JP2004283728A - Magnetic separator for magnetic particulate - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To miniaturize a magnetism separator for hybridization and improve magnetism-shielding capability during off of magnetism. <P>SOLUTION: A magnet holder 32 holds a magnet 34. The end 50 in the magnetization direction on a shielding side is held in such a way that the end 48 in the magnetization direction on an open side is exposed. The on-off of magnetism is controlled by rotation of the holder 32. A non-magnetic spacer 52 is disposed between the end 50 and the holder 32. A shielding-enhancing cover is optionally provided so as to cover the end 48 during off of magnetism and contact with the holder 32 on both sides of the covered end 48. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a magnetic separation device for magnetic fine particles, and more particularly, to a small-sized magnetic separation device having improved magnetic force on / off control capability.
[0002]
[Prior art]
2. Description of the Related Art Conventionally, it has been known to extract biological substances such as nucleic acids in cells and identify the base sequence of nucleic acids using magnetic fine particles. One of such techniques is a hybridization method described below.
[0003]
The nucleic acid hybridization method is used to specifically detect a specific gene. For example, using a nucleic acid probe-immobilized particle as a probe, a target nucleic acid of a liquid sample is hybridized with a nucleic acid probe in a reaction vessel, and then solid / liquid separation (B / F separation) is performed to hybridize on the particle. The amount of the target nucleic acid thus determined is measured. In the hybridization method, magnetic fine particles have attracted attention as particles for immobilizing nucleic acid probes from the viewpoint of simplicity of B / F separation.
[0004]
When using magnetic fine particles, it is necessary to control to turn on / off the magnetic force generated by the magnetic force generation source. Conventionally, current control of an electromagnet is generally performed. Further, the position of the magnet (distance from the sample) is controlled such that the permanent magnet is moved closer to or away from the sample.
[0005]
B / F separation using magnetic fine particles is described, for example, in Patent Documents 1 to 3 below.
[0006]
[Patent Document 1]
Patent No. 3115501
[Patent Document 2]
JP-A-11-156231
[Patent Document 3]
JP-A-8-29425
[0007]
[Problems to be solved by the invention]
The B / F separation device using the magnetic fine particles as described above is referred to as a magnetic separation device in this specification. Conventionally, on a hybridization device, a magnetic separation device is separated from a temperature control portion (a portion where a sample reaction is caused by temperature control such as heating and cooling). On the other hand, if temperature control and magnetic separation are performed in one place, the size of the magnetic separation device needs to be reduced.
[0008]
That is, in the temperature control, it is required that the temperature is rapidly changed by heating and cooling. To this end, it is effective to reduce the heat capacity of the sample holding member, and to reduce the heat capacity, it is effective to reduce the volume of the sample holding member. Then, in order to reduce the volume of the sample holding member, it is required to reduce the size of the magnetic separation device provided in the sample holding member.
[0009]
However, the conventional technology for controlling electromagnets has a lower magnetic flux density volume efficiency than permanent magnets, and is too large to obtain sufficient magnetic force, and is not suitable for miniaturization.
[0010]
In addition, when an electromagnet is used, the controllability of the magnetic force is good, but the coil generates heat when a current flows through the electromagnet. This is disadvantageous in integrating temperature control and magnetic separation into one place.
[0011]
Further, with respect to a technique for controlling the distance between the sample and the permanent magnet, the magnet must be kept away from the sample when the magnetic force is turned off, and a space for the magnet is required, and miniaturization is difficult. The use of stronger magnets requires more space.
[0012]
In addition, it is conceivable to move the sample container away from the magnet, which means that the sample is also moved away from the temperature control device, and there is a high possibility that the temperature of the sample will greatly change.
[0013]
As described above, it is desired to reduce the size of the magnetic separation device. In addition, the magnetic separation device is required to reliably shut off the magnetic force when the magnetic force is turned off.
[0014]
For example, if the solvent of the sample is an electrically neutral liquid such as pure water and the surface of the magnetic fine particles is charged, the particles are less likely to aggregate because the repulsion between the particles is large. is there. In such a case, it is conceivable to employ a strong magnet in order to avoid an increase in the time required for immobilization. However, when the magnet is made strong, the ability to cut off the magnetic force when the magnetic force is turned off is reduced, and the magnetic force may act on the sample. As a result, when the sample is to react while the magnetic force is off, there is a possibility that the leaked magnetic force acts to collect the magnetic fine particles.
[0015]
Therefore, in order to avoid such a problem, even when a strong magnet is used, it is required to sufficiently shut off the magnetic force when the magnetic force is turned off.
[0016]
The present invention has been made in view of the above background, and an object of the present invention is to provide a magnetic separation device which is small in size and has a high magnetic shielding ability.
[0017]
[Means for Solving the Problems]
The magnetic separation device according to the present invention includes at least one magnet serving as a magnetic force source and a ferromagnetic material, and magnetizes the at least one magnet on the shield side so that an end in the open magnetization direction is exposed. The magnet holder includes a magnet holder that is held at the direction end, a rotating unit that rotates the magnet holder, and a non-magnetic body disposed between the magnetized end on the shielding side and the magnet holder.
[0018]
According to the present invention, the configuration in which the magnet holder holding the magnet is rotated is employed, so that the magnetic separation device can be downsized. Further, in the present invention, since the non-magnetic material is arranged between the magnetized end on the shielding side and the magnet holder, the magnetic force can be more reliably cut off when the magnetic force is turned off.
[0019]
The magnet holder is preferably a ferromagnetic material, and is made of, for example, stainless steel such as iron or martensite, to which a magnet can be attracted. Preferably, the plurality of permanent magnets are arranged so as to line up on the rod-shaped holder. The non-magnetic material is made of, for example, paper, resin, or aluminum. The non-magnetic material may be air.
[0020]
Preferably, the magnetic separation device of the present invention is arranged such that, when the magnet holder is rotated by the rotating means and the open-side magnetized direction end faces a different direction from the sample, the open-side magnetized direction end And a shielding enhancement cover made of a magnetic material, which is disposed so as to be in contact with the magnet holder on both sides of the open end in the magnetization direction.
[0021]
According to the present invention, when the magnetic force is turned off, the cut-off reinforcing cover covers the open end in the magnetization direction and contacts the magnet holder on both sides. A magnetic circuit is formed by the shielding enhancement cover and the magnet holder, and the end of the open side in the magnetization direction is arranged therein, so that the influence of the magnetic force from the open side can be suppressed, and the magnetic force can be more reliably shut off. .
[0022]
The barrier enhancement cover is preferably ferromagnetic. More preferably, the shielding enhancement cover is made of a material having a high magnetic permeability and a high saturation magnetic flux density, and is made of, for example, pure iron or permalloy.
[0023]
Preferably, the outer peripheral surface of the magnet holder and the inner peripheral surface of the shielding enhancement cover are both cylindrical surfaces, and slide with the rotation of the magnet holder. With a small configuration, it is possible to realize an apparatus provided with a shielding enhancement cover.
[0024]
Preferably, the magnetic separation device is provided on the magnet holder so as to be located outside an end in the magnetization direction on the shield side when viewed from the center of rotation by the rotating means, and has a higher magnetic permeability than the magnet holder. It has a blocking reinforcement member made of a large material.
[0025]
According to the present invention, the leakage magnetic flux from the end portion in the magnetization direction on the shielding side is captured by the shielding reinforcing member, so that the magnetic force can be more reliably shielded. The blocking reinforcing member is, for example, permalloy. According to the present invention, since a member having high magnetic permeability is used for a part of the holder instead of the entire holder, an expensive material may be reduced and the cost is advantageous.
[0026]
Note that the cutoff reinforcing member may be provided at a distance from the end in the magnetization direction with the magnet holder interposed therebetween. Then, the blocking enhancement member may be attached to the outer surface of the magnet holder. Materials having physical properties that have high maximum magnetic permeability but low saturation magnetic flux density can also be used. Further, the cut-off reinforcing member may be interposed between the magnet direction end on the magnetic force break side and the magnet holder.
[0027]
Another embodiment of the present invention is a hybridization device provided with the magnetic separation device for magnetic fine particles described above. Another embodiment of the present invention is a nucleic acid extracting apparatus provided with the above magnetic fine particle magnetic separation apparatus. Further, a nucleic acid extraction amplification treatment or a nucleic acid amplification treatment may be performed.
[0028]
Further, another embodiment of the present invention is a nucleic acid extraction and hybridization apparatus provided with the magnetic separation apparatus for magnetic fine particles described above. Here, a plurality of magnetic separation devices may be provided in a plurality of reaction units, respectively, and each of the plurality of reaction units may be a nucleic acid extraction reaction unit for performing nucleic acid extraction or a hybridization reaction unit for performing hybridization. The nucleic acid extraction process and the hybridization process can be performed by one device. Further, a nucleic acid extraction amplification treatment or a nucleic acid amplification treatment may be performed.
[0029]
Another aspect of the present invention is a nucleic acid processing apparatus including the magnetic separation device for magnetic fine particles described above, and further including a reaction unit, wherein the reaction unit includes a reaction container holder for holding a reaction container, Temperature adjusting means for adjusting the temperature of the container holder, wherein the magnet holder of the magnetic separation device is rotatably provided on the reaction container holder. The nucleic acid processing device is, for example, a device that performs nucleic acid extraction, nucleic acid amplification, hybridization, or two or more of these processes.
[0030]
In this embodiment, temperature control and magnetic separation are performed at the same location. According to the present invention, the space for the built-in magnetic separator can be reduced by downsizing the magnetic separator. Since the heat capacity of the reaction container holder can be reduced as the space is reduced, the temperature control ability can be improved. The reaction performance in the reaction section can be improved by improving the temperature control capability and the above-described magnetic blocking capability.
[0031]
BEST MODE FOR CARRYING OUT THE INVENTION
FIG. 1 shows a hybridization device provided with the magnetic separation device of the present invention. The hybridization apparatus 10 has a reaction section 12, a chip rack / waste liquid section 14, a cleaning liquid section 16, and a head section 18. The reaction section 12, chip rack / waste liquid section 14, and cleaning liquid section 16 are arranged on a table.
[0032]
The reaction section 12 includes a reaction container holder, and further includes a temperature control device and a magnetic separation device. The reaction unit 12 converts the sample nucleic acid into a single strand by heating and cooling the sample (denature), and then performs hybridization between the single-stranded sample nucleic acid and a specific nucleic acid probe (annealing). A temperature control device performs heating and cooling to control the denature and annealing temperatures. Further, in the reaction section 12, B / F separation is performed by the operation of the magnetic separation device.
[0033]
The chip rack / waste liquid unit 14 includes a chip rack and a waste liquid storage container. The tip rack holds a disposable tip for dispensing a washing solution or a reagent. The tip rack is provided with holes shaped to support the tapered portion of the disposal tip, and holds the tip before the start of measurement.
[0034]
The waste liquid container is located below the chip rack. The waste liquid storage container is used for storing the waste liquid sucked up from the reaction unit 12 during B / F separation and washing. Space is saved by arranging the tip rack and the waste liquid container at the same position.
[0035]
The cleaning liquid unit 16 includes a cleaning liquid container and a temperature controller. The temperature control device is a device that performs heating and cooling, and controls the temperature of the cleaning liquid to the same temperature as the annealing temperature. This can prevent non-specific adsorption and dissociation of the nucleic acid in the reaction vessel from occurring due to a temperature change during washing. A plurality of cleaning liquid units 16 may be provided as necessary. For example, when performing an immune reaction to detect a hybridized nucleic acid, two washing parts are preferably provided.
[0036]
The head section 18 has a mechanism equipped with a plurality of chip nozzles, and chips are detached from the chip nozzles. Further, the head section 18 includes a mechanism for suctioning and injecting the processing liquid by the chip mounted on the chip nozzle. Further, the head section 18 is configured by an arm unit that can move in the XYZ directions. The arm unit moves the head unit 18.
[0037]
The hybridization device 10 may be provided with a reagent section further including a reagent storage container as needed. For example, to detect a hybridized nucleic acid, a labeling reagent and an enzyme chromogenic substrate are contained. The labeling reagent is, for example, an alkaline phosphatase-labeled anti-DIG Fab ′ fragment (anti-DIG-AP), and the enzyme coloring substance is, for example, an afcaliphosphatase luminescent substrate.
[0038]
The nucleic acid hybridization method includes a one-step method and a two-step method (sandwich method). The hybridization device 10 of the present embodiment may be used for either method. The nucleic acid probe may be any of single-stranded DNA, RNA and PNA.
[0039]
The hybridization apparatus 10 typically performs the following steps (1) to (8). Then, the amount of the labeled nucleic acid in the reaction container is measured, and the nucleic acid in the sample is detected.
[0040]
(1) A reaction vessel into which the nucleic acid probe-immobilized magnetic particles and the labeled sample nucleic acid are injected and mixed is set in the reaction section 12, and the temperature in the reaction vessel is set to the nucleic acid denature temperature by a heating / cooling device. Then, the temperature is maintained for a predetermined time to make the sample nucleic acid single-stranded. At this time, the magnetic particles in the reaction vessel are mobilized by magnetic force control (magnetic force off).
[0041]
(2) The temperature in the reaction vessel is changed to the nucleic acid annealing temperature, and the temperature is maintained for a predetermined time to perform annealing.
[0042]
(3) The magnetic separation device operates to immobilize the sample nucleic acid bound to the magnetic particles (magnetic on). In the present embodiment, immobilization is performed at the bottom of the container.
[0043]
(4) The arm unit operates to move to the chip rack / waste liquid section 14, and the chip is mounted on the chip nozzle.
[0044]
(5) The arm unit moves to the reaction section 12, and the chip nozzle sucks the supernatant in the reaction vessel.
[0045]
(6) The arm unit moves to the chip rack / waste liquid section 14, and the supernatant in the chip nozzle is discharged to the waste liquid container.
[0046]
(7) The arm unit moves to the cleaning liquid section 16, and the cleaning liquid adjusted to the annealing temperature in advance by the temperature control device is sucked from the cleaning liquid storage container. The cleaning liquid is injected into the reaction vessel of the reaction section 12.
[0047]
(8) The above cleaning operations (5) to (7) are repeated a predetermined number of times. Finally, the cleaning liquid is injected into the reaction vessel.
[0048]
In the above processing, the magnetic force of the magnetic separation device is turned off in the denature of (1) and the annealing of (2). Then, the magnetic force is turned on in (3). It is also considered preferable to repeatedly turn on and off the magnetic force while the cleaning liquid is being injected.
[0049]
FIG. 2 shows the configuration of the reaction unit 12. The magnetic separation device of the present invention is built in the reaction section 12. The reaction unit 12 is capable of combining, for example, both binding / separation of a target DNA immobilized on magnetic microparticles (magnetic beads) and a fluorescent-labeled probe nucleic acid and magnetic collection / stirring of magnetic microparticles by integrating a temperature control function and a magnetic separation function. Can be effectively controlled.
[0050]
As shown in FIG. 2, the reaction section 12 has a rectangular parallelepiped heat block 20 as a sample holding member. On the heat block 20, a sample container plate 22 (container assembly) is mounted. The sample container plate 22 includes a plurality of sample containers 24 (container pieces). The number of sample containers is 96 (8 × 12). The heat block 20 has a container holding hole 26 (well) at a position corresponding to each sample container 24. Each sample container 24 containing a sample is inserted into each container holding hole 26 and held. The bottom of the container 24 and the holding hole 26 have a wedge shape having the same angle, and when the container 24 is inserted into the holding hole 26, they are in close contact with each other, and the temperature transmission efficiency is good.
[0051]
A Peltier device 28 is arranged below the heat block 20. The Peltier device 28 constitutes a temperature control device, and the heat block 20 is heated and cooled by the Peltier device 28.
[0052]
Below the heat block 20, a circular elongated magnet storage hole 30 is provided along the direction in which the container holding holes 26 are arranged. The magnet housing hole 30 is arranged between the bottom of the container holding hole 26 and the lower surface of the heat block 20. A magnet holder 32 which is a magnetic force control rod is inserted into the magnet housing hole 30. The magnet holder 32 is rod-shaped, and its cross section is a semicircle. The magnet holders 32 are provided in each of the plurality of container holding hole rows, and thus the number of the magnet holders 32 is twelve. The magnet holder 32 holds a plurality of magnets 34. Further, although not shown, a rotating device for rotating the magnet holder 32 in the magnet housing hole 30 is provided. The rotating device includes a rack and a pinion.
[0053]
The magnet holder 32, the magnet 34, and the rotating device constitute the magnetic separation device of the present embodiment.
[0054]
FIG. 3 is a sectional view of the reaction section 12. As described above, the sample container plate 22 is placed on the heat block 20, and the Peltier element 28 is arranged on the lower surface of the heat block 20. The heat block 20 is further provided with a temperature sensor 36. The temperature controller 38 controls the Peltier device 28 based on the temperature detected by the temperature sensor 36 to adjust the sample temperature.
[0055]
Further, as the magnetic separation device, the magnet holder 32 is inserted into the magnet storage hole 30 as described above, and the magnet holder 32 holds a plurality of magnets 34. The magnet holder 32 is made of a ferromagnetic material such as iron. The magnet holder 32 is cylindrical at both ends, but is semi-cylindrical in the range where the container holding hole 26 is provided.
[0056]
The magnets 34 are arranged on the magnet holder 32 so that each magnet 34 is located below the container holding hole 26. The plurality of magnets 34 are arranged such that the directions of the north pole and the south pole of the adjacent magnets 34 are reversed.
[0057]
Each magnet 34 is a permanent magnet, and is constituted by a high heat-resistant magnet having thermoreversibility up to a high temperature so as to withstand a temperature of about 100 degrees at the maximum. In the present embodiment, the magnet 34 is a neodymium boron magnet.
[0058]
The magnet 34 is held by the magnet holder 32 as described below. That is, the magnet 34 has a cylindrical shape, and its cross section is circular. A circular opening 40 corresponding to this cross section is provided on the flat surface of the semi-cylindrical portion of the magnet holder 32. The magnet 34 is inserted and fixed in the opening 40 such that half of the magnet 34 is hidden in the opening 40.
[0059]
Since half of each magnet 34 is embedded in the magnet holder 32, one end 48 of the two magnetized ends of the magnet 34 is exposed, and the other end 50 is covered by the magnet holder 34. Is The former end is open and provides magnetic force, while the latter end is shielded by a magnet holder 32. Therefore, the former end is referred to as an open-side magnetization direction end 48, and the latter end is referred to as a shield-side magnetization direction end 50.
[0060]
A pinion gear 42 is attached to an end of the magnet holder 32, and the pinion gear 42 meshes with a rack 44. The rack 44 is provided in a direction perpendicular to the longitudinal direction of the magnet holder 32, that is, along the end of the magnet holder 32. The rack 44 and the pinion 42 constitute a rotating device for the magnet holder 32.
[0061]
The magnetic force control device 46 controls the position of the rack 44 by controlling the rotation of a motor (not shown). When the rack 44 moves, the magnet holder 32 rotates. Thus, the magnetic force control device 46 controls the angle of the magnet holder 32, and thereby controls on / off of the magnetic force as described below.
[0062]
FIG. 4 shows the on / off control of the magnetic force. In the magnetic force ON state, the angle of the magnet holder 32 is set such that the open-side magnetization direction end 48 faces the sample, that is, the exposed magnet end faces the sample. When the magnetic force is turned off, the rotating device rotates the magnet holder 32 by 180 degrees. As a result, the magnetization direction end 50 on the shield side faces the sample. In this state, the ferromagnetic magnet holder 32 is interposed between the magnet 34 and the sample and hinders the action of the magnetic force on the sample. Thus, the on / off of the magnetic force is controlled by the reversal of the magnet holder 32.
[0063]
FIG. 5 shows a magnetic state when the magnetic force is on and the magnetic force is off. As shown, the magnetic force acts on the sample when the magnetic force is on.
[0064]
As described above, in the present embodiment, the magnetic force when the magnetic force is turned off is blocked by using the ferromagnetic magnet holder 32. However, from the viewpoint of the performance of the magnetic separation device, the magnetic force blocking capability is higher. High is desired. In particular, when a stronger magnet is used, it is required to improve the magnetic force blocking ability.
[0065]
For example, if the solvent of the sample is an electrically neutral liquid such as pure water and the surface of the magnetic fine particles is charged, the particles are less likely to aggregate because the repulsion between the particles is large. is there. In such a case, it is conceivable to increase the strength of the magnet, but with the strengthening of the magnet, it is also required to improve the ability to interrupt the magnetic force when the magnetic force is off. In order to meet such a demand, the magnetic separation device of the present embodiment is configured as follows.
[0066]
FIG. 6 shows a sectional view of the magnet holder 32. As described above, the magnet holder 32 is a semi-cylindrical column, and its cross section is semi-circular. A circular opening 40 is provided in the magnet holder 32, and a cylindrical magnet 34 is held in the opening 40. The magnetized direction end 50 on the shield side of the magnet 34 is located in the opening 40, and the magnetized end 48 on the open side is exposed.
[0067]
As a feature of the present embodiment, a spacer 52 that is a non-magnetic material is disposed at the bottom of the opening 40. That is, the spacer 52 is disposed between the magnetized end 50 of the shield side and the magnet holder 32. The spacer 52 provides a magnetic gap outside the magnetization direction end 50. The spacer 52 may be paper, resin, aluminum, or the like. The thickness of the spacer 52 may be, for example, 0.1 mm or less.
[0068]
In the present embodiment, the provision of the non-magnetic material weakens the magnetic flux in the magnetization direction on the shield side. It is believed that the magnetic flux does not go in the direction of magnetization and, as a result, is efficiently directed in the direction of the open side. Thus, it is considered that the magnetic flux density in the magnetic force blocking direction can be effectively reduced without changing the magnetic flux density in the opening direction.
[0069]
FIG. 7 shows a measurement result of a magnetic shielding effect when a paper spacer is used. The measurement was performed using a Gauss meter placed at a position corresponding to the sample. As shown, the values when the magnetic force is on are almost the same regardless of the presence or absence of the spacer. On the other hand, the value when the magnetic force is off is reduced to about half by inserting the spacer.
[0070]
As described above, according to the present embodiment, the configuration in which the magnet holder that holds the magnet is rotated is employed, so that the size of the magnetic separation device can be reduced. That is, as compared with the configuration in which the distance between the magnet and the sample is changed, the magnet can be rotated on the spot, so that the apparatus can be downsized.
[0071]
This means that the volume of the sample holder (the heat block 20 in FIG. 2) can be reduced, thereby reducing the heat capacity. This is advantageous for temperature control because the temperature can be changed quickly.
[0072]
Further, according to the present embodiment, since the non-magnetic material is arranged between the end portion in the magnetization direction on the shield side and the magnet holder, as described above, the ability to interrupt the magnetic force when the magnetic force is off can be improved.
[0073]
In this embodiment, the nonmagnetic material is a spacer, but the present invention is not limited to this. The non-magnetic material may be air. In this case, a gap (space) is provided between the magnet and the magnet holder.
[0074]
Next, another embodiment will be described. In the present embodiment, a shielding enhancement cover is provided.
[0075]
FIG. 8 is a cross-sectional view of the magnetic separation device according to the present embodiment. As in the above-described embodiment, the semi-cylindrical magnet holder 32 is rotatable, and the magnet 34 is held by the magnet holder 32. Hereinafter, description of matters already described in the above-described embodiment will be omitted.
[0076]
As shown in FIG. 8, the magnetic separation device of the present embodiment has, as a feature thereof, a shielding enhancement cover 54 made of a ferromagnetic material. As shown in the lower part of FIG. 8, the cut-off strengthening cover 54 is arranged so as to cover the open-side magnetization direction end 48 in the magnetic force-off state, and in this arrangement, the open-side magnetization direction end 48 is opened. The contact portion 56 is configured to contact the magnet holder 32 on both sides of the portion 48. The magnetic off state is a state in which the open-side magnetization direction end 48 faces in a direction different from that of the sample. In short, the shielding enhancement cover 54 is arranged on the magnetic separation device on the side opposite to the side emitting the magnetic flux.
[0077]
More specifically, the cover 54 is substantially semi-cylindrical. Thus, the outer peripheral surface of the magnet holder 32 and the inner peripheral surface of the shielding enhancement cover 54 are both cylindrical surfaces. Since the diameters of both cylindrical surfaces are set substantially equal, both surfaces slide with the rotation of the magnet holder 32.
[0078]
In the cross section of FIG. 8, the magnet holder 32 is a perfect semicircle, and its central angle is 180 degrees. On the other hand, the range of the arc of the shielding enhancement cover 54 is wider than a semicircle. That is, the central angle is larger than 180 degrees. Thereby, the contact portion 56 for contacting the magnet holder 32 and the shielding enhancement cover 54 when the magnet holder 32 is turned over is secured.
[0079]
According to the present embodiment, when the magnetic force is turned on, the magnet holder 32 is located on the same side as the shield enhancement cover 54, and the magnet holder 32 is housed in the shield enhancement cover 54. In this state, magnetic force is provided to the upper sample as in the above-described embodiment.
[0080]
On the other hand, when the magnetic force is off, the open side magnetization direction end 48 faces downward and is covered by the cut-off strengthening cover 54. Since the contact portions 56 at both ends of the shield enhancement cover 54 are in contact with the magnet holder 32, the magnetization direction ends 48 are housed in the space created by the shield enhancement cover 54 and the magnet holder 32.
[0081]
Thereby, the magnet 34 is magnetically isolated from the outside, and the leakage of the magnetic flux from the open side is prevented. That is, as shown in FIG. 8, a magnetic circuit is formed inside the magnetic body along the outer peripheral portion by the shielding enhancement cover 54 and the magnet holder 32, thereby blocking leakage magnetic flux from the outer peripheral portion to the outside. Is done. The magnetic flux of the magnet does not leak outside.
[0082]
In this manner, in the present embodiment, when the magnetic force is turned off, it is possible to effectively suppress the magnetic force of the open-side magnetization direction end 48 from affecting the sample.
[0083]
The material of the shielding enhancement cover 54 may be a ferromagnetic material, but is preferably a material having a high magnetic permeability and a high saturation magnetic flux density. Suitable materials are, for example, pure iron or permalloy.
[0084]
Further, as shown in FIG. 9, in the present embodiment, since the shielding enhancement cover 54 is provided, the configuration of the magnetic separation device may be arranged so as to face the side surface of the sample container. That is, the magnet holder 32 may be arranged so as to be inserted between adjacent sample arrays.
[0085]
Explaining the reason, in the configuration in which the shielding enhancement cover 54 is not provided, when the magnetic force is turned off, the magnetic force from the open-side magnetization direction end portion 48 acts on the sample containers in the next row. On the other hand, when the shielding enhancement cover 54 is provided, even when the magnetic force is turned off, there is no leakage magnetic flux from the open-side magnetization direction end portion 48, so that the action of the magnetic force on the sample containers in the next row can be avoided. Therefore, it is possible to dispose the magnet near the side surface of the sample container. As seen from this example, according to the present embodiment, it is possible to arrange magnets at arbitrary positions around the sample.
[0086]
As described above, according to the present embodiment, when the magnetic force is turned off, the cut-out reinforcing cover covers the open end in the magnetization direction, and contacts the magnet holder on both sides. Since a magnetic circuit is formed by the shielding enhancement cover and the magnet holder, and the open side magnetization direction end is disposed therein, the magnetic force can be reliably shielded.
[0087]
Further, according to the present embodiment, both the outer peripheral surface of the magnet holder and the inner peripheral surface of the shielding reinforcement cover are cylindrical surfaces, and slide with the rotation of the magnet holder. Since a concentric cylindrical member may be provided outside the magnet holder, it is possible to realize a device having a small-sized configuration and a shielding enhancement cover, and the magnetic force shielding ability can be further improved.
[0088]
Further, according to the present embodiment, since the shielding enhancement cover is provided, the magnet can be arranged at an arbitrary position in a wider range such as the side surface of the sample container other than the bottom of the sample container. Thereby, for example, a magnet can be arranged near the side of the container, so that the supernatant can be separated by immobilizing the magnetic fine particles by moving the tip end of the dispenser to near the bottom of the container, Separation accuracy is improved.
[0089]
Further, according to the present embodiment, the shielding effect of the magnetic force can be further enhanced by using a material having a small saturation magnetic flux and a large maximum magnetic permeability for the shielding enhancement cover.
[0090]
Next, another embodiment of the present invention will be described. In the present embodiment, the magnet holding member is provided with the shielding reinforcing member.
[0091]
FIG. 10 is a cross-sectional view of the magnetic separation device according to the present embodiment. Similarly to the above-described embodiment, the semi-cylindrical magnet holder 32 is rotatable, and the magnet 34 is held by the magnet holder 32. Hereinafter, description of matters already described in the above-described embodiment will be omitted.
[0092]
As shown in FIG. 10, the magnetic separation device according to the present embodiment is characterized in that a shielding reinforcing member 58 is provided on the magnet holder 32. The blocking reinforcing member 58 is a ferromagnetic material, and is made of a material having a higher magnetic permeability than iron or the like forming the magnet holder 32. In the present embodiment, the blocking reinforcing member 58 is made of permalloy.
[0093]
The shielding reinforcing member 58 is provided so as to be located outside the shield-side magnetization direction end 50 when viewed from the center of rotation of the magnet holder 32. In the present embodiment, the cut-off reinforcing member 58 is attached to the outer surface of the magnet holder 32, whereby the cut-off reinforcing member 58 is provided at a distance from the magnetization direction end 50 with the magnet holder 32 interposed therebetween. I have.
[0094]
More specifically, the blocking reinforcing member 58 is formed of a rectangular plate. The blocking reinforcement member 58 has a size and a shape that covers below the plurality of magnets 34. Further, a flat portion is provided on the outer surface of the magnet holder 32, and the blocking reinforcing member 58 is installed on the flat portion.
[0095]
According to the present embodiment, when the magnetic force is turned on, similarly to the above-described embodiment, the open-side magnetization direction end 48 faces the sample, from which magnetic force is provided to the sample. At this time, the magnet holder 32 and the end 50 in the magnetization direction on the shield side are located on the opposite side to the sample. In this portion, since the cut-off reinforcing member 58 is disposed, a magnetic circuit for capturing the leakage magnetic flux is formed. Therefore, the leakage flux is effectively reduced.
[0096]
On the other hand, when the magnetic force is off, the open side magnetization direction end 48 faces in the opposite direction to the sample. Then, the outer peripheral surface of the magnet holder 32 faces the sample. When the magnetic force is turned off, as in the case of the magnetic force being turned on, the cut-off reinforcing member 58 is provided, so that a magnetic circuit for capturing the leakage magnetic flux is formed. Thereby, the magnetic flux from the magnetization direction end 50 on the shield side to the sample is effectively cut off.
[0097]
FIG. 11 shows a modified example of the configuration including the blocking reinforcement member. In the configuration of FIG. 11, the shielding reinforcement member 60 is disposed so as to directly contact the magnetized direction end 50 on the shielding side of the magnet 34. Here, the blocking reinforcement member 60 is also a rectangular plate made of permalloy, and is provided so as to cover the plurality of magnets 34. In the configuration of FIG. 11 as well, since the shielding reinforcement member 60 is provided, the magnetic force is effectively blocked as in the configuration of FIG.
[0098]
In FIG. 11, the blocking reinforcing member 60 is provided inside the magnet holder 32. For example, the magnet holder 32 has a divided structure. Then, the blocking reinforcing member 60 is sandwiched between the members constituting the magnet holder 32.
[0099]
As described above, according to the present embodiment, the magnetic flux leaking from the end portion in the magnetization direction on the shielding side is captured by the shielding reinforcing member, so that the magnetic force can be more reliably shielded.
[0100]
In the present embodiment, in short, the magnet holder is constituted by a plurality of types of members. Among them, the blocking reinforcement member is made of a member having high magnetic permeability, for example, permalloy, but such a material is generally expensive. In the present embodiment, a member having high magnetic permeability is used for a part of the magnet holder, not for the whole magnet holder. The material of the magnet holder is inexpensive and has good workability, such as iron, and a complicated shape for holding the magnet can be easily created. In this manner, in the present embodiment, since a part of the magnet holder is constituted by the shielding reinforcing member, a high magnetic shielding ability can be obtained at low cost.
[0101]
In the configuration of FIG. 10, the cut-off reinforcing member is provided on the outer surface of the magnet holder, away from the magnet. In the present embodiment, a material having a large maximum magnetic permeability but a small saturation magnetic flux density can be adopted. And the magnetic shielding ability can be enhanced by the effective arrangement of the shielding reinforcing member made of such a material.
[0102]
Next, another embodiment of the present invention will be described. This embodiment has the configuration of all the above-described embodiments, that is, includes a nonmagnetic material on the shielding side, a shielding enhancement cover, and a shielding enhancement member.
[0103]
FIG. 12 is a cross-sectional view of the magnetic separation device according to the present embodiment. Similarly to the above-described embodiment, the semi-cylindrical magnet holder 32 is rotatable, and the magnet 34 is held by the magnet holder 32.
[0104]
The configurations of the nonmagnetic material on the shielding side, the shielding enhancement cover, and the shielding enhancement member are as described in each of the above embodiments.
[0105]
That is, a disc-shaped spacer 52 made of a non-magnetic material is disposed at the bottom of the opening 40 in which the magnet 34 is embedded, so that the spacer 52 is positioned between the shield-side magnetized end 50 and the magnet holder 32. Be placed.
[0106]
In addition, a semi-cylindrical shielding enhancement cover 54 is arranged so as to house the magnet holder 32 when the magnetic force is turned on. When the magnetic force is off, the cut-off strengthening cover 54 does not move, the magnet holder 32 is inverted, and the open-side magnetization direction end 48 is covered with the cut-off reinforcing cover 54.
[0107]
Further, a blocking reinforcement member 58 is provided on the outer surface of the magnet holder 32. As a result, the cutoff reinforcing member 58 covers the shield-side magnetization direction end 50.
[0108]
In the present embodiment, the non-magnetic material on the shielding side, the shielding enhancement cover, and the shielding enhancement member have the magnetic shielding ability. The non-magnetic material weakens the magnetic force in the direction of magnetization on the shield side. When the magnetic force is turned off, the shielding enhancement cover reduces the influence of the magnetic force on the sample from the open end in the magnetization direction. Further, the shielding enhancement member forms a magnetic circuit that effectively prevents the leakage of the magnetic flux from the shield-side end in the magnetization direction. In this way, according to the present embodiment, the magnetic force blocking ability can be further improved.
[0109]
Next, a modified example of the above-described embodiment will be described. Although the above-described embodiment is a hybridization device, this modified example is a nucleic acid processing device that performs nucleic acid extraction and hybridization. The nucleic acid processing apparatus includes a plurality of reaction units, and each reaction unit has the above-described configuration. Each of the plurality of reaction sections is a nucleic acid extraction reaction section for performing nucleic acid extraction or a hybridization reaction section for performing hybridization.
[0110]
As a more detailed configuration example, the nucleic acid processing device includes two magnetic separation units with a temperature control function. Each unit corresponds to the reaction section described above, that is, includes a reaction vessel holder, a temperature controller, and a magnetic separator.
[0111]
In addition to the above two units, a chip rack, a waste liquid tank and the like are provided. For example, five chip racks, two waste liquid tanks, a chip disposal stage, a detection probe reagent stage, and a nucleic acid amplification stage unit are provided. Two magnetic separation units with temperature control function are assigned to nucleic acid extraction and hybridization, the first unit performs nucleic acid extraction, and the second unit performs hybridization.
[0112]
These components such as units, racks, and stages are arranged in a matrix on a table (for example, three rows horizontally and four rows vertically). A dispensing head that is movable in three dimensions is provided so as to be able to move on these components. The dispensing head operates, and nucleic acid extraction is performed in the first magnetic separation unit with a temperature control function, and hybridization is performed in the second magnetic separation unit with a temperature control function. In the first unit, further, nucleic acid amplification, typically PCR, may be performed.
[0113]
Further, a plate-shaped cover unit may be provided so as to be interposed between the configuration of the dispensing head and the lower unit and the like. The cover unit has a size slightly larger than the dispensing head so as to cover below the dispensing head. The cover unit is located below the dispensing head when the dispensing head moves, and prevents contamination. Further, it is also preferable to provide a heater on the lower surface of the cover unit to maintain the reagent at an appropriate temperature.
[0114]
As is evident from the above modifications, the present invention is not limited to a hybridization device. The present invention may be a nucleic acid processing device, which is typically a nucleic acid extraction device, a nucleic acid extraction / amplification device or a nucleic acid sequence detection device, and a device that performs a plurality of these processes. In the above example, nucleic acid extraction and hybridization are performed. Furthermore, the magnetic separation device of the present invention may be applied to any device that extracts biological substances such as cells themselves or nucleic acids in cells and identifies the base sequence of nucleic acids.
[0115]
Further, in the above-described embodiment, as shown in FIG. 1, a technique in which the temperature control and the magnetic separation are performed in the same place is taken up. In this case, as described above, the present invention works suitably. However, the invention is not limited to such devices. For example, the present invention may be applied even when the temperature control part and the magnetic separation part are separated on the analyzer, and the advantages of the present invention such as miniaturization and improvement of the magnetic force control ability are obtained. Becomes possible.
[0116]
In addition, the present invention is not limited to the above-described embodiment, and it goes without saying that the above-described embodiment can be modified by those skilled in the art within the scope of the present invention.
[0117]
【The invention's effect】
As described above, according to the present invention, the configuration in which the magnet holder that holds the magnet is rotated is adopted, so that the size of the magnetic separation device can be reduced. Further, in the present invention, since the non-magnetic material is arranged between the magnetized end on the shielding side and the magnet holder, the magnetic force can be more reliably cut off when the magnetic force is turned off.
[0118]
Further, according to the present invention, when the magnetic force is turned off, the cut-off strengthening cover covers the open end in the magnetization direction and comes into contact with the magnet holder on both sides. A magnetic circuit is formed by the shielding enhancement cover and the magnet holder, and the end of the open side in the magnetization direction is arranged therein, so that the influence of the magnetic force from the open side can be suppressed, and the magnetic force can be more reliably shut off. .
[0119]
Further, according to the present invention, the leakage magnetic flux from the end portion in the magnetization direction on the shielding side is captured by the shielding reinforcing member, so that the magnetic force can be more reliably shielded. According to the present invention, since a member having high magnetic permeability is used for a part of the holder instead of the entire holder, an expensive material may be reduced and the cost is advantageous.
[0120]
According to the present invention, the magnet holder of the above-described magnetic separation device is rotatably provided on the reaction container holder of the reaction section. By reducing the size of the magnetic separator, the space for the built-in magnetic separator can be reduced. Since the heat capacity of the reaction container holder can be reduced as the space is reduced, the temperature control ability can be improved. The reaction performance in the reaction section can be improved by improving the temperature control capability and the above-described magnetic blocking capability.
[Brief description of the drawings]
FIG. 1 is a diagram showing a hybridization device provided with a magnetic separation device according to an embodiment.
FIG. 2 is a diagram showing a configuration of a reaction unit of the hybridization device.
FIG. 3 is a cross-sectional view of a reaction unit of the hybridization device, showing a configuration of a magnetic separation device.
FIG. 4 is a diagram showing magnetic force on / off control by rotation of a magnet holder.
FIG. 5 is a diagram showing a state of magnetism when a magnetic force is turned on and a magnetic force is turned off.
FIG. 6 is a cross-sectional view of a magnetic separation device provided with a nonmagnetic spacer on a shielding side.
FIG. 7 is a diagram showing a magnetic force blocking ability of the magnetic separation device.
FIG. 8 is a cross-sectional view of a magnetic separator provided with a shielding enhancement cover according to another embodiment.
FIG. 9 is a diagram showing an application example of a magnetic separation device provided with a shielding enhancement cover.
FIG. 10 is a cross-sectional view of a magnetic separation device provided with a blocking reinforcing member according to another embodiment.
FIG. 11 is a cross-sectional view of a modified example of the magnetic separation device provided with the shielding reinforcement member.
FIG. 12 is a cross-sectional view of a magnetic separation device including a nonmagnetic body on a shielding side, a shielding enhancement cover, and a shielding enhancement member according to another embodiment.
[Explanation of symbols]
20 heat blocks
22 Sample container plate
24 sample containers
26 Container holding hole
28 Peltier element
30 magnet storage hole
32 magnet holder
34 magnet
42 racks
44 Pinion
46 Magnetic force control device
48 Open end of magnetization direction
50 End of magnetization direction on shield side
52 Spacer
54 Enhancement cover
56 Contact
58 Blocking reinforcement

Claims (11)

At least one magnet that is a magnetic force source;
A magnet holder configured of a ferromagnetic material and holding the at least one magnet at a magnetized end on a shield side such that an open end in a magnetized direction is exposed,
Rotating means for rotating the magnet holder,
A non-magnetic member disposed between the magnetized end of the shield side and the magnet holder;
A magnetic separation device for magnetic fine particles, comprising: The magnetic separation device for magnetic fine particles according to claim 1,
When the magnet holder is rotated by the rotating means and the open-side magnetized direction end faces a different direction from the sample, the magnet-side holder covers the open-side magnetized direction end, and the open-side magnetized direction end is A magnetic separation device for separating magnetic fine particles, comprising: a shielding enhancement cover made of a magnetic material, which is disposed so as to be in contact with the magnet holder on both sides of the magnetic member. The magnetic separation device for magnetic fine particles according to claim 1 or 2,
A shielding reinforcing member that is provided on the magnet holder so as to be located outside an end in the magnetization direction on the shield side when viewed from the center of rotation by the rotating means, and is made of a material having a higher magnetic permeability than the magnet holder; A magnetic separation device for magnetic fine particles, comprising: At least one magnet that is a magnetic force source;
A magnet holder which is made of a ferromagnetic material and holds the at least one magnet such that an open-side magnetization direction end is exposed and a shield-side magnetization direction end is covered.
Rotating means for rotating the magnet holder,
When the magnet holder is rotated by the rotating means and the open-side magnetized direction end faces a different direction from the sample, the magnet-side holder covers the open-side magnetized direction end, and the open-side magnetized direction end is A shielding enhancement cover made of a magnetic material, which is arranged to be in contact with the magnet holder on both sides of
A magnetic separation device for magnetic fine particles, comprising: A magnetic separation device for magnetic fine particles according to claim 4,
An outer peripheral surface of the magnet holder and an inner peripheral surface of the shielding enhancement cover are both cylindrical surfaces, and slide with the rotation of the magnet holder. At least one magnet that is a magnetic force source;
A magnet holder which is made of a ferromagnetic material and holds the at least one magnet such that an open-side magnetization direction end is exposed and a shield-side magnetization direction end is covered.
Rotating means for rotating the magnet holder,
A shielding reinforcing member provided on the magnet holder so as to be located outside the shield-side magnetization direction end when viewed from the center of rotation by the rotating means, and made of a material having a higher magnetic permeability than the magnet holder; ,
A magnetic separation device for magnetic fine particles, comprising: A hybridization device comprising the magnetic separation device for magnetic fine particles according to claim 1. A nucleic acid extraction device comprising the magnetic separation device for magnetic fine particles according to claim 1. A nucleic acid extraction and hybridization device comprising the magnetic separation device for magnetic fine particles according to claim 1. A plurality of magnetic separation devices are provided in a plurality of reaction units, respectively, and each of the plurality of reaction units is a nucleic acid extraction reaction unit for performing nucleic acid extraction or a hybridization reaction unit for performing hybridization. 10. The nucleic acid extraction and hybridization device according to 9. The magnetic separation device for magnetic fine particles according to any one of claims 1 to 6, further comprising a reaction unit, wherein the reaction unit has a reaction container holder for holding a reaction container, and a temperature of the reaction container holder. Temperature control means for adjusting the
The nucleic acid processing apparatus, wherein the magnet holder of the magnetic separation device is rotatably provided on the reaction container holder.

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