WO2018179841A1

WO2018179841A1 - Microparticle trapping device, microparticle trapping system, and microparticle trapping method

Info

Publication number: WO2018179841A1
Application number: PCT/JP2018/003822
Authority: WO
Inventors: 健介小嶋; 渡辺　俊夫
Original assignee: ソニー株式会社
Priority date: 2017-03-31
Filing date: 2018-02-05
Publication date: 2018-10-04

Abstract

The present technique provides a microparticle trapping device that improves on the efficiency of trapping microparticles passing along the middle of a flow path. To this end, the present technique provides a microparticle trapping device which is provided with: a flow path through which microparticles flow; recesses formed on the inner wall surface of the flow path; and a drawing path for drawing in the microparticles. The recesses and the drawing path communicate with each other. A structure for directing the flow of microparticles toward the inner wall surface is formed on the inner wall surface.

Description

Fine particle capturing apparatus, fine particle capturing system, and fine particle capturing method

The present invention relates to a fine particle capturing apparatus, a fine particle capturing system, and a fine particle capturing method.

Recently, techniques such as flow cytometry have been developed to analyze cells and select and capture them with a cell sorter. The captured cells are then subjected to analysis and culture.

Here, cells are the smallest functional units that make up living organisms, and even cells that look morphologically identical are not actually uniform, but the amount and type of genomes, expressed proteins, sugar chains / lipids and various metabolites, It is considered that there is a great difference between individual cells when discriminating at the molecular level including the modification mode. In addition, comprehensive and quantitative analysis of molecular information carried by a diverse group of biomolecules at the level of one cell greatly increases the current state in which cell characteristics at the molecular level can only be evaluated as the average value of a cell population. It is a new approach to life science research that breaks down.

According to recent one-cell research results, even in a monoclonal colony derived from the same cell, heterogeneity due to stochastic fluctuation occurs between the cells, and the desired trait deteriorates during colony formation, resulting in elite It has been pointed out that cells are buried. On the other hand, a cell that is actually used in the production of a biologic by a pharmaceutical company or the like has been bred for one colony over a long time and enormous cost. By such breeding, it is possible to achieve both high productivity and high stability and reduce all labor if cells that show the most favorable traits before proliferation can be isolated from a huge number of cell libraries in units of one cell. Connected.

For this reason, at the forefront of the research field, as a trend in the technical field, it can be isolated in a single cell unit in a microchamber of the order of 10 ^ 5, and it is possible to extract target cells by parallel processing in a cell array under any culture conditions Such a fully automatic single cell isolation analyzer is desired.

However, for the isolation of single cells, it is generally assumed that a cell sorter is used, but it is difficult to separate cells with high chemical and physical stress on cells and positive frequency of less than 0.1%. is there. On the other hand, in order to capture and isolate a large number of cells with high density while reducing chemical and physical stress on the cells, a hole array type apparatus is the mainstream. However, it is structurally difficult to add many functions such as parallel processing and observation to the micro chamber of the hole array, and it is necessary to check the progress of the sequential workflow. In addition, IFC-type 1-cell prep devices such as Fluidigm C1, which perform workflow processing by combining chambers in a two-dimensional plane, are the mainstream.

For example, a technique described in Patent Document 1 has been developed as a method for capturing such cells. Patent Document 1 discloses a structure in which a well having a size into which a cell enters is engraved in a flow path in which a cell-containing sample flows, and a cell or bead is sucked by providing a slit in the well ( FIG. 23, FIG. 25, etc.).

US Patent Application Publication No. 2013/0078163

However, in the flow channel structure of Patent Document 1, the liquid flow in the micro flow channel is a laminar flow, and the flow rate at the center of the flow channel is always faster than the vicinity of the side surface of the flow channel. When particles are routed around the center of the flow path, they pass through vigorously, and there is a possibility that the cells or beads do not reach the vicinity of the microwell on the side wall where the slit is arranged.

Therefore, the present technology has been made in view of such a situation, and an object thereof is to provide a particulate trapping device that improves the trapping efficiency of particulates that pass through the center of a flow path.

In order to solve the above-mentioned problem, a particulate trapping apparatus as an example of the present technology includes a flow path for flowing fine particles, a recess formed in an inner wall surface of the flow path, and a drawing passage for drawing the fine particles, The lead-in passage is communicated, and a structure for guiding the flow of fine particles in the direction of the inner wall surface is formed on the inner wall surface. Moreover, the structure of the particulate trapping apparatus that is an example of the present technology can have a protrusion.

In addition, a particulate trapping system that is an example of the present technology includes a channel for flowing particulates on a substrate, a recess formed on the inner wall surface of the channel, and a passage for drawing in the particulates. The passage for communication can include a fine particle trapping portion in which a structure for guiding the flow of fine particles in the direction of the inner wall surface is formed on the inner wall surface, and a liquid feeding portion connected to the fine particle trapping portion. .

In addition, the fine particle capturing method as an example of the present technology includes a flow path for flowing the fine particles on the base material, a recess formed on the inner wall surface of the flow path, and a drawing passage for drawing the fine particles. The sample passage containing the particles to be trapped is supplied to a fine particle capturing device in which a structure for guiding the flow of fine particles in the direction of the inner wall surface is formed on the inner wall surface, and the sample is sent to the inner passage. However, the particles to be captured can be captured from the recess through the drawing-in passage to the outside.

According to the present technology, it is possible to provide a particle capturing apparatus that improves the efficiency of capturing particles passing through the center of the flow path. Note that the effects of the present technology are not necessarily limited to the above effects, and may be any of the effects described in the present disclosure.

It is a cross-sectional view of the particulate trapping device of the present technology. It is a perspective view which shows the peak part, trough part, recessed part, passage for drawing-in of the particulate trap of this technique. It is a schematic diagram which shows the mode of the sample flow and particle | grain capture | acquisition in the microparticles | fine-particles capture apparatus of this technique. It is a schematic diagram showing an example of the size of the particulate trapping device of the present technology. A is a schematic diagram showing an example of the particulate trapping device of the present technology, and B is a partially enlarged view of the particulate trapping device of the present technology. It is a mimetic diagram showing an example of particulate collection device of this art. It is a block diagram which shows the experimental structure using the microparticles | fine-particles capture apparatus of this technique. It is a mimetic diagram showing an example of particulate collection device of this art. It is a mimetic diagram showing an example of particulate collection device of this art. It is a mimetic diagram showing an example of particulate collection device of this art. It is a mimetic diagram showing an example of particulate collection device of this art. It is a mimetic diagram showing an example of a channel of a particulate trap of this art. It is a mimetic diagram showing an example of a channel of a particulate trap of this art. It is a mimetic diagram showing an example of a channel of a particulate trap of this art. It is a mimetic diagram showing an example of a channel of a particulate trap of this art. It is a mimetic diagram showing an example of a channel of a particulate trap of this art. It is a mimetic diagram showing an example of a channel of a particulate trap of this art. It is a mimetic diagram showing an example of a channel of a particulate trap of this art. It is a mimetic diagram showing an example of a channel of a particulate trap of this art. It is a graph which shows the relationship between the microparticles | fine-particles which flow through the inside of the microparticles | fine-particles capture device of this technique, and the flow velocity. It is a graph which shows the relationship between the microparticles | fine-particles which flow through the inside of the microparticles | fine-particles capture device of this technique, and the flow velocity. It is a table | surface which shows the relationship between the flow-path shape of the fine particle capture device of this technique, and the number of capture | acquisition of particles. It is a graph which shows the relationship between the flow-path shape and particle | grain capture | acquisition number of the microparticles | fine-particles capture apparatus of this technique. It is a mimetic diagram showing an example of a channel of a particulate trap of this art. It is a graph which shows the relationship between the microparticles | fine-particles which flow through the inside of the microparticles | fine-particles capture device of this technique, and the flow velocity. It is a mimetic diagram showing an example of a channel of a particulate trap of this art. It is a graph which shows the relationship between the microparticles | fine-particles which flow through the inside of the microparticles | fine-particles capture device of this technique, and the flow velocity. It is a mimetic diagram showing an example of a channel of a particulate trap of this art. It is a graph which shows the relationship between the microparticles | fine-particles which flow through the inside of the microparticles | fine-particles capture device of this technique, and the flow velocity. It is a mimetic diagram showing an example of particulate collection device of this art. It is a mimetic diagram showing an example of particulate collection system of this art. It is a mimetic diagram showing an example of the channel shape of the particulate trap of this art.

Hereinafter, preferred embodiments for implementing the present technology will be described. In addition, embodiment described below shows typical embodiment of this technique, and, thereby, the range of this technique is not interpreted narrowly. In addition, in the present technology, any of the following embodiments and modifications thereof can be combined with each other.

The description will be given in the following order.
1. 1. Particle capturing device Embodiment (1) Embodiment 1
(2) Embodiment 2
(3) Embodiment 3
(4) Embodiment 4
(5) Embodiment 5
(6) Embodiment 6
(7) Embodiment 7
(8) Embodiment 8
(9) Embodiment 9
2. 2. Particle capture system Particulate capture method4. Flow path shape of particle trap

<1. Fine particle capture device>
[Configuration example of particulate trap]
The type of particles to be captured by the particulate capturing device of the present technology is not particularly limited. For example, a cell, a bead, a semiconductor chip, a micro bump as a terminal of a semiconductor connection portion, a bead type solar cell, and the like can be given. Further, the size and shape of the particles are not particularly limited.

For example, hybrid bio / inorganic materials, nano-hybrid environmental sensors, environmental sensors: sensor array formation technology, concentrating materials for solar cells, and high-density mounting modules. Forming technology using self-organized pattern as a template, organic light switching device with periodic uneven structure of sub-wavelength (sub-μm) size necessary for self-organizing arrangement of chip-shaped parts, improving light extraction efficiency of light-emitting device, etc. Formation of quasi-phase-matching structure by optical poling of non-linear organic dyes for self-assembly, self-assembly of metal or semiconductor nanoparticles for quantum dot memory, and polymer self-assembly material for nanocrystal memory .

Hereinafter, description will be made with reference to FIG. 1 and FIG. The fine particle capturing apparatus 10 of the present technology includes a flow path 12 in a base material 11. The substrate 11 is not particularly limited, and polyethylene, polypropylene, vinyl chloride resin, polystyrene, polyethylene terephthalate, acrylic resin, polycarbonate, fluororesin, polybutylene terephthalate, phenol resin, melamine resin, epoxy resin, unsaturated polyester resin, polydimethyl It is formed of a resin such as siloxane, glass, metal or the like. The flow channel 12 can determine the width and height of the flow channel based on the size, shape, and type of particles to be captured, the amount of sample flowing through the flow channel, the viscosity, and the like.

On the flow path 12, it has a corrugated structure having a peak portion 13 and a valley portion 14, and a concave portion 16 is formed on the top portion 15 of the peak portion 13. Particles in the sample are captured in the recess 16. The flow path 12 has a top surface 19 on the opposite side of the corrugated structure. By making the bottom surface in the flow channel 12 into a corrugated structure, it is possible to prevent other cells from adhering to the cells trapped in the concave portions at the tops of the corrugations, thus preventing cells from accumulating. it can.

Further, as shown in FIG. 3, the liquid flow of the sample is a laminar flow in the flow channel 12, and there is a characteristic that the flow velocity at the center of the flow channel 12 is always faster than the vicinity of the side surface of the flow channel (FIG. 3). 4 arrows at the top left). Therefore, the flow velocity of the top portion 15 is increased by providing the concave portion 16 in the corrugated top portion 15 of the corrugated structure. Therefore, by providing the concave portion 16 in the top portion 15, it is possible to prevent doublets in which two or more particles try to enter the concave portion 16 (dotted circle). In other words, even if the second cell and beads adhere to the doublet, the flow rate is fast, so it is thought that the second and subsequent cells are less likely to enter the central laminar flow. For example, the central laminar flow is about 20% faster than the overall flow rate of the liquid flow.

The recess 16 further has a retracting passage 17. When the sample proceeds in the liquid flow direction and a valve (not shown) is opened and proceeds downstream, the flow path 12 is formed by the presence of the drawing-in path 17 that communicates the recess 16 and the outside (downstream flow path) 18. A pulling force is generated by positive pressure from the side toward the outside 18. Due to the pressure difference between the inside and outside of the flow path 12, the particles easily enter the recess 16. The external 18 is a downstream flow path 12 and is in a series with the flow path 12.

Note that the valve installation is not limited to this. For example, a valve for flowing the sample liquid may be installed upstream of the flow path 12 where the recesses 16 are connected, and a valve for sucking the sample liquid may be installed downstream.

The shape of the recess 16 can be determined in accordance with the shape of the particles to be captured. The shape of the concave portion 16 is, for example, a cylindrical shape, a truncated cone shape, an inverted truncated cone shape, an elliptical column shape, an elliptical truncated cone shape, an inverted elliptical truncated cone shape, a tapered shape, an inverted tapered shape, a polygonal column having a triangular shape or more. Can be mentioned.

Further, it is preferable that the depth of the concave portion 16 is equal to or smaller than the particle size of the particles to be captured. With such a depth, it is possible to prevent doublets of particles in the recesses 16 and other particles from accumulating on the captured particles.

Here, the “particle size” of the particles refers to the average value of the major axis diameter and minor axis diameter of the fine particles. Specifically, in the case of fine particles, the particle diameter can be calculated by measuring a considerable number (for example, 100) of arbitrary fine particles using image processing software or the like using a microscope and obtaining the number average.

For example, the depth of the recess 16 can be preferably 2 or less, more preferably 1 or less, as a ratio to the particle size of the particles to be captured.

Alternatively, the depth of the recess 16 can be preferably 2 or less, more preferably 1 or less, as a ratio to the diameter of the inscribed circle in the opening of the recess 16.

Furthermore, the depth of the concave portion 16 is preferably 1 or less, more preferably 0.8 or less, in a ratio with the height from the valley portion 14 to the mountain portion 13.

In addition, when the three-dimensional shape of the recess 16 is circular, for example, a columnar shape, a truncated cone shape, an inverted truncated cone shape, a tapered shape, or an inverted tapered shape, the diameter of the recessed portion 16 is set to be a particle to be captured. It is preferable that the particle size is 1 time or more and less than 2 times the particle size. Further, in the case where the opening of the recess 16 is a polygon of a triangle or more, if it is an odd-numbered n-gon, the vertical line can be regarded as a perpendicular line, and if it is an even-numbered n-angle, a diagonal line can be regarded as a diameter. If the diameter is less than 1 time, it is difficult for a single cell to enter the recess 16, and if it is 2 times or more, a plurality of cells may enter.

The height from the valley 14 to the peak 13 is preferably the same as or higher than the particle size of the particles to be captured. The flow rate of the liquid in the flow path 12 increases as it approaches the center. For this reason, when the height of the crest 13 and the trough 14 is lower than the particle size of the particles, the flow velocity received by the particles also in the vicinity of the crest 13 is slow. When the flow velocity in the vicinity of the mountain portion 13 is slow, particles that have flowed later easily adhere to the particles captured in the recess 16. Due to the low flow velocity, the energy of the particles that flow after the collision also decreases, and the particles adhere to the trapped particles and accumulate.

The pitch between the peaks 13 can be set to a length that is not less than 2 times and not more than 20 times the particle size of the particles to be captured. Specifically, the distance from the top 15 of the peak 13 to one valley 14 and the top 15 of the adjacent peak 13 is not less than 2 times and not more than 20 times the particle size of the particles to be captured. It is. If it is less than 2 times, particles may enter the valley 14, and if it exceeds 20 times, depending on the height of the peak 13, the corrugated structure approaches a flat structure, and the effect of the present technology is fully exhibited. There are things that cannot be done.

It should be noted that the pitch between the peaks 13 is more preferably 5 times to 15 times the particle size of the particles to be captured. By making it into this range, the effect produced by the waveform structure of the present technology can be exhibited. Further, in the case where the fine particle capturing apparatus 10 of the present technology is for capturing a single micro-order microparticle, a fine corrugated structure or a concave portion must be formed on the base material. In view of ease of manufacture, the above range can be adopted.

Note that the left and right pitches of the mountain portion 13 may be the same or different.

Further, when the channel 12 has a bottom surface and a top surface parallel to each other and a corrugated structure is formed on the bottom surface, the channel width of the channel 12 can be relatively small at the peak portion 13 and can be increased at the valley portion 14. . By using such a road width, since the central laminar flow of the liquid flow is fast, particles staying at the top 15 can be flowed.

An example of the size of each part of the fine particle capturing apparatus 10 described above is shown in FIG. Here, it is assumed that the particle capturing apparatus 10 captures a single cell or bead having a diameter of 10 μm.

In FIG. 4, the width of the peak 13 is 70 μm, the height of the peak 13 is 15 μm, the width of the top 15 is 20 μm, the diameter of the opening of the recess 16 is 15 μm, the depth of the recess 16 is 10 μm, and the drawing passage 17. Has a length of 35 μm and the width of the pull-in passage is 3 μm.

<2. Embodiment>
(1) Embodiment 1
[Parallel operation of flow paths]
FIG. 5A shows the fine particle capturing apparatus 10 of the first embodiment. FIG. 5B shows an enlarged plane of the flow path 12 in the particle capturing apparatus 10. The particles to be captured in the microparticle capturing apparatus 10 are 15 μmφ polystyrene beads. The substrate was made of polydimethylsiloxane (PDMS) as a material, and a chip provided with a flow path and a microwell prepared by molding a PDMS resin in a mold serving as a master. A PDMS substrate as a manufactured chip was subjected to direct plasma (DP) ashing with O ₂ : 10 cc, 100 W, 30 sec to make the surface hydrophilic, and bonded to a cover glass in the air.

In the fine particle capturing apparatus 10 manufactured by the above production method, a flow path 12 is formed at the center of the base plate. The channel 12 is formed with the corrugated structure and the recess 16 described above, and two systems can be operated in parallel with the upper channel and the lower channel. An inlet port IN1 at the upper left of the base plate is connected to the flow path 12, and a particle-containing sample (a cell culture solution containing trypan blue) is introduced into the inlet port IN1. Similarly, the lower left inlet port IN2 of the base plate is also connected to the flow path 12, and water or D-PBS (−) is introduced into the inlet port IN2. Then, the particle-containing sample passes through the flow path 12 and is sucked into the upper right outlet port OUT1 of the base plate. Further, water or D-PBS (−) is sucked through the flow path 12 to the lower right outlet port OUT2 of the base plate. As shown in FIGS. 5A and 5B, the particulate trapping apparatus 10 can perform these two systems of operations in parallel.

The particle-containing sample and water or D-PBS (-) are the force for introducing them, the force flowing downstream, the force for flowing the sample liquid generated by opening and closing a valve installed in the bypass, etc., from OUT1 and OUT2. The sample liquid can be flowed into the flow path 12 by any one of the force for sucking the sample liquid or a combination thereof.

(2) Embodiment 2
[Example of parallel flow paths]
FIG. 6 shows a particulate trapping device 60 in which flow paths are arranged in parallel. The fine particle capturing device 60 of FIG. 6 is formed in a two-layer structure of 1,500 well that can be highly integrated by disposing the flow path of the collecting pipe in the lower layer. FIG. 6A is an enlarged view in which five rows of channels are arranged, and FIG. 6B is enlarged so that the structure at the left end of the channel can be seen. As shown in the perspective views of FIGS. 6C and 6E, each channel has a corrugated structure, a recess, and a pull-in passage on both sides (the left and right inner sides of the channel).

FIGS. 6D, 6F, and 6G show an example of the size of each part of the fine particle capturing apparatus 60 of the present embodiment. Here, it is assumed that the particle capturing device 60 captures a single cell or bead having a diameter of 10 μm. 6D, the width of the peak is 70 μm, the height of the peak is 15 μm, the width of the top is 20 μm, the diameter of the opening of the recess is 15 μm, the depth of the recess is 10 μm, and the length of the lead-in passage 17 is 70 μm. The width of the drawing-in passage is 3 μm. In FIG. 6F, the width of the external groove on both sides of the flow path is 500 μm. In FIG. 6G, the width of the channel is 70 μm and the height of the channel is 100 μm.

In the fine particle capturing apparatus 60 of the present embodiment, the particle-containing sample is supplied from the introduction part on the left side of FIG. 6A, passes through each flow path, and the flow is divided into two at the right end, so that the sample liquid flows outside. A positive pressure is generated by the presence of the use passage, and the particles are trapped in each recess.

[Experimental configuration example]
FIG. 7 shows an experimental configuration example in which a bead capturing experiment was performed using the particle capturing apparatus 60 of FIG.

First, one end of the first PEAK tube is connected to the outlet port OUT1 of the jig, and the other end of the first PEAK tube is connected to the Alternative Pump (AP) via the drain bottle. Similarly, one end of the second PEAK tube is connected to the outlet port OUT2 of the jig, and the other end of the second PEAK tube is connected to the Primming Pump (PP) via the drain bottle. Then, a stock solution of 15 μmφ polystyrene beads was diluted 1000 times to prepare a particle-containing sample.

The fine particle capturing device 60 is mounted on a jig, and PBS and sheath liquid (water) for replacing the inside of the flow path of the fine particle capturing device 60 are prepared in each reservoir tank. Next, one of each reservoir tank and each inlet PEAK tube was connected, and the other of each inlet PEAK tube was connected to each inlet port IN1 and IN2 of the jig. Then, the inside of the flow path is decompressed by the suction pumps PP-line and AP-line from each of the outlet ports OUT1 and OUT2 (the right side portion of the particulate trapping device 60), thereby facilitating the flow of the sheath liquid and expelling bubbles in the flow path. Thereafter, the inside of the channel was completely replaced with liquid. Next, the diluted solution of beads was loaded into a reservoir tank of PBS solution, and inserted into the particle capturing device 60 from the inlet port IN1 (left side portion of the particle capturing device) by suction of AP-line.

Here, the suction was -5 kPa on the PP side and -2 kPa on the AP side. Further, as shown in FIG. 7, the height of the liquid surface was set to 10 cm above the surface of the fine particle capturing apparatus 60 on the sheath liquid side, and 1 cm above the PBS side on which the particle-containing sample was loaded.

(3) Embodiment 3
FIG. 8 shows a particle trapping device 80 that realizes 3,500 wells, which is more than twice as many as the number of flow paths, with respect to the 1,500 well particle trapping device 60 of FIG. 8A shows an upper layer 81 that distributes sheath fluid, FIG. 8B shows a lower layer 82 that distributes cell fluid, and FIG. 8C shows a two-layer structure 83 in which the upper layer 81 and the lower layer 82 are laminated. FIG. 8D is an enlarged view of the region A8 into which the sheath liquid in FIG. 8A is injected, and FIG. 8E is an enlarged view of the region D8 in FIG. 8D. The fine particle capturing device 80 forms an upper and lower two-layer structure 83, but the cell fluid flows in the lower layer 82 through the through-hole by switching the sheath fluid piping and the cell channel piping up and down, and the cell channel in the channel of the upper layer 81 Designed to be transported to

Here, a configuration for increasing the cell utilization efficiency of the particulate trap 80 will be described with reference to FIGS. 9 to 11. Here, the upper layer 81 in FIG. 8A is not changed, and the lower layer pattern is changed.

First, the lower layer 91 and the upper layer 81 shown in FIG. 9A are stacked to form a two-layer structure 92 shown in FIG. 9B. In the two-layer structure 92, a plurality of main flow paths are arranged in parallel. In this case, cell utilization efficiency is lowered.

Next, the lower layer 101 and the upper layer 81 shown in FIG. 10A are laminated to form the two-layer structure 102 shown in FIG. 10B. The two-layer structure 102 has a continuous main flow path. In this case, the flow path resistance is large and bubbles cannot be removed.

Then, the lower layer 111 and the upper layer 81 shown in FIG. 11A are stacked to form a two-layer structure 112 shown in FIG. 11B. In the two-layer structure 112, a plurality of main flow paths are parallel and continuous. In this case, the flow path resistance becomes appropriate and bubbles are easily removed. Therefore, it can be seen that the two-layer structure 112 is the configuration that increases the cell utilization efficiency most.

(4) Embodiment 4
A particulate trapping apparatus according to Embodiment 4 will be described with reference to FIGS. In the particulate trapping device of this embodiment, a concave array that captures particulates is formed on both sides of the inner wall surface of the flow path, and a structure that guides the flow of particulates toward the inner wall surface on the bottom surface of the inner wall surface of the flow path. Is formed.

FIG. 12A is a perspective view showing a structure formed in the particle capturing apparatus 120 of the present embodiment, and FIG. 12B is a center in the width direction (vertical direction in FIG. 12B) of the structure formed in the particle capturing apparatus 120. It is sectional drawing which shows the cross section which cut | disconnected the part in the extension direction (left-right direction of FIG. 12B) of a flow path. As shown in FIGS. 12A and 12B, in the particle capturing device 120 of the present embodiment, a prism shape 121 is formed as a structure on the bottom surface of the inner wall surface of the flow path.

FIG. 13A is a perspective view showing a structure formed in the particle trapping apparatus 130 of Modification 1 of the present embodiment, and FIG. 13B shows a structure formed in the particle trapping apparatus 130 as in FIG. 12B. It is sectional drawing shown. As shown in FIGS. 13A and 13B, in the fine particle trapping device 130 of the first modification, a single diamond shape 131 as a structure is formed near the inlet of the flow channel on the bottom surface of the inner wall surface of the flow channel.

FIG. 14A is a perspective view showing a structure formed in the particle trapping apparatus 140 of Modification 2 of the present embodiment, and FIG. 14B shows a structure formed in the particle trapping apparatus 140 as in FIG. 12B. It is sectional drawing shown. As shown in FIGS. 14A and 14B, in the fine particle capturing apparatus 140 of Modification 2, an array of pole shapes 141 as structures is periodically arranged in the center of the bottom surface of the inner wall surface of the flow path in the extending direction of the flow path. Has been. Note that these arrangements may be random, not periodic.

FIG. 15A is a perspective view showing a structure formed in the particle trapping apparatus 150 of Modification 3 of the present embodiment, and FIG. 15B shows a structure formed in the particle trapping apparatus 150 as in FIG. 12B. It is sectional drawing shown. As shown in FIGS. 15A and 15B, the particulate trapping apparatus 150 of Modification 3 has an array of pyramid shapes 141 as periodic structures periodically arranged in the extending direction of the flow channel on the bottom surface of the inner wall surface of the flow channel. Yes.

FIG. 16A is a perspective view showing a structure formed in the particle trapping device 160 of Modification 4 of the present embodiment, and FIG. 16B shows a structure formed in the particle trapping device 160 as in FIG. 12B. FIG. 16C is a plan view showing a structure formed in the fine particle capturing device 160. FIG. As shown in FIGS. 16A to 16C, in the fine particle capturing apparatus 160 of the fourth modification, an array of torus shapes 161 as structures are periodically arranged in the extending direction of the flow path on the bottom surface of the inner wall surface of the flow path. Yes.

FIG. 17A is a perspective view showing a structure formed in the particle capturing device 170 of Modification 5 of the present embodiment, and FIG. 17B shows a structure formed in the particle capturing device 170 in the same manner as FIG. 12B. It is sectional drawing shown. As shown in FIGS. 17A and B, in the particulate capturing device 170 of the modified example 5, an array of octagon (octagonal) shape 171 as a structure on the bottom surface of the inner wall surface of the flow path is periodically arranged in the extending direction of the flow path. Is arranged.

FIG. 18A is a perspective view showing a structure formed in the particle trapping apparatus 180 of Modification 6 of the present embodiment, and FIG. 18B shows a structure formed in the particle trapping apparatus 180 similarly to FIG. 12B. It is sectional drawing shown. As shown in FIGS. 18A and 18B, the particle trapping device 180 of Modification 6 has an array of dome-shaped 181 as a structure periodically arranged in the extending direction of the flow channel on the bottom surface of the inner wall surface of the flow channel. Yes. Moreover, the dome shape 181 can make the height of a top part equivalent to the height of the recessed part which capture | acquires microparticles | fine-particles. In this way, the fine particles can be pushed into the recess (well) by being compressed by matching the height of the top.

FIG. 19A is a perspective view illustrating a structure formed in the particle capturing apparatus 190 according to Modification 7 of the present embodiment, and FIG. 19B illustrates a structure formed in the particle capturing apparatus 190 as in FIG. 12B. It is sectional drawing shown. As shown in FIGS. 19A and B, in the fine particle capturing apparatus 190 of Modification 7, an array of phase-shifted dome-shaped (Phase （shift) 191 is extended on the bottom surface of the inner wall surface of the flow path. It is periodically arranged in the direction.

In addition, the shape of the structure is not limited to the shape of the present embodiment, and may be a shape having a protrusion such as an elliptical shape, a conical shape, or a combination of these shapes. Moreover, it is preferable to arrange | position the said structure so that the position of the extension direction of a flow path may become equal to a recessed part. Thereby, the flow of many microparticles | fine-particles can be induced | guided | derived to the recessed part which capture | acquires microparticles | fine-particles.

20 to FIG. 23, the tendency of the fine particle induction due to the shape of the structure according to the present embodiment will be described. FIG. 20 shows the tendency of particle induction when the flow rate is 4E-4 m / sec. FIG. 21 shows the tendency of particle induction when the flow rate is 2E-3 m / sec. 22 and 23 show the relationship between the shape, flow velocity and pressure of the structure and the number of trapped particles.

As shown in FIGS. 20 to 23, it was found that when the shape of the structure is a dome shape 181, the number of trapped particles is the highest. It was also found that the default number of trapped particles was the lowest. The “default shape” refers to a shape in which a recess is formed only on one side surface of the flow path and no structure is formed on the bottom surface of the flow path.

As described above, the particulate trapping device of the present embodiment has a structure on the inner wall surface (bottom surface) of the flow path so that the concave portion for trapping particulates is formed in the direction of the inner wall surface compared to the conventional particulate trapping device. Since the flow of the fine particles can be induced, the capture efficiency of the fine particles passing through the center of the flow path can be improved.

(5) Embodiment 5
A particle capturing device 240 according to the fifth embodiment will be described with reference to FIGS. 24 and 25. FIG. 24A is a perspective view showing a structure formed in the particle trapping apparatus 240 of the present embodiment, and FIG. 24B is a cross-sectional view showing the structure formed in the particle trapping apparatus 240 similarly to FIG. 12B. FIG. 24C is a plan view showing the structure formed in the particulate trapping device 240. As shown in FIGS. 24A to 24C, in the fine particle capturing apparatus 240 of this embodiment, an array of oval shapes 241 as structures is periodically formed on the bottom surface of the inner wall surface of the flow path in the extending direction of the flow path. Has been placed.

FIG. 25A shows the tendency of particle induction when the flow rate is 4E-4 m / sec, and FIG. 25B shows the tendency of particle induction when the flow rate is 2E-3 m / sec. As shown in FIGS. 25A and 25B, when the shape of the structure is the oval shape 241, the number of trapped particles is higher especially when the flow velocity is 4E-4 m / sec, compared to the case of the default shape. I understood.

Therefore, the particulate trapping device 240 of the present embodiment can improve the trapping efficiency of particulates passing through the center of the flow path, as compared with the conventional particulate trapping device, like the particulate trapping devices 120 to 190 of the fourth embodiment. it can.

(6) Embodiment 6
A particle capturing device 260 according to the sixth embodiment will be described with reference to FIGS. 26 and 27. FIG. 26A is a perspective view showing a structure formed in the particle trapping apparatus 260 of the present embodiment, and FIG. 26B is a cross-sectional view showing the structure formed in the particle trapping apparatus 260 similarly to FIG. 12B. FIG. 26C is a plan view showing a structure formed in the particulate trapping device 260. As shown in FIGS. 26A to 26C, the particulate trapping apparatus 260 of the present embodiment has a protrusion that is lower than the height of the protrusion of the torus shape 161 of FIG. 16 on the bottom surface of the inner wall surface of the flow path. An array of thin torus shapes 261 is periodically arranged in the extending direction of the flow path.

FIG. 27A shows the tendency of particle induction when the flow rate is 4E-4 m / sec, and FIG. 27B shows the tendency of particle induction when the flow rate is 2E-3 m / sec. As shown in FIGS. 27A and 27B, the number of trapped particles is higher in the case of the thin torus shape 261 as compared with the default shape, particularly when the flow velocity is 4E-4 m / sec. I understood it.

Therefore, the particulate trapping device 260 of the present embodiment can improve the trapping efficiency of particulates passing through the center of the flow path, as compared with the conventional particulate trapping device, as in the particulate trapping devices 120 to 190 of the fourth embodiment. it can.

(7) Embodiment 7
A particle capturing device 280 according to the seventh embodiment will be described with reference to FIGS. 28 and 29. FIG. 28A is a perspective view showing a structure formed in the particle trapping device 280 of this embodiment, and FIG. 28B is a cross-sectional view showing a structure formed in the particle trapping device 280 similarly to FIG. 12B. FIG. 28C is a plan view showing the structure formed in the particle capturing device 280. As shown in FIGS. 28A to 28C, the fine particle capturing apparatus 280 of the present embodiment has a structure on the bottom surface of the inner wall surface of the flow path in the arrangement direction of the torus shape 281 in addition to the torus shape 281 as shown in FIG. An array of pole-shaped torus shapes 283 having pole shapes 282 formed on both side surfaces is periodically arranged in the extending direction of the flow path.

FIG. 29A shows the tendency of particle induction when the flow rate is 4E-4 m / sec, and FIG. 29B shows the tendency of particle induction when the flow rate is 2E-3 m / sec. As shown in FIGS. 27A and 27B, when the shape of the structure is the torus shape with a pole 281, the number of trapped particles is high particularly when the flow velocity is 4E-4 m / sec, compared to the case of the default shape. I found out that

Therefore, the particulate trapping device 280 of the present embodiment can improve the trapping efficiency of the particulates passing through the center of the flow path, as compared with the conventional particulate trapping device, similarly to the particulate trapping devices 120 to 190 of the fourth embodiment. it can.

(8) Embodiment 8
[Example of mounting technology for self-aligning IC chips]
A fine particle capturing apparatus of the present technology was manufactured from an on-chip IC (SoC: system on silicon) substrate.

As the particles to be captured, a high-density IC chip fabricated on a silicon wafer by a semiconductor process is cut out from the wafer into a 100 μm square using a dicer. Although the number of IC chips depends on the size to be cut out and the width of the margin for cutting, the number of IC chips is prepared as many as 7 million on a 300 mm wafer.

Conventionally, there has been a limit (0.4 mm × 0.2 mm square) in a chip mounter in order to mount it in a state where it is self-aligned and arranged at an equal interval and narrow pitch. However, by using a self-assembly method using a flow path having a corrugated structure 31 according to the present technology, it is possible to mount narrow pitch minute chips in a single unit at regular intervals.

The IC chip placed in the concave portion at the top of the corrugated structure can be combined with another chip for subsequent wiring by a subsequent process. Also, another electrical circuit board is built around the top of the corrugated flow path, and when the IC chip is captured in the recess, the wiring is expanded with a wire bonder or the like, and integrated with the flow path board. Can be produced. Further, by cutting out, an on-chip IC device can be efficiently manufactured.

(9) Embodiment 9
[Application to fabrication of micro LED display]
A fine particle capturing apparatus shown in FIG. 30 was produced. Three independent lanes having a corrugated structure are prepared, and different micro LED chips are dispersed in the liquid in each lane, and are fed in the direction of the arrow on the left side of FIG. By flowing the LED and the green LED, the LEDs can be mounted at equal intervals of 150 μm pitch.

The LED chip captured at the top of the corrugated structure 31 can be used as a micro LED display by wiring with a wire bonder to the captured concave portion and the global electrode 27 disposed below the concave portion.

Further, even in the case of an active drive display such as an organic EL, this mounting technique can be applied to mount an IC circuit currently made of polysilicon on each pixel at an equal interval pitch. . Therefore, an active matrix polysilicon circuit that is expensive and has a poor yield can be replaced with an IC chip that operates stably.

<2. Particle capture system>
The particulate trapping system of the present technology includes a liquid feeding section in the particulate trapping device.

FIG. 31 shows an example of the particle capturing system 301. The fine particle capturing unit 302 is connected to the liquid feeding unit 303 via the valve 307. The liquid feeding unit 303 supplies the particle-containing sample to the fine particle capturing unit 302. Sample flow can be controlled by opening and closing valve 307. This control can be performed by the liquid feeding control unit 306. A control program may be provided in a computer to automatically control liquid feeding. By controlling the liquid feeding, not only can the sample flow / stop, but also a reverse flow and a pulsating flow that changes the flow at regular intervals can be generated.

Further, the particle capturing system 301 may include a particle observation unit 305. The particle observation unit 305 is not particularly limited, but the flow path and particles flowing and captured may be magnified with a microscope or the like and observed with the naked eye, or data processing may be performed with an image processing apparatus or the like without depending on the naked eye. It may be. The observation result here is fed back to the liquid feeding control unit 306 to further control the flow of the sample.

Furthermore, the particulate trapping system 301 may include a waste liquid portion 304 on the downstream side, and can collect a sample liquid having a reduced particle content as a waste liquid. A valve or a pump may be further provided on the upstream side or the downstream side of the waste liquid unit 304, and a suction force may be applied to the flow path of the particle capturing unit 302.

<3. Fine particle capture method>
The fine particle capture method of this technology supplies the sample containing the particles to be captured to the particle capture device and feeds the sample, while sucking it out from the recess through the pull-in passage to capture the particles to be captured. It is a method to do. A fine particle capturing method as an example of the present technology includes a flow path for flowing fine particles on a substrate, a recess formed on an inner wall surface of the flow path, and a drawing passage for drawing the fine particles. Then, the recess and the lead-in passage are communicated with each other, and a sample containing particles to be captured is supplied to a fine particle capturing device in which a structure for guiding the flow of fine particles in the direction of the inner wall surface is formed on the inner wall surface. While feeding the sample, the sample can be sucked out from the recess through the drawing-in passage to capture the target particles.

<4. Flow path shape of particulate trapping device>
The optimization of the channel shape of the particulate trapping device according to the present technology will be described with reference to FIG.

In the conventional particle trapping device, the connection flow path from the INLET to the main flow path where the microwell array is arranged was connected with a steep curve. . In addition, when polystyrene beads of Φ20.000.10 ± 0.10 um are used, there is a possibility that traffic congestion will increase if a 1000-fold diluted bead can be caught. However, it has been found that it is less likely to be congested if the water is allowed to flow appropriately to increase the particle spacing.

Therefore, in order to solve the above problem, in the particulate trapping device according to the present technology, the flow path has a shape having a gentle slope obliquely from INLET (IN1 and IN2) toward the

flow paths

321 and 322, and the connection portion is It is close to a straight line. Furthermore, the shapes of the

flow paths

321 and 322 are tapered toward the direction in which the fine particles flow (direction from IN to OUT).

With the above configuration, the particle trapping device according to the present technology avoids accumulation due to sudden deceleration of particles by connecting the connection channel from INLET to the main channel where the microwell array is arranged with a gentle curve. can do. Furthermore, the particle trapping device according to the present technology has a tapered asymmetry channel shape, and the pressure decreases toward the back side of the microwell array. The pressure distribution by tapering the flow path can be made uniform.

The embodiments of the present technology are not limited to the above-described embodiments, and various modifications can be made without departing from the gist of the present technology. For example, the form which combined all or one part of several embodiment mentioned above is employable.

Moreover, this technique can take the following structures.
[1] A flow path for flowing fine particles, a recess formed on an inner wall surface of the flow path, and a drawing passage for drawing the fine particles,
The recess and the retracting passage communicate with each other,
A structure for guiding the flow of fine particles in the direction of the inner wall surface is formed on the inner wall surface.
Particulate trap.
[2] The structure according to [1], in which the structure has a protrusion,
Particulate trap.
[3] The fine particle capturing apparatus according to [2], wherein the structure is formed at a position where an opening direction of the concave portion and a protruding direction of the protruding portion intersect.
[4] The fine particle capturing apparatus according to [1], wherein the recess is formed on a side wall of the inner wall surface, and the structure is formed on a bottom surface of the inner wall surface.
[5] The fine particle capturing apparatus according to [1], wherein a plurality of the structures are arranged in an extending direction of the flow path.
[6] The fine particle capturing apparatus according to [5], wherein the plurality of the structures arranged in a row are periodically arranged.
[7] The fine particles according to [1], wherein the structure has any one of a prism shape, a diamond shape, a pole shape, a torus shape, a pyramid shape, an octagonal pyramid shape, a dome shape, an elliptical shape, and a conical shape. Capture device.
[8] The particulate trapping device according to [7], wherein the dome shape is a phase-shifted shape.
[9] The fine particle trapping device according to [7], wherein the dome shape has a height of a top portion equal to a height of the concave portion.
[10] The particulate trapping device according to [7], wherein a pole shape is further formed on a side surface in the extending direction of the torus shape.
[11] The particulate trapping device according to [1], wherein the flow path has a shape that tapers in a direction in which the particulate flows.
[12] The particulate trapping device according to [1], wherein the flow path has a gentle slope.
[13] A flow path for flowing fine particles on the substrate, a recess formed on the inner wall surface of the flow path, and a drawing-in passage for drawing the fine particles,
The recess and the pull-in passage are communicated with each other, and the inner wall surface has a fine particle capturing portion formed with a structure that guides the flow of the fine particles toward the inner wall surface;
A particulate trapping system comprising a liquid feeding section connected to the particulate trapping section.
[14] A flow path through which fine particles flow on the substrate, a recess formed in an inner wall surface of the flow path, and a drawing-in path for drawing in the fine particles, and the recess and the drawing-in path communicate with each other In the inner wall surface, a particle capturing device in which a structure for guiding the flow of particles in the inner wall direction is formed,
A fine particle capturing method, wherein a sample containing particles to be captured is supplied and the sample is sucked to the outside through the pull-in passage from the recess to capture the particles to be captured.

10, 60, 80, 120, 130, 140, 150, 160, 170, 180, 190, 240, 260, 280 Particulate capture device 11

Base material

12, 321, 322 Channel 13 Peak 14 Valley 15 Top 16 Recess 17 Passage 18 External 19 Top surface 27 Global wiring 31 Wave structure 81

Upper layer

82, 91, 101, 111

Lower layer

83, 92, 102, 112 Two

layer structure

121, 131, 141, 151, 161, 171, 181, 191 , 241, 261, 281, 282, 283 Structure 301 Fine particle capture system 302 Bead 303 Liquid supply part 304 Waste liquid part 305 Single particle observation part 306 Liquid supply control part 307 Valve

Claims

A flow path for flowing fine particles, a recess formed on the inner wall surface of the flow path, and a retracting passage for drawing the fine particles,
The recess and the retracting passage communicate with each other,
A structure for guiding the flow of fine particles in the direction of the inner wall surface is formed on the inner wall surface.
Particulate trap.
The fine particle capturing apparatus according to claim 1, wherein the structure has a protrusion.
3. The fine particle capturing apparatus according to claim 2, wherein the structure is formed at a position where an opening direction of the concave portion and a protruding direction of the protruding portion intersect.
The fine particle capturing apparatus according to claim 1, wherein the concave portion is formed on a side wall of the inner wall surface, and the structure is formed on a bottom surface of the inner wall surface.
The fine particle capturing apparatus according to claim 1, wherein a plurality of the structures are arranged in the extending direction of the flow path.
The fine particle capturing apparatus according to claim 5, wherein the plurality of the structures arranged in a row are periodically arranged.
2. The fine particle capturing apparatus according to claim 1, wherein the structure has any one of a prism shape, a diamond shape, a pole shape, a torus shape, a pyramid shape, an octagonal pyramid shape, a dome shape, an elliptical shape, and a conical shape.
The fine particle trapping device according to claim 7, wherein the dome shape is a phase shifted shape.
The fine particle trapping device according to claim 7, wherein the dome shape has a height at the top equal to a height of the concave portion.
The fine particle capturing apparatus according to claim 7, wherein a pole shape is further formed on a side surface of the torus shape in the extending direction.
2. The particle capturing apparatus according to claim 1, wherein the shape of the flow path is a tapered shape in a direction in which the particles flow.
The fine particle capturing apparatus according to claim 1, wherein the shape of the flow path is a shape having a gentle inclination.
A flow path for allowing fine particles to flow on the substrate, a recess formed on the inner wall surface of the flow path, and a retracting passage for drawing the fine particles,
The recess and the pull-in passage are communicated with each other, and the inner wall surface has a fine particle capturing portion formed with a structure that guides the flow of the fine particles toward the inner wall surface;
A particulate trapping system comprising a liquid feeding section connected to the particulate trapping section.
A flow path for allowing fine particles to flow on the substrate, a recess formed in an inner wall surface of the flow path, and a drawing passage for drawing the fine particles, and the depression and the drawing passage are communicated with each other, In the inner wall surface, a particle capturing device in which a structure for guiding the flow of particles in the inner wall direction is formed,
A fine particle capturing method, wherein a sample containing particles to be captured is supplied and the sample is sucked to the outside through the pull-in passage from the recess to capture the particles to be captured.