WO2021100619A1 - Dispositif et procédé de dispersion d'échantillon, trousse d'aliquotage d'échantillon et dispositif d'aliquotage de microparticules - Google Patents

Dispositif et procédé de dispersion d'échantillon, trousse d'aliquotage d'échantillon et dispositif d'aliquotage de microparticules Download PDF

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Publication number
WO2021100619A1
WO2021100619A1 PCT/JP2020/042365 JP2020042365W WO2021100619A1 WO 2021100619 A1 WO2021100619 A1 WO 2021100619A1 JP 2020042365 W JP2020042365 W JP 2020042365W WO 2021100619 A1 WO2021100619 A1 WO 2021100619A1
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Prior art keywords
sample
sample liquid
storage bag
liquid storage
flow path
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PCT/JP2020/042365
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English (en)
Japanese (ja)
Inventor
聡 西村
尚英 宮本
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ソニーグループ株式会社
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Publication of WO2021100619A1 publication Critical patent/WO2021100619A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M1/00—Apparatus for enzymology or microbiology
    • C12M1/26—Inoculator or sampler
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/0006—Modification of the membrane of cells, e.g. cell decoration
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/02—Devices for withdrawing samples
    • G01N1/10—Devices for withdrawing samples in the liquid or fluent state
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume, or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N15/14—Electro-optical investigation, e.g. flow cytometers

Definitions

  • This technology relates to a sample dispersion device, a sample dispersion method, a sample sorting kit, and a fine particle sorting device.
  • a laminar flow composed of a sample liquid containing fine particles and a sheath liquid is discharged from an orifice formed in a flow cell or a microchip.
  • a predetermined vibration is applied to the laminar flow to form droplets.
  • the moving direction of the formed droplets is electrically controlled depending on whether or not the target fine particles are contained, and the target fine particles are separated.
  • a technique for separating target fine particles in a microchip without forming droplets has also been developed.
  • Patent Document 1 "a sample liquid introduction flow path through which a sample liquid containing fine particles flows, and a sheath liquid that joins the sample liquid introduction flow path from both sides and introduces a sheath liquid around the sample liquid.
  • a negative pressure suction part that communicates with the merging flow path and sucks and draws in the fine particles to be collected, and at least one pair of disposal flow paths that are provided on both sides of the negative pressure suction part and communicate with the merging flow path.
  • the tube When the sample liquid flows into the microchip or the device, if the liquid is sent without stirring, the tube is likely to be clogged due to the high concentration of the liquid, which impairs the stability of the sample liquid supply destination. It is known that there is. In particular, when the liquid is sent to the fine particle sorting device, the high-concentration sample liquid may flow, so that the sorting process may not be in time and the sample liquid may be wasted.
  • the sample liquid often has a higher specific gravity than water, the sample will settle if it is left to stand.
  • the target sample can be selectively separated from various sample suspensions, but the separation efficiency depends on the concentration of the sample solution.
  • the sample concentration is high, the sample is flowed in a close state, which greatly affects the abort rate and purity. Therefore, the sample is uniformly dispersed during sorting, and the sample solution is sent at a constant concentration. Is desired.
  • the main purpose of this technology is to provide a sample disperser capable of efficiently dispersing samples.
  • a sample liquid storage bag for storing the sample liquid and a sample liquid storage bag A plurality of oscillators attached to the sample liquid storage bag, A sample disperser is provided.
  • the sample disperser according to the present technology may further include an oscillator control unit that controls the vibration of the plurality of oscillators.
  • the oscillator control unit may sequentially switch the drive of the plurality of oscillators.
  • the plurality of oscillators may be attached near the lower end of the sample liquid storage bag.
  • the upper end, the lower end and the horizontal end of the sample liquid storage bag are defined. The upper end has an outflow port from which the sample liquid is discharged.
  • the outflow port has a conduit through which the sample fluid is fed and extends toward the lower end.
  • the lower end may have a bottom that accommodates the sample solution and has a gradient at least in part.
  • the tip of the conduit may extend to a position close to the bottom.
  • the conduit may be provided with at least one of the plurality of oscillators.
  • the plurality of oscillators may be provided on both the outer surface and the outer back surface of the sample liquid storage bag.
  • the sample disperser according to the present technology may further include a fixture for suspending the sample liquid storage bag.
  • the plurality of oscillators may be electric actuators.
  • the sample may be a biological particle.
  • the biological particle may be a cell.
  • at least a part of the inner surface of the sample liquid storage bag may be coated.
  • a plurality of vibrators attached to the sample liquid storage bag for storing the sample liquid are attached to the sample liquid storage bag, and the plurality of vibrators are operated to oscillate the sample liquid storage bag.
  • a sample distribution method is also provided.
  • the sample liquid storage bag may be suspended from a fixture.
  • a sample disperser including a sample liquid storage bag for storing the sample liquid and a plurality of oscillators attached to the sample liquid storage bag.
  • a micro having a sample liquid inlet into which a sample liquid is introduced, a main flow path through which the sample liquid introduced from the sample liquid inlet flows, and a preparative flow path in which a target sample is separated from the sample liquid.
  • a sample sorting kit in which the sample liquid storage bag and the microchip are connected is also provided.
  • the present technology also provides a fine particle sorting device equipped with a sample disperser, which comprises a sample liquid storage bag for storing the sample liquid and a plurality of oscillators attached to the sample liquid storage bag.
  • a sample disperser which comprises a sample liquid storage bag for storing the sample liquid and a plurality of oscillators attached to the sample liquid storage bag.
  • the target sample is sorted from the sample liquid inlet into which the sample liquid is introduced, the main flow path through which the sample liquid introduced from the sample liquid inlet flows, and the sample liquid.
  • the microparticle sorting device has a sample sorting kit in which the sample liquid storage bag and the microchip are connected. It may further have a sample liquid feeding mechanism for feeding a sample from the sample liquid containing bag to the microchip.
  • A is a graph showing the relationship between the event rate and time when one oscillator is attached to the sample liquid storage bag, and B is the event rate when five oscillators are attached to the sample liquid storage bag. It is a graph which shows the relationship with time. It is a drawing substitute photograph which shows an example of an oscillator. It is a drawing substitute photograph which shows an example of an oscillator.
  • A is a diagram showing a configuration example of a sample liquid storage bag, and B is a partially enlarged view of A. It is a figure which shows the modification of the sample disperser. It is a figure which shows the example of the drive waveform by the oscillator control part.
  • FIG. 1 is a diagram showing a configuration example of the sample dispersion device 1.
  • the configuration of the sample dispersion device 1 according to the present embodiment will be described.
  • the embodiment shows a suitable example, and the sample dispersion device 1 according to the present technology is not limited to the configuration.
  • the sample dispersion device 1 includes a sample liquid storage bag 2 for storing the sample liquid, and a plurality of vibrators 11 attached to the sample liquid storage bag 2. Further, in the embodiment shown in FIG. 1, a fixture 12 for suspending the sample liquid storage bag 2 is further provided, and the fixture 12 has a stand 121 including a hook 122.
  • the sample liquid storage bag 2 contains the sample liquid, but the sample liquid is not necessarily included in the sample dispersion device 1 according to the present technology.
  • the “sample” contained in the sample solution is particularly fine particles, and the fine particles may be appropriately selected by those skilled in the art.
  • the microparticles may include, for example, biological microparticles such as cells, cell clumps, microorganisms, liposomes, and synthetic microparticles such as gel particles, beads, latex particles, polymer particles, industrial particles and the like.
  • Biological microparticles also referred to as "biological particles” can include chromosomes, liposomes, mitochondria, organelles (organelles), etc. that make up various cells.
  • Cells can include animal cells (eg, blood cell lineage cells, etc.), plant cells.
  • the cell can be, in particular, a blood-based cell or a tissue-based cell.
  • the blood line cell may be, for example, a floating line cell such as a T cell or a B cell.
  • the tissue-based cells may be, for example, adherent cultured cells or adherent cells separated from the tissue.
  • the cell mass may include, for example, spheroids, organoids and the like.
  • Microorganisms may include bacteria such as Escherichia coli, viruses such as tobacco mosaic virus, and fungi such as yeast.
  • the biological microparticles may also include biological macromolecules such as nucleic acids, proteins, and complexes thereof.
  • Synthetic fine particles can be, for example, fine particles made of an organic or inorganic polymer material, a metal, or the like.
  • Organic polymer materials may include polystyrene, styrene / divinylbenzene, polymethylmethacrylate and the like.
  • the inorganic polymer material may include glass, silica, magnetic material and the like.
  • the metal may include colloidal gold, aluminum and the like.
  • the synthetic microparticles may be, for example, gel particles, beads, etc., particularly gel particles or beads to which one or more combinations selected from oligonucleotides, peptides, proteins, and enzymes are bound. You can.
  • the shape of the fine particles may be spherical, substantially spherical, or non-spherical.
  • the size and mass of the fine particles may be appropriately selected by those skilled in the art.
  • the microparticles may be optionally attached with chemical or biological labels such as fluorescent dyes, fluorescent proteins and the like.
  • the label may facilitate the detection of the microparticles.
  • the sign to be attached can be appropriately selected by those skilled in the art. Molecules that specifically react with microparticles (eg, antibodies, aptamers, DNA, RNA, etc.) can bind to the label.
  • the fine particles are preferably biological particles, and in particular, can be cells.
  • the fixture 12 suspends the sample liquid storage bag 2, thereby supporting the uprightness of the sample liquid storage bag 2.
  • the stand 121 which is an example of the fixture 12, has two hooks 122, for example, a hole made in the upper part of the sample liquid storage bag 2 for suspending the bag from the hook 122.
  • the fixture 12 has two hooks 122, but the number of hooks 122 in the present embodiment is not limited to this.
  • the hook 122 is used in the present embodiment, the hook 122 is not limited to the hook 122 as long as the structure can suspend the sample liquid storage bag 2 in the present embodiment, and for example, a clip or the like is used. May be good.
  • the sample liquid storage bag 2 has one in the conduit 22 of the bag, two on the left and right near the lower end of the outer surface of the bag with the conduit 22 in between, and the left and right near the lower end of the outer back surface of the bag.
  • a total of five oscillators 11 are attached to the device, but the number of oscillators 11 is not limited to this in the present embodiment. That is, the sample liquid storage bag 2 may be provided with a plurality of oscillators 11 such as 2, 3, 4, or 5. Further, the mounting positions of the plurality of vibrators 11 on the sample liquid storage bag 2 can be appropriately selected, and the plurality of vibrators 11 can be provided on both the outer front surface and the outer back surface of the bag.
  • one vibrator 11 is attached to the sample liquid storage bag 2.
  • the sample in the bag gradually settles to the bottom, and a lump of marble-shaped sample is generated in the bag, so that the concentration of the sample becomes non-uniform.
  • the event rate during the sample liquid feeding becomes unstable, and the sample sorting performance when the sample is sorted by the fine particle sorting device 300 or the like described later. It also affects the stability of.
  • the present technology by attaching a plurality of oscillators 11 to the sample liquid storage bag 2, the range in which the bag is vibrated and the direction of the vibration are increased to a plurality, so that the sample in the bag can be sampled. It was possible to promote dispersion and further prevent the sample from settling in the bag.
  • FIG. 2A shows the event rate (vertical axis: EPS) and time when one oscillator 11 is attached to the sample liquid storage bag 2 (more specifically, when one is attached near the lower end of the bag). It is a graph which shows the relationship with (horizontal axis: minute), and B of FIG. 2 is an event rate (vertical axis::) when five oscillators 11 are attached to the sample liquid storage bag 2 as shown in this embodiment. It is a graph which shows the relationship between EPS) and time (horizontal axis: minute). Comparing these graphs, the fluctuation from the initial event rate (+ 13%, -4) in the case of five oscillators 11 is compared with the fluctuation ( ⁇ 34%) in the case of one oscillator 11. %) Is small, and it can be judged that it is stable. Therefore, by attaching the plurality of vibrators 11 to the sample liquid storage bag 2, the range and direction in which the bag is vibrated can be expanded, and the stirring capacity can be enhanced.
  • EPS event rate
  • the oscillator 11 is particularly used for suppressing the sedimentation of the sample.
  • a typical electric actuator is an electric actuator, and for example, a current / piezoelectric driven element such as a piezoelectric element, a linear vibration actuator, a cylindrical eccentric AC / DC motor, or a coin-type eccentric AC / DC motor can be used.
  • the oscillator 11 is a coin-type eccentric motor and the rotation speed is about 5000 to 20000 rpm, the sedimentation of the fine particles can be suppressed when they are cells.
  • a commercially available coin-type eccentric motor (see FIG. 3) is mounted together with a torsion spring to form a clip-shaped oscillator 11 (see FIG. 4).
  • the plurality of oscillators 11 are used by being attached to the sample liquid storage bag 2.
  • the plurality of oscillators 11 may be attached to the sample liquid storage bag 2 directly by using, for example, an adhesive, tape, or the like, or may be press-fitted, inserted, screwed, clipped, magnetically actuated, or springed. It may be fixed by using a member or the like.
  • Power may be supplied from the power source to the plurality of oscillators 11 by wire.
  • the length of the cord connecting the vibrator 11 and the power supply can be adjusted as appropriate.
  • the plurality of oscillators 11 can be easily installed or replaced by the user regardless of whether the power supply from the power source is wired or battery-powered, and the maintainability is high.
  • FIG. 5 is a diagram showing a configuration example of a sample liquid storage bag 2 that can be used in the present technology.
  • the upper end 201, the lower end 202, and the horizontal end 203 are defined, and the upper end 201 has an outflow port 21 from which the sample liquid is discharged, and the outflow.
  • the port 21 has a conduit 22 through which the sample liquid is fed and extends toward the lower end 202, the lower end 202 having a bottom 23 containing the sample liquid and having a gradient at least in part. ..
  • the length of the conduit 22 is preferably close to the lower end of the bag so that most of the sample liquid can flow out, and can be appropriately adjusted depending on the amount of residual liquid in the bag and the like, but in particular, ,
  • the tip of the conduit 22 may extend to a position close to but not in contact with the bottom 23.
  • the conduit 22 is arranged so as to be in contact with the bottom 23 of the bag, the sample settled on the bottom 23 may be sucked at once, and the event rate becomes unstable.
  • the tip of the conduit 22 by arranging the tip of the conduit 22 at a position close to but not in contact with the bottom 23, it is possible to secure a place where the sample liquid can flow even at the bottom 23. Further, as compared with the case where the tip of the conduit 22 is abutted against the bottom 23, the fluctuation range of the event rate can be reduced, and the increase in the event rate due to the suction of the settled sample can be suppressed. ..
  • the lower limit of the distance d (see B in FIG. 5) from the inner tip of the bag of the bottom 23 to the tip of the conduit 22 is preferably 1 mm or more, more preferably 3 mm or more. It is more preferably 5 mm or more, further preferably 7 mm or more, and particularly preferably 9 mm or more.
  • the upper limit of the distance d is not particularly limited as long as the sample liquid can flow out, but it is preferably 20 mm or less.
  • Typical examples of the conduit 22 include a PEEK tube having an outer diameter of 1/16 inch, an inner diameter of 0.5 mm, or an inner diameter of 1 mm, but the present technology is not limited to this.
  • the conduit 22 is provided with at least one of a plurality of oscillators 11. As a result, the sample liquid in the bag can be agitated by the conduit 22, and the sample can be dispersed more effectively.
  • the lower end 202 of the bag preferably has a bottom 23 that is at least partially sloped so that samples can be stored, but in particular the entire bottom 23 can be sloped. Further, in the present embodiment, it is preferable that the lower end 202 and / or the lateral end 203 of the bag has a width such that a plurality of vibrators 11 can be attached and detached.
  • the upper end 201 of the bag has an outflow port 21.
  • the sample liquid sucked up from the conduit 22 is sent to the outer tube connected to the outflow port 21 through the outflow port 21.
  • the material of the outflow port 21 is not particularly limited, and for example, from rubbers such as butyl rubber, isoprene rubber, and natural rubber, to polymer elastomers such as styrene elastomers, olefin elastomers, polyester elastomers, and nylon elastomers. Examples thereof include those made of thermoplastic resins such as low-density polyethylene, high-density polyethylene, polypropylene, and cyclic elastomer.
  • the upper end 201 of the bag and the upper end 201 and the outflow port 21 are sealed so as not to cause contamination or the like.
  • the material of the sample liquid storage bag 2 is not particularly limited, but may be an olefin plastic in particular.
  • it may be polyethylene, polypropylene, polyamide (nylon), or cyclic polyolefin such as cycloolefin polymer or cycloolefin copolymer.
  • cyclic polyolefin such as cycloolefin polymer or cycloolefin copolymer.
  • it may be an olefin-based elastomer in which polyethylene, polypropylene or the like is used as a hard segment and polybutadiene rubber or the like is used as a soft segment.
  • it may be a polyethylene-based elastomer, or a thermoplastic elastomer such as a polyester-based elastomer, a polyurethane-based elastomer, or a polyvinyl chloride-based elastomer.
  • the upper end 201, the lower end 202, and the horizontal end 203 of the sample liquid storage bag 2 can be defined. If the material is as described above, it can be easily defined by sealing or the like. Further, in this case, the lower end 201 and the horizontal end 203 can be used as attachment / detachment portions of the plurality of oscillators 11.
  • the coating agent is not particularly limited, but it is preferably one or more selected from the group consisting of low molecular weight proteins, silicon, and water-soluble polymers.
  • the low molecular weight protein is preferably albumin
  • the water-soluble polymer is at least one selected from the group consisting of casein, gelatin, dextran, polyacrylamide, polyvinyl alcohol, polyvinyl proridone, and polyethylene glycol. It is preferable to have.
  • a lid, various ports, tubes, etc. can be installed in the sample liquid storage bag 2 as needed.
  • a plurality of opening valves for storing the sample liquid in the bag are formed in the lids, and each opening valve is a check valve.
  • the configuration can be adopted. Therefore, when the sample liquid is contained in the bag through the opening valve, the sample liquid does not flow out of the bag. Further, the configuration of the opening valve allows the sample liquid to be sealed with respect to the external atmosphere.
  • FIG. 6 is a diagram showing a modified example of the sample dispersion device 1.
  • the oscillator control unit 13 is further provided.
  • Other configurations are the same as those of the embodiment shown in FIG.
  • the configuration of the sample dispersion device 1 according to the present embodiment will be described.
  • the embodiment shows a suitable example, and the sample dispersion device 1 according to the present technology is not limited to the configuration.
  • the oscillator control unit 13 controls a plurality of oscillators 11.
  • the vibration mode is changed by changing the drive waveform of the current / voltage of the vibrators 11 to a pulse shape, a sweep shape, a step shape, a multi-stage shape (see FIG. 7), or the like. Methods may be included to make convection more complex and faster to prevent sample settling.
  • the drive waveform is selected from, for example, a group consisting of a pulse waveform, a sine waveform, a sweep waveform, a triangle waveform, a saw waveform, a square waveform, a trapezoidal waveform, and these stepped waveforms and multistage waveforms.
  • the waveform can be one or more, but the present technology is not limited to these, and the combination thereof is not limited.
  • the oscillator control unit 13 can also manually or automatically select a waveform according to the dispersion state in the sample liquid.
  • the dispersed state of the sample may be visually observed, an imaging device or the like may be used, or the sample may be labeled with a phosphor or the like for detection.
  • the drive time of the vibrator can be, for example, until the sample is completely separated or until the sample liquid in the sample liquid storage bag 2 runs out. However, the drive time is appropriately set according to the dispersion state of the sample. It may be separated.
  • the movement of these oscillators 11 can be executed by a predetermined program incorporated or connected to the oscillator control unit 13.
  • the oscillator control unit 13 can sequentially switch the drive of the plurality of oscillators 11.
  • the oscillators 11 attached one by one on the left and right can be driven alternately on the left and right.
  • the drive time is not particularly limited, but for example, if the left oscillator 11 is driven in 15 seconds to 45 seconds (particularly 30 seconds), then the drive of the left oscillator 11 is stopped and the drive is stopped. The oscillator 11 on the right side is driven for 15 to 45 seconds (particularly 30 seconds), and these operations are repeated.
  • the plurality of oscillators 11 are attached near the lower end of the sample liquid storage bag 2, and in particular, the plurality of oscillators 11 are attached. It can be attached to the vicinity of the left and right lower ends of the bag with the conduit 22 in between. As a result, the bag can be vibrated alternately from the left side and the right side to generate an unsteady flow, so that the generation of lumps of the marb sample can be further eliminated.
  • FIG. 8 is a diagram showing another embodiment of the sample dispersion device 1.
  • the sample dispersion device 1 has a sample liquid storage bag 2 for storing the sample liquid and a stirring unit 14 for pushing the outer surface of the sample liquid storage bag 2. Since the sample liquid storage bag 2 is the same as that described above, the description thereof is omitted here.
  • the configuration of the sample dispersion device 1 according to the present embodiment will be described.
  • the embodiment shows a suitable example, and the sample dispersion device 1 according to the present technology is not limited to the configuration.
  • the stirring unit 14 may be composed of, for example, a motor 141 and a rotating body 142 driven by the motor 141. Further, in the present embodiment, the stirring unit 14 is provided with a pressing portion 143 that presses at least a part of the outer surface of the sample liquid storage bag 2, and the pressing portion 143 is located on the opposite side of the bag. A support 144 may be provided.
  • the shape of the pressing portion 143 is not particularly limited as long as it can press at least a part of the outer surface of the sample liquid storage bag 2.
  • the shape extends from the lower end 202 of the bag toward the upper end 201 and is continuous.
  • the shape may be continuous in the direction of the left and right horizontal ends 203 of the bag, or a combination of these shapes may be used.
  • the pressing portion 143 is configured to come into contact with the rotating body 142, for example, near the lower end 202 of the bag, and in this case, presses a part of the outer surface of the sample liquid storage bag 2 together with the support 144. ..
  • the pressing portion 143 pushes a part of the outer surface of the sample liquid storage bag 2 toward the support 144 at a desired time interval according to the drive of the motor 141, or the pressing portion 143 of the bag.
  • the entire outer surface of the sample liquid storage bag 2 can be pushed and the sample in the bag can be agitated.
  • a plurality of vibrators 11 attached to a sample liquid storage bag 2 for storing a sample liquid are attached to the sample liquid storage bag 2, and the plurality of vibrators 11 are operated to operate the sample.
  • the liquid storage bag 2 is oscillated. Since the sample liquid storage bag 2 and the plurality of oscillators 11 are the same as those described above, the description thereof is omitted here.
  • the sample liquid storage bag 2 is hung on the hook 122 of the stand 121, which is an example of the fixture 12. However, if the sample is left to stand as it is, the sample will settle, so a plurality of oscillators 11 are attached to the sample liquid storage bag 2 to give vibration.
  • the sample liquid accommodating bag 2 is swung by the plurality of oscillators 11, a shearing force is generated on the inner wall of the bag and the sample liquid, and a complicated flow field is formed due to inertial resistance, viscous resistance, etc., so that the sample settles. Can be deterred. Furthermore, since the water surface of the sample liquid in the bag serves as the release end of vibration transmission, the degree of freedom of vibration of the water surface is high, that is, strong convection is likely to be formed. It is characterized by forming a flow.
  • FIG. 9 is a diagram showing a configuration example of a sample sorting kit 200 according to the present technology.
  • the configuration of the sample sorting kit 200 according to the present embodiment will be described.
  • the embodiment shows a suitable example, and the sample sorting kit 200 according to the present technology is not limited to the configuration.
  • the sample preparative kit 200 includes the sample dispersion device 1 described above, a sample liquid inlet into which the sample liquid is introduced, a main flow path through which the sample liquid introduced from the sample liquid inlet flows, and the sample liquid. It has a microchip 100 having a preparative flow path from which a target sample is preparative, and the sample liquid storage bag 2 and the microchip 100 are connected to each other. Since the sample disperser 1 is the same as that described above, the description thereof is omitted here.
  • FIG. 10 is a diagram showing a configuration example of the microchip 100.
  • the configuration of the microchip 100 according to the present embodiment will be described. It should be noted that the embodiment shows a preferable example, and the present technology is not limited to the configuration.
  • the microchip 100 according to the present embodiment may have a flow path structure as shown in FIG. That is, in the microchip 100 according to the present embodiment, the sample liquid inlet 101 and the end 1091 of the preparative flow path 109 are formed on the same side surface. Further, the microchip 100 is provided with a sample liquid inlet 101 into which the sample liquid is introduced and a sheath liquid inlet 103 into which the sheath liquid is introduced, and the sheath liquid inlet 103 includes the sample liquid inlet 101 and the preparative flow path. It is formed on the same side surface as the end 1091 of the 109.
  • the sample liquid and the sheath liquid are introduced into the sample liquid flow path 102 and the sheath liquid flow path 104, respectively.
  • the sample liquid contains fine particles.
  • the sheath liquid flowing through the sheath liquid introduction flow path 104 merges with the sample liquid flowing from both sides of the sample liquid flow path 102 at the confluence portion 111 to form a laminar flow in which the sample liquid is surrounded by the sheath liquid.
  • the laminar flow flows through the main flow path 105 toward the particle sorting unit 107.
  • the main flow path 105 is provided with an optical detection region 106.
  • the fine particles in the sample liquid are irradiated with light. Based on the fluorescence and / or scattered light generated by the irradiation of the light, it can be determined whether or not the fine particles should be recovered.
  • the particle sorting unit 107 in the microchip 100 the laminar flow that has flowed through the main flow path 105 is separated into two branch flow paths 108.
  • the particle sorting unit 107 in the embodiment shown in FIG. 10 has two branch flow paths 108, but the number of branch flow paths is not limited to two.
  • the particle sorting unit 107 may be provided with, for example, one or a plurality (for example, two, three, or four) branch flow paths.
  • the end 1081 of the branch flow path 108 is formed on the same side surface as the end 1091 of the sample liquid inlet 101 and the preparative flow path 109.
  • a flow entering the sorting flow path 109 is formed and the fine particles are recovered. ..
  • the formation of the flow entering the preparative flow path 109 can be performed, for example, by generating a negative pressure in the preparative flow path 109.
  • a vibration region 1092 is provided as in the present embodiment, and an actuator or the like can be attached to the outside of the microchip 100 so that the wall of the region can be deformed. Deformation of the wall in the region can change the inner space of the excitation region 1092 and generate negative pressure.
  • the actuator can be, for example, a piezo actuator.
  • the sample liquid constituting the laminar flow or the sample liquid and the sheath liquid constituting the laminar flow can also flow into the preparative flow path 109. In this way, the fine particles to be recovered can be recovered.
  • the main flow path 105 and the preparative flow path 109 are communicated with each other via an orifice portion coaxial with the main flow path 105.
  • the fine particles to be collected flow through the orifice to the preparative flow path 109.
  • the orifice portion may be provided with a buffer liquid flow path 110 in order to prevent fine particles that should not be collected from entering the preparative flow path 109 through the orifice portion.
  • the buffer solution is introduced from the buffer solution flow path 110, and a part of the introduced buffer solution forms a flow from the orifice portion to the main flow path 105, so that fine particles that should not be collected are separated and flowed. It is possible to prevent entering the road 109.
  • the buffer solution inlet 1101 into which the buffer solution is introduced is formed on the same side surface as the sample solution inlet 101 and the end 1091 of the preparative flow path 109. The rest of the introduced buffer solution can flow into the preparative flow path 109.
  • the laminar flow flowing into the branch flow path 108 can be discharged to the outside of the microchip 100 at the end 1081 of the branch flow path 108. Further, the fine particles collected in the preparative flow path 109 can be discharged to the outside of the microchip at the end 1091 of the preparative flow path. In this way, the target sample is separated by the microchip 100.
  • a flow path connecting member is inserted into the sample liquid inlet 101, the end 1091 of the preparative flow path 109, the sheath liquid inlet 103, the buffer liquid inlet 1101, and the end 1081 of the branch flow path 108. Then, it can be connected to each part of the sample preparative kit 200 via the flow path connecting member.
  • the member for connecting the flow path is typically a tube, and the material of the tube may be appropriately selected by those skilled in the art from those used in the art.
  • the tube may be, for example, a polyvinyl chloride (PVC) tube, a silicone tube, a polyetheretherketone (PEEK) tube, a polytetrafluoroethylene (PTFE) tube, or a thermoplastic elastomer tube, or a plurality of types of tubes. May be concatenated.
  • PVC polyvinyl chloride
  • PEEK polyetheretherketone
  • PTFE polytetrafluoroethylene
  • thermoplastic elastomer tube or a plurality of types of tubes. May be concatenated.
  • micro means that at least a part of the flow path included in the microchip has a dimension of ⁇ m order, particularly a cross-sectional dimension of ⁇ m order. That is, in the present technology, the “microchip” refers to a chip including a flow path on the order of ⁇ m, particularly a chip including a flow path having a cross-sectional dimension on the order of ⁇ m. For example, a chip including a particle sorting portion composed of a flow path having a cross-sectional dimension of ⁇ m order can be called a microchip according to the present technology.
  • the microchip 100 can be manufactured by methods known in the art.
  • the microchip 100 can be manufactured by laminating two or more substrates on which a predetermined flow path is formed.
  • Examples of the material for forming the microchip 100 include polycarbonate, cycloolefin polymer, polypropylene, PDMS (polydimethylsiloxane), polymethylmethacrylate (PMMA), polyethylene, polystyrene, glass, silicon, and the like. It is not limited to.
  • the pre-sample storage unit 2011 is provided upstream of the sample liquid storage bag 2.
  • the pre-sample storage unit 2011, and the target sample storage unit 203, the disposal unit 204, the sheath liquid storage unit 205, and the buffer liquid storage unit 206, which will be described later, may be, for example, a plastic bag.
  • the plastic bag may be, for example, a bag made of polyethylene, polypropylene, polyvinyl chloride, or an ethylene vinyl acetate copolymer.
  • the filter portion 202 includes at least a filter and a tapered portion, and if necessary, has an outer diameter of a flow path connecting member for connecting to the sample liquid storage bag 2 and / or the microchip 100. It may be provided with a fitting portion. As a result, it is possible to prevent the fine particles in the sample liquid that have passed through the filter from settling on the inner wall surface of the filter unit 202, and it is possible to reduce the amount of loss of the fine particles.
  • the filter unit 202 can be appropriately arranged at any position by those skilled in the art. For example, as shown in FIG. 9, by providing the filter unit 202 upstream of the sample liquid storage bag 2, foreign matter in the sample storage unit 201 can be provided. Intrusion can be prevented at an early stage. Further, as shown in FIG. 9, the filter unit 202 may be arranged between the sample liquid storage bag 2 and the microchip 100. In particular, the filter unit 202 may be arranged immediately before the microchip 100.
  • the target sample storage unit 203 contains fine particles to be collected.
  • the target sample storage unit 203 is formed in a bag shape, for example, and includes an opening valve connected to the end 1091 of the preparative flow path 109 of the microchip 100.
  • the opening valve employs a so-called check valve configuration, and when the fine particles to be collected via the opening valve are housed in the target sample storage unit 203, the fine particles are stored in the target sample storage unit 203. It is designed not to go outside. Further, the structure of the opening valve prevents the fine particles from coming into contact with the external atmosphere.
  • the configuration of the target sample storage unit 203 described above is only an example, and a known configuration can be adopted as long as the target sample does not come into contact with the external atmosphere.
  • the sample sorting kit 200 In the sample sorting kit 200 according to the present technology, fine particles that should not be collected when only the target sample is sorted from the sample solution by the above-mentioned microchip 100 (hereinafter, also referred to as “non-purpose sample”). Need to be eliminated. Further, since the target sample is separated by forming a sheath flow with the microchip 100, it is necessary to eliminate the sample liquid containing the non-purpose sample, the so-called waste liquid. Therefore, the sample preparative kit 200 may include a disposal unit 204. Non-purpose samples other than the target sample can be discarded in the disposal unit 204.
  • the waste liquid unit 204 may include, for example, a flow path connecting member for the waste liquid to flow in, and the member may communicate with the end 1081 of the branch flow path 108 of the microchip 100. As a result, the target sample can be separated and the non-purpose sample can be discarded in the closed space including the waste liquid portion 204.
  • the sample preparative kit 200 may include a sheath liquid accommodating portion 205.
  • the sheath liquid can be stored in the sheath liquid storage portion 205.
  • the sheath liquid accommodating portion 205 may include, for example, a flow path connecting member into which the sheath liquid flows, and the member may communicate with the sheath liquid inlet 103 of the microchip 100.
  • the sheath liquid flows into the sheath liquid flow path 104 of the microchip 100, and a sheath flow is formed.
  • the configuration of the sheath liquid accommodating portion 205 is not particularly limited, and a known configuration can be adopted. Further, the configuration for discharging the sheath liquid from the sheath liquid accommodating portion 205 is not particularly limited, and for example, a drive source such as an actuator can be used.
  • the buffer solution is stored in the buffer solution storage unit 206.
  • the buffer solution accommodating portion 206 may include, for example, a flow path connecting member into which the buffer solution flows, and the member may communicate with the buffer solution inlet 1101 of the microchip 100. As a result, the buffer solution flows into the flow path of the microchip 100, and the target sample is sorted.
  • the configuration of the buffer solution accommodating portion 206 is not particularly limited, and a known configuration can be adopted. Further, the configuration for discharging the buffer solution from the buffer solution accommodating portion 206 is not particularly limited, and for example, a drive source such as an actuator can be used.
  • the flow rate fluctuation (for example, pulsation) by the pump causes the flow rate in the microchip 100, particularly.
  • the flow rate in the preparative flow path 109 and the fine particles in the particle preparative unit 107 can also affect the preparative use, they can be provided to reduce the influence and make the pressure due to the liquid feeding as constant as possible.
  • a pressure gauge sensor 208 for measuring the pressure may be provided for each damper 207. This makes it possible to stably feed the liquid to each part.
  • the damper 207 and the pressure gauge sensor 208 may be particularly located downstream of the sheath fluid accommodating portion 205 and / or the buffer fluid accommodating portion 206 and between the microchip 100.
  • Each part of the sample sorting kit 200 according to the present technology may be connected in part or in whole.
  • the connection can be, in particular, a closed connection. Therefore, the target sample can be sorted and the target sample can be stored in a closed space, and the sampling accuracy of the target sample can be improved.
  • the sample preparation kit 200 according to the present technology can also be applied to clinical practice such as immuno-cell therapy in which the purity of the target sample is required. Further, the sample preparation kit 200 itself can be made disposable, and the risk of contamination between samples can be avoided to improve usability.
  • a plurality of each part of the sample preparation kit 200 described above may be provided as needed.
  • FIG. 11 is a diagram showing a configuration example of the fine particle sorting device 300.
  • the configuration of the fine particle sorting device 300 according to the present embodiment will be described.
  • the embodiment shows a suitable example, and the fine particle sorting device 300 according to the present technology is not limited to the configuration.
  • the fine particle sorting device 300 is equipped with the above-mentioned sample dispersing device 1. Since the sample disperser 1 is the same as that described above, the description thereof is omitted here.
  • the microparticle sorting device 300 irradiates the above-mentioned microchip 100, the chip insertion portion 301 into which the microchip 100 is inserted, and the microparticles flowing through the main flow path with light.
  • the light detection unit 303 that detects scattered light and / or fluorescence emitted from the fine particles, and the data detected by the light detection unit 303, the fine particles that flow through the main flow path. It has a control unit 304 that controls the traveling direction of the light particles.
  • the chip insertion unit 301 may be appropriately selected by a person skilled in the art from the structures adopted in the art as long as it has a structure into which the above-mentioned microchip 100 can be inserted.
  • the microparticle sorting device 300 detects the light irradiation unit 302 that irradiates the microparticles flowing through the optical detection region 106 in the microchip 100 with light, and the scattered light and / or fluorescence generated by the light irradiation. It has an optical detection unit 303 to be used.
  • the control unit 304 controls the traveling direction of the fine particles passing through the main flow path 105 based on the data detected by the photodetection unit 303 (for example, information about light).
  • the light irradiation unit 302 the light detection unit 303, and the control unit 304 will be described.
  • the light irradiation unit 302 irradiates the fine particles flowing through the optical detection region 106 in the microchip 100 with light (for example, excitation light).
  • the light irradiation unit 302 may include a light source that emits light and an objective lens that collects excitation light for fine particles flowing in the detection region.
  • the light source may be appropriately selected by a person skilled in the art according to the purpose of sorting, and may be, for example, a laser diode, an SHG laser, a solid-state laser, a gas laser, or a high-intensity LED, or any of these. It may be a combination of two or more.
  • the light irradiation unit 302 may include other optical elements, if necessary, in addition to the light source and the objective lens.
  • the light irradiation unit 302 may, for example, irradiate one position in the optical detection region 106 with light, or may irradiate each of a plurality of positions with light.
  • the light irradiation unit 302 can irradiate each of two different positions in the optical detection region 106 with light.
  • the light detection unit 303 detects scattered light and / or fluorescence generated from the fine particles by irradiation by the light irradiation unit 302.
  • the photodetector 303 may include a condenser lens and a detector that collect the fluorescence and / or scattered light generated from the fine particles.
  • the detector PMT, photodiode, CCD, CMOS and the like can be used, but the present technology is not limited to these.
  • the light detection unit 303 may include other optical elements, if necessary, in addition to the condenser lens and the detector.
  • the photodetector 303 may further include, for example, a spectroscopic unit.
  • the optical component constituting the spectroscopic unit include a grating, a prism, an optical filter, and the like.
  • the spectroscopic unit can detect, for example, light having a wavelength to be detected separately from light having another wavelength.
  • the fluorescence detected by the light detection unit 303 may be fluorescence generated from the fine particles themselves or a substance labeled on the fine particles, for example, fluorescence generated from a fluorescent substance or the like, but is limited to these in the present technology. is not it.
  • the scattered light detected by the light detection unit 303 may be forward scattered light, side scattered light, Rayleigh scattering, or Mie scattering, or may be a combination thereof.
  • the control unit 304 controls the traveling direction of the fine particles passing through the main flow path 105 based on the data detected by the photodetection unit 303 (for example, information about light). For example, the control unit 304 controls the sorting of the fine particles based on the data. For example, the control unit 304 can determine that the fine particles are separated when the light detected by the photodetection unit 303 satisfies a predetermined criterion. Information about the light can be generated from the light (fluorescence and / or scattered light) detected by the photodetector 303. The information can be generated, for example, by converting the light into an electrical signal.
  • the microparticle sorting device 300 of the present technology may include an information generating unit that generates information about the light from the light detected by the photodetector 303.
  • the information generation unit may be included in the control unit 304, may not be included in the control unit 304, and may be provided in the fine particle sorting device 300 as a component separate from the control unit 304.
  • the control unit 304 can determine whether or not the light detected by the photodetection unit 303 satisfies a predetermined criterion based on the information about the light.
  • the control unit 304 can control the sorting of fine particles based on the result of the determination.
  • the control unit 304 changes the flow in the flow path so that the fine particles travel through the orifice and into the preparative flow path 109 when the fine particles should be recovered. Can be done.
  • the change in flow can be made, for example, by reducing the pressure in the preparative flow path 109.
  • the control unit 304 can change the flow in the flow path again. The re-change of the flow can be made by increasing the pressure in the particle preparative flow path. That is, the control unit 304 may control the pressure in the particle preparative flow path based on the information about the light detected by the light detection unit 303.
  • the control unit 304 may have the same function as the drive unit described in, for example, Japanese Patent Application Laid-Open No. 2014-036604. That is, the control unit 304 can control an actuator configured to be able to generate a negative pressure in the preparative flow path 109. When it is determined that the fine particles should be recovered based on the information about the light, the control unit 304 drives the actuator to generate a negative pressure in the preparative flow path 109. As a result, the fine particles to be collected are collected in the preparative flow path 109. The control unit 304 does not drive the actuator when it is determined that the fine particles should not be recovered based on the information about the light. As a result, the fine particles that should not be recovered flow into the branch flow path 108.
  • the actuator may be, for example, a piezoelectric element such as a piezo element.
  • the control unit 304 applies a voltage that causes piezo contraction to the piezo element to increase the volume in the preparative flow path 109. Due to the increase in volume, a negative pressure is generated in the preparative flow path 109. As a result, a flow from the main flow path 105 to the preparative flow path 109 is formed, and the fine particles are collected in the preparatory flow path 109. If it is determined that the fine particles should not be recovered, the voltage is not applied. As a result, the flow into the preparative flow path 109 is not formed, and the fine particles flow into the branch flow path 108.
  • the fine particle sorting device 300 may have the sample sorting kit 200 described above.
  • the microparticle sorting device 300 may have a sample liquid feeding mechanism 305 that feeds a sample from the sample liquid storage bag 2 to the microchip 100, as shown in FIG.
  • the sample liquid feeding mechanism 305 may be a pump in particular. Further, in particular, it may be arranged downstream of the sample accommodating portion 201 and between the microchip 100 and the microchip 100.
  • the pump may be, for example, a peristaltic pump (tube pump), a roller pump, a syringe pump, or a centrifugal pump, but the present technology is not limited to these.
  • the pump can be a peristaltic pump or a roller pump, in particular, for more precise control of the flow rate.
  • a plurality of the sample liquid feeding mechanisms 305 may be provided as needed.
  • the microchip 100 and the disposal unit 204 downstream of the sheath liquid storage unit 205 and the microchip 100, and downstream of the buffer solution storage unit 206 and the microchip 100. Etc. can be placed.
  • the present technology can adopt the following configurations.
  • a sample liquid storage bag for storing the sample liquid and A plurality of oscillators attached to the sample liquid storage bag, A sample disperser.
  • the sample disperser according to [2], wherein the oscillator control unit sequentially switches the drive of the plurality of oscillators.
  • the sample disperser according to [3], wherein the plurality of oscillators are attached near the lower end of the sample liquid storage bag.
  • the upper end, the lower end, and the lateral end of the sample liquid storage bag are defined.
  • the upper end has an outflow port from which the sample liquid is discharged.
  • the outflow port has a conduit through which the sample fluid is fed and extends toward the lower end.
  • the sample disperser according to any one of [1] to [4], wherein the lower end has a bottom portion containing the sample liquid and having a gradient at least in a part thereof.
  • sample dispersion device according to any one of claims [5] to [8], wherein at least a part of the inner surface of the sample liquid storage bag is coated.
  • a sample dispersion method in which a plurality of vibrators attached to a sample liquid storage bag for storing a sample liquid are attached to the sample liquid storage bag, and the plurality of vibrators are operated to shake the sample liquid storage bag.
  • the sample dispersion method according to [14], wherein the sample liquid storage bag is suspended from a fixture.
  • a sample disperser including a sample liquid storage bag for storing a sample liquid and a plurality of oscillators attached to the sample liquid storage bag.
  • the fine particle sorting device according to [17]. [19] It has a sample preparative kit in which the sample liquid storage bag and the microchip are connected.

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Abstract

La présente invention concerne un dispositif de dispersion d'échantillons pouvant disperser efficacement des échantillons.　Un dispositif de dispersion d'échantillon est prévu, comprenant un sac contenant un fluide échantillon, et une pluralité d'oscillateurs configurés pour être fixés au sac contenant le fluide échantillon. L'invention concerne également un procédé de dispersion d'un échantillon dans lequel la pluralité d'oscillateurs à fixer au sac contenant le fluide échantillon est fixée au sac contenant le fluide échantillon, et la pluralité d'oscillateurs est activée pour secouer le sac contenant le fluide échantillon.
PCT/JP2020/042365 2019-11-22 2020-11-13 Dispositif et procédé de dispersion d'échantillon, trousse d'aliquotage d'échantillon et dispositif d'aliquotage de microparticules WO2021100619A1 (fr)

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JP2019211233A JP2021081380A (ja) 2019-11-22 2019-11-22 サンプル分散装置、サンプル分散方法、サンプル分取キット及び微小粒子分取装置

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023074548A1 (fr) * 2021-10-29 2023-05-04 ソニーグループ株式会社 Dispositif pour isoler les microparticules et kit pour isoler les microparticules

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JP2002340779A (ja) * 2001-05-16 2002-11-27 Shimadzu Corp 粒度分布測定装置
JP2005127789A (ja) * 2003-10-22 2005-05-19 Sysmex Corp 撹拌装置とそれを用いた粒子分析装置
JP2006226911A (ja) * 2005-02-18 2006-08-31 Mitsui Eng & Shipbuild Co Ltd フローサイトメータ
JP2007117861A (ja) * 2005-10-27 2007-05-17 Nikken Seibutsu Igaku Kenkyusho:Kk 液体攪拌装置
WO2018163943A1 (fr) * 2017-03-08 2018-09-13 ソニー株式会社 Poche d'alimentation en liquide d'échantillon cellulaire, procédé d'alimentation en liquide d'échantillon cellulaire et dispositif d'alimentation en liquide d'échantillon cellulaire
WO2018235383A1 (fr) * 2017-06-21 2018-12-27 ソニー株式会社 Dispositif d'alimentation en liquide d'échantillon, cytomètre de flux et procédé d'alimentation en liquide d'échantillon

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002340779A (ja) * 2001-05-16 2002-11-27 Shimadzu Corp 粒度分布測定装置
JP2005127789A (ja) * 2003-10-22 2005-05-19 Sysmex Corp 撹拌装置とそれを用いた粒子分析装置
JP2006226911A (ja) * 2005-02-18 2006-08-31 Mitsui Eng & Shipbuild Co Ltd フローサイトメータ
JP2007117861A (ja) * 2005-10-27 2007-05-17 Nikken Seibutsu Igaku Kenkyusho:Kk 液体攪拌装置
WO2018163943A1 (fr) * 2017-03-08 2018-09-13 ソニー株式会社 Poche d'alimentation en liquide d'échantillon cellulaire, procédé d'alimentation en liquide d'échantillon cellulaire et dispositif d'alimentation en liquide d'échantillon cellulaire
WO2018235383A1 (fr) * 2017-06-21 2018-12-27 ソニー株式会社 Dispositif d'alimentation en liquide d'échantillon, cytomètre de flux et procédé d'alimentation en liquide d'échantillon

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023074548A1 (fr) * 2021-10-29 2023-05-04 ソニーグループ株式会社 Dispositif pour isoler les microparticules et kit pour isoler les microparticules

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