnetic particles T1 in the well 210 are not magnetized. Next, as shown in step (f) of Figure 16, the washing solution W2 is dispensed into the well 210, and the well 210 is filled with liquid L2 (containing the sample, magnetic particles T1, and washing solution W2). At this time, the magnetic particles T1 are dispersed in the liquid L2. Also, any impurities that were bound to the magnetic particles T1 are dissolved into the liquid L2.

[0040] Next, as shown in step (g) of Figure 17, the multiple bar-shaped magnets 50 rise to a first height position next to the well 210 and enter a magnetizing state. By maintaining this magnetizing state for a predetermined time, as shown in step (h) of Figure 17, in each well 210, the magnetic particles T1 in each well 210 are magnetized by the two bar-shaped magnets 50 positioned on both sides of the well 210. The magnetic particles T1 in each well 210 are divided into two opposing parts within the well 210 and magnetized. At this time, for example, the target substance in the sample is bound to the magnetic particles T1, and the target substance in the sample is magnetized together with the magnetic particles T1. Impurities remain in the washing solution W2.

[0041] Next, as shown in step (i) of Figure 17, the multiple bar magnets 50 descend to a second horizontal height position at the bottom of the well 210 while maintaining the magnetization state of the magnetic particles T1, moving the magnetized magnetic particles T1 to the lower part of the well 210. As the multiple bar magnets 50 descend from the first height position to the second height position, they descend while repeatedly moving up and down.

[0042] For example, as shown in Figure 18, multiple bar magnets 50 descend from a first height position H1 to a third height position H3, which is higher than the second height position, then rise to a fourth height position H4, which is lower than the first height position H1, and then descend to a fifth height position H5, which is lower than the third height position H3. The multiple bar magnets 50 repeat this process until they finally descend to the second height position. The number of repetitions of the vertical movement may be one or more.

[0043] Next, as shown in step (j) of Figure 19, the cleaning liquid W2 is removed with the multiple bar-shaped magnets 50 positioned at a second height and the magnetic particles T1 at the bottom of the well 210 magnetized. This removes impurities from the cleaning liquid W2 from the well 210. The target substance is bound to the magnetic particles T1.

[0044] Next, as shown in step (k) of Figure 19, the multiple bar magnets 50 are moved to the bottom of the well 210, resulting in a non-magnetizing state where the magnetic particles T1 in the well 210 are not magnetized. Next, as shown in step (l) of Figure 19, the elution solution W3 is dispensed into the well 210, and the well 210 contains liquid L3 (containing the sample, magnetic particles T1, and elution solution W3). At this time, the magnetic particles T1 are dispersed in the liquid L3. Also, the target substance that was bound to the magnetic particles T1 is eluted into the liquid L3.

[0045] Next, as shown in step (m) of Figure 20, multiple bar magnets 50 rise to a second height position and magnetize the magnetic particles T1 in the well 210 at the bottom of the well 210. Subsequently, the eluate W3 is recovered from the well 210. The target substance is contained in this eluate W3.

[0046] <How to prepare a bar magnet> Next, an example of a method for preparing multiple bar magnets 50 in the magnetic collector 1 will be described. First, multiple first members 51 are prepared, and bar magnets 50 are inserted into multiple insertion holes 80 in each of the multiple first members 51. The insertion holes 80 into which bar magnets 50 are inserted and the insertion holes 80 into which bar magnets 50 are not inserted in each first member 51 are determined as appropriate. For example, as shown in Figure 10, in the first members 51 that are planned to be arranged in odd-numbered rows in the second horizontal direction X, bar magnets 50 are inserted into five insertion holes 80. In the first members 51 that are planned to be arranged in even-numbered rows in the second horizontal direction X, bar magnets 50 are inserted into four insertion holes 80.

[0047] In each first member 51, the bar magnet 50 rotates due to the magnetic force of the adjacent bar magnets 50, and the magnetic poles of the multiple bar magnets 50 are aligned so that the north and south poles of adjacent bar magnets face each other. After the magnetic poles are aligned, the bar magnets 50 are fixed in each insertion hole 80 by the fixing mechanism 81.

[0048] Next, each of the multiple first members 51 is attached to the second member 52. At this time, the bolts 111 are fitted into the fixing holes 100, 110, thereby fixing the first members 51 to the second member 52. The multiple first members 51 are attached in a row in the second horizontal direction X, with the rows of multiple bar magnets 50 of each first member 51 facing the first horizontal direction Y. In this way, the multiple bar magnets 50 are arranged in a row and column direction. Note that the insertion holes 80 into which the bar magnets 50 are inserted and the insertion holes 80 into which the bar magnets 50 are not inserted in each first member 51 may be changed as appropriate.

[0049] According to this embodiment, the magnetizing device 1 comprises a holding part 12 configured to hold a multiwell plate 200, a magnet unit 13 having a plurality of vertically arranged bar-shaped magnets 50, and a vertical movement mechanism 14 configured to move the magnet unit 13 up and down. The vertical movement mechanism 14 is configured to generate a magnetizing state in which the plurality of bar-shaped magnets 50 are placed next to the corresponding plurality of wells 210 of the multiwell plate 200 held by the holding part 12 to magnetize the magnetic particles in each of the plurality of wells 210, and a non-magnetizing state in which the plurality of bar-shaped magnets 50 are placed below the multiwell plate 200 to not magnetize the magnetic particles in each of the wells 210. In a plan view, the plurality of bar-shaped magnets 50 are placed at two locations on both sides of each well 210. As a result, the magnetic particles in the liquid in the well 210 are divided into two opposing locations and magnetized, so magnetization can be performed in a short time. Furthermore, since the magnetic particles are divided into two locations within the well 210, the clusters of magnetic particles collected at each location become larger. The larger the cluster of magnetic particles, the greater the magnetic attraction force to the magnet. Therefore, the magnetic particles collected within the well 210 exert a greater magnetic attraction force on the bar magnet 50, and as a result, the magnetic particles collected within the well 210 become more likely to follow the downward movement of the bar magnet 50. As a result, the magnetic collection and tracking ability of the magnetic particles within the well 210 by the bar magnet 50 can be improved.

[0050] Unlike this embodiment, if a bar-shaped magnet 50 is placed in one location for each well 210 in a plan view, the magnetic collection of magnetic particles within the well 210 decreases. Also, if three or more bar-shaped magnets 50 are placed in each well 210 in a plan view, the magnetic particles are collected over the entire inner surface of the well by the three or more bar-shaped magnets. When magnetic particles are collected over the entire inner surface of the well, a uniform magnetic field is formed in the well. Therefore, if three or more bar-shaped magnets 50 are placed in each well 210, the clusters of magnetic particles collected by each bar-shaped magnet become smaller, reducing the magnetic adhesion force of the magnetic particles to each bar-shaped magnet, and decreasing the ability of the magnetic particles to follow the bar-shaped magnets.

[0051] Each of the multiple bar-shaped magnets 50 has two magnetic poles S and N aligned horizontally, and the multiple bar-shaped magnets 50 are arranged so that the direction in which the two magnetic poles S and N are aligned is constant. As a result, the multiple bar-shaped magnets 50 create a regular magnetic field over the multiple wells 210 of the multiwell plate 200, and magnetic particles in each well 210 can be appropriately divided and magnetized.

[0052] The multiple bar magnets 50 are arranged such that, in a plan view, the direction A1 in which two bar magnets 50 positioned on either side of the corresponding well 210 are aligned and the direction A2 in which the two magnetic poles S and N are aligned have an angle α1 of 45 degrees. This reduces the variation in the magnetic field across the multiple wells 210, and ensures even magnetic collection across the multiple wells 210.

[0053] In a virtual planar grid D1 having grid points at planar coordinates (x,y) (where x is an integer from 1 to n and y is an integer from 1 to m), multiple wells 210 are arranged between the grid points, and multiple bar magnets 50 are placed at grid points where both x and y are odd, and where both x and y are even. Multiple bar magnets 50 are not placed at grid points where x is odd and y is even, and where x is even and y is odd. This allows magnetic particles to be appropriately divided and collected in each well 210.

[0054] Multiple bar-shaped magnets 50 are arranged in multiple rows and columns in a plan view, and are positioned at a pitch P1 that is twice the outer diameter R1 of the well 210 in both the row and column directions. This allows for the magnetic particles in each well 210 to be appropriately divided and collected.

[0055] The vertical movement mechanism 14 is configured to arrange multiple bar-shaped magnets 50 at multiple height positions lateral to multiple wells 210, and to generate a magnetized state at each of the multiple height positions. This allows the magnetized magnetic particles to be moved to a desired height position within the wells 210.

[0056] The control unit 15 controls the drive of the vertical movement mechanism 14 to raise the multiple bar magnets 50 to a first height position where they are in a magnetizing state, and then lowers the multiple bar magnets 50 to a second height position while maintaining the magnetizing state. This allows the magnetized magnetic particles in the well 210 to be moved to a lower position within the well 210, and then the amount of liquid in the well 210 can be reduced so that the magnetic particles do not escape from the liquid. This allows, for example, a liquid containing a target substance to be suitably concentrated.

[0057] The control unit 15 is configured to lower the multiple bar-shaped magnets 50 from the first height position to the second height position while repeatedly moving up and down. This prevents some of the magnetic particles collected in the well 210 by the bar-shaped magnets 50 from being left behind when moving them to a lower position in the well 210. As a result, the tracking ability of the magnetic particles can be improved.

[0058] The control unit 15 controls the drive of the vertical movement mechanism 14 so that the tip position of the rod magnet 50 does not rise above the liquid level in the well 210. This prevents the rod magnet 50 from causing magnetic particles in the well 210 to rise above the liquid level, and as a result, the loss of some magnetic particles remaining on the wall of the well 210 is suppressed.

[0059] Since the length of the bar-shaped magnet 50 is more than half the length of the well 210, magnetic particles in the well 210 can be effectively magnetized.

[0060] Since the bar magnet 50 has a plated surface, its surface can be protected while its smoothness can be improved. As a result, even if the bar magnet 50 comes into contact with the outer wall of the well 210, the bar magnet 50 can be moved smoothly alongside the well 210. Consequently, the bar magnet 50 can be moved up and down as close as possible to the outer wall of the well 210, improving the magnetic collection and tracking ability of the magnetic particles. In addition, the plating treatment can suppress corrosion of the bar magnet 50.

[0061] Since the bar-shaped magnet 50 has a tapered tip, it can be inserted into the narrow gap formed by the multiple wells 210. As a result, the bar-shaped magnet 50 can be brought close to the outer wall of the wells 210 and moved up and down, improving the magnetic collection and tracking ability of the magnetic particles.

[0062] Since the bar-shaped magnet 50 is a neodymium magnet, a strong magnetic force can be ensured. As a result, the bar-shaped magnet 50 can appropriately divide and collect the magnetic particles in each well 210.

[0063] The magnet unit 13 includes a plurality of first members 51 configured to hold a plurality of bar-shaped magnets 50 arranged in a row in a first horizontal direction Y, and a second member 52 configured to hold the plurality of first members 51 arranged in a second horizontal direction X perpendicular to the first horizontal direction, wherein the plurality of first members 51 are detachably attached to the second member 52. This allows the plurality of bar-shaped magnets 50 to be attached to the magnetic collector 1 by first attaching the bar-shaped magnets 50 in a row to each of the plurality of first members 51, and then attaching the plurality of first members 51 to the second member 52. As a result, when the plurality of bar-shaped magnets 50 are arranged in close proximity, damage due to collisions between the plurality of bar-shaped magnets 50 due to magnetic force can be suppressed. This makes it easy to attach the plurality of bar-shaped magnets 50 to the magnetic collector 1. Furthermore, since the process of attaching multiple bar-shaped magnets 50 to the magnetic collecting device 1 is simplified, it becomes possible to use bar-shaped magnets 50 with stronger magnetic force, and as a result, the magnetic collection and tracking performance of magnetic particles in the well 210 can be improved. In addition, since the bar-shaped magnets 50 can be attached in a line to each of the multiple first members 51, it is easier to align the orientation of the magnetic poles of the bar-shaped magnets 50.

[0064] The first member 51 has a plurality of insertion holes 80 into which a plurality of bar-shaped magnets 50 are inserted, and a fixing mechanism 81 configured to fix the bar-shaped magnets 50 inserted into each of the plurality of insertion holes 80. This makes it easy to attach a plurality of bar-shaped magnets 50 to each of the first members 51.

[0065] The multiple insertion holes 80 are configured such that when multiple bar magnets 50 are inserted, the magnetic force of adjacent bar magnets 50 causes the bar magnets 50 to rotate, aligning the orientation of the magnetic poles of the multiple bar magnets 50. This makes it easy to align the orientation of the magnetic poles of multiple bar magnets 50.

[0066] In the above embodiment, the multiple bar magnets 50 are arranged such that the direction in which the two magnetic poles N and S of the bar magnets are aligned is constant. In the above embodiment, the multiple bar magnets 50 were arranged such that, in a plan view, the direction in which two bar magnets 50 arranged on either side of the corresponding well 210 are aligned A1 and the direction in which the two magnetic poles S and N are aligned A2 have an angle α1 of 45 degrees. However, as shown in Figure 21, in a plan view, the direction in which two bar magnets 50 arranged on either side of the corresponding well 210 are aligned A1 and the direction in which the two magnetic poles S and N are aligned A2 may be the same direction or perpendicular to each other. The direction in which the two magnetic poles S and N of the bar magnets 50 are aligned A2 and the direction in which two bar magnets 50 arranged on either side of the corresponding well 210 are aligned A1 may be at a 45-degree angle with respect to the horizontal directions X and Y.

[0067] Embodiments of this disclosure further include the following embodiments:

[0068] (Note 1) A magnetizing device for collecting magnetic particles in a liquid, A holding unit configured to hold a multiwell plate in which a plurality of wells for containing the aforementioned liquid are arranged in multiple rows and multiple columns, A magnet unit having a plurality of rod magnets arranged upright below the multiwell plate held by the holding part, corresponding to the spaces between the plurality of wells, The system includes a vertical movement mechanism configured to move the aforementioned magnet unit up and down, The vertical movement mechanism is configured to generate a magnetizing state in which the plurality of bar-shaped magnets are positioned next to the corresponding plurality of wells of the multiwell plate held in the holding part, thereby magnetizing the magnetic particles in each of the plurality of wells, and a non-magnetizing state in which the plurality of bar-shaped magnets are positioned below the multiwell plate, thereby not magnetizing the magnetic particles in each of the wells, by moving the magnet unit up and down. The plurality of bar-shaped magnets are arranged in a plan view at two locations on either side of each well in the magnetic collecting device.

[0069] (Note 2) Each of the aforementioned bar-shaped magnets has two magnetic poles arranged horizontally, The magnetic collecting device described in Appendix 1, wherein the plurality of bar-shaped magnets are arranged such that the direction in which the two magnetic poles are aligned is constant.

[0070] (Note 3) The magnetic collecting device according to Appendix 2, wherein the plurality of bar-shaped magnets are arranged such that, in a plan view, the direction in which the two bar-shaped magnets positioned on both sides of each well are aligned and the direction in which the two magnetic poles are aligned have an angle of 45 degrees.

[0071] (Note 4) A magnetic collecting device according to any one of the appendices 1 to 3, wherein in a virtual planar grid having grid points at planar coordinates (x,y) (where x is an integer from 1 to n and y is an integer from 1 to m), the plurality of wells are arranged between the grids, the plurality of bar magnets are arranged at grid points where both x and y are odd and at grid points where both x and y are even, and the plurality of bar magnets are not arranged at grid points where x is odd and y is even and at grid points where x is even and y is odd.

[0072] (Note 5) The magnetic collecting device according to any one of the appendices 1 to 4, wherein the plurality of bar-shaped magnets are arranged in multiple rows and multiple columns in a plan view, and are arranged at a pitch of twice the outer diameter of the well in both the row direction and the column direction.

[0073] (Note 6) The magnetic collecting device according to any one of the appendices 1 to 5, wherein the vertical movement mechanism is configured to arrange the plurality of bar-shaped magnets at a plurality of height positions next to the plurality of wells, and to generate the magnetic collecting state at each of the plurality of height positions.

[0074] (Note 7) A magnetic collecting device according to any one of the appendices 1 to 6, further comprising a control unit for controlling the drive of the vertical movement mechanism.

[0075] (Note 8) The magnetic collecting device according to Appendix 7, wherein the control unit controls the drive of the vertical movement mechanism to raise the plurality of bar-shaped magnets to a first height position in which the magnetic collecting state is achieved, and then lowers the plurality of bar-shaped magnets to a second height position while maintaining the magnetic collecting state.

[0076] (Note 9) The magnetic collecting device according to Appendix 8, wherein the control unit is configured to lower the plurality of bar-shaped magnets from the first height position to the second height position while repeatedly moving up and down.

[0077] (Note 10) The magnetic collecting device according to any one of the appendices 7 to 9, wherein the control unit controls the drive of the vertical movement mechanism so that the tip position of the bar-shaped magnet does not rise above the liquid level in the well.

[0078] (Note 11) The magnetic collecting device according to any one of the appendices 1 to 10, wherein the length of each of the plurality of bar-shaped magnets is more than half the length of the well.

[0079] (Note 12) The magnetic collecting device according to any one of the appendices 1 to 11, wherein each of the plurality of bar-shaped magnets has a plated surface.

[0080] (Note 13) The magnetic collecting device according to any one of the appendices 1 to 12, wherein each of the plurality of bar-shaped magnets has a tapered tip.

[0081] (Note 14) A magnetic collecting device according to any one of the appendices 1 to 13, wherein each of the plurality of bar-shaped magnets is a neodymium magnet.

[0082] (Note 15) The aforementioned magnet unit is A plurality of first members configured to hold the plurality of bar-shaped magnets arranged in a line in the first horizontal direction, The present invention comprises a second member configured to hold the plurality of first members in a second horizontal direction perpendicular to the first horizontal direction, The magnetic collecting device according to any one of the appendices 1 to 14, wherein the plurality of first members are configured to be detachably attached to the second member.

[0083] (Note 16) The magnetic collecting device according to Appendix 15, wherein each of the plurality of first members has a plurality of insertion holes configured for inserting the plurality of bar-shaped magnets, and a fixing mechanism configured for fixing the bar-shaped magnets inserted into each of the plurality of insertion holes.

[0084] (Note 17) The magnetic collecting device according to Appendix 15 or 16, wherein the plurality of insertion holes are configured such that when the plurality of bar magnets are inserted, the bar magnets rotate due to the action of the magnetic force of adjacent bar magnets, and the orientation of the magnetic poles of the plurality of bar magnets is aligned.

[0085] (Note 18) A magnetic collecting device according to any one of the appendices 1 to 17, wherein the ratio of the inner diameter of the well to the outer diameter of the bar-shaped magnet (ratio of inner diameter of the well / outer diameter of the bar-shaped magnet) is 1.5 or more and 3.2 or less.

[0086] (Note 19) A magnetization method for collecting magnetic particles in a liquid, (a) A step in which a holding unit holds a multiwell plate in which a plurality of wells for containing the liquid are arranged in a plurality of rows and a plurality of columns, (b) A step of placing a magnet unit having a plurality of rod-shaped magnets arranged upright below the multiwell plate held in the holding part, (c) The process of raising the magnet unit and positioning the plurality of bar magnets next to the corresponding plurality of wells of the multiwell plate held in the holding part, and collecting the magnetic particles in each of the plurality of wells, In the above (c), the plurality of bar-shaped magnets are arranged at two locations on both sides of each well, and the magnetic particles in each well are divided into two opposing locations within the well and magnetized, in a magnetization method.

[0087] The embodiments described above are for illustrative purposes only and are not intended to limit the scope of this disclosure. The embodiments described above can be modified in various ways without departing from the scope and spirit of this disclosure. For example, some components of one embodiment can be added to other embodiments, or some components of one embodiment can be replaced with corresponding components of other embodiments. [Industrial applicability]

[0088] This invention is useful in providing a magnetizing device and magnetizing method that can improve the magnetization and tracking ability of magnetic particles in a well using a magnet. [Explanation of Symbols]

[0089] 1... Magnetic collector, 12... Holding unit, 13... Magnet unit, 14... Up / down movement mechanism, 15... Control unit, 50... Bar magnet, 200... Multiwell plate, 210... Well

Claims

1. A magnetizing device for collecting magnetic particles in a liquid, A holding unit configured to hold a multiwell plate in which a plurality of wells for containing the aforementioned liquid are arranged in multiple rows and multiple columns, A magnet unit having a plurality of rod magnets arranged upright below the multiwell plate held by the holding part, corresponding to the spaces between the plurality of wells, The system includes a vertical movement mechanism configured to move the aforementioned magnet unit up and down, The vertical movement mechanism is configured to generate a magnetizing state in which the plurality of bar-shaped magnets are positioned next to the corresponding plurality of wells of the multiwell plate held in the holding part, thereby magnetizing the magnetic particles in each of the plurality of wells, and a non-magnetizing state in which the plurality of bar-shaped magnets are positioned below the multiwell plate, thereby not magnetizing the magnetic particles in each of the wells, by moving the magnet unit up and down. The plurality of bar-shaped magnets are arranged in a magnetic collecting device at two locations on either side of each well in a plan view.

2. Each of the aforementioned bar-shaped magnets has two magnetic poles arranged horizontally. The magnetic collecting device according to claim 1, wherein the plurality of bar-shaped magnets are arranged such that the direction in which the two magnetic poles are aligned is constant.

3. The magnetic collecting device according to claim 2, wherein the plurality of bar-shaped magnets are arranged such that, in a plan view, the direction in which the two bar-shaped magnets positioned on both sides of each well are aligned and the direction in which the two magnetic poles are aligned have an angle of 45 degrees.

4. A magnetic collecting device according to any one of claims 1 to 3, wherein in a virtual planar grid having grid points at planar coordinates (x, y) (where x is an integer from 1 to n and y is an integer from 1 to m), the plurality of wells are arranged between the grids, the plurality of bar magnets are arranged at grid points where both x and y are odd and at grid points where both x and y are even, and the plurality of bar magnets are not arranged at grid points where x is odd and y is even and at grid points where x is even and y is odd.

5. The magnetic collecting device according to any one of claims 1 to 3, wherein the plurality of bar-shaped magnets are arranged in multiple rows and multiple columns in a plan view, and are arranged at a pitch of twice the outer diameter of the well in both the row direction and the column direction.

6. The magnetic collecting device according to claim 1, wherein the vertical movement mechanism is configured to arrange the plurality of bar-shaped magnets at a plurality of height positions lateral to the plurality of wells, and to generate the magnetic collecting state at each of the plurality of height positions.

7. The magnetic collecting device according to claim 1, further comprising a control unit for controlling the drive of the vertical movement mechanism.

8. The magnetic collecting device according to claim 7, wherein the control unit is configured to control the drive of the vertical movement mechanism to raise the plurality of bar-shaped magnets to a first height position in which the magnetic collecting state is achieved, and then lower the plurality of bar-shaped magnets to a second height position while maintaining the magnetic collecting state.

9. The magnetic collecting device according to claim 8, wherein the control unit is configured to lower the plurality of bar-shaped magnets from a first height position to a second height position while repeatedly moving up and down.

10. The magnetic collecting device according to claim 7, wherein the control unit controls the drive of the vertical movement mechanism so that the tip position of the bar-shaped magnet does not rise above the liquid level in the well.

11. The magnetic collecting device according to claim 1, wherein the length of each of the plurality of bar-shaped magnets is more than half the length of the well.

12. The magnetic collecting device according to claim 1, wherein each of the plurality of bar-shaped magnets has a plated surface.

13. The magnetic collecting device according to claim 1, wherein each of the plurality of bar-shaped magnets has a tapered tip.

14. The magnetic collecting device according to claim 1, wherein each of the plurality of bar-shaped magnets is a neodymium magnet.

15. The aforementioned magnet unit is A plurality of first members configured to hold the plurality of bar-shaped magnets arranged in a line in the first horizontal direction, The present invention comprises a second member configured to hold the plurality of first members in a second horizontal direction perpendicular to the first horizontal direction, The magnetic collecting device according to claim 1, wherein the plurality of first members are configured to be detachably attached to the second member.

16. The magnetic collecting device according to claim 15, wherein each of the plurality of first members has a plurality of insertion holes configured for inserting the plurality of bar-shaped magnets, and a fixing mechanism configured for fixing the bar-shaped magnets inserted into each of the plurality of insertion holes.

17. The magnetic collecting device according to claim 16, wherein the plurality of insertion holes are configured such that when the plurality of bar magnets are inserted, the bar magnets rotate due to the action of the magnetic force of adjacent bar magnets, and the orientation of the magnetic poles of the plurality of bar magnets is aligned.

18. The magnetic collecting device according to claim 1, wherein the ratio of the inner diameter of the well to the outer diameter of the bar-shaped magnet (ratio of inner diameter of the well / outer diameter of the bar-shaped magnet) is 1.5 or more and 3.2 or less.

19. A magnetization method for collecting magnetic particles in a liquid, (a) A step in which a holding unit holds a multiwell plate in which a plurality of wells for containing the liquid are arranged in a plurality of rows and a plurality of columns, (b) A step of placing a magnet unit having a plurality of rod-shaped magnets arranged upright below the multiwell plate held in the holding part, (c) The process of raising the magnet unit and positioning the plurality of bar-shaped magnets next to the corresponding plurality of wells of the multiwell plate held in the holding part, and collecting the magnetic particles in each of the plurality of wells, In the above (c), the plurality of bar-shaped magnets are arranged at two locations on both sides of each well, in a magnetizing method.

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