WO2007057989A1 - 液滴生成搬送方法及び装置、並びに粒子操作装置 - Google Patents
液滴生成搬送方法及び装置、並びに粒子操作装置 Download PDFInfo
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- WO2007057989A1 WO2007057989A1 PCT/JP2006/304382 JP2006304382W WO2007057989A1 WO 2007057989 A1 WO2007057989 A1 WO 2007057989A1 JP 2006304382 W JP2006304382 W JP 2006304382W WO 2007057989 A1 WO2007057989 A1 WO 2007057989A1
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
- G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
- G01N35/1009—Characterised by arrangements for controlling the aspiration or dispense of liquids
- G01N35/1016—Control of the volume dispensed or introduced
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0046—Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
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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
- B01L3/02—Burettes; Pipettes
- B01L3/0241—Drop counters; Drop formers
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F33/00—Other mixers; Mixing plants; Combinations of mixers
- B01F33/30—Micromixers
- B01F33/302—Micromixers the materials to be mixed flowing in the form of droplets
- B01F33/3021—Micromixers the materials to be mixed flowing in the form of droplets the components to be mixed being combined in a single independent droplet, e.g. these droplets being divided by a non-miscible fluid or consisting of independent droplets
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00277—Apparatus
- B01J2219/00279—Features relating to reactor vessels
- B01J2219/00306—Reactor vessels in a multiple arrangement
- B01J2219/00313—Reactor vessels in a multiple arrangement the reactor vessels being formed by arrays of wells in blocks
- B01J2219/00315—Microtiter plates
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00277—Apparatus
- B01J2219/00351—Means for dispensing and evacuation of reagents
- B01J2219/00364—Pipettes
- B01J2219/00367—Pipettes capillary
- B01J2219/00369—Pipettes capillary in multiple or parallel arrangements
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00277—Apparatus
- B01J2219/00351—Means for dispensing and evacuation of reagents
- B01J2219/00373—Hollow needles
- B01J2219/00376—Hollow needles in multiple or parallel arrangements
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00277—Apparatus
- B01J2219/00457—Dispensing or evacuation of the solid phase support
- B01J2219/00459—Beads
- B01J2219/00468—Beads by manipulation of individual beads
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00277—Apparatus
- B01J2219/00497—Features relating to the solid phase supports
- B01J2219/005—Beads
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00583—Features relative to the processes being carried out
- B01J2219/00603—Making arrays on substantially continuous surfaces
- B01J2219/00646—Making arrays on substantially continuous surfaces the compounds being bound to beads immobilised on the solid supports
- B01J2219/00648—Making arrays on substantially continuous surfaces the compounds being bound to beads immobilised on the solid supports by the use of solid beads
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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
- B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
- B01L2200/06—Fluid handling related problems
- B01L2200/0605—Metering of fluids
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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
- 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
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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
- B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
- B01L2200/06—Fluid handling related problems
- B01L2200/0673—Handling of plugs of fluid surrounded by immiscible fluid
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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
- B01L2300/00—Additional constructional details
- B01L2300/08—Geometry, shape and general structure
- B01L2300/0832—Geometry, shape and general structure cylindrical, tube shaped
- B01L2300/0838—Capillaries
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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
- B01L2400/00—Moving or stopping fluids
- B01L2400/04—Moving fluids with specific forces or mechanical means
- B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
- B01L2400/0487—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics
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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
- B01L3/02—Burettes; Pipettes
- B01L3/0289—Apparatus for withdrawing or distributing predetermined quantities of fluid
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
- G01N2035/00465—Separating and mixing arrangements
- G01N2035/00564—Handling or washing solid phase elements, e.g. beads
- G01N2035/00574—Means for distributing beads
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
- G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
- G01N2035/1027—General features of the devices
- G01N2035/1034—Transferring microquantities of liquid
- G01N2035/1046—Levitated, suspended drops
Definitions
- the present invention relates to generation of a droplet and its transport technology, and also relates to a technique for operating a transported object such as a particle using a droplet or a trace liquid sample.
- the chip can be made by synthesizing oligomers of sequences designed in a large number of partitioned cells one by one by using photochemical reaction and lithography widely used in the semiconductor industry (Science 2 51, 767-773 (1991)) and a method of implanting multiple types of probes one by one in each compartment (Science 270, 467-470 (1995); Nat. Biotechnol. 18, 438-441 (2000)) is there.
- the probe type is identified by the oligomer production position or the spot position of each probe.
- each probe is color-coded.
- a method using particles (Clinical Chemi stry 43, 1749-1756 (1997); US Pat. No. 6,023,540), or a method for identifying probe species in the order in which they are arranged in a pillar or a microchannel chip (Nucleic Acids Res earch 30, e87 (2002), Japanese Patent No. 3593525, Japanese Patent Laid-Open No. 2005-17224).
- Patent Document 1 US Pat. No. 6,023,540
- Patent Document 2 Japanese Patent Laid-Open No. 11-243997
- Patent Document 3 Japanese Patent Laid-Open No. 2000-346842
- Patent Document 4 Patent No. 3593525
- Patent Document 5 Japanese Patent Laid-Open No. 2005-17224
- Non-Patent Document 1 Science 251, 767-773 (1991)
- Non-Patent Document 2 Science 270, 467-470 (1995)
- Non-Patent Document 3 Nat. Biotechnol. 18, 438-441 (2000)
- Non-Patent Document 4 Clinical Chemistry 43, 1749-1756 (1997)
- Non-Patent Document 5 Nucleic Acids Research 30, e87 (2002)
- Non-Patent Document 6 nalytical Chemistry 75, 3250-3255 (2003)
- the trapped particles are released from the tip of the particle trapping nozzle, and introduced into a capillary or a microchannel chip to produce a particle array.
- the released particles may not follow the flow.
- the frequency of the above-mentioned problem has been increasing in proportion to the number of particles arranged in the flow path in the gill. This is because the flow resistance in the girder channel increases in proportion to the number of particles arranged. This is because the force required to pull the particles decreases with the number.
- An object of the present invention is to provide means and a method for solving the above-described problems. It is another object of the present invention to provide an apparatus for efficiently transporting or sorting not only particles but also a transported object including a liquid sample.
- droplets are generated at the entrance of the capillary or at the entrance of the microchannel chip, and the particles released from the tip of the particle trapping nozzle are included in the droplets, so that the inside of the capillary or the micro- Particles are introduced into the channel chip.
- the particles are stably transported together with the droplets because they are less likely to be released outside the droplet force due to the surface tension of the gas-liquid interface.
- the droplet generating and conveying means will be described.
- the two liquid transport pipes are referred to as a first liquid transport pipe and a second liquid transport pipe, respectively.
- Insert one end of the first liquid transfer pipe into the liquid container absorb the liquid in the container using the pressure pump, and move toward the other end of the first liquid transfer pipe at the liquid feed speed VI.
- Deliver liquid The other end is open to the atmosphere, and the liquid that has passed through the first liquid transport pipe flows out at a constant speed at the other end.
- the liquid forms spherical droplets (droplets) due to surface tension.
- one end of the second liquid transport pipe is connected to a suction pump, and the liquid transport speed is set to V2 and the liquid transport pipe is set to a negative pressure.
- the other end of the second liquid transport pipe can absorb the liquid and transport the inside of the second liquid transport pipe by contact with the liquid.
- the liquid outflow liquid droplets are not affected by the gravity drop and the liquid If the distance reaches the inflow port, the liquid can be transferred from the first liquid transport pipe to the second liquid transport pipe and transported.
- the gap between the liquid outlet and the liquid inlet is referred to as an air gap.
- the droplet sucked into the second liquid transport pipe is torn off at the air gap.
- the continuous fluid supplied from the first liquid transport pipe generates liquid droplets in the air gap, and forms an intermittent flow of liquid and gas (air) in the second liquid transport pipe. become.
- the particle trapping means includes a particle storage container for storing a solution containing a plurality of particles, an elongated particle capture nozzle for capturing particles at the tip, a suction device and a pressurizer connected to the particle capture nozzle, and a particle capture nozzle. It has an actuator for inserting the tip into the solution in the container and pulling it up.
- the hole that opens at the tip of the particle trapping nozzle is smaller than the particle diameter.
- a particle trapping nozzle with a hole smaller than the diameter of the particle is inserted at the tip into a solution containing a plurality of particles with a biomolecular probe immobilized on the surface, and a suction force is applied to the tip of the particle trapping nozzle. In this way, the particle trapping nozzle that sucks and holds one particle at the tip is bowed out of the solution in the container, and the particles that are sucked and held at the tip of the particle trapping nozzle are pressurized and released.
- the particle manipulating apparatus includes the droplet generating and conveying means and the particle supplementing means described above. Specifically, the first liquid conveying tube and the liquid are supplied to the tube. The first liquid feeding means, the second liquid feeding pipe and the second liquid feeding means for sucking and transporting the liquid, the stage holding the plurality of containers for storing the solution containing a plurality of particles, and the stage are transferred. An actuating actuator, a particle trapping nozzle having a hole smaller than the diameter of the particle at the tip, an actuator for driving the particle trapping nozzle, a suction pressurizing means for generating positive or negative pressure at the tip of the particle trapping nozzle, A control unit for controlling these is provided.
- the particle trapping nozzle moves in an air gap between the first liquid transport pipe and the second liquid transport pipe so as not to contact the first liquid transport pipe and the second liquid transport pipe.
- the particles captured at the tip of the particle capturing nozzle are released into the formed droplets by driving the pressurizing machine.
- the released particles are encapsulated by coming into contact with the droplets, and are transported into the second liquid transport pipe.
- the particles contained in the droplets can be reliably guided into the channel inside the capillary, and the particle array. Can be produced.
- This method uses the surface tension of the gas-liquid interface. Therefore, it is possible to carry in the particles without depending on the flow velocity at which the particles are poured.
- the micro liquid sample can be transported and sorted.
- the volume of the droplet can be controlled by controlling the distance between the air gap formed by the first liquid conveying tube and the second liquid conveying tube. It can also be used as a micro dispenser.
- the present invention it is possible to reliably introduce and arrange particles with fixed biomolecules one by one into a particle array container, and to produce a particle array in which a plurality of different particles are arranged with high efficiency at a low production cost can do. Further, since the liquid sample can be collected in a small amount by using the apparatus of the present invention, not only particles but also a transported object including a liquid can be easily operated.
- FIG. 1 is a schematic diagram showing a droplet generation method and an intermittent fluid conveyance method according to the present invention.
- FIG. 2 is a schematic diagram showing the principle of liquid conveyance according to the present invention.
- FIG. 3 is a schematic diagram showing a result of generating 10 2 L liquid compartments in a second liquid transport pipe.
- FIG. 4 is a schematic diagram showing an example of a method for controlling the size of droplets generated in an air gap portion.
- FIG. 5 is a schematic view showing a microdispensing device as an application example of the present invention.
- FIG. 6 is a schematic view showing a particle manipulation device of the present invention.
- FIG. 7 (A) is a schematic diagram showing a state immediately before inserting a particle trapping nozzle into a target storage unit.
- FIG. 7 (B) is a schematic diagram showing a state in which a particle trapping nozzle having a negative pressure inside is inserted into a storage portion.
- FIG. 7 (C) is a schematic diagram showing a state where only one particle is held at the tip of the particle capturing nozzle.
- FIG. 7 (D) is a schematic diagram showing a state immediately before particles are released into a droplet.
- FIG. 7 (E) is a schematic diagram showing a state where particles are released into a droplet.
- FIG. 7 (F) is a schematic diagram showing a state in which particles contained in droplets are conveyed to a second droplet conveyance tube.
- FIG. 7 (G) is a schematic diagram showing a state in which particles contained in the liquid compartment are conveyed.
- FIG. 8 is a schematic diagram of a particle manipulation device of the present invention using a microchannel chip as a particle array container.
- FIG. 9 is a schematic diagram showing an example of an apparatus configuration of the present invention in which particle manipulation means are arranged in parallel.
- FIG. 10 is a schematic diagram showing an example of a device configuration of the present invention in which particle manipulation means are arranged in parallel.
- FIG. 11 is a schematic diagram showing a state in which particles are arranged in five second liquid transport pipes.
- FIG. 12 is a schematic view showing an example of an apparatus according to the present invention in which second liquid transport pipes are arranged in parallel.
- FIG. 13 is a schematic diagram showing an example of an apparatus according to the present invention in which second liquid transport pipes are arranged in parallel.
- FIG. 14 (A) is a schematic diagram showing a form in which a first liquid transport pipe and a second liquid transport pipe are arranged radially.
- FIG. 14 (B) is a schematic diagram showing a state in which particles encapsulated in a droplet are introduced into a second liquid transport pipe.
- FIG. 14 (C) is a schematic diagram showing a state in which particles encapsulated in droplets are introduced into the second liquid transport pipe.
- FIG. 14 (D) is a schematic diagram showing a state in which a particle array is formed in a plurality of second liquid transport pipes.
- FIG. 15 is an explanatory diagram of a particle preparation method and a configuration example of a particle storage plate.
- FIG. 16 is a schematic cross-sectional view of m particle array containers in which particles are arranged.
- FIG. 17 (A) is a schematic diagram showing the form of a hybridization experiment using a particle array.
- FIG. 17 (B) is a schematic diagram showing how fluorescence is detected after hybridization.
- FIG. 18 (A) is a schematic diagram showing how oil flows through the first liquid transport pipe.
- FIG. 18 (B) is a schematic diagram showing how oil droplets are generated.
- FIG. 18 (C) is a schematic diagram showing a state in which a minute amount of liquid discharged from a dispensing nozzle is enclosed in an oil droplet.
- FIG. 18 (D) A schematic diagram showing a state in which an oil droplet containing a trace amount of liquid moves to a second liquid transport pipe.
- FIG. 18 (E) is a schematic diagram showing a state in which particles contained in the liquid compartment are conveyed.
- FIG. 19 is a schematic view showing an example of a trace liquid operation device of the present invention.
- the droplet generation method and the intermittent fluid conveyance method of the present invention will be described based on experiments using pure water.
- FIG. 1 is a schematic diagram showing an experimental system of the droplet generation method and the intermittent fluid conveyance method of the present invention.
- This experimental system is composed of a liquid container 1, a first liquid feed pump 2, a first liquid transport pipe 3, a second liquid transport pipe 4, a liquid collection container 5, and a suction pump 6.
- Liquid container 1 is stocked with pure water 7.
- a three-way valve 8 is inserted between the liquid container 1 and the first liquid feed pump 2.
- a peristaltic pump is used for the first liquid feed pump 2 and an aspirator is used for the suction pump 6.
- a diaphragm pump instead of the peristaltic pump, a diaphragm pump may be used, and a peristaltic pump, a diaphragm pump, a rotary pump, an oil rotary pump, etc. may be used instead of the aspirator.
- the vicinity of the open end of the first liquid transport pipe 3 and the vicinity of the open end of the second liquid transport pipe 4 are on the same axis as the y axis, and the respective open ends face each other.
- the opening end of the first liquid transfer pipe 3 is described as a liquid outlet 9 and the opening end of the second liquid transfer pipe is described as a liquid inlet 10.
- the air gap 11, which is the distance between the liquid outlet 9 and the liquid inlet 10, is variable between O.Omm and 2. Omm.
- the inner diameters of the first liquid transport pipe 3 and the second liquid transport pipe 4 are preferably about O. Olmm to lmm. As will be described later, when the volume of the droplet generated in the air gap 11 is reduced, or when reproducibility of the volume of the droplet is emphasized, and when a larger volume variable range is desired, the wall thickness is reduced with a smaller inner diameter. It is better to use a simple tube. In this embodiment, a pipe having an inner diameter of 0.5 mm and an outer diameter of 1 mm is used.
- the pure water 7 is supplied to the first liquid transport pipe 3 using the first liquid feed pump 2 and is sent at a constant speed VI.
- the inside of the second liquid transport pipe 4 is depressurized by about 1 atm by the suction pump 6 of the aspirator.
- VI was changed in the range of 0.1 ⁇ L / sec. To 20 ⁇ L / sec.
- the pure water 7 sent through the first liquid transport pipe 3 reaches the air gap 11 via the liquid outlet 9 as shown in FIG.
- droplets 12 are generated in the air gap 11.
- the droplet 12 swelled in a spherical shape reaches the liquid inlet 10 of the second liquid transport pipe 4 as shown in FIG. 2 (D), the second liquid transport pipe 4 as shown in FIG. 2 (E).
- FIG. 2 (E) Drawn into.
- FIG. 3 is a schematic diagram showing an example in which the air compartment 14 is forcibly inserted into the first liquid transport pipe 3 by switching the three-way solenoid 8 at a certain timing using the experimental system of FIG. It is.
- By inserting the air compartment 14 with timing control it is possible to control the number of the liquid compartments 13 that can keep the liquid amount of the liquid compartment 13 of the pure water 7 described in FIG.
- Fig. 3 shows an example in which about 20 L of pure water 7 is sucked up by the first liquid pump 2 and then the three-way valve 8 is switched to the air side, and 10 2 L liquid compartments 13 are generated. It is a schematic diagram which shows a result
- FIG. 4 is a schematic diagram showing an example of a method for controlling the liquid volume in the liquid compartment 13 by controlling the size of the droplet 12.
- the spherical diameter of the droplet 12 that is, the volume of the droplet 12 to be sorted and the volume of the liquid compartment 13 can be arbitrarily changed.
- Fig. 4 (A) shows a state in which the air gap 11 interval is 1 mm and a 4 L droplet is generated in the air gap 11!
- Fig. 4 (B) shows the air gap 11 in Fig. 4 (A) halved. By halving the air gap, it becomes 0. ), A droplet 12 having a liquid volume of 1/3 of 2 can be generated in the air gap 11 parts.
- the air gap 11 is set to 2 mm or less so that the true spherical structure is maintained.
- the distance of the air gap 11 is preferably controlled to 0.5 mm or less.
- the reproducibility of the liquid volume to be sorted is improved by using a tube having a small inner diameter.
- the force received by the velocity gradient in the vicinity of the liquid outlet 9 increases.
- the liquid can be cut even with a weak force, so that the place where the droplet 12 is torn off is accurately reproduced.
- the cross-sectional area of the liquid to be sent is small, it is suitable for a small amount of liquid fractionation.
- the first liquid transport pipe 3 and the second liquid transport pipe 4 having an inner diameter of 0. Olmm are used, the liquid can be well separated in the range of 500 ⁇ -5 / ⁇ L.
- FIG. 5 is a schematic diagram showing an example in which the droplet generating and conveying means described in FIGS. 1 to 4 is applied to a minute amount dispensing.
- a second liquid feeding pump 15 such as a peristaltic pump or a diaphragm pump is used as a pump for setting the inside of the second liquid transport pipe 4 to a negative pressure.
- a chamber surrounding the air gap is prepared and the inside of the chamber is pressurized, it can be used as a liquid feed pump.
- the separated liquid fraction 13 can be dropped on the reaction vessel, the slide glass plate 16 and the membrane.
- FIG. 5 shows a state of dropping on the glass slide plate 16.
- DNA professional Prepare a protein probe, control the position of the glass slide plate 16 with an actuator, drop the preparative droplet 17 that has passed through the second liquid transport tube 4 as the liquid compartment 13, and drop it into the V Chips and protein chips can be produced.
- the means and method of the present embodiment described with reference to Figs. 1 to 5 are based on the microdispenser for microtiter plates, microspotters for DNA chips and protein chips, and protein samples.
- Matrix-assisted laser desorption ion method can be used as a spotter for pretreatment slides in mass spectrometry systems.
- a particle manipulation device and method thereof will be described.
- a method of producing a particle array in the second liquid transfer tube 4 will be taken up.
- An example of preparing a plurality of types with a fixed particle diameter and a biomolecular probe fixed on the particle surface and arranging them in a row in the second liquid transport pipe 4 in a predetermined order This will be explained using the principle of operation.
- FIG. 6 is a schematic diagram showing an example of the particle manipulation device of the present invention.
- a particle storage plate 20 On the first plate-shaped member 18, there are a particle storage plate 20 and a plate installation jig 21 in which particles having biological probes that bind to biomolecules such as DNA, RNA, and protein are fixed and held in a plurality of storage portions 19. Installed via the first electric actuator 22 and the second electric actuator 23!
- the particle storage plate 20 is preferably a 96 (8 ⁇ 12) hole microtiter plate or a 384 (16 ⁇ 24) hole microtiter plate.
- the position of the particle storage plate 20 is controlled by a first electric actuator 22 movable in the X direction and a second electric actuator 23 movable in the y direction.
- the plate installation jig 21 is equipped with a vibration generator that can arbitrarily control the amplitude and vibration frequency.
- a particle trapping nozzle 25 and a particle trapping nozzle installation jig 26 having an inner diameter capable of sucking and holding only one particle at the tip are provided with a third electric actuator 27. Is fixed through.
- the inner diameter ID of the particle trapping nozzle 25 In order for the particle trapping nozzle 25 to suck and hold only one particle at the tip, when the particle diameter is R, the inner diameter ID of the particle trapping nozzle 25 must satisfy the relationship ID ⁇ R. If the outer diameter of the particle trapping nozzle 25 is OD, the OD should satisfy the relationship of R ⁇ OD and 2R.
- the particle diameter force S is 100 m
- the outer diameter of the particle trapping nozzle 25 used often exceeds twice.
- the vibration generator of the plate installation jig 21 described above is used. At that time, vibration with a frequency of 20Hz or more and an amplitude of 0.1mm or more should be added in the X-axis direction and y-axis direction in the figure.
- One end of the particle capturing nozzle 25 is connected to a particle suction pump 29 and a particle releasing pressure pump 30 via an electromagnetic three-way valve 28.
- the first liquid feed pump 2, the first liquid transport pipe 3, the second liquid transport pipe 4, and the suction pump 6 are the same as those described in FIG.
- the first liquid feed pump 2 sends pure water stocked in the liquid container 1 to the first liquid transport pipe 3 (not shown).
- the second liquid conveying tube 4 is connected to the third liquid conveying tube 31 via the first socket 32, and the third liquid conveying tube 4
- the liquid transfer pipe 31 is connected to the suction pump 6.
- the first socket 32 is a member that can be handled integrally with the second liquid transport pipe 4 and has one side that is slightly smaller than the diameter of the particles to be handled that is smaller than the inner diameter of the second liquid transport pipe 4. It is desirable to have a square hole. Furthermore, it is preferable that the cross-sectional shape is uneven. As a result, the particles do not get stuck in the first socket 32, and the flow path resistance can be lowered. Further, by inserting the first socket 32 between the second liquid transport pipe 4 and the third liquid transport pipe 31, the particles can be held inside the second liquid transport pipe 4.
- the inner diameter ID of the second liquid transfer tube 4 needs to satisfy the relationship of R ⁇ ID and 2R.
- the inner diameter ID of the second liquid transfer tube 4 can be about 0.15 mm.
- a commercially available glass capillary having an inner diameter of 0.15 mm and an outer diameter of 0.38 mm can be used.
- the reason for using glass material for the second liquid transfer tube 4 is that the particle array This is because the autofluorescence is the smallest over a wide wavelength range during the fluorescence measurement of the used assembly.
- the material may be changed depending on the application. For example, in measurement using bioluminescence or chemical light emission, using a transparent plastic tube does not work.
- Example 5 explains the fluorescence measurement of Atsey using a particle array.
- the vibration generators of the pressurizing pump 30, the first liquid feeding pump 2, the suction pump 6, and the plate installation jig 21 are controlled by a control device (computer) 33.
- FIGS. 7 (A) to 7 (G) show that, using the particle manipulating device of FIG. 6 of the present invention, one particle 35 from a plurality of particles stored together with the solution 34 is stored in the storage unit 19.
- It is a cross-sectional schematic diagram which shows the process to capture
- the first liquid transport pipe 3 and the second liquid transport pipe 4 have an inner diameter of 150 / ⁇ ⁇ and an outer diameter of 500 m.
- the solution 34 is pure water. Of course, the solution 34 may be pure water, buffer solution, alcohol or the like. For the sake of simplicity, no vibration is applied to the particle storage plate 20 here.
- the first portion of the container 19 that holds the target particles 35 is positioned so as to face the opening of the particle trapping nozzle 25 in the z direction.
- the state in which the particle storage plate 20 is moved by the electric actuator 22 and the second electric actuator 23 is shown. This is where the particle trapping nozzle 25 is inserted into the intended storage section 19.
- the electromagnetic three-way valve 28 is driven so that the particle trapping nozzle 25 and the particle suction pump 29 are connected to bring the tip of the particle trapping nozzle 25 into a negative pressure state.
- FIG. 7 (B) shows that the particle trapping nozzle installation jig 26 is lowered in the z direction by the control of the third electric actuator 27, and the lower end of the particle trapping nozzle 25 having a negative pressure inside is the storage portion.
- 19 shows the state of being inserted into the interior. In the inserted state, it is preferable that the tip surface of the particle capturing nozzle 25 is in contact with the bottom of the storage unit 19. This is because when the amount of particles 35 stored is small, the tip of the particle trapping nozzle 25 cannot contact the particles 35, and the trapping efficiency is reduced. At this time, if the particle storage plate 20 is shaken, the particle capturing efficiency of the particle capturing nozzle is improved.
- the droplet generation method and the liquid transport method are as described in FIG.
- the particle trapping nozzle 25 moves between the first liquid transport pipe 3 and the second liquid transport pipe 4, the air compartment 14 described in FIG. If the catch nozzle 25 is small enough for the droplet to be formed, the air compartment 14 need not be inserted.
- the diameter of droplet 12 is R and the outer diameter of particle trapping nozzle 25 is R, the condition of R / R ⁇ 5 is satisfied.
- FIG. 7C shows a state in which the tip of the particle trapping nozzle 25 is completely extracted from the solution 34 in the storage unit 19 into the atmosphere. At this time, only one particle 35 is held at the tip of the particle capturing nozzle 25. Although not shown, the physical phenomenon described below occurs between the steps of FIG. 7 (B) to FIG. 7 (C).
- FIGS. 7D and 7E are schematic views showing the moment when the trapped particles 35 are released into the droplets generated in the air gap 11.
- the pure water 7 of the droplet 12 partially flows toward the particle suction pump also in the nozzle.
- FIG. 7E when the electromagnetic three-way valve 28 is switched, the particle trapping nozzle 25 is connected to the particle releasing pressurization pump 30, and the inside of the particle trapping nozzle 25 is opened to the atmosphere. As a result, the particles 35 are released into the droplets 12.
- the air release is controlled by the control device (combination (Uter) 33 is used to synchronize with the droplet generation interval.
- an image sensor or a line sensor may be used as a detection means for synchronizing. While observing the droplet directly, send a signal to the control device 33 to release it to the atmosphere. Alternatively, the interval between the liquid compartments flowing in the second liquid transport pipe 4 may be monitored, the regularity may be read, and the data may be sent to the control device 33 so that the atmosphere is released to the atmosphere with good timing.
- the pressurization by the pressurizing pump 30 for releasing the particles is for release to the atmosphere, and the particles 35 are not blown by the pressure. Therefore, it is necessary to set the pressure to be applied and the pressure application time in advance in consideration of the length of the pipe between the particle trapping nozzle 25 and the particle releasing suction pump 30 and the inner diameter of the pipe.
- FIGS. 7 (F) and 7 (G) are schematic views showing how the particles 35 contained in the droplets 12 are transported to the second liquid transport pipe 4.
- the encapsulated particles 35 are stably introduced into the second liquid transport pipe 4 without being discharged to the outside due to the surface tension and internal pressure of the droplet 12.
- FIG. 7 (G) shows a state where the particles 35 are transported along with the liquid compartment 13 in the second liquid transport pipe 4.
- the particles 35 can be reliably operated and introduced into the second liquid transport pipe 4 one by one.
- a particle array can be produced by operating this process one particle 35 at a time for each storage section 19 of the particle storage plate 20. If a 384-well microtiter plate is used, 384 types of particle arrays for multi-item inspection can be produced.
- FIG. 8 shows an example in which the particle array container serving as the second liquid transport tube 4 is replaced with a microchannel chip 36.
- a particle array can be produced in the microchannel chip 36 by the method shown in FIG.
- the microchannel chip 36 is generally made of quartz glass or Pyrex (registered trademark) slide glass or PDMS with a particle arrangement channel patterned on the surface by wet etching or the like.
- a glass substrate made by attaching a glass slide, which must not be processed, to the substrate and bonding it.
- the particle arrangement channel has a cross-sectional area through which only one particle can pass, and a weir is provided in the arrangement channel end region on the third liquid transport pipe 31 side to prevent the particles from flowing out. ing.
- a gap is provided between the weir and the particle arrangement channel wall so as not to block the channel.
- FIG. 9 and FIG. 10 are two examples showing apparatus configurations in which the particle operation means described in FIG. 6 and FIG. 7 are arranged in parallel.
- the particle trapping nozzles 25 are parallel to the Xz plane and are arranged at regular intervals in the X-axis direction. These openings are all in the same position in the z-axis direction.
- five first liquid transport pipes 3 and five second liquid transport pipes 4 are provided.
- the first liquid transport pipe 3 and the second liquid transport pipe 4 are parallel to the xy plane and are arranged at a certain interval in the X-axis direction. These openings are all in the same position in the y-axis direction.
- the five particle trapping nozzles 25, the five first liquid transport pipes 3 and the five second liquid transport pipes 4 are installed so that each exists on the same y-z plane. is there. On the extension of the central axis of the five particle trapping nozzles 25, the positions of the openings of the five storage portions 19 on the air gap 11 and the particle storage plate 20 correspond to each other!
- FIG. 11 is a schematic diagram showing a state in which the particles 35 are arranged in the second liquid transport pipe 4 arranged on the XY plane. Exactly, the eighth particle 35 is introduced while being encapsulated in the liquid compartment 13. As described above, by paralleling the particle operation means in FIG. 9, it is possible to simultaneously produce five particle arrays in which the eight kinds of particles 35 are arranged in the second liquid transport pipe 4. In this example, for the sake of simplicity, the force described in the particle storage plate 20 having a storage portion of 5 X 8 is actually a 384-hole titer plate is used for the particle storage plate 20, and the particle trapping nozzle 25, Prepare 16 first liquid transport pipes 3 and 16 second liquid transport pipes 4 each.
- FIG. 10 shows an example in which a plurality of first liquid transport pipes 3 and second liquid transport pipes 4 are collectively arranged in n layers.
- the figure shows a structure with three layers stacked in the z-axis direction for simplicity, but many layers can be stacked as space permits.
- the user can automatically create a 16 X n particle array in one setting. I will become.
- FIGS. 12 and 13 are used as a particle array for one particle trapping nozzle 25 and one first liquid transport tube 3 in the particle manipulating apparatus described in FIGS. 6 and 7. These are two examples showing an apparatus configuration in which the second liquid transfer pipes 4 are arranged in parallel.
- Figures 14 (A) to 14 (D) show cross-sectional views taken along the same plane of x—y arranged at 90 ° intervals. Forces related to the outer diameter of the first liquid transfer pipe 3 and the second liquid transfer pipe 4 and also the air gap 11 distance. Up to 24 of these transfer pipes can be installed at intervals of 15 °. Of course, it is not necessary to arrange them at regular intervals.
- FIG. 14B shows a state in which the particles 35 contained in the droplets are introduced into the second liquid transport pipe 37.
- FIG. 14C shows a state in which the particles 35 contained in the droplets are introduced into the second liquid transport pipe 38.
- the particle sorting control as shown in FIGS. 14B and 14C can be changed by the control of the suction pump 6 connected to the second liquid transfer pipe 4. These controls are performed by a control device (computer) 33 based on dedicated software having a timing control function. Specifically, in FIG. 14 (B), only the second liquid transfer pipe 37 is in a negative pressure state, and in FIG. 14 (C), only the second liquid transfer pipe 38 is in a negative pressure state.
- FIG. 14 (D) is a schematic diagram showing a state in which a particle array is produced in order counterclockwise from the second liquid transport pipe 37.
- a feature of the apparatus configuration described in FIGS. 12 and 14 is that all the particles 35 in the storage portion 19 of the particle storage plate 20 can be arranged in the second liquid transport pipe 4.
- a 384-well titer plate is used for the particle storage plate 20, and one first liquid transport pipe 3 and 23 second liquid transport pipes 4 are prepared. This makes it possible to simultaneously produce 23 particle arrays in which 384 types of particles 35 are arranged.
- a plurality of particle storage plates 20 may be installed on the second electric actuator 23.
- FIG. 13 shows an example in which a plurality of first liquid transport pipes 3 and second liquid transport pipes 4 are collectively arranged in n layers in the z-axis direction. The figure shows a structure with two layers stacked in the z-axis direction for the sake of simplicity More layers can be stacked as long as the force space allows. This allows the user to automatically create a 23 x n particle array with a single setting.
- a particle storage plate 20 having m X n storage portions 19, a particle group, and a plurality of types of biomolecular probes such as DNA, RNA, or protein that modify the particles 35 are prepared.
- the storage units 19 on the particle storage plate 20 to be prepared are arranged at equal intervals at the first center interval in the X direction, and are arranged at equal intervals at the second interval in the y direction perpendicular to the X direction.
- the storage unit 19 has a circular top opening, a central axis parallel to the z direction, and a circular column with a bottom or a conical hole.
- a particle storage plate 20 having a plurality of storage portions 19 a commercially available 96-well microtiter plate or 384-well microtiter plate can be used.
- the size of the particles 35 is preferably a spherical shape having a diameter of 10 m or more when used for the particle capturing nozzle 25 made of glass.
- the particle 35 prepared in units of several mg is distributed from the particle container 39 to each storage unit 19 of the particle storage plate 20 using a spoon, and each storage unit 19 is stored in units of one row.
- different types of probes are introduced, and the probes are immobilized on all particle surfaces.
- n types of biomolecule probes are prepared, the No. 1 biomolecule probe is provided in the first row of m storage units, and the No. 1 biomolecule probe is provided in the second row of m storage units. 2 No. n biomolecule probes were introduced into the m storage units in the n-th row, and the probes were fixed to the particles 35 stored in the respective storage units 19. .
- the particle storage plate 20 is prepared once when the probe immobilized on the particle 35 is a chemically relatively stable biomolecule such as DNA. Since the particle storage plate 20 can be stored in a desiccator or stored in a refrigerator, it can be prepared.
- the particle storage plate 20 in which a solution such as pure water is introduced into each storage unit 19 is installed on the plate installation jig 21 of the particle array device of FIG. 9, and a particle array is produced by the operation process described with reference to FIG.
- FIG. 16 is a cross-sectional view schematically showing an example of m particle array containers 41 obtained by using a particle storage plate 20 having m X n storage portions 19 according to this embodiment.
- the particle array container 41 is the second liquid transport pipe 4.
- the second particle array container 41 has a hollow thin tube having an inner diameter as an outer diameter. Insert the socket 42 on the open end side. As a result, the movement of particles can be prevented by sandwiching the particle array between the first socket 32 and the second socket 42.
- a 384-well microtiter plate is used for the particle storage plate 20, and 24 types of DNA-immobilized particles are sequentially arranged using the particle manipulation device shown in FIG. A particle array was simultaneously prepared.
- Fig. 17 (A) and Fig. 17 (B) it has sequence 1 out of 24 types of probe DNA of 24 types of 18-base synthetic oligonucleotides modified with 5'-thiol groups with different base sequences.
- a particle array container 41 each having a single-stranded DNA probe 43 and a single-stranded DNA probe 44 having sequence 2 immobilized thereon, Cy3 labeled sequence 3 complementary to sequence 1
- a sample containing TexasRed-labeled single-stranded target DNA 46 having single-stranded target DNA 45 and sequence 4 complementary to sequence 2 was run to verify whether the target DNA binds to probe DNA as intended. .
- 20 mM phosphate buffer (pH 7.0) solution 47 containing the solution is flowed into the particle array container 41 where the DNA probe array has been prepared, and a noble hybridization reaction is performed at 45 ° C. went.
- the liquid feeding was performed using a syringe pump.
- the residual target DNA that did not contribute to the hybridization reaction was washed with 20 mM phosphate buffer (pH 7.0) solution 47 and pure water in order and dried.
- each particle in the particle array container 41 is examined with a fluorescence microscope 48 using a Cy3 long pass filter and a Texas Red long pass filter centering on the emission wavelength of Cy 3 and Texas Red. Observed.
- the predetermined particles emit Cy3 fluorescence 49 and another predetermined particle force TexasRed fluorescence 50, respectively. Observed. This indicates that the single-stranded target DNA 45 is surely hybridized to the single-stranded DNA probe 43 and the single-stranded target DNA 46 is hybridized to the single-stranded DNA probe 44. Thus, it was confirmed that a DNA probe array could be produced in the particle array container 41 without affecting the probe in an arbitrary permutation.
- an analyzer for detecting the amount of components contained in a sample such as blood or serum white light from a halogen lamp or the like is irradiated onto a reaction solution that is a mixture of a sample and a reagent, and passes through the reaction solution.
- a reaction solution that is a mixture of a sample and a reagent
- FIGS. 18 (A) to 18 (E) are schematic views showing a state in which the trace liquid 52 is contained in the oil droplet 51 and conveyed.
- FIG. 18 (A) shows just before the oil droplet 51 is formed from the first liquid transport pipe 3.
- FIG. 18B shows that oil has flowed out from the liquid outlet 9 of the first liquid transfer pipe 3 and oil droplets 51 have been generated in the air gap 11.
- FIG. 18 (C) shows a state in which the minute liquid 53 discharged from the liquid dispensing nozzle 52 is encapsulated in the oil droplet 51 toward the oil droplet 51.
- the contained micro liquid 53 is retained in the oil droplet 51 and is contained in the second liquid transport pipe 4. Transported.
- the discharge timing of the minute liquid 53 from the liquid dispensing nozzle 52 is synchronized with the generation of the oil droplet 51 using the control device (computer) 33.
- An image sensor or a line sensor is preferably used as the detection means for synchronizing. While observing the oil droplet 51 directly, a signal is sent to the control device 33 so that the trace liquid 53 is discharged. Alternatively, the interval between the oil compartments flowing in the second liquid transport pipe 4 is monitored, the regularity is read, the data is sent to the control device 33, and the minute liquid 53 is discharged in a timely manner. Also good
- FIG. 19 is a schematic diagram showing an example of the trace liquid operation device of the present invention.
- the figure shows an example in which the air gap 11 is inserted at two locations, and the sample droplet 57 and the reagent droplet 58 can be supplied into the oil droplet 51 transported from the liquid container 1 at the air gap 11 portion.
- the first liquid transport pipe 3, the second liquid transport pipe 4, and the detection cell liquid transport pipe 54 are provided with the first liquid feed pump 2, the second liquid feed pump 15, and the third liquid feed pump. It can be transported while holding the liquid compartment.
- the flow rate condition of each pipe is V1 ⁇ V2 ⁇ V3, and it is easy to use a peristaltic pump for these controls.
- a light source 55 and a detector 56 are provided in a part of the detection region of the detection cell liquid transport tube, and a mixed liquid of the sample droplet 57 and the reagent droplet 58 mixed in the oil droplet 51. Measure the absorbance at 59.
- the spectroscope and the condenser lens are omitted from the drawing.
- the reason why the oil droplet 51 is used in this embodiment is to prevent contamination in the transport pipe and crossover during continuous measurement. By using oil, it is possible to prevent the sample or reagent from adsorbing to the wall of the transfer tube.
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Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
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US12/084,990 US8029744B2 (en) | 2005-11-16 | 2006-03-07 | Method of liquid droplet formation and transport apparatus therefor and particle manipulating apparatus |
CN2006800430126A CN101310169B (zh) | 2005-11-16 | 2006-03-07 | 液滴生成运送方法和装置以及粒子操作装置 |
JP2007545160A JP4571193B2 (ja) | 2005-11-16 | 2006-03-07 | 液滴生成搬送方法及び装置、並びに粒子操作装置 |
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JP2005-331865 | 2005-11-16 | ||
JP2005331865 | 2005-11-16 |
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WO2007057989A1 true WO2007057989A1 (ja) | 2007-05-24 |
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PCT/JP2006/304382 WO2007057989A1 (ja) | 2005-11-16 | 2006-03-07 | 液滴生成搬送方法及び装置、並びに粒子操作装置 |
Country Status (4)
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US (1) | US8029744B2 (ja) |
JP (1) | JP4571193B2 (ja) |
CN (1) | CN101310169B (ja) |
WO (1) | WO2007057989A1 (ja) |
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JP2015142784A (ja) * | 2010-03-26 | 2015-08-06 | 株式会社湯山製作所 | 分注装置 |
JP2015527592A (ja) * | 2012-09-06 | 2015-09-17 | エフ.ホフマン−ラ ロッシュ アーゲー | 試料を緩衝液に分注するシステム |
KR20180095441A (ko) * | 2015-12-18 | 2018-08-27 | 인텔리전트 바이러스 이미징 아이엔씨. | 서브-비져블의 고정밀 정량화 |
JP2022037655A (ja) * | 2020-08-25 | 2022-03-09 | 株式会社オンチップ・バイオテクノロジーズ | 粒子の純化方法、単一粒子分注方法、及び細胞クラスター解析方法、並びそれに用いる装置 |
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CA2808118C (en) | 2010-07-22 | 2016-04-19 | Kieran Curran | Composite liquid cells |
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AU2013350823B2 (en) | 2012-11-27 | 2017-11-16 | Gencell Biosystems Ltd. | Handling liquid samples |
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JP2012042309A (ja) * | 2010-08-18 | 2012-03-01 | Sony Corp | 生理活性物質採取装置 |
JP2015527592A (ja) * | 2012-09-06 | 2015-09-17 | エフ.ホフマン−ラ ロッシュ アーゲー | 試料を緩衝液に分注するシステム |
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KR102150748B1 (ko) * | 2015-12-18 | 2020-09-01 | 인텔리전트 바이러스 이미징 아이엔씨. | 서브-비져블의 고정밀 정량화 |
JP2022037655A (ja) * | 2020-08-25 | 2022-03-09 | 株式会社オンチップ・バイオテクノロジーズ | 粒子の純化方法、単一粒子分注方法、及び細胞クラスター解析方法、並びそれに用いる装置 |
JP7440905B2 (ja) | 2020-08-25 | 2024-02-29 | 株式会社オンチップ・バイオテクノロジーズ | 粒子の純化方法、単一粒子分注方法、及び細胞クラスター解析方法、並びそれに用いる装置 |
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CN101310169A (zh) | 2008-11-19 |
CN101310169B (zh) | 2011-06-08 |
JPWO2007057989A1 (ja) | 2009-04-30 |
JP4571193B2 (ja) | 2010-10-27 |
US8029744B2 (en) | 2011-10-04 |
US20090020555A1 (en) | 2009-01-22 |
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