WO2009139246A1 - Microsorting mechanism and microchip - Google Patents

Microsorting mechanism and microchip Download PDF

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Publication number
WO2009139246A1
WO2009139246A1 PCT/JP2009/057382 JP2009057382W WO2009139246A1 WO 2009139246 A1 WO2009139246 A1 WO 2009139246A1 JP 2009057382 W JP2009057382 W JP 2009057382W WO 2009139246 A1 WO2009139246 A1 WO 2009139246A1
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WO
WIPO (PCT)
Prior art keywords
microtool
microsort
fine particles
magnetic field
microchip
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PCT/JP2009/057382
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French (fr)
Japanese (ja)
Inventor
新井史人
山西陽子
佐久間臣耶
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国立大学法人東北大学
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Application filed by 国立大学法人東北大学 filed Critical 国立大学法人東北大学
Priority to JP2010511928A priority Critical patent/JPWO2009139246A1/en
Publication of WO2009139246A1 publication Critical patent/WO2009139246A1/en

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502738—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by integrated valves
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502761—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads, for physically stretching molecules
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0647—Handling flowable solids, e.g. microscopic beads, cells, particles
    • B01L2200/0652—Sorting or classification of particles or molecules
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0864—Configuration of multiple channels and/or chambers in a single devices comprising only one inlet and multiple receiving wells, e.g. for separation, splitting
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/043—Moving fluids with specific forces or mechanical means specific forces magnetic forces
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/06—Valves, specific forms thereof
    • B01L2400/0622—Valves, specific forms thereof distribution valves, valves having multiple inlets and/or outlets, e.g. metering valves, multi-way valves
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/06—Valves, specific forms thereof
    • B01L2400/0633—Valves, specific forms thereof with moving parts
    • G01N15/1023—
    • G01N2015/1028—

Definitions

  • the present invention is mainly used in the bio-industrial field such as the medical field, the pharmaceutical field, and the breed improvement, and the micro-sorting mechanism that automatically separates and classifies target fine particles at high speed without depending on human operation and the mechanism.
  • the present invention relates to a microchip using
  • Non-contact operation in a microchannel includes a series of operations such as separation, classification, processing, selection, and processing of microparticles, and a method using a single microchannel as a cell nuclear transfer technique having these steps Has been proposed (see, for example, Patent Document 1).
  • this technique since there is one microchannel, in order to continuously perform bio-operation, it is necessary to prepare by separating and classifying particles having the same shape and characteristics in advance.
  • a plurality of fine particles are mixed, and there is a problem that an enormous amount of time is required for a prior sorting operation.
  • Patent Document 1 In order to solve these problems, the inventors have proposed a method using an ultra-small magnetic microtool (MMT) as a microsort mechanism capable of efficiently separating and classifying microparticles (for example, non-microscopic mechanism).
  • MMT ultra-small magnetic microtool
  • Patent Document 1 In this method, in a series of bio-operations, eggs with nuclei and eggs without nuclei are detected with a microscope, and only the eggs without nuclei are separated into the next step using a microsort mechanism. Yes.
  • Non-Patent Document 1 the magnetic microtool (MMT) is displaced by moving an external electromagnet, which is large in order to operate the magnetic microtool (MMT) with certainty. There was a problem that a driving force was required and a considerably large magnetic driving mechanism was required.
  • the present invention has been made by paying attention to such a problem.
  • a micro sort mechanism and a micro that can stably drive a micro tool with a smaller drive mechanism and can efficiently separate and classify fine particles.
  • the purpose is to provide chips.
  • a microsort mechanism for selectively guiding fine particles flowing through a microchannel having a plurality of branch paths to one of the branch paths.
  • a microtool and a drive mechanism wherein the microtool has magnetism, and the microparticles pass through any one branch path with respect to all branch paths. And is configured to be movable to a position that closes the other branch path, and is configured such that movement in the microchannel is limited to movement to a position that blocks the other branch path, and the drive mechanism is An electromagnet is provided outside the microchannel and controls movement of the microtool so that a branch path through which the fine particles pass can be selected.
  • the microsort mechanism selectively guides microparticles such as eggs, cells, and fungi flowing in a microchannel having a plurality of branch paths to one of the branch paths in a microchip or the like. Used to. Since the micro tool having magnetism is provided so as to be movable to a position that closes the other branch path in the micro flow path so that the fine particles pass through any one branch path for all the branch paths, By controlling the movement of the microtool with the electromagnet of the drive mechanism, the branch path through which the fine particles pass can be arbitrarily selected. At this time, since the movement of the micro tool in the micro flow path is limited to the movement to the position where the other branch path is blocked, the micro tool can be driven stably. By configuring the micro tool to move smoothly, the micro tool can be stably driven with a smaller driving force, and the driving mechanism can be configured to be smaller.
  • the microsort mechanism according to the present invention can efficiently separate and classify the fine particles by selecting a branch passage through which the fine particles pass according to the kind of the fine particles flowing through the micro flow path. This makes it possible to perform complex separation / classification bio-operations that have been performed under a microscope using a pipette or the like at high speed and efficiently without human intervention.
  • the microtool may be made of any material such as metal or magnetized material as long as it has magnetism.
  • the microtool may be made of, for example, a so-called magnetic microtool (MMT), may contain a rare earth metal, and may be magnetized at the time of manufacture.
  • MMT magnetic microtool
  • the electromagnet may have any mechanism or arrangement as long as the movement of the microtool can be controlled. The electromagnet can control the movement of the microtool, for example, by changing the direction and strength of the flowing current or turning the current on / off.
  • the drive mechanism has a magnetic field concentration member between the electromagnet and the minute flow path, and the magnetic field concentration member has a high magnetic permeability portion having a larger magnetic permeability than other portions. It is preferable to have.
  • the magnetic field generated by the electromagnet is concentrated on the high permeability portion of the magnetic field concentration member, the movement of the micro tool can be efficiently controlled by adjusting the position of the high permeability portion. It can be made smaller.
  • surroundings can be made small.
  • the micro flow path has two branch paths
  • the micro tool has a first closed position that blocks one branch path and a second closed position that blocks the other branch path.
  • the drive mechanism is configured to be movable between the first closed position and the second closed position.
  • An electromagnet that controls movement of the microtool between the first closed position and the second closed position may be included. In this case, by controlling the movement of the microtool with the electromagnet and moving the microtool to the first closed position or the second closed position, the fine particles can be guided and passed through one of the branch paths.
  • the micro tool is elongated and has a magnetic drive unit at one end, and the drive unit is between the first closed position and the second closed position. It is preferable that it is provided so as to be able to rotate smoothly around the other end so that it can be moved. In this case, since the elongated microtool is provided so as to be smoothly rotatable around the other end, the microtool can be stably driven with a smaller driving force, and the driving mechanism can be further reduced in size. it can.
  • the electromagnet is composed of two, and is provided at a position corresponding to each branch path with a predetermined interval so as not to be interfered with each other's magnetic field. It is preferable.
  • the microtool can be easily moved between the first closed position and the second closed position by switching the electromagnet through which the current flows so that the current flows only through one of the electromagnets.
  • the microchip according to the present invention is characterized by having a micromodule having the microchannel and the microsort mechanism according to the present invention.
  • the microtool can be driven stably with a smaller driving mechanism. Further, the fine particles can be efficiently separated and classified by selecting the branch passage through which the fine particles pass according to the kind of the fine particles flowing through the micro flow path of the micromodule. This makes it possible to perform complex separation / classification bio-operations that have been performed under a microscope using a pipette or the like at high speed and efficiently without human intervention. Since the driving mechanism of the microsort mechanism can be made smaller, the microsort mechanism can be arranged in multiple stages.
  • the microchip according to the present invention is configured to selectively identify the microparticles that flow through the microchannel and the microparticles in one branch path based on the type of the microparticles identified by the identification unit. It is preferable to have a control unit that controls the drive mechanism to guide. In this case, the branch path through which the fine particles pass can be selected according to the type of fine particles, and the fine particles can be automatically and efficiently separated and classified.
  • the identification means may identify the type of the fine particles by detecting the shape and characteristics of the fine particles, for example.
  • the micromodule and the microsort mechanism may be arranged in multiple stages.
  • fine particles can be more finely separated and classified according to the type of fine particles.
  • microsort mechanism and a microchip that can stably drive a microtool with a smaller drive mechanism and can efficiently separate and classify fine particles.
  • FIG. 1A is a plan view showing a microchip according to a first embodiment of the present invention
  • FIG. 2B is an enlarged view when the micro tool of the micro sort mechanism is moved to the first closing position
  • FIG. 2C is a micro view of the micro sort mechanism. It is an enlarged view when a tool moves to the 2nd blockade position.
  • 2A is a plan view of the microchip drive mechanism shown in FIG. 1
  • FIG. 2B is a front view of the manufacturing process
  • FIG. It is a block diagram which shows the specific example of the identification means and control part of the microchip shown in FIG.
  • FIG. 5A is a front view of a modification of the microchip according to the first embodiment of the present invention in which the magnetic field concentrating member is formed of a triangular nickel pin
  • FIG. 5B is a plan view illustrating a driving state of the microtool. .
  • FIG. 5A is a plan view showing a microchip according to a second embodiment of the present invention
  • FIG. 5B is a cross-sectional view at the position of a drive mechanism. It is a top view which shows the microchip of the 3rd Embodiment of this invention.
  • the microchip according to the first embodiment of the present invention includes a micromodule 11 and a microsort mechanism 12.
  • the micromodule 11 includes any animal cell such as an egg (egg cell) or somatic cell, a plant cell, an ES cell, a microorganism, a fungus, a DNA molecule, a nanotube, a nanomaterial, or the like.
  • a microchannel 21 for flowing the fine particles 1 is provided.
  • the microchannel 21 has two branch paths 22a and 22b.
  • the micromodule 11 has a mounting chamber 23 that communicates with the microchannel 21 at the crotch portions of the branch paths 22a and 22b between the branch paths 22a and 22b.
  • the mounting chamber 23 has a mounting pillar 24 in the center.
  • the micro sort mechanism 12 includes a micro tool 25, a drive mechanism 26, an identification unit 27, and a control unit 28.
  • the microtool 25 is made of a polymer and has flexibility, and is made of a so-called magnetic microtool (MMT).
  • MMT magnetic microtool
  • the microtool 25 is elongated and has a drive portion 25a at one end and a support portion 25b at the other end.
  • the drive unit 25a is magnetized at the time of production and has magnetism.
  • the drive unit 25a has a thin plate shape, and has a planar shape with a pointed arrow.
  • the support portion 25b has a through hole 25c in the center and forms an annular shape.
  • the drive unit 25a is disposed at the branch position of each branch path 22a, 22b of the micro flow path 21, and the pillar 24 of the mounting chamber 23 is passed through the through hole 25c of the support part 25b, so that the micro module 11 It is attached.
  • the microtool 25 has a first closed position shown in FIG. 1B in which the driving unit 25a blocks one branch path 22b so that the particulate 1 flowing through the microchannel 21 passes through one of the branch paths 22a and 22b.
  • the other branch path 22a is attached so as to be movable between the second closed position shown in FIG. 1C and rotatable about the support portion 25b at the other end.
  • the support part 25b is loosely fitted to the pillar 24, and the microtool 25 can rotate smoothly around the support part 25b.
  • the microtool 25 is configured such that the movement of the driving unit 25a in the micro flow path 21 is limited to movement between the first closed position and the second closed position.
  • the moving distance between the first closed position and the second closed position of the drive unit 25a is several hundred ⁇ m or less.
  • the drive mechanism 26 includes a pair of electromagnets 29 a and 29 b, a pair of magnetic field concentration members 30 a and 30 b, and a glass plate 31.
  • Each of the electromagnets 29a and 29b is made of a thin film microcoil and is formed by winding a thin wire around a ferrite core having a diameter of about 2 mm.
  • the electromagnets 29a and 29b are provided with a predetermined interval between the coils so as not to be interfered with each other's magnetic field.
  • the electromagnets 29a and 29b are arranged with a 1 mm gap between the coils.
  • Each of the magnetic field concentrating members 30a and 30b is made by a MEMS technique and is formed by combining a high magnetic permeability material and a low magnetic permeability material.
  • the magnetic field concentrating members 30a and 30b are formed by sequentially plating, electroforming or patterning a high permeability material and a low permeability material on a wall surface of a glass or silicon wafer substrate patterned with a photoresist. Alternatively, it is manufactured by removing the mold by wet etching.
  • Each of the magnetic field concentrating members 30a and 30b is provided above the electromagnets 29a and 29b so that the high magnetic permeability portions 32a and 32b formed of a high magnetic permeability material are located inside.
  • the drive mechanism 26 is configured such that the magnetic lines of force of the electromagnets 29a and 29b are guided upward.
  • the glass plate 31 is bridged over the magnetic field concentrating members 30a and 30b.
  • the drive mechanism 26 is provided at the branch position of each branch path 22 a, 22 b, outside the microchannel 21.
  • the drive mechanism 26 is provided so that the electromagnets 29a and 29b are disposed at positions corresponding to the branch paths 22a and 22b, respectively, with the minute flow path 21 interposed therebetween.
  • the electromagnets 29 a and 29 b and the magnetic field concentration members 30 a and 30 b are arranged in parallel on both sides of the microtool 25, and the magnetic field concentration members 30 a and 30 b are interposed between the electromagnets 29 a and 29 b and the microchannel 21. Is arranged.
  • the magnetic fields generated by the electromagnets 29a and 29b are concentrated on the high magnetic permeability portions 32a and 32b of the magnetic field concentration members 30a and 30b, respectively, so that the drive unit 25a of the microtool 25 can be translated. ing.
  • the drive mechanism 26 controls the movement of the microtool 25 between the first closed position and the second closed position by the electromagnets 29a and 29b, and selects the branch paths 22a and 22b through which the fine particles 1 pass. It is possible.
  • the identification means 27 is provided on the outside of the microchannel 21 and slightly upstream from the branching positions of the branch channels 22 a and 22 b, and the shape or coloring of the fine particles 1 flowing through the microchannel 21 It consists of sensors that can detect characteristics such as fluorescence intensity.
  • the identification means 27 identifies the type of the fine particles 1 by detecting the shape or characteristics of the fine particles 1.
  • the control unit 28 is connected to the identification unit 27 and the electromagnets 29 a and 29 b, and a current amplification amplifier 33 that amplifies a detection signal from the identification unit 27, and an AC amplified by the current amplification amplifier 33.
  • An AC / DC converter 34 for converting the signal into a DC signal, and a DC signal converted by the AC / DC converter 34 are input, and based on the DC signal corresponding to the type of the particulate 1 identified by the identification means 27.
  • the computer 35 outputs a control signal for controlling the electromagnets 29a and 29b, and the DC / AC converter 36 converts the control signal composed of the DC signal output from the computer 35 into an AC signal.
  • the control unit 28 can electromagnetically drive the electromagnets 29a and 29b by transmitting the AC signal converted by the DC / AC converter 36 to the electromagnets 29a and 29b.
  • the controller 28 turns on and off the electromagnets 29a and 29b and switches the electromagnets 29a and 29b through which the current flows so that the current flows only through one of the electromagnets 29a and 29b.
  • 29b a micro magnetic field is formed on the upper part, and the micro tool 25 is moved.
  • the control unit 28 can control the drive mechanism 26 so as to selectively guide the fine particles 1 to one of the branch paths 22a and 22b.
  • the identification means 27 is composed of a CCD camera, and the control unit 28 has an image board that doubles as a current amplification amplifier 33 and an AC / DC converter 34, a computer 35, and an amplifier function.
  • DC / AC converter 36 In this case, first, the particle 1 flowing through the microchannel 21 is photographed with a CCD camera, and an image of the particle 1 is input to the computer 35 via the image board. The computer 35 calculates the cross-correlation between the input image of the fine particle 1 and the fine particle calibration image recorded in advance to identify the fine particle.
  • the correlation coefficient is not less than a predetermined value (for example, 0.9 or more), it is determined that it is the same as the fine particle of the calibration image, and the fine particle 1 is guided to one branch path (for example, the branch path 22a).
  • the electromagnets 29 a and 29 b are electromagnetically driven via the DC / AC converter 36 to control the drive mechanism 26.
  • the correlation coefficient is smaller than a predetermined value (for example, smaller than 0.9)
  • the electromagnets 29 a and 29 b are electromagnetically driven via the DC / AC converter 36 to control the drive mechanism 26.
  • the microchip according to the first embodiment of the present invention has fine particles such as eggs, cells, and fungi that flow through the microchannel 21 having two branch paths 22a and 22b by the microsort mechanism 12 according to the embodiment of the present invention. 1 can be selectively guided to one of the branch paths 22a and 22b.
  • the microsort mechanism 12 switches the electromagnets 29a and 29b through which current flows so that current flows only through one of the electromagnets 29a and 29b, thereby moving the microtool 25 between the first closed position and the second closed position. It can be moved easily.
  • the microsort mechanism 12 attracts the drive unit 25a of the microtool 25 to the electromagnet 29b, as shown in FIG. Since it moves to the first closed position, the fine particles 1 can be guided to the branch path 22a. Further, when the electromagnet 29a is turned on and the electromagnet 29b is turned off, the microsort mechanism 12 is attracted to the electromagnet 29a and moves to the second closed position shown in FIG. The fine particles 1 can be guided to the branch path 22b.
  • the movement of the microtool 25 is controlled by the electromagnets 29a and 29b, and the microtool 25 is moved to the first closed position or the second closed position, so that either one of the branch paths 22a and 22b is selectively used.
  • the fine particles 1 can be induced to pass through.
  • the micro tool 25 can be driven stably. Can do. Since the microtool 25 is provided so as to be smoothly rotatable around the support portion 25b, the microtool 25 can be stably driven with a smaller driving force, and the drive mechanism 26 can be configured to be smaller. . Since the magnetic fields created by the electromagnets 29a and 29b are concentrated on the high magnetic permeability portions 32a and 32b of the magnetic field concentrating members 30a and 30b, the movement of the microtool 25 can be controlled efficiently. Further, the magnetic field concentrating members 30a and 30b can reduce the influence of the magnetic field created by the electromagnets 29a and 29b on the surroundings.
  • the identification means 27 and the control unit 28 can select the branch paths 22a and 22b through which the fine particles 1 pass according to the type of the fine particles 1, and the fine particles 1 can be automatically and efficiently separated and classified. This makes it possible to perform complex separation / classification bio-operations that have been performed under a microscope using a pipette or the like at high speed and efficiently without human intervention.
  • the microsort mechanism 12 includes a drive unit 25a of an arrow-shaped microtool 25 in which a support unit 25b at the other end is supported by a pin support mechanism by a change in the magnetic field of each electromagnet 29a, 29b. It can be moved left and right within the microchannel 21. Further, the micro tool 25 has a magnetizing force sufficient to operate even when the magnetic field strength of the electromagnetic coil is small due to the smooth rotation by the pin support mechanism and the magnetizing process at the time of manufacturing the micro tool 25. Therefore, the drive unit 25a can be moved smoothly even with a small magnetic field strength. By the movement of the microtool 25, the fine particles 1 can be separated into the target branch path 22a or 22b. Since the microtool 25 is made of polymer and has flexibility, the valve effect for fine particles can be obtained at the same time, and necessary microchannels can be opened and closed.
  • the microchip according to the first embodiment of the present invention does not need to insert a magnetic material directly into a minute flow path or move an external electromagnet with an electromagnetic coil as in the prior art.
  • the micro tool 25 can be moved to separate the microparticles 1 simply by magnetizing the electromagnets 29a and 29b made of two thin film microcoils alternately in a small space. Since the drive mechanism 26 and the identification means 27 are provided outside the microchannel 21, the microparticles 1 can be separated in a non-contact / non-invasive manner.
  • the drive mechanism 26 of the micro sort mechanism 12 is more In addition to being able to be configured small, it is possible to maintain a sufficient driving force to drive the microtool 25 stably. For this reason, the microsort mechanism 12 can be arranged in multiple stages, whereby the fine particles 1 can be separated and classified more finely according to the type of the fine particles 1 and the like.
  • the drive unit 25a of the microtool 25 may be magnetized in N or S.
  • the drive unit 25a since the magnetic field concentrating members 30a and 30b have opposite polarities by flowing currents in the opposite directions to the electromagnet 29a and the electromagnet 29b, the drive unit 25a is attracted to the electromagnet 29a or the electromagnet 29b, Move to the 1 occlusion position or the 2nd occlusion position.
  • the drive unit 25a is attracted to the opposite electromagnet, and the opposite blocking position is reached. Move to. In this way, the movement of the microtool 25 can be controlled by the electromagnets 29a and 29b.
  • the microtool 25 is preferably made of a magnetic microtool (MMT) containing magnetite or neodymium.
  • MMT magnetic microtool
  • an MMT that contains 50% neodymium and is magnetized contains 50% magnetite, and a performance improvement of about 44 times the magnetic force is recognized compared to a magnetized MMT.
  • the magnetized MMT containing 50% neodymium contains 50% magnetite, and an improvement in magnetic force performance of about 100 times is recognized as compared with an unmagnetized MMT.
  • the pair of magnetic field concentrating members 30a and 30b may be formed of elongated pins, respectively, and may be embedded in the glass substrate spanned over the electromagnets 29a and 29b.
  • the magnetic field concentrating members 30a and 30b are disposed on the upper portions of the electromagnets 29a and 29b, respectively, and are inclined so as to approach each other from the lower portion to the upper portion of the glass substrate.
  • the magnetic field concentrating members 30 a and 30 b are provided so that the upper ends thereof are arranged on both sides of the tip of the driving unit 25 a of the microtool 25.
  • the magnetic fields generated by the electromagnets 29a and 29b can be concentrated on the pin-shaped magnetic field concentrating members 30a and 30b, and the driving unit 25a of the microtool 25 can be translated. Further, since the magnetic field is concentrated on each of the pin-shaped magnetic field concentrating members 30a and 30b, the magnetic field interference region can be further narrowed. In this configuration, when the microtool 25 is made of MMT containing neodymium, it has been confirmed that the drive unit 25a of the microtool 25 can be driven at a maximum speed of about 10 Hz.
  • the pair of magnetic field concentrating members 30a and 30b may be composed of triangular nickel pins each having a pointed tip, and may be embedded in the micromodule 11.
  • Each magnetic field concentrating member 30a, 30b is not limited to the embodiment as long as it has a sharp shape.
  • the magnetic field concentrating members 30a and 30b are arranged with their sharp tips facing each other so as to sandwich the microchannel 21.
  • the magnetic fields generated by the electromagnets 29a and 29b can be concentrated on the magnetic field concentration members 30a and 30b, and the drive unit 25a of the microtool 25 can be translated.
  • the magnetic field interference region can be further narrowed.
  • the drive unit 25a of the microtool 25 can be driven at a maximum speed of about 180 Hz.
  • FIG. 7 shows a microchip according to a second embodiment of the present invention.
  • the same members as those in the configuration of the microchip according to the first embodiment of the present invention are denoted by the same reference numerals, and redundant description is omitted.
  • the microchip according to the second embodiment of the present invention includes a multistage microsort mechanism, and includes a micromodule 51 and a microsort mechanism 12.
  • the micromodule 51 has a microchannel 21 for flowing the microparticles 1, and the microchannel 21 includes two first-stage branch paths 52 a and 52 b and each first-stage branch path 52 a. , 52b has four second-stage branch paths 53a, 53b, 53c, 53d that are further branched into two.
  • Three microsort mechanisms 12 are provided in total at the branch positions of the first stage branch paths 52a and 52b and the two branch positions of the second stage branch paths 53a, 53b, 53c and 53d.
  • the identification means 27 of each microsort mechanism 12 identifies the type of the fine particle 1 so that the fine particle 1 flowing through the micro flow channel 21 is further separated and classified according to the type of the fine particle 1 as it goes to the downstream branch path. It is possible.
  • a signal obtained by detecting the shape or characteristic of the fine particles 1 by the identification means 27 of each microsort mechanism 12 is converted into an electric signal by the control unit 28, and each identification means 27, each electromagnet 29a, 29b composed of a thin film microcoil in each first stage branch 52a, 52b, or each electromagnet 29a, composed of a thin film microcoil in each second stage branch 53a, 53b, 53c, 53d, 29b is electromagnetically driven.
  • the separation / classification sequence of the multistage microsort mechanism shown in FIG. 7 will be described.
  • the electromagnets 29a and 29b made of the first-stage thin film microcoil are turned on and off based on the electric signal from the control unit 28, and the pin support mechanism supports the support part by the micro magnetic field generated.
  • the drive unit 25a of the micro tool 25, which is an arrow-shaped magnetic body supported by 25b, moves to the left and right in the micro flow path 21, and the fine particles 1 are guided to the second-stage micro sort mechanism 12.
  • the electromagnets 29 a and 29 b formed of the second-stage thin film microcoil are turned on and off by the electric signal from the control unit 28, and the driving unit 25 a of the microtool 25 is moved to the microchannel 21.
  • the fine particles 1 are guided to the second-stage branching passage 53a, 53b, 53c or 53d at the rear stage.
  • the target second-stage branch path 53a, 53b, 53c or 53d is selected from the four second-stage branch paths 53a, 53b, 53c, and 53d.
  • the fine particles 1 can be separated and classified.
  • FIG. 8 shows a microchip according to a third embodiment of the present invention.
  • the same members as those in the configuration of the microchip according to the first embodiment of the present invention are denoted by the same reference numerals, and redundant description is omitted.
  • the microchip according to the third embodiment of the present invention is a multi-channel microchip.
  • the microchip according to the third embodiment of the present invention separates the individual fine particles 1 one by one by the loading mechanism 71, and the separated fine particles 1 are separated into the multistage microsort mechanism according to the second embodiment of the present invention.
  • 72 the light is guided to the target microchannel 21 in the branch path group 73 including the four microchannels 21.
  • the microparticles 1 guided to the target microchannel 21 are guided to the identification means 27 of the microsort mechanism 12 through the cell processing step 74.
  • a signal obtained by detecting the shape and characteristics of the fine particles 1 by the identification means 27 is determined by the computer 35 of the control unit 28 and the micro tool 25 is controlled to select the processed fine particles 1. Only the microparticles 1 selected as the necessary microparticles 1 by the microsort mechanism 12 are guided to the cell coupling and fusion system 75. The fine particles 1 selected as unnecessary fine particles 1 by the microsort mechanism 12 are removed.
  • the biooperations such as loading, separation / classification, processing, sorting, coupling, and fusion necessary for cell nuclear transfer are reliant on human operations. Can be realized automatically at high speed.
  • extremely small microsort mechanisms 12 are arranged in multiple stages in one microchip, and target microparticles 1 are sorted at high speed into necessary microchannels 21 to process microparticles 1. Therefore, it is possible to improve a series of processing capabilities for separation, classification, processing, selection, and processing of particles (egg, cells, bacteria, etc.) that increase at an accelerated rate in the future.
  • particles egg, cells, bacteria, etc.
  • humans can perform complex bio-operations such as separation, processing, selection, and fusion that have been performed under a microscope with a pipette. Without this, it becomes possible to automatically perform at high speed and efficiently.
  • multi-channel capable of automatically and rapidly realizing the loading, separation / classification, processing, sorting, coupling, and fusion process of bio-related fine particles that increase at an accelerated rate.
  • Type microchip can be supplied. Moreover, it has sufficient processing capacity industrially and can contribute to the development of the bio industry.

Abstract

Provided are a microsorting mechanism capable of stably driving a microtool by a smaller drive mechanism and capable of efficiently separating/sorting a particulate, and a microchip. A magnetized microtool (25) is provided movably between a first blockage position at which one branch path (22b) is blocked therewith and a second blockage position at which the other branch path (22a) is blocked therewith. The microtool (25) is configured such that the movement thereof in a microchannel (21) is limited to the movement between the first blockage position and the second blockage position. A drive mechanism (26) comprises electromagnets (29a, 29b) for controlling the movement of the microtool (25) between the first blockage position and the second blockage position so as to be able to select the branch path (22a, 22b) through which a particulate (1) passes. The drive mechanism (26) comprises magnetic field concentration members (30a, 30b) comprising high magnetic permeability portions (32a, 32b) having higher magnetic permeability than other portions between the electromagnets (29a, 29b) and the microchannel (21).

Description

マイクロソート機構およびマイクロチップMicrosort mechanism and microchip
　本発明は、主に医療分野、医薬分野、品種改良といったバイオ系産業分野において用いられ、人間の操作に頼ることなく、目的の微粒子を高速で自動的に分離・分類するマイクロソート機構およびその機構を用いたマイクロチップに関する。 The present invention is mainly used in the bio-industrial field such as the medical field, the pharmaceutical field, and the breed improvement, and the micro-sorting mechanism that automatically separates and classifies target fine particles at high speed without depending on human operation and the mechanism. The present invention relates to a microchip using
　従来、マイクロチップ内での卵子、細胞、菌などの微粒子の操作は、顕微鏡から得られる画像情報に基づいて人間が行うことがほとんどであった。しかし、人間が直接、微粒子をバイオ操作することにより、汚れや細菌の付着等の外乱が発生していた。この外乱の影響を防ぐため、マイクロ流路内で、非接触で微粒子を操作する手法の開発が必要とされている。 Conventionally, manipulation of fine particles such as eggs, cells, and fungi in a microchip has been mostly performed by humans based on image information obtained from a microscope. However, humans directly manipulated the microparticles to cause disturbances such as dirt and bacteria. In order to prevent the influence of this disturbance, it is necessary to develop a technique for manipulating fine particles in a non-contact manner in a microchannel.
　マイクロ流路内での非接触操作には、微粒子の分離、分類、加工、選択、処理等の一連の操作があり、これらの工程を有する細胞核移植技術として、一個のマイクロ流路を用いた方法が提案されている（例えば、特許文献１参照）。この技術では、マイクロ流路が一個のため、連続的にバイオ操作を行うには、前もって同一の形状や特性をもつ微粒子を分離・分類して、準備しておかなければならない。しかし、実際の生体試料では、複数の微粒子が混在しており、事前の選別作業に膨大な時間を要するという問題があった。また、分離・分類から一連のバイオ操作までの時間的ロスによる微粒子の変化や変質等も発生するため、バイオ操作に制約を受けるおそれがあるという問題もあった。 Non-contact operation in a microchannel includes a series of operations such as separation, classification, processing, selection, and processing of microparticles, and a method using a single microchannel as a cell nuclear transfer technique having these steps Has been proposed (see, for example, Patent Document 1). In this technique, since there is one microchannel, in order to continuously perform bio-operation, it is necessary to prepare by separating and classifying particles having the same shape and characteristics in advance. However, in an actual biological sample, a plurality of fine particles are mixed, and there is a problem that an enormous amount of time is required for a prior sorting operation. In addition, there is also a problem that there is a risk that the bio-operation may be restricted because the change or alteration of the fine particles due to the time loss from the separation / classification to the series of bio-operation occurs.
　これらの問題を解決するため、発明者らは、微粒子を効率よく分離・分類することができるマイクロソート機構として、超小型の磁気マイクロツール（ＭＭＴ）を用いる方法を提案している（例えば、非特許文献１参照）。この方法では、バイオ操作の一連の操作の中で、核のある卵子と核のない卵子とを顕微鏡で検出し、核の無い卵子のみを次の工程に分離する部分にマイクロソート機構を用いている。 In order to solve these problems, the inventors have proposed a method using an ultra-small magnetic microtool (MMT) as a microsort mechanism capable of efficiently separating and classifying microparticles (for example, non-microscopic mechanism). Patent Document 1). In this method, in a series of bio-operations, eggs with nuclei and eggs without nuclei are detected with a microscope, and only the eggs without nuclei are separated into the next step using a microsort mechanism. Yes.
特開２００６－３２５４２９号公報JP 2006-325429 A
　しかしながら、非特許文献１に記載のマイクロソート機構では、磁気マイクロツール（ＭＭＴ）を外部の電磁石を移動して変位させており、この磁気マイクロツール（ＭＭＴ）を確実に動作させるためには、大きい駆動力が必要となり、かなり大きな磁気駆動機構が必要であるという課題があった。 However, in the microsort mechanism described in Non-Patent Document 1, the magnetic microtool (MMT) is displaced by moving an external electromagnet, which is large in order to operate the magnetic microtool (MMT) with certainty. There was a problem that a driving force was required and a considerably large magnetic driving mechanism was required.
　本発明は、このような課題に着目してなされたもので、より小さい駆動機構でマイクロツールを安定して駆動させることができ、微粒子を効率よく分離・分類することができるマイクロソート機構およびマイクロチップを提供することを目的としている。 The present invention has been made by paying attention to such a problem. A micro sort mechanism and a micro that can stably drive a micro tool with a smaller drive mechanism and can efficiently separate and classify fine particles. The purpose is to provide chips.
　上記目的を達成するために、本発明に係るマイクロソート機構は、複数の分岐路を有する微小流路を流れる微粒子を、各分岐路のうちの一つに選択的に誘導するためのマイクロソート機構であって、マイクロツールと駆動機構とを有し、前記マイクロツールは磁性を有し、全ての分岐路に対して、前記微粒子が任意の一つの分岐路を通過するよう、前記微小流路内で他の分岐路を塞ぐ位置に移動可能に設けられ、前記微小流路内での動きが前記他の分岐路を塞ぐ位置への移動に制限されるよう構成されており、前記駆動機構は前記微小流路の外部に設けられ、前記微粒子が通過する分岐路を選択可能に前記マイクロツールの移動を制御する電磁石を有することを、特徴とする。 In order to achieve the above object, a microsort mechanism according to the present invention is a microsort mechanism for selectively guiding fine particles flowing through a microchannel having a plurality of branch paths to one of the branch paths. A microtool and a drive mechanism, wherein the microtool has magnetism, and the microparticles pass through any one branch path with respect to all branch paths. And is configured to be movable to a position that closes the other branch path, and is configured such that movement in the microchannel is limited to movement to a position that blocks the other branch path, and the drive mechanism is An electromagnet is provided outside the microchannel and controls movement of the microtool so that a branch path through which the fine particles pass can be selected.
　本発明に係るマイクロソート機構は、マイクロチップ内などで、複数の分岐路を有する微小流路を流れる卵子、細胞、菌などの微粒子を、各分岐路のうちの一つに選択的に誘導するのに使用される。磁性を有するマイクロツールが、全ての分岐路に対して、微粒子が任意の一つの分岐路を通過するよう、微小流路内で他の分岐路を塞ぐ位置に移動可能に設けられているため、駆動機構の電磁石でマイクロツールの移動を制御することにより、微粒子が通過する分岐路を任意に選択することができる。このとき、マイクロツールの微小流路内での動きが、他の分岐路を塞ぐ位置への移動に制限されるよう構成されているため、マイクロツールを安定して駆動させることができる。マイクロツールを滑らかに移動するよう構成することにより、より小さい駆動力でマイクロツールを安定して駆動させることができ、駆動機構をより小さく構成することができる。 The microsort mechanism according to the present invention selectively guides microparticles such as eggs, cells, and fungi flowing in a microchannel having a plurality of branch paths to one of the branch paths in a microchip or the like. Used to. Since the micro tool having magnetism is provided so as to be movable to a position that closes the other branch path in the micro flow path so that the fine particles pass through any one branch path for all the branch paths, By controlling the movement of the microtool with the electromagnet of the drive mechanism, the branch path through which the fine particles pass can be arbitrarily selected. At this time, since the movement of the micro tool in the micro flow path is limited to the movement to the position where the other branch path is blocked, the micro tool can be driven stably. By configuring the micro tool to move smoothly, the micro tool can be stably driven with a smaller driving force, and the driving mechanism can be configured to be smaller.
　本発明に係るマイクロソート機構は、微小流路を流れる微粒子の種類等に応じて、微粒子が通過する分岐路を選択することにより、微粒子を効率よく分離・分類することができる。これにより、今までピペットなどを用いて顕微鏡下で行われてきた複雑な分離・分類のバイオ操作を、人手を介することなく、高速かつ効率的に行うことができる。 The microsort mechanism according to the present invention can efficiently separate and classify the fine particles by selecting a branch passage through which the fine particles pass according to the kind of the fine particles flowing through the micro flow path. This makes it possible to perform complex separation / classification bio-operations that have been performed under a microscope using a pipette or the like at high speed and efficiently without human intervention.
　マイクロツールは、磁性を有していれば、金属製や磁化した材料など、いかなるものから成っていてもよい。マイクロツールは、例えば、いわゆる磁気マイクロツール（ＭＭＴ）から成っていてもよく、希土類金属が含まれていてもよく、製作時に着磁されてもよい。電磁石は、マイクロツールの移動を制御可能であれば、いかなる機構や配置を成していてもよい。電磁石は、例えば、流れる電流の向きや強さを変えたり、電流をＯＮ／ＯＦＦしたりすることにより、マイクロツールの移動を制御することができる。 The microtool may be made of any material such as metal or magnetized material as long as it has magnetism. The microtool may be made of, for example, a so-called magnetic microtool (MMT), may contain a rare earth metal, and may be magnetized at the time of manufacture. The electromagnet may have any mechanism or arrangement as long as the movement of the microtool can be controlled. The electromagnet can control the movement of the microtool, for example, by changing the direction and strength of the flowing current or turning the current on / off.
　本発明に係るマイクロソート機構で、前記駆動機構は前記電磁石と前記微小流路との間に磁場集中部材を有し、前記磁場集中部材は透磁率が他の部分よりも大きい高透磁率部を有することが好ましい。この場合、電磁石が作る磁場が、磁場集中部材の高透磁率部に集中するため、高透磁率部の位置を調整することにより、マイクロツールの移動を効率よく制御することができ、駆動機構をより小さく構成することができる。また、電磁石が作る磁場が周囲に及ぼす影響を小さくすることができる。電磁石に流れる電流の強さによっては、電磁石の発熱、電磁石を大型化する必要性、電磁石による磁場干渉などの周囲に対する悪影響が発生する可能性があるが、磁場集中部材により電磁石に流す電流を小さくすることができるため、それらの悪影響を軽減または排除することができる。 In the microsort mechanism according to the present invention, the drive mechanism has a magnetic field concentration member between the electromagnet and the minute flow path, and the magnetic field concentration member has a high magnetic permeability portion having a larger magnetic permeability than other portions. It is preferable to have. In this case, since the magnetic field generated by the electromagnet is concentrated on the high permeability portion of the magnetic field concentration member, the movement of the micro tool can be efficiently controlled by adjusting the position of the high permeability portion. It can be made smaller. Moreover, the influence which the magnetic field which an electromagnet produces has on the circumference | surroundings can be made small. Depending on the strength of the current flowing through the electromagnet, there may be adverse effects on the surroundings, such as the heat generation of the electromagnet, the necessity of enlarging the electromagnet, and magnetic field interference by the electromagnet. Therefore, those adverse effects can be reduced or eliminated.
　本発明に係るマイクロソート機構で、前記微小流路は２つの分岐路を有し、前記マイクロツールは、一方の分岐路を塞ぐ第１閉塞位置と他方の分岐路を塞ぐ第２閉塞位置との間で移動可能に設けられ、前記微小流路内での動きが前記第１閉塞位置と前記第２閉塞位置との間での移動に制限されるよう構成されており、前記駆動機構は、前記マイクロツールの前記第１閉塞位置と前記第２閉塞位置との間の移動を制御する電磁石を有していてもよい。この場合、電磁石でマイクロツールの移動を制御して、マイクロツールを第１閉塞位置または第２閉塞位置に移動させることにより、いずれか一方の分岐路に微粒子を誘導して通過させることができる。 In the microsort mechanism according to the present invention, the micro flow path has two branch paths, and the micro tool has a first closed position that blocks one branch path and a second closed position that blocks the other branch path. Between the first closed position and the second closed position, and the drive mechanism is configured to be movable between the first closed position and the second closed position. An electromagnet that controls movement of the microtool between the first closed position and the second closed position may be included. In this case, by controlling the movement of the microtool with the electromagnet and moving the microtool to the first closed position or the second closed position, the fine particles can be guided and passed through one of the branch paths.
　また、この微小流路が２つの分岐路を有する場合、前記マイクロツールは細長く、一端に磁性を有する駆動部を有し、前記駆動部が前記第１閉塞位置と前記第２閉塞位置との間で移動するよう、他端を中心として滑らかに回転可能に設けられていることが好ましい。この場合、細長いマイクロツールが、他端を中心として滑らかに回転可能に設けられているため、さらに小さい駆動力でマイクロツールを安定して駆動させることができ、駆動機構をさらに小さく構成することができる。 Further, when the micro flow path has two branch paths, the micro tool is elongated and has a magnetic drive unit at one end, and the drive unit is between the first closed position and the second closed position. It is preferable that it is provided so as to be able to rotate smoothly around the other end so that it can be moved. In this case, since the elongated microtool is provided so as to be smoothly rotatable around the other end, the microtool can be stably driven with a smaller driving force, and the driving mechanism can be further reduced in size. it can.
　この微小流路が２つの分岐路を有する場合、前記電磁石は２つから成り、それぞれ各分岐路に対応する位置に、互いの磁場の干渉を受けないよう所定の間隔をあけて設けられていることが好ましい。この場合、例えば、いずれか一方の電磁石にのみ電流が流れるよう、電流を流す電磁石を切り替えることにより、第１閉塞位置と第２閉塞位置との間でマイクロツールを容易に移動させることができる。 When this microchannel has two branch paths, the electromagnet is composed of two, and is provided at a position corresponding to each branch path with a predetermined interval so as not to be interfered with each other's magnetic field. It is preferable. In this case, for example, the microtool can be easily moved between the first closed position and the second closed position by switching the electromagnet through which the current flows so that the current flows only through one of the electromagnets.
　本発明に係るマイクロチップは、前記微小流路を有するマイクロモジュールと、本発明に係るマイクロソート機構とを有することを、特徴とする。 The microchip according to the present invention is characterized by having a micromodule having the microchannel and the microsort mechanism according to the present invention.
　本発明に係るマイクロチップは、本発明に係るマイクロソート機構を有するため、より小さい駆動機構でマイクロツールを安定して駆動させることができる。また、マイクロモジュールの微小流路を流れる微粒子の種類等に応じて、微粒子が通過する分岐路を選択することにより、微粒子を効率よく分離・分類することができる。これにより、今までピペットなどを用いて顕微鏡下で行われてきた複雑な分離・分類のバイオ操作を、人手を介することなく、高速かつ効率的に行うことができる。マイクロソート機構の駆動機構をより小さく構成することができるため、マイクロソート機構を多段に配置することができる。 Since the microchip according to the present invention has the microsort mechanism according to the present invention, the microtool can be driven stably with a smaller driving mechanism. Further, the fine particles can be efficiently separated and classified by selecting the branch passage through which the fine particles pass according to the kind of the fine particles flowing through the micro flow path of the micromodule. This makes it possible to perform complex separation / classification bio-operations that have been performed under a microscope using a pipette or the like at high speed and efficiently without human intervention. Since the driving mechanism of the microsort mechanism can be made smaller, the microsort mechanism can be arranged in multiple stages.
　本発明に係るマイクロチップは、前記微小流路を流れる微粒子の種類を識別する識別手段と、前記識別手段で識別された前記微粒子の種類に基づいて、前記微粒子を一つの分岐路に選択的に誘導するよう前記駆動機構を制御する制御部とを、有することが好ましい。この場合、微粒子の種類に応じて、微粒子が通過する分岐路を選択することができ、微粒子を自動的に効率よく分離・分類することができる。識別手段は、例えば、微粒子の形状や特性を検出することにより微粒子の種類を識別するようになっていてもよい。 The microchip according to the present invention is configured to selectively identify the microparticles that flow through the microchannel and the microparticles in one branch path based on the type of the microparticles identified by the identification unit. It is preferable to have a control unit that controls the drive mechanism to guide. In this case, the branch path through which the fine particles pass can be selected according to the type of fine particles, and the fine particles can be automatically and efficiently separated and classified. The identification means may identify the type of the fine particles by detecting the shape and characteristics of the fine particles, for example.
　本発明に係るマイクロチップは、前記マイクロモジュールおよび前記マイクロソート機構が多段に配置されていてもよい。この場合、微粒子の種類等に応じて、より細かく微粒子を分離・分類することができる。 In the microchip according to the present invention, the micromodule and the microsort mechanism may be arranged in multiple stages. In this case, fine particles can be more finely separated and classified according to the type of fine particles.
　本発明によれば、より小さい駆動機構でマイクロツールを安定して駆動させることができ、微粒子を効率よく分離・分類することができるマイクロソート機構およびマイクロチップを提供することができる。 According to the present invention, it is possible to provide a microsort mechanism and a microchip that can stably drive a microtool with a smaller drive mechanism and can efficiently separate and classify fine particles.
本発明の第１の実施の形態のマイクロチップを示す（ａ）平面図、（ｂ）マイクロソート機構のマイクロツールが第１閉塞位置に移動したときの拡大図、（ｃ）マイクロソート機構のマイクロツールが第２閉塞位置に移動したときの拡大図である。1A is a plan view showing a microchip according to a first embodiment of the present invention, FIG. 2B is an enlarged view when the micro tool of the micro sort mechanism is moved to the first closing position, and FIG. 2C is a micro view of the micro sort mechanism. It is an enlarged view when a tool moves to the 2nd blockade position. 図１に示すマイクロチップの駆動機構の（ａ）平面図、（ｂ）製造過程の正面図、（ｃ）正面図である。2A is a plan view of the microchip drive mechanism shown in FIG. 1, FIG. 2B is a front view of the manufacturing process, and FIG. 図１に示すマイクロチップの識別手段および制御部の具体例を示すブロック図である。It is a block diagram which shows the specific example of the identification means and control part of the microchip shown in FIG. 本発明の第１の実施の形態のマイクロチップの、マグネタイトまたはネオジムを含んだマイクロツールの磁束密度と温度との関係を示すグラフである。It is a graph which shows the relationship between the magnetic flux density and temperature of the microtool containing the magnetite or neodymium of the microchip of the 1st Embodiment of this invention. 本発明の第１の実施の形態のマイクロチップの、磁場集中部材が細長いピンから成る変形例の（ａ）平面図、（ｂ）正面図である。It is the (a) top view of the modification which the magnetic field concentration member consists of an elongate pin of the microchip of the 1st Embodiment of this invention, (b) The front view. 本発明の第１の実施の形態のマイクロチップの、磁場集中部材が三角形状のニッケル製のピンから成る変形例の（ａ）正面図、（ｂ）マイクロツールの駆動状態を示す平面図である。FIG. 5A is a front view of a modification of the microchip according to the first embodiment of the present invention in which the magnetic field concentrating member is formed of a triangular nickel pin, and FIG. 5B is a plan view illustrating a driving state of the microtool. . 本発明の第２の実施の形態のマイクロチップを示す（ａ）平面図、（ｂ）駆動機構の位置での断面図である。FIG. 5A is a plan view showing a microchip according to a second embodiment of the present invention, and FIG. 5B is a cross-sectional view at the position of a drive mechanism. 本発明の第３の実施の形態のマイクロチップを示す平面図である。It is a top view which shows the microchip of the 3rd Embodiment of this invention.
　以下、図面に基づき、本発明の実施の形態について説明する。
　図１および図６は、本発明の第１の実施の形態のマイクロチップおよび本発明の実施の形態のマイクロソート機構を示している。
　図１に示すように、本発明の第１の実施の形態のマイクロチップは、マイクロモジュール１１とマイクロソート機構１２とを有している。 Hereinafter, embodiments of the present invention will be described with reference to the drawings.
1 and 6 show a microchip according to a first embodiment of the present invention and a microsort mechanism according to an embodiment of the present invention.
As shown in FIG. 1, the microchip according to the first embodiment of the present invention includes a micromodule 11 and a microsort mechanism 12.
　図１に示すように、マイクロモジュール１１は、卵子(卵細胞)、体細胞等の任意の動物細胞、植物細胞、ＥＳ細胞、微生物、菌、ＤＮＡ分子、ナノチューブ、ナノ材料等の微小物体などから成る微粒子１を流すための微小流路２１を有している。微小流路２１は、２つの分岐路２２ａ，２２ｂを有している。マイクロモジュール１１は、各分岐路２２ａ，２２ｂの間に、各分岐路２２ａ，２２ｂの股部で微小流路２１に連通した取付室２３を有している。取付室２３は、中央に取付用のピラー２４を有している。 As shown in FIG. 1, the micromodule 11 includes any animal cell such as an egg (egg cell) or somatic cell, a plant cell, an ES cell, a microorganism, a fungus, a DNA molecule, a nanotube, a nanomaterial, or the like. A microchannel 21 for flowing the fine particles 1 is provided. The microchannel 21 has two branch paths 22a and 22b. The micromodule 11 has a mounting chamber 23 that communicates with the microchannel 21 at the crotch portions of the branch paths 22a and 22b between the branch paths 22a and 22b. The mounting chamber 23 has a mounting pillar 24 in the center.
　図１に示すように、マイクロソート機構１２は、マイクロツール２５と駆動機構２６と識別手段２７と制御部２８とを有している。マイクロツール２５は、ポリマー製で柔軟性を有し、いわゆる磁気マイクロツール（ＭＭＴ）から成っている。図１（ｂ）および（ｃ）に示すように、マイクロツール２５は、細長く、一端に駆動部２５ａを有し、他端に支持部２５ｂを有している。駆動部２５ａは、制作時に着磁されて磁性を有している。駆動部２５ａは、薄い板状を成し、先が尖った矢印形状の平面形状を成している。支持部２５ｂは、中央に貫通孔２５ｃを有して円環状を成している。 As shown in FIG. 1, the micro sort mechanism 12 includes a micro tool 25, a drive mechanism 26, an identification unit 27, and a control unit 28. The microtool 25 is made of a polymer and has flexibility, and is made of a so-called magnetic microtool (MMT). As shown in FIGS. 1B and 1C, the microtool 25 is elongated and has a drive portion 25a at one end and a support portion 25b at the other end. The drive unit 25a is magnetized at the time of production and has magnetism. The drive unit 25a has a thin plate shape, and has a planar shape with a pointed arrow. The support portion 25b has a through hole 25c in the center and forms an annular shape.
　マイクロツール２５は、駆動部２５ａを微小流路２１の各分岐路２２ａ，２２ｂの分岐位置に配置し、支持部２５ｂの貫通孔２５ｃに取付室２３のピラー２４を貫通させて、マイクロモジュール１１に取り付けられている。マイクロツール２５は、微小流路２１を流れる微粒子１がいずれかの分岐路２２ａ，２２ｂを通過するよう、駆動部２５ａが一方の分岐路２２ｂを塞ぐ図１（ｂ）に示す第１閉塞位置と、他方の分岐路２２ａを塞ぐ図１（ｃ）に示す第２閉塞位置との間で移動可能に、他端の支持部２５ｂを中心として回転可能に取り付けられている。マイクロツール２５は、支持部２５ｂがピラー２４に緩く嵌合されており、支持部２５ｂを中心として滑らかに回転可能になっている。こうして、マイクロツール２５は、駆動部２５ａの微小流路２１内での動きが第１閉塞位置と第２閉塞位置との間での移動に制限されるよう構成されている。具体的な一例では、駆動部２５ａの第１閉塞位置と第２閉塞位置との間での移動距離は、数百μｍ以下である。 In the microtool 25, the drive unit 25a is disposed at the branch position of each branch path 22a, 22b of the micro flow path 21, and the pillar 24 of the mounting chamber 23 is passed through the through hole 25c of the support part 25b, so that the micro module 11 It is attached. The microtool 25 has a first closed position shown in FIG. 1B in which the driving unit 25a blocks one branch path 22b so that the particulate 1 flowing through the microchannel 21 passes through one of the branch paths 22a and 22b. The other branch path 22a is attached so as to be movable between the second closed position shown in FIG. 1C and rotatable about the support portion 25b at the other end. The support part 25b is loosely fitted to the pillar 24, and the microtool 25 can rotate smoothly around the support part 25b. Thus, the microtool 25 is configured such that the movement of the driving unit 25a in the micro flow path 21 is limited to movement between the first closed position and the second closed position. In a specific example, the moving distance between the first closed position and the second closed position of the drive unit 25a is several hundred μm or less.
　図２に示すように、駆動機構２６は、１対の電磁石２９ａ，２９ｂと１対の磁場集中部材３０ａ，３０ｂとガラス板３１とを有している。各電磁石２９ａ，２９ｂは、それぞれ薄膜マイクロコイルから成り、直径２ｍｍ程度のフェライトコアに細線を巻きつけて形成されている。各電磁石２９ａ，２９ｂは、互いの磁場の干渉を受けないよう、それぞれのコイル間に所定の間隔をあけて設けられている。具体的な一例では、各電磁石２９ａ，２９ｂは、それぞれのコイル間に１ｍｍの間隔をあけて配置されている。 As shown in FIG. 2, the drive mechanism 26 includes a pair of electromagnets 29 a and 29 b, a pair of magnetic field concentration members 30 a and 30 b, and a glass plate 31. Each of the electromagnets 29a and 29b is made of a thin film microcoil and is formed by winding a thin wire around a ferrite core having a diameter of about 2 mm. The electromagnets 29a and 29b are provided with a predetermined interval between the coils so as not to be interfered with each other's magnetic field. In a specific example, the electromagnets 29a and 29b are arranged with a 1 mm gap between the coils.
　各磁場集中部材３０ａ，３０ｂは、ＭＥＭＳ技術により作成され、高透磁率の材料と低透磁率の材料とを組み合わせて形成されている。各磁場集中部材３０ａ，３０ｂは、ガラスもしくはシリコンウェハ基板にフォトレジストでパターニングした壁面に、高透磁率の材料と低透磁率の材料とを順々にめっき、電鋳加工もしくはパターニングし、剥離液もしくはウェットエッチングにより型を取り除くことより製造されている。各磁場集中部材３０ａ，３０ｂは、高透磁率の材料で形成された高透磁率部３２ａ，３２ｂが内側になるよう、各電磁石２９ａ，２９ｂの上部に設けられている。これにより、駆動機構２６は、各電磁石２９ａ，２９ｂの磁力線が上方に誘導されるようになっている。ガラス板３１は、各磁場集中部材３０ａ，３０ｂの上部に架け渡されている。 Each of the magnetic field concentrating members 30a and 30b is made by a MEMS technique and is formed by combining a high magnetic permeability material and a low magnetic permeability material. The magnetic field concentrating members 30a and 30b are formed by sequentially plating, electroforming or patterning a high permeability material and a low permeability material on a wall surface of a glass or silicon wafer substrate patterned with a photoresist. Alternatively, it is manufactured by removing the mold by wet etching. Each of the magnetic field concentrating members 30a and 30b is provided above the electromagnets 29a and 29b so that the high magnetic permeability portions 32a and 32b formed of a high magnetic permeability material are located inside. As a result, the drive mechanism 26 is configured such that the magnetic lines of force of the electromagnets 29a and 29b are guided upward. The glass plate 31 is bridged over the magnetic field concentrating members 30a and 30b.
　図１に示すように、駆動機構２６は、微小流路２１の外部の下部の、各分岐路２２ａ，２２ｂの分岐位置に設けられている。駆動機構２６は、各電磁石２９ａ，２９ｂが微小流路２１を挟んで、それぞれ各分岐路２２ａ，２２ｂに対応する位置に配置されるよう設けられている。駆動機構２６は、マイクロツール２５の両側に各電磁石２９ａ，２９ｂおよび各磁場集中部材３０ａ，３０ｂが並行に配置され、各電磁石２９ａ，２９ｂと微小流路２１との間に磁場集中部材３０ａ，３０ｂが配置されている。駆動機構２６は、各電磁石２９ａ，２９ｂで発生した磁界が、各磁場集中部材３０ａ，３０ｂの高透磁率部３２ａ，３２ｂにそれぞれ集中するため、マイクロツール２５の駆動部２５ａを併進移動可能になっている。このように、駆動機構２６は、各電磁石２９ａ，２９ｂによりマイクロツール２５の第１閉塞位置と第２閉塞位置との間の移動を制御して、微粒子１が通過する分岐路２２ａ，２２ｂを選択可能になっている。 As shown in FIG. 1, the drive mechanism 26 is provided at the branch position of each branch path 22 a, 22 b, outside the microchannel 21. The drive mechanism 26 is provided so that the electromagnets 29a and 29b are disposed at positions corresponding to the branch paths 22a and 22b, respectively, with the minute flow path 21 interposed therebetween. In the drive mechanism 26, the electromagnets 29 a and 29 b and the magnetic field concentration members 30 a and 30 b are arranged in parallel on both sides of the microtool 25, and the magnetic field concentration members 30 a and 30 b are interposed between the electromagnets 29 a and 29 b and the microchannel 21. Is arranged. In the drive mechanism 26, the magnetic fields generated by the electromagnets 29a and 29b are concentrated on the high magnetic permeability portions 32a and 32b of the magnetic field concentration members 30a and 30b, respectively, so that the drive unit 25a of the microtool 25 can be translated. ing. Thus, the drive mechanism 26 controls the movement of the microtool 25 between the first closed position and the second closed position by the electromagnets 29a and 29b, and selects the branch paths 22a and 22b through which the fine particles 1 pass. It is possible.
　図１に示すように、識別手段２７は、微小流路２１の外部の、各分岐路２２ａ，２２ｂの分岐位置よりやや上流に設けられ、微小流路２１を流れる微粒子１の形状または、着色や蛍光強度などの特性を検出可能なセンサから成っている。識別手段２７は、微粒子１の形状または特性を検出することにより、微粒子１の種類を識別するようになっている。 As shown in FIG. 1, the identification means 27 is provided on the outside of the microchannel 21 and slightly upstream from the branching positions of the branch channels 22 a and 22 b, and the shape or coloring of the fine particles 1 flowing through the microchannel 21 It consists of sensors that can detect characteristics such as fluorescence intensity. The identification means 27 identifies the type of the fine particles 1 by detecting the shape or characteristics of the fine particles 1.
　図１に示すように、制御部２８は、識別手段２７および各電磁石２９ａ，２９ｂに接続され、識別手段２７からの検出信号を増幅する電流増幅アンプ３３と、電流増幅アンプ３３で増幅されたＡＣ信号をＤＣ信号に変換するＡＣ／ＤＣ変換器３４と、ＡＣ／ＤＣ変換器３４で変換されたＤＣ信号を入力し、識別手段２７で識別された微粒子１の種類に対応するそのＤＣ信号に基づいて、各電磁石２９ａ，２９ｂを制御する制御信号を出力するコンピュータ３５と、コンピュータ３５で出力されたＤＣ信号から成る制御信号をＡＣ信号に変換するＤＣ／ＡＣ変換器３６とを有している。制御部２８は、ＤＣ／ＡＣ変換器３６で変換されたＡＣ信号を各電磁石２９ａ，２９ｂに送信することにより、各電磁石２９ａ，２９ｂを電磁駆動可能になっている。制御部２８は、いずれか一方の電磁石２９ａ，２９ｂにのみ電流が流れるよう、各電磁石２９ａ，２９ｂをオン、オフして、電流を流す電磁石２９ａ，２９ｂを切り替えることにより、電流を流した電磁石２９ａ，２９ｂの上部に微小磁界を形成して、マイクロツール２５を移動させるようになっている。このように、制御部２８は、微粒子１をいずれかの分岐路２２ａ，２２ｂに選択的に誘導するよう駆動機構２６を制御可能になっている。 As shown in FIG. 1, the control unit 28 is connected to the identification unit 27 and the electromagnets 29 a and 29 b, and a current amplification amplifier 33 that amplifies a detection signal from the identification unit 27, and an AC amplified by the current amplification amplifier 33. An AC / DC converter 34 for converting the signal into a DC signal, and a DC signal converted by the AC / DC converter 34 are input, and based on the DC signal corresponding to the type of the particulate 1 identified by the identification means 27. The computer 35 outputs a control signal for controlling the electromagnets 29a and 29b, and the DC / AC converter 36 converts the control signal composed of the DC signal output from the computer 35 into an AC signal. The control unit 28 can electromagnetically drive the electromagnets 29a and 29b by transmitting the AC signal converted by the DC / AC converter 36 to the electromagnets 29a and 29b. The controller 28 turns on and off the electromagnets 29a and 29b and switches the electromagnets 29a and 29b through which the current flows so that the current flows only through one of the electromagnets 29a and 29b. , 29b, a micro magnetic field is formed on the upper part, and the micro tool 25 is moved. Thus, the control unit 28 can control the drive mechanism 26 so as to selectively guide the fine particles 1 to one of the branch paths 22a and 22b.
　図３に示す具体的な一例では、識別手段２７はＣＣＤカメラから成り、制御部２８は、電流増幅アンプ３３とＡＣ／ＤＣ変換器３４とを兼ねる画像ボードと、コンピュータ３５と、アンプ機能を内蔵したＤＣ／ＡＣ変換器３６とから成っている。この場合、まず、ＣＣＤカメラで微小流路２１を流れる微粒子１を撮影し、その微粒子１の画像を、画像ボードを介してコンピュータ３５に入力する。コンピュータ３５で、その入力された微粒子１の画像と、微粒子を識別するためにあらかじめ記録しておいた微粒子の校正用画像との相互相関を計算する。相関係数が所定の値以上（例えば、０．９以上）のとき、校正用画像の微粒子と同じものと判断し、微粒子１を一方の分岐路（例えば、分岐路２２ａ）に誘導するよう、ＤＣ／ＡＣ変換器３６を介して各電磁石２９ａ，２９ｂを電磁駆動し、駆動機構２６を制御するようになっている。また、相関係数が所定の値より小さい（例えば、０．９より小さい）とき、校正用画像の微粒子と異なるものと判断し、微粒子１を他方の分岐路（例えば、分岐路２２ｂ）に誘導するよう、ＤＣ／ＡＣ変換器３６を介して各電磁石２９ａ，２９ｂを電磁駆動し、駆動機構２６を制御するようになっている。 In the specific example shown in FIG. 3, the identification means 27 is composed of a CCD camera, and the control unit 28 has an image board that doubles as a current amplification amplifier 33 and an AC / DC converter 34, a computer 35, and an amplifier function. DC / AC converter 36. In this case, first, the particle 1 flowing through the microchannel 21 is photographed with a CCD camera, and an image of the particle 1 is input to the computer 35 via the image board. The computer 35 calculates the cross-correlation between the input image of the fine particle 1 and the fine particle calibration image recorded in advance to identify the fine particle. When the correlation coefficient is not less than a predetermined value (for example, 0.9 or more), it is determined that it is the same as the fine particle of the calibration image, and the fine particle 1 is guided to one branch path (for example, the branch path 22a). The electromagnets 29 a and 29 b are electromagnetically driven via the DC / AC converter 36 to control the drive mechanism 26. Further, when the correlation coefficient is smaller than a predetermined value (for example, smaller than 0.9), it is determined that it is different from the fine particles in the calibration image, and the fine particle 1 is guided to the other branch path (for example, the branch path 22b). Thus, the electromagnets 29 a and 29 b are electromagnetically driven via the DC / AC converter 36 to control the drive mechanism 26.
　次に、作用について説明する。
　本発明の第１の実施の形態のマイクロチップは、本発明の実施の形態のマイクロソート機構１２により、２つの分岐路２２ａ，２２ｂを有する微小流路２１を流れる卵子、細胞、菌などの微粒子１を、いずれかの分岐路２２ａ，２２ｂに選択的に誘導することができる。マイクロソート機構１２は、いずれか一方の電磁石２９ａ，２９ｂにのみ電流が流れるよう、電流を流す電磁石２９ａ，２９ｂを切り替えることにより、第１閉塞位置と第２閉塞位置との間でマイクロツール２５を容易に移動させることができる。 Next, the operation will be described.
The microchip according to the first embodiment of the present invention has fine particles such as eggs, cells, and fungi that flow through the microchannel 21 having two branch paths 22a and 22b by the microsort mechanism 12 according to the embodiment of the present invention. 1 can be selectively guided to one of the branch paths 22a and 22b. The microsort mechanism 12 switches the electromagnets 29a and 29b through which current flows so that current flows only through one of the electromagnets 29a and 29b, thereby moving the microtool 25 between the first closed position and the second closed position. It can be moved easily.
　図１に示す具体的な一例では、マイクロソート機構１２は、電磁石２９ａをオフ、電磁石２９ｂをオンにしたとき、マイクロツール２５の駆動部２５ａが電磁石２９ｂに引きつけられて図１（ｂ）に示す第１閉塞位置に移動するため、微粒子１を分岐路２２ａに誘導することができる。また、マイクロソート機構１２は、電磁石２９ａをオン、電磁石２９ｂをオフにしたとき、マイクロツール２５の駆動部２５ａが電磁石２９ａに引きつけられて図１（ｃ）に示す第２閉塞位置に移動するため、微粒子１を分岐路２２ｂに誘導することができる。このように、電磁石２９ａ，２９ｂでマイクロツール２５の移動を制御して、マイクロツール２５を第１閉塞位置または第２閉塞位置に移動させることにより、いずれか一方の分岐路２２ａ，２２ｂに選択的に微粒子１を誘導して通過させることができる。 In the specific example shown in FIG. 1, when the electromagnet 29a is turned off and the electromagnet 29b is turned on, the microsort mechanism 12 attracts the drive unit 25a of the microtool 25 to the electromagnet 29b, as shown in FIG. Since it moves to the first closed position, the fine particles 1 can be guided to the branch path 22a. Further, when the electromagnet 29a is turned on and the electromagnet 29b is turned off, the microsort mechanism 12 is attracted to the electromagnet 29a and moves to the second closed position shown in FIG. The fine particles 1 can be guided to the branch path 22b. In this way, the movement of the microtool 25 is controlled by the electromagnets 29a and 29b, and the microtool 25 is moved to the first closed position or the second closed position, so that either one of the branch paths 22a and 22b is selectively used. The fine particles 1 can be induced to pass through.
　マイクロツール２５の微小流路２１内での動きが、第１閉塞位置と第２閉塞位置との間での移動に制限されるよう構成されているため、マイクロツール２５を安定して駆動させることができる。マイクロツール２５が支持部２５ｂを中心として滑らかに回転可能に設けられているため、より小さい駆動力でマイクロツール２５を安定して駆動させることができ、駆動機構２６をより小さく構成することができる。各電磁石２９ａ，２９ｂが作る磁場が各磁場集中部材３０ａ，３０ｂの高透磁率部３２ａ，３２ｂに集中するため、マイクロツール２５の移動を効率よく制御することができる。また、各磁場集中部材３０ａ，３０ｂにより、各電磁石２９ａ，２９ｂが作る磁場が周囲に及ぼす影響を小さくすることができる。 Since the movement of the micro tool 25 in the micro flow path 21 is limited to the movement between the first closed position and the second closed position, the micro tool 25 can be driven stably. Can do. Since the microtool 25 is provided so as to be smoothly rotatable around the support portion 25b, the microtool 25 can be stably driven with a smaller driving force, and the drive mechanism 26 can be configured to be smaller. . Since the magnetic fields created by the electromagnets 29a and 29b are concentrated on the high magnetic permeability portions 32a and 32b of the magnetic field concentrating members 30a and 30b, the movement of the microtool 25 can be controlled efficiently. Further, the magnetic field concentrating members 30a and 30b can reduce the influence of the magnetic field created by the electromagnets 29a and 29b on the surroundings.
　識別手段２７および制御部２８により、微粒子１の種類に応じて、微粒子１が通過する分岐路２２ａ，２２ｂを選択することができ、微粒子１を自動的に効率よく分離・分類することができる。これにより、今までピペットなどを用いて顕微鏡下で行われてきた複雑な分離・分類のバイオ操作を、人手を介することなく、高速かつ効率的に行うことができる。 The identification means 27 and the control unit 28 can select the branch paths 22a and 22b through which the fine particles 1 pass according to the type of the fine particles 1, and the fine particles 1 can be automatically and efficiently separated and classified. This makes it possible to perform complex separation / classification bio-operations that have been performed under a microscope using a pipette or the like at high speed and efficiently without human intervention.
　本発明の実施の形態のマイクロソート機構１２は、各電磁石２９ａ，２９ｂの磁界の変化により、ピン支持機構により他端の支持部２５ｂを支持された矢印形状のマイクロツール２５の駆動部２５ａを、微小流路２１内で左右に移動させることができる。また、マイクロツール２５は、ピン支持機構により滑らかに回転することや、マイクロツール２５の製作時の着磁工程により、電磁コイルの磁界強度が小さくても十分に動作するだけの磁化力を保有していることから、小さな磁界強度でも駆動部２５ａをスムーズに移動させることができる。このマイクロツール２５の移動により、目的の分岐路２２ａまたは２２ｂに微粒子１を分離することができる。なお、マイクロツール２５は、ポリマー製で柔軟性を有するため、微粒子用のバルブ効果も同時に得ることができ、必要な微小流路を開閉することも可能である。 The microsort mechanism 12 according to the embodiment of the present invention includes a drive unit 25a of an arrow-shaped microtool 25 in which a support unit 25b at the other end is supported by a pin support mechanism by a change in the magnetic field of each electromagnet 29a, 29b. It can be moved left and right within the microchannel 21. Further, the micro tool 25 has a magnetizing force sufficient to operate even when the magnetic field strength of the electromagnetic coil is small due to the smooth rotation by the pin support mechanism and the magnetizing process at the time of manufacturing the micro tool 25. Therefore, the drive unit 25a can be moved smoothly even with a small magnetic field strength. By the movement of the microtool 25, the fine particles 1 can be separated into the target branch path 22a or 22b. Since the microtool 25 is made of polymer and has flexibility, the valve effect for fine particles can be obtained at the same time, and necessary microchannels can be opened and closed.
　本発明の第１の実施の形態のマイクロチップは、従来のように、直接、磁性体を微小流路に挿入したり、外部の電磁石を電磁コイルで移動させたりする必要がなく、極めて小型の磁気による駆動機構２６を用いて、小スペースで、２個の薄膜マイクロコイルからなる電磁石２９ａ，２９ｂを交互に磁化させるだけで、マイクロツール２５を移動させて微粒子１を分離することができる。駆動機構２６や識別手段２７が微小流路２１の外部に設けられているため、非接触・非侵襲で微粒子１を分離することができる。 The microchip according to the first embodiment of the present invention does not need to insert a magnetic material directly into a minute flow path or move an external electromagnet with an electromagnetic coil as in the prior art. Using the magnetic drive mechanism 26, the micro tool 25 can be moved to separate the microparticles 1 simply by magnetizing the electromagnets 29a and 29b made of two thin film microcoils alternately in a small space. Since the drive mechanism 26 and the identification means 27 are provided outside the microchannel 21, the microparticles 1 can be separated in a non-contact / non-invasive manner.
　従来の電磁石駆動機構では、マイクロツールを微小領域に多数設置することは困難であったが、本発明の第１の実施の形態のマイクロチップによれば、マイクロソート機構１２の駆動機構２６をより小さく構成することができるとともに、マイクロツール２５を安定に駆動するために十分な駆動力を保持することができる。このため、マイクロソート機構１２を多段に配置することができ、これにより、微粒子１の種類等に応じて、より細かく微粒子１を分離・分類することができる。 In the conventional electromagnet drive mechanism, it was difficult to install a large number of micro tools in a minute region. However, according to the microchip of the first embodiment of the present invention, the drive mechanism 26 of the micro sort mechanism 12 is more In addition to being able to be configured small, it is possible to maintain a sufficient driving force to drive the microtool 25 stably. For this reason, the microsort mechanism 12 can be arranged in multiple stages, whereby the fine particles 1 can be separated and classified more finely according to the type of the fine particles 1 and the like.
　なお、マイクロソート機構１２は、マイクロツール２５の駆動部２５ａがＮまたはＳに着磁されていてもよい。この場合、電磁石２９ａおよび電磁石２９ｂに互いに逆向きに電流を流すことにより、各磁場集中部材３０ａ，３０ｂが互いに反対の極性を有するため、駆動部２５ａが電磁石２９ａまたは電磁石２９ｂに引きつけられて、第１閉塞位置または第２閉塞位置に移動する。また、電磁石２９ａおよび電磁石２９ｂに逆向きに電流を流すことにより、各磁場集中部材３０ａ，３０ｂの極性が逆になるため、駆動部２５ａが反対側の電磁石に引きつけられて、反対側の閉塞位置に移動する。こうして、電磁石２９ａ，２９ｂでマイクロツール２５の移動を制御することができる。 In the microsort mechanism 12, the drive unit 25a of the microtool 25 may be magnetized in N or S. In this case, since the magnetic field concentrating members 30a and 30b have opposite polarities by flowing currents in the opposite directions to the electromagnet 29a and the electromagnet 29b, the drive unit 25a is attracted to the electromagnet 29a or the electromagnet 29b, Move to the 1 occlusion position or the 2nd occlusion position. Moreover, since the polarities of the magnetic field concentrating members 30a and 30b are reversed by flowing currents in the opposite directions to the electromagnet 29a and the electromagnet 29b, the drive unit 25a is attracted to the opposite electromagnet, and the opposite blocking position is reached. Move to. In this way, the movement of the microtool 25 can be controlled by the electromagnets 29a and 29b.
　マイクロツール２５は、マグネタイトやネオジムを含んだ磁気マイクロツール（ＭＭＴ）から成ることが好ましい。特に、ネオジムを含む場合には、磁力の性能向上が著しいため、ネオジムを含んだＭＭＴから成ることが好ましい。例えば、図４に示すように、ネオジムを５０％含み、着磁されたＭＭＴは、マグネタイトを５０％含み、着磁されたＭＭＴと比べて、約４４倍の磁力の性能向上が認められる。なお、ネオジムを５０％含み、着磁されたＭＭＴは、マグネタイトを５０％含み、着磁されていないＭＭＴと比べると、約１００倍の磁力の性能向上が認められる。 The microtool 25 is preferably made of a magnetic microtool (MMT) containing magnetite or neodymium. In particular, in the case of containing neodymium, it is preferable to be made of MMT containing neodymium because the performance of magnetic force is remarkably improved. For example, as shown in FIG. 4, an MMT that contains 50% neodymium and is magnetized contains 50% magnetite, and a performance improvement of about 44 times the magnetic force is recognized compared to a magnetized MMT. It should be noted that the magnetized MMT containing 50% neodymium contains 50% magnetite, and an improvement in magnetic force performance of about 100 times is recognized as compared with an unmagnetized MMT.
　また、図５に示すように、１対の磁場集中部材３０ａ，３０ｂは、それぞれ細長いピンから成り、各電磁石２９ａ，２９ｂの上部に架け渡されたガラス基板の内部に埋め込まれていてもよい。この場合、各磁場集中部材３０ａ，３０ｂは、それぞれ各電磁石２９ａ，２９ｂの上部に配置され、ガラス基板の下部から上部にかけて互いに近づくよう、傾斜して設けられている。また、各磁場集中部材３０ａ，３０ｂは、上端が、マイクロツール２５の駆動部２５ａの先端両側に配置されるよう設けられている。これにより、各電磁石２９ａ，２９ｂで発生した磁界を、ピン状の各磁場集中部材３０ａ，３０ｂに集中させることができ、マイクロツール２５の駆動部２５ａを併進移動させることができる。また、磁界がピン状の各磁場集中部材３０ａ，３０ｂに集中するため、磁場干渉領域をより狭くすることができる。なお、この構成では、マイクロツール２５がネオジムを含んだＭＭＴから成る場合、マイクロツール２５の駆動部２５ａを、最速約１０Ｈｚで駆動可能であることが確認されている。 Further, as shown in FIG. 5, the pair of magnetic field concentrating members 30a and 30b may be formed of elongated pins, respectively, and may be embedded in the glass substrate spanned over the electromagnets 29a and 29b. In this case, the magnetic field concentrating members 30a and 30b are disposed on the upper portions of the electromagnets 29a and 29b, respectively, and are inclined so as to approach each other from the lower portion to the upper portion of the glass substrate. The magnetic field concentrating members 30 a and 30 b are provided so that the upper ends thereof are arranged on both sides of the tip of the driving unit 25 a of the microtool 25. As a result, the magnetic fields generated by the electromagnets 29a and 29b can be concentrated on the pin-shaped magnetic field concentrating members 30a and 30b, and the driving unit 25a of the microtool 25 can be translated. Further, since the magnetic field is concentrated on each of the pin-shaped magnetic field concentrating members 30a and 30b, the magnetic field interference region can be further narrowed. In this configuration, when the microtool 25 is made of MMT containing neodymium, it has been confirmed that the drive unit 25a of the microtool 25 can be driven at a maximum speed of about 10 Hz.
　また、図６に示すように、１対の磁場集中部材３０ａ，３０ｂは、それぞれ先端が尖った三角形状のニッケル製のピンから成り、マイクロモジュール１１に埋め込まれていてもよい。なお、各磁場集中部材３０ａ，３０ｂは、先鋭形状のものであれば実施例に限るものではない。この場合、各磁場集中部材３０ａ，３０ｂは、微小流路２１を挟むようにして、尖った先端を互いに向かい合わせて配置されている。これにより、各電磁石２９ａ，２９ｂで発生した磁界を、各磁場集中部材３０ａ，３０ｂに集中させることができ、マイクロツール２５の駆動部２５ａを併進移動させることができる。また、磁界が、尖った先端を互いに向かい合わせて配置された各磁場集中部材３０ａ，３０ｂに集中するため、磁場干渉領域をより狭くすることができる。なお、この構成では、マイクロツール２５がネオジムを含んだＭＭＴから成る場合、マイクロツール２５の駆動部２５ａを、最速約１８０Ｈｚで駆動可能であることが確認されている。 Further, as shown in FIG. 6, the pair of magnetic field concentrating members 30a and 30b may be composed of triangular nickel pins each having a pointed tip, and may be embedded in the micromodule 11. Each magnetic field concentrating member 30a, 30b is not limited to the embodiment as long as it has a sharp shape. In this case, the magnetic field concentrating members 30a and 30b are arranged with their sharp tips facing each other so as to sandwich the microchannel 21. As a result, the magnetic fields generated by the electromagnets 29a and 29b can be concentrated on the magnetic field concentration members 30a and 30b, and the drive unit 25a of the microtool 25 can be translated. In addition, since the magnetic field is concentrated on each of the magnetic field concentration members 30a and 30b arranged with the sharp tips facing each other, the magnetic field interference region can be further narrowed. In this configuration, when the microtool 25 is made of MMT containing neodymium, it has been confirmed that the drive unit 25a of the microtool 25 can be driven at a maximum speed of about 180 Hz.
　図７は、本発明の第２の実施の形態のマイクロチップを示している。
　なお、以下の説明では、本発明の第１の実施の形態のマイクロチップの構成と同一の部材には同一の符号を付して、重複する説明を省略する。
　図７に示すように、本発明の第２の実施の形態のマイクロチップは、多段マイクロソート機構から成り、マイクロモジュール５１とマイクロソート機構１２とを有している。 FIG. 7 shows a microchip according to a second embodiment of the present invention.
In the following description, the same members as those in the configuration of the microchip according to the first embodiment of the present invention are denoted by the same reference numerals, and redundant description is omitted.
As shown in FIG. 7, the microchip according to the second embodiment of the present invention includes a multistage microsort mechanism, and includes a micromodule 51 and a microsort mechanism 12.
　図７に示すように、マイクロモジュール５１は、微粒子１を流すための微小流路２１を有し、微小流路２１は２つの第１段分岐路５２ａ，５２ｂと、各第１段分岐路５２ａ，５２ｂがさらに２つに分岐した４つの第２段分岐路５３ａ，５３ｂ，５３ｃ，５３ｄとを有している。 As shown in FIG. 7, the micromodule 51 has a microchannel 21 for flowing the microparticles 1, and the microchannel 21 includes two first- stage branch paths 52 a and 52 b and each first-stage branch path 52 a. , 52b has four second- stage branch paths 53a, 53b, 53c, 53d that are further branched into two.
　マイクロソート機構１２は、各第１段分岐路５２ａ，５２ｂの分岐位置と、各第２段分岐路５３ａ，５３ｂ，５３ｃ，５３ｄの２つの分岐位置とに、全部で３つ設けられている。各マイクロソート機構１２の識別手段２７は、微小流路２１を流れる微粒子１が下流の分岐路に行くに従って、微粒子１の種類に応じてより細かく分離・分類されるよう、微粒子１の種類を識別可能になっている。 Three microsort mechanisms 12 are provided in total at the branch positions of the first stage branch paths 52a and 52b and the two branch positions of the second stage branch paths 53a, 53b, 53c and 53d. The identification means 27 of each microsort mechanism 12 identifies the type of the fine particle 1 so that the fine particle 1 flowing through the micro flow channel 21 is further separated and classified according to the type of the fine particle 1 as it goes to the downstream branch path. It is possible.
　本発明の第２の実施の形態のマイクロチップでは、各マイクロソート機構１２の識別手段２７で微粒子１の形状または特性を検出した信号が制御部２８で電気信号に変換されて、それぞれの識別手段２７に対応する各第１段分岐路５２ａ，５２ｂの薄膜マイクロコイルから成る各電磁石２９ａ，２９ｂ、または、各第２段分岐路５３ａ，５３ｂ，５３ｃ，５３ｄの薄膜マイクロコイルから成る各電磁石２９ａ，２９ｂを電磁駆動する。 In the microchip according to the second embodiment of the present invention, a signal obtained by detecting the shape or characteristic of the fine particles 1 by the identification means 27 of each microsort mechanism 12 is converted into an electric signal by the control unit 28, and each identification means 27, each electromagnet 29a, 29b composed of a thin film microcoil in each first stage branch 52a, 52b, or each electromagnet 29a, composed of a thin film microcoil in each second stage branch 53a, 53b, 53c, 53d, 29b is electromagnetically driven.
　ここで、図７に示す多段マイクロソート機構の分離・分類シーケンスを説明する。まず最初に、１段目で、制御部２８の電気信号に基づき、１段目の薄膜マイクロコイルから成る各電磁石２９ａ，２９ｂがオン、オフされ、生じた微小磁界により、ピン支持機構で支持部２５ｂを支持された矢印形状の磁性体であるマイクロツール２５の駆動部２５ａが微小流路２１内で左右に移動し、微粒子１が２段目のマイクロソート機構１２に導かれる。２段目のマイクロソート機構１２では、制御部２８の電気信号により、２段目の薄膜マイクロコイルから成る各電磁石２９ａ，２９ｂがオン、オフされ、マイクロツール２５の駆動部２５ａが微小流路２１内で左右に移動し、後段の第２段分岐路５３ａ，５３ｂ，５３ｃまたは５３ｄに微粒子１が導かれる。 Here, the separation / classification sequence of the multistage microsort mechanism shown in FIG. 7 will be described. First, at the first stage, the electromagnets 29a and 29b made of the first-stage thin film microcoil are turned on and off based on the electric signal from the control unit 28, and the pin support mechanism supports the support part by the micro magnetic field generated. The drive unit 25a of the micro tool 25, which is an arrow-shaped magnetic body supported by 25b, moves to the left and right in the micro flow path 21, and the fine particles 1 are guided to the second-stage micro sort mechanism 12. In the second-stage microsort mechanism 12, the electromagnets 29 a and 29 b formed of the second-stage thin film microcoil are turned on and off by the electric signal from the control unit 28, and the driving unit 25 a of the microtool 25 is moved to the microchannel 21. The fine particles 1 are guided to the second- stage branching passage 53a, 53b, 53c or 53d at the rear stage.
　このように、各マイクロツール２５の移動点を適宜コントロールすることにより、４つの第２段分岐路５３ａ，５３ｂ，５３ｃ，５３ｄのうち、目的の第２段分岐路５３ａ，５３ｂ，５３ｃまたは５３ｄに微粒子１を分離・分類することができる。マイクロソート機構１２を２段に限らず多段に連続配置することにより、省スペースで磁場干渉なく、複数の分岐路に目的の微粒子１をソートすることが可能である。 In this way, by appropriately controlling the movement point of each microtool 25, the target second- stage branch path 53a, 53b, 53c or 53d is selected from the four second- stage branch paths 53a, 53b, 53c, and 53d. The fine particles 1 can be separated and classified. By continuously arranging the microsort mechanism 12 in multiple stages as well as in two stages, it is possible to sort the target fine particles 1 into a plurality of branch paths without space and magnetic field interference.
　図８は、本発明の第３の実施の形態のマイクロチップを示している。
　なお、以下の説明では、本発明の第１の実施の形態のマイクロチップの構成と同一の部材には同一の符号を付して、重複する説明を省略する。
　図８に示すように、本発明の第３の実施の形態のマイクロチップは、マルチチャネル型マイクロチップから成っている。 FIG. 8 shows a microchip according to a third embodiment of the present invention.
In the following description, the same members as those in the configuration of the microchip according to the first embodiment of the present invention are denoted by the same reference numerals, and redundant description is omitted.
As shown in FIG. 8, the microchip according to the third embodiment of the present invention is a multi-channel microchip.
　本発明の第３の実施の形態のマイクロチップは、ローディング機構７１により個々の微粒子１を１個ずつ分離し、分離された微粒子１は、本発明の第２の実施の形態の多段マイクロソート機構７２を経て、４つの微小流路２１から成る分岐路群７３のうち目的の微小流路２１に導かれる。目的の微小流路２１に導かれた微粒子１は、細胞加工工程７４を経て、マイクロソート機構１２の識別手段２７に導かれる。この識別手段２７で、微粒子１の形状や特性を検出した信号は、制御部２８のコンピュータ３５により判定されてマイクロツール２５を制御し、加工後の微粒子１を選別する。マイクロソート機構１２により必要な微粒子１として選別された微粒子１のみが、細胞カップリングおよび融合システム７５に導かれる。マイクロソート機構１２により不要な微粒子１として選別された微粒子１は、除去される。 The microchip according to the third embodiment of the present invention separates the individual fine particles 1 one by one by the loading mechanism 71, and the separated fine particles 1 are separated into the multistage microsort mechanism according to the second embodiment of the present invention. 72, the light is guided to the target microchannel 21 in the branch path group 73 including the four microchannels 21. The microparticles 1 guided to the target microchannel 21 are guided to the identification means 27 of the microsort mechanism 12 through the cell processing step 74. A signal obtained by detecting the shape and characteristics of the fine particles 1 by the identification means 27 is determined by the computer 35 of the control unit 28 and the micro tool 25 is controlled to select the processed fine particles 1. Only the microparticles 1 selected as the necessary microparticles 1 by the microsort mechanism 12 are guided to the cell coupling and fusion system 75. The fine particles 1 selected as unnecessary fine particles 1 by the microsort mechanism 12 are removed.
　この図８に示すマルチチャネル型マイクロチップでは、極めて僅かな面積内で、細胞核移植に必要なローディング、分離・分類、加工、選別、カップリング、融合等のバイオ操作を人的な操作に頼ることなく、高速で、自動的に実現することができる。 In the multichannel microchip shown in FIG. 8, within a very small area, the biooperations such as loading, separation / classification, processing, sorting, coupling, and fusion necessary for cell nuclear transfer are reliant on human operations. Can be realized automatically at high speed.
　図８に示すように、一個のマイクロチップ内に、極めて小型のマイクロソート機構１２を多段に配置し、目的の微粒子１を必要な微小流路２１に高速にソートし、微粒子１を加工することができるため、今後、加速度的に増加する微粒子（卵子、細胞、細菌等）の分離、分類、加工、選択、処理の一連の処理能力を向上させることができる。この高スループットで多機能なマイクロチップを利用することで、今までピペットなどを用いて顕微鏡下で行われてきた分離・加工・選択・融合等の複雑なバイオ操作を、人的な操作を行わないで、自動的に高速で、効率的に行うことが可能になる。  As shown in FIG. 8, extremely small microsort mechanisms 12 are arranged in multiple stages in one microchip, and target microparticles 1 are sorted at high speed into necessary microchannels 21 to process microparticles 1. Therefore, it is possible to improve a series of processing capabilities for separation, classification, processing, selection, and processing of particles (egg, cells, bacteria, etc.) that increase at an accelerated rate in the future. By using this high-throughput, multifunctional microchip, humans can perform complex bio-operations such as separation, processing, selection, and fusion that have been performed under a microscope with a pipette. Without this, it becomes possible to automatically perform at high speed and efficiently.
　本発明によれば、今後のバイオ技術分野の発展に伴い、加速度的に増加するバイオ関連微粒子のローディング、分離・分類、加工、選別、カップリング、融合プロセスを自動的に高速で実現できるマルチチャネル型マイクロチップを供給することができる。また、産業的にも充分な処理能力を有しており、バイオ産業の発展に貢献することができる。 According to the present invention, with the development of the biotechnology field in the future, multi-channel capable of automatically and rapidly realizing the loading, separation / classification, processing, sorting, coupling, and fusion process of bio-related fine particles that increase at an accelerated rate. Type microchip can be supplied. Moreover, it has sufficient processing capacity industrially and can contribute to the development of the bio industry.
　　１　微粒子
　１１　マイクロモジュール
　１２　マイクロソート機構
　２１　微小流路
　２２ａ，２２ｂ　分岐路
　２３　取付室
　２４　ピラー
　２５　マイクロツール
　　２５ａ　駆動部
　　２５ｂ　支持部
　　２５ｃ　貫通孔
　２６　駆動機構
　２７　識別手段
　２８　制御部
　２９ａ，２９ｂ　電磁石
　３０ａ，３０ｂ　磁場集中部材
　３１　ガラス板
　３２ａ，３２ｂ　高透磁率部
　３３　電流増幅アンプ
　３４　ＡＣ／ＤＣ変換器
　３５　コンピュータ
　３６　ＤＣ／ＡＣ変換器
  DESCRIPTION OF SYMBOLS 1 Fine particle 11 Micro module 12 Micro sort mechanism 21 Micro flow path 22a, 22b Branch path 23 Mounting chamber 24 Pillar 25 Micro tool 25a Drive part 25b Support part 25c Through-hole 26 Drive mechanism 27 Identification means 28 Control part 29a, 29b Electromagnet 30a, 30b Magnetic field concentrating member 31 Glass plate 32a, 32b High permeability part 33 Current amplification amplifier 34 AC / DC converter 35 Computer 36 DC / AC converter

Claims (6)

  1. 　一端に磁性を有し、他端を中心として滑らかに回転可能とすることにより、微小流路を流れる微粒子を分岐路のうちの一つに選択的に誘導するマイクロツールと、
    　前記微小流路の外部に設けられる電磁石と磁場集中部材とによって前記マイクロツールの前記回転を可能とする駆動機構とを、
    　有することを特徴とするマイクロソート機構。     Having a magnet at one end and being able to rotate smoothly around the other end, a micro tool for selectively guiding fine particles flowing through the micro channel to one of the branch channels;
    A drive mechanism that enables the rotation of the microtool by an electromagnet and a magnetic field concentrating member provided outside the microchannel;
    A microsort mechanism comprising:
  2. 　前記磁場集中部材は、高透磁率部を有し、前記駆動機構が動作状態ではないときに、前記マイクロツールの磁性を有する前記一端に対して両側に配置することを特徴とする請求項１記載のマイクロソート機構。 The magnetic field concentrating member has a high magnetic permeability portion, and is arranged on both sides with respect to the one end having magnetism of the microtool when the driving mechanism is not in an operating state. Microsort mechanism.
  3. 　前記電磁石は２つから成り、それぞれ各分岐路に対応する位置に、互いの磁場の干渉を受けないよう所定の間隔をあけて設けられていることを、特徴とする請求項１または２記載のマイクロソート機構。 The said electromagnet consists of two, and it is provided in the position corresponding to each branch path with a predetermined space | interval so that it may not receive interference of a mutual magnetic field, The Claim 1 or 2 characterized by the above-mentioned. Microsort mechanism.
  4. 　前記微小流路を有するマイクロモジュールと、請求項１、２または３記載のマイクロソート機構とを有することを、特徴とするマイクロチップ。 A microchip comprising the micromodule having the minute flow path and the microsort mechanism according to claim 1, 2 or 3.
  5. 　前記微小流路を流れる微粒子の種類を識別する識別手段と、
    　前記識別手段で識別された前記微粒子の種類に基づいて、前記微粒子を一つの分岐路に選択的に誘導するよう前記駆動機構を制御する制御部とを、
    　有することを特徴とする請求項４記載のマイクロチップ。     Identifying means for identifying the type of particulate flowing through the microchannel;
    A control unit that controls the drive mechanism to selectively guide the fine particles to one branch path based on the type of the fine particles identified by the identification means;
    5. The microchip according to claim 4, further comprising:
  6. 　前記マイクロモジュールおよび前記マイクロソート機構が多段に配置されていることを、特徴とする請求項４または５記載のマイクロチップ。
          The microchip according to claim 4 or 5, wherein the micromodule and the microsort mechanism are arranged in multiple stages.
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