Patent Publication Number: US-2019168222-A1

Title: Single-particle capturing apparatus, single-particle capturing system, and single-particle capturing method

Description:
TECHNICAL FIELD 
     The present invention relates to a single-particle capturing apparatus, a single-particle capturing system, and a single-particle capturing method. 
     BACKGROUND ART 
     In recent years, a technology in which a cell is captured alone as typified by flow cytometry or the like, has been developed. The cell, after being captured alone, is used for analysis or culture. 
     As a method for capturing a single cell, for example, a technology described in Patent Document 1 has been developed. Patent Document 1 discloses a single-cell capturing array in which a well large enough for a single cell is formed on a flow channel through which a cell-containing sample flows and the single cell is captured in the well while the cell-containing sample flows ( FIGS. 1 to 8 ). Furthermore, a structure in which a cell is sucked through a slit provided on the well is disclosed ( FIGS. 23, 25  and the like). 
     CITATION LIST 
     Patent Document 
     
         
         Patent Document 1: US 2013/0078163 A 
       
    
     SUMMARY OF THE INVENTION 
     Problems to be Solved by the Invention 
     However, with the structure of the flow channel of the aforementioned Patent Document 1, a phenomenon occurs in which, even after the cell is trapped in the well, another cell is sucked to the well and adhered to the captured cell, resulting in accumulation of a plurality of cells. 
     One of possible causes is an excessive number of supplied cells. Once the cells are accumulated, an accumulation starts snowballing at the accumulation point and grows until the flow channel is clogged. The cells once accumulated are difficult to move, resulting in inconvenient operability. 
     Solutions to Problems 
     In order to solve the aforementioned problem, the present technology provides a single-particle capturing apparatus including a flow channel on a substrate, a wave structure with a mountain portion and a valley portion on the flow channel, and a recess portion at a top portion of the mountain portion, the recess portion including a draw-in passage. 
     The depth of the recess portion can be equal to or less than the particle diameter of a particle to be captured, and the diameter of the recess portion can be a size equal to or more than one time and less than two times of the particle diameter of the particle to be captured. 
     Furthermore, the height from the valley portion to the mountain portion can be equal to or larger than the particle diameter of the particle to be captured, the pitch between the mountain portions can be a length equal to or more than 2 times and equal to or less than 20 times of the particle diameter of a particle to be captured, and the channel width of the flow channel can be relatively small at the mountain portion and relatively large at the valley portion. 
     Furthermore, the draw-in passage can make communication between the recess portion and the outside. 
     Moreover, a plurality of mountain portions and valley portions may be aligned on the bottom surface of the flow channel. 
     Moreover, the flow channel and the wave structure may be curved or bent. 
     For example, the flow channel and the wave structure are curved in a U-shape, and an inner side of the U-shape is the outside. 
     The present technology can provide a single-particle capturing system including 
     a single-particle capturing unit including 
     a flow channel on a substrate, a wave structure with a mountain portion and a valley portion on the flow channel, and a recess portion at a top portion of the mountain portion, the recess portion including a draw-in passage; and 
     a liquid supply unit. 
     The flow channel can include a valve. Furthermore, the single-particle capturing system may include a waste liquid unit, a single-particle capturing observing unit, and a liquid supply control unit. 
     Moreover, the present technology provides a single-particle capturing method in which a specimen containing a particle to be captured is supplied to a single-particle capturing apparatus including 
     a flow channel on a substrate, the flow channel including a wave structure with a mountain portion and a valley portion, and a recess portion at a top portion of the mountain portion, the recess portion including a draw-in passage, and 
     the specimen is, while being supplied, sucked from the recess portion to an outside via the draw-in passage such that the particle to be captured is captured. 
     The single-particle capturing method can include flowing the supplied liquid backward. 
     Effects of the Invention 
     According to the present technology, one particle can be captured in one recess portion while preventing another particle from being accumulated on a captured particle. 
     Note that effects described herein are not necessarily limited, but may also be any of those described in the present disclosure. 
    
    
     
       BRIEF DESCRIPTION OF DRAWINGS 
         FIG. 1  is a longitudinal sectional view of a single-particle capturing apparatus of the present technology. 
         FIG. 2  is a perspective view illustrating a mountain portion, a valley portion, a recess portion, and a draw-in passage of a single-particle capturing apparatus of the present technology. 
         FIG. 3  is a schematic view illustrating a flow of a sample and a state of capturing of particles in a single-particle capturing apparatus of the present technology. 
         FIG. 4  is a schematic view illustrating a flow of a sample and a state of capturing of particles in a single-particle capturing apparatus of the present technology. 
         FIG. 5  is a schematic view illustrating an example of a size of a single-particle capturing apparatus of the present technology. 
         FIG. 6  is a schematic view illustrating an example of a single-particle capturing apparatus of the present technology. 
         FIG. 7  is a drawing-substitute photograph illustrating a single-particle capturing apparatus of a conventional technology and a state of capturing of particles. 
         FIG. 8  is a drawing-substitute photograph illustrating a single-particle capturing apparatus of a conventional technology and a state of capturing of particles. 
         FIG. 9  is drawing-substitute photographs illustrating a single-particle capturing apparatus and a state of capturing of particles. 
         FIG. 10  is drawing-substitute photographs illustrating a single-particle capturing apparatus and a state of capturing of particles. 
         FIG. 11  is drawing-substitute photographs illustrating a single-particle capturing apparatus of the present technology and a state of capturing of particles. 
         FIG. 12  is a drawing-substitute photograph illustrating a single-particle capturing apparatus of the present technology and a conventional technology and a state of capturing of particles. 
         FIG. 13  is a drawing-substitute photograph illustrating a single-particle capturing apparatus of the present technology and a state of capturing of particles. 
         FIG. 14  is a drawing-substitute photograph illustrating an example of a single-particle capturing apparatus of the present technology. 
         FIG. 15  is schematic views illustrating an example of a single-particle capturing apparatus of the present technology. 
         FIG. 16  is diagrams illustrating an example of a single-particle capturing apparatus of the present technology. 
         FIG. 17  is a diagram illustrating an example of a single-particle capturing apparatus of the present technology. 
         FIG. 18  is a schematic diagram illustrating an example of a single-particle capturing system of the present technology. 
     
    
    
     MODE FOR CARRYING OUT THE INVENTION 
     Preferred aspects for carrying out the present technology are described below. Note that embodiments described below indicate representative embodiments of the present technology, and they do not make the scope of the present technology to be understood narrowly. The description is provided in the order set forth below. 
     1. Single-particle capturing apparatus 
     2. Embodiments
         (1) Embodiment 1   (2) Conventional Technology Example 1   (3) Conventional Technology Example 2 and Embodiment 2   (4) Embodiment 3   (5) Embodiment 4   (6) Embodiment 5   (7) Embodiment 6   (8) Embodiment 7   (9) Embodiment 8   (10) Embodiment 9   (11) Embodiment 10       

     3. Single-particle capturing system 
     4. Single-particle capturing method 
     1. SINGLE-PARTICLE CAPTURING APPARATUS 
     The type of particles to be captured by a single-particle capturing apparatus of the present technology is not particularly limited. Examples of the type include cells, beads, semiconductor chips, micro bumps as a terminal of a connection portion of a semiconductor, bead-type solar cells, and the like. Furthermore, the size, shape, and the like of particles are also not particularly limited. 
     Examples of the technical field to which the single-particle capturing apparatus of the present technology can be applied include a hybrid bio/inorganic material, nanohybrid environmental sensor, environmental sensor: sensor array formation technology, light condensing material for solar cell, self-organization arrangement of a chip-shaped component for a high-density package module, a formation technology using a template of a self-organization pattern of a cyclic recess and protrusion structure with a sub-wavelength (sub μm) size necessary for increased light extraction efficiency of a light emitting device or the like, formation of a quasi-phase matching structure by optical polling of a non-linear organic dye for an organic light switching device, self-organization of a metal or semiconductor nanoparticle for quantum dot memory, a polymeric self-organizing material for nanocrystal memory, and the like. 
     A description is given below with reference to  FIGS. 1 and 2 . 
     A single-particle capturing apparatus of the present technology includes a flow channel  12  in a substrate  11 . 
     The substrate  11  is not particularly limited, and includes: resin such as polyethylene, polypropylene, vinyl chloride resin, polystyrene, polyethylene terephthalate, acrylic resin, polycarbonate, fluororesin, polybutylene terephthalate, phenolic resin, melamine resin, epoxy resin, unsaturated polyester resin, and polydimethylsiloxane; glass; metal; and the like. 
     For the flow channel  12 , the width and the height of the flow channel can be determined according to the size, shape, and type of a particle to be captured, or the amount, viscosity or the like of a sample that flows in the flow channel. 
     A wave structure with a mountain portion  13  and a valley portion  14  is included on the flow channel  12 , and a recess portion  16  is formed on a top portion  15  of the mountain portion  13 . A particle in the sample is captured in the recess portion  16 . 
     By a wave structure on a bottom surface in the flow channel  12 , another cell is prevented from adhering to a cell captured in the recess portion at a top portion of the wave. Therefore, it is possible to prevent accumulation of cells. 
     Furthermore, as illustrated in  FIG. 3 , the flow channel  12  including a top surface  19  has a characteristic that a liquid flow of the sample therein is laminar and the flow speed at the center of the flow channel  12  is always faster than the flow speed near a side surface of the flow channel (four arrows at the upper left). Therefore, the flow speed at the top portion  15  becomes faster as a result of providing the recess portion  16  at the wave-shaped top portion  15  of the wave structure. Thus, by providing the recess portion  16  at the top portion  15 , it is possible to prevent doublet—two or more particles enter the recess portion  16  (dotted line circles). That is, it is though that even if the second cell or bead adheres to make doublet, because of faster flow speed, the second and subsequent cells and beads hardly enter by being flown by a central laminar flow. For example, the central laminar flow is faster by about 20% than the general flow speed of the liquid flow. 
     The recess portion  16  further includes a draw-in passage  17 . As illustrated in  FIG. 4 , the sample moves in a liquid flow direction  22  and moves downstream as a valve  21  is opened. Then, because of the presence of the draw-in passage  17  through which the recess portion  16  communicates with the outside (downstream side of the valve  21 ), a force of draw-in by positive pressure  23  occurs in a direction from the flow channel  12  side to an outside  18 . A particle easily enters the recess portion  16  because of a pressure difference between the inside of the flow channel  12  and the outside. Note that, in  FIG. 4 , the outside is a flow channel  12  of the downstream side of the valve  21  and is contiguous with the flow channel  12 . 
     Note that the installment of the valve is not limited to the above. For example, a valve for flowing a sample liquid can be installed upstream of the flow channel  12  contiguous with the recess portion  16 , and a valve for sucking the sample liquid can be installed downstream. 
     The shape of the recess portion  16  can be determined in accordance with the shape or the like of a particle to be captured. Examples of the shape of the recess portion  16  include a cylindrical shape, a circular truncated conical shape, an inverted circular truncated conical shape, an elliptic cylindrical shape, an elliptic truncated shape, an inverted elliptic truncated conical shape, a tapered shape, an inverted tapered shape, a polygonal column of a triangular column or a column with more corners, and the like. 
     Furthermore, the depth of the recess portion  16  is preferably equal to or less than the particle diameter of a particle to be captured. With such depth, it is possible to prevent doublet of particles in the recess portion  16  and accumulation of another particle on a captured particle. 
     Here, the “particle diameter” of a particle indicates an average value of a major axis diameter and a minor axis diameter of a microparticle. Specifically, in the case of a microparticle, the particle diameter can be calculated in such a manner that a microscope is used to measure a considerable number of (e.g.,  100 ) any microparticles using image processing software or the like to determine the average number. 
     For example, the depth of the recess portion  16  can be preferably two or less, more preferably one or less in the ratio to the particle diameter of a particle to be captured. 
     Alternatively, the depth of the recess portion  16  can be preferably two or less, more preferably one or less in the ratio to the diameter of an inscribed circle at the opening of the recess portion  16 . 
     Furthermore, the depth of the recess portion  16  can be preferably one or less, more preferably 0.8 or less in the ratio to the height from the valley portion  14  to the mountain portion  13 . 
     Furthermore, in a case where the opening has a circular shape in which a the three-dimensional shape of the recess portion  16  is, for example, a cylindrical shape, a circular truncated conical shape, an inverted circular truncated conical shape, a tapered shape, or an inverted tapered shape, the diameter of the recess portion  16  is preferably a size equal to or more than one time and less than two times of the particle diameter of a particle to be captured. Furthermore, in a case where the opening of the recess portion  16  has a polygonal shape of a triangular column or a column with more corners, in the case of a polygon with n sides, which is an odd number, the normal from the apex angle to the base can be regarded as the diameter and in the case of a polygon with n sides, which is an even number, the diagonal can be regarded as the diameter. If the diameter is less than one time, a single cell hardly enters into the recess portion  16 . In the case of two times or more, a plurality of cells can enter into the recess portion  16 . 
     The height from the valley portion  14  to the mountain portion  13  is preferably equal to or larger than the particle diameter of a particle to be captured. The flow speed of the liquid in the flow channel  12  increases toward a central portion. Therefore, in a case where the height of the mountain portion  13  and the valley portion  14  is smaller than the particle diameter of the particle, the flow speed to which the particle is subjected is slow even in the vicinity of the mountain portion  13 . When the flow speed in the vicinity of the mountain portion  13  is slow, particles that flow subsequently tend to adhere to the particle trapped in the recess portion  16 . The particles that flow subsequently also have a reduced impact energy because of slow flow speed and increasingly adhere to the captured particle, resulting in accumulation of particles. 
     The pitch between the mountain portions  13  can be a length equal to or more than 2 times and equal to or less than 20 times of the particle diameter of a particle to be captured. Specifically, the distance from the top portion  15  of the mountain portion  13  to a top portion  15  of an adjacent mountain portion  13  across one valley portion  14  is equal to or more than 2 times and equal to or less than 20 times of the particle diameter of a particle to be captured. In the case of less than two times, the particle can enter the valley portion  14 . In the case of exceeding 20 times, depending on the height of the mountain portion  13 , the wave structure becomes close to a flat structure and there is a possibility that the effect of the present technology cannot be fully exhibited. 
     Note that the pitch between the mountain portions  13  is more preferably a length equal to or more than 5 times and equal to or less than 15 times of the particle diameter of a particle to be captured. Within the aforementioned range, the effect to be provided by the wave structure of the present technology can be exhibited. Furthermore, in a case where the single-particle capturing apparatus of the present technology is to capture a micro-order single microparticle, a fine wave structure or recess portion needs to be formed on the substrate. The aforementioned range can be made in view also of manufacturability in that case. 
     Note that the right and left pitch of the mountain portion  13  may be equal and may be different. 
     Furthermore, regarding the flow channel  12 , when the bottom surface and the top surface are parallel and the wave structure is formed on the bottom surface, the channel width of the flow channel  12  can be relatively small at the mountain portion  13  and large at the valley portion  14 . With such a channel width, the particle remaining at the top portion  15  can be flown because the central laminar flow of the liquid flow is fast. 
     An example of sizes of the portions of the single-particle capturing apparatus described above is illustrated in  FIG. 5 . The single-particle capturing apparatus herein is assumed to capture a single cell or bead with a diameter size of 10 μm. 
     In  FIG. 5 , the mountain portion  13  has a width of 70 μm, the mountain portion  13  has a height of 15 μm, the top portion  15  has a width of 20 μm, the opening of the recess portion  16  has a diameter of 15 μm, the recess portion  16  has a depth of 10 μm, the draw-in passage  17  has a length of 35 μm, and the draw-in passage has a width of 3 μm. 
     2. EMBODIMENTS 
     (1) Embodiment 1 
       FIG. 6  illustrates a single-particle capturing apparatus of Embodiment 1. The particle to be captured by the single-particle capturing apparatus was a polystyrene bead having a diameter of 15 μm. For the substrate, polydimethylsiloxane (PDMS) was used as a material and poured into a mold, which was a master, to form a PDMS resin to produce a chip including a produced flow channel and micro wells. The PDMS substrate, which was a produced chip, was hydrophilized on the surface by direct plasma (DP) asking with O 2 : 10 cc, at 100 W, for 30 seconds, and was bonded to a cover glass in the atmosphere. 
     A single-particle capturing apparatus  100  manufactured by the aforementioned production method includes the flow channel  12  at a central portion of a substrate plate. The flow channel  12  includes a wave structure  31  and the recess portion  16 , described above, on the top surface side, and includes an outside  18  on the bottom surface side. Thus, the wave structure  31  configures a top surface side flow channel and a bottom surface side flow channel (outside  28 ). An upper left port of the substrate plate is connected to the flow channel  12 , and a particle-containing sample is introduced into the port. Then, a bypass  24  is installed on the right side of the substrate plate. The bypass  24  connects the top surface side flow channel and the bottom surface side flow channel. The valve  21  is installed on the bypass  24 . A lower left port is a part into which the sample liquid flowing from the top surface side flow channel to the bottom surface side flow channel flows. 
     The particle-containing sample introduced through the upper left well can be flown into the flow channel  12  by any one of a force for introducing the particle-containing sample in the top surface side flow channel, a downstream flow force, a sample liquid flowing force generated by opening and closing of the valve  21  installed at the bypass  24 , a force of sucking the sample liquid through the lower left port, and the like, or an appropriate combination thereof. 
     (2) Conventional Technology Example 1 
       FIGS. 7 and 8  illustrate a single-particle capturing apparatus of a conventional technology. The single-particle capturing apparatus was produced in a similar way to Embodiment 1 except that the wave structure was a flat surface structure. 
     As illustrated in  FIG. 7 , the single-particle capturing apparatus of the conventional technology includes the recess portion  16  on a flat surface of the flow channel  12  on the top surface side and includes the draw-in passage  17  for communication between the recess portion  16  and the outside  18 . The particle-containing sample is introduced into the flow channel  12  on the top surface side in a direction of the upper left arrow of  FIG. 7 , the sample liquid flow moves to the outside  18  through a tube  25  that includes an increment  26  and couples the flow channel  12  on the top surface side to the outside  18 , and is discharged in a direction of the lower left arrow of  FIG. 7 . 
     A bead capture experiment was conducted using the single-particle capturing apparatus of the aforementioned conventional technology of  FIG. 7 . 
     First, in order to prepare a particle-containing sample, a liquid concentrate of polystyrene bead having a diameter of 20 μm was diluted 1000 times. 
     The single-particle capturing apparatus was mounted on a jig, the bead diluted liquid was inserted by a syringe pump through an inlet port (part indicated by the upper left arrow of  FIG. 7 ), and the pressure in the flow channel was reduced by a suction pump through an outlet port (part indicated by the lower left arrow of  FIG. 7 ) for easy liquid flow. 
     Suction was started with—10 kPa, and the suction amount was gradually increased to—35 kPa. The suction pressure was adjusted by compression of the tube  25  about 0.7 mm using the increment  26  with 1.1 mm. The first flow speed at which the liquid is supplied by the syringe pump was set to 50 μL/min, the flow speed was gradually increased to 100 μL/min. 
     As illustrated in  FIG. 7 , a bead  102  began being captured in the recess portion  16  of the single-particle capturing apparatus of the conventional technology. However, when the bead diluted liquid was continuously flown, as illustrated in  FIG. 8 , a phenomenon was seen in which two or more beads entered into the recess portion  16  or another bead adhered to a captured bead. 
     (3) Conventional Technology Example 2 and Embodiment 2 
     A single-particle capturing apparatus including a wave structure was indicated as Embodiment 2 at  9 A of  FIG. 9 . A single-particle capturing apparatus including a flat surface was indicated at  9 C as Conventional Technology Example 2. A single-particle capturing apparatus including a flat surface structure on the left side and a wave structure on the right side of the dotted line was indicated at  9 B. 
     As the particle-containing sample, a liquid concentrate of polystyrene bead having a diameter of 15 μm was diluted 1000 times, and a bead diluted liquid was prepared to have a bead concentration of 1.7 μl and Tween20 of 0.05%. 
     The bead diluted liquid was flown to the single-particle capturing apparatuses indicated at  9 A,  9 B, and  9 C. In the case of  9 A, it was observed that one or two beads were captured in each of the recess portions at the top portion of the wave structure. 
     In the case of  9 C, it was observed that beads were captured in the recess portions present on the flat surface structure and other beads were adhered to the captured beads and accumulated. 
     In the case of  9 B, it was observed that, although the flat surface structure and the wave structure were arranged on the same flow channel, beads were accumulated in the recess portions of the flat surface structure but beads were not accumulated in the recess portions of the wave structure. 
     Note that the sizes of the recess portions are indicated at  10 A and  10 B of  FIG. 10 . 
     The recess portion of the wave structure of  10 A has a diameter of 15 μm and a depth of 25 μm. The depth was larger than the diameter of 15 μm of the bead particle diameter, and two beads were captured in the recess portion. 
     The recess portion of the flat surface structure of  10 B had a diameter of 15 μm and a depth of 25 μm. Not only a plurality of beads was captured in the recess portion, but also other beads were adhered to and accumulated on the captured beads. 
     (4) Embodiment 3 
       FIG. 11  illustrates the single-particle capturing apparatus of the present technology at  11 A and  11 B. The single-particle capturing apparatus was produced in a similar way to Embodiment 1. Note that the recess portion had a depth of 10 μm. 
     The single-particle capturing apparatus was mounted on a jig, the bead diluted liquid was inserted by a syringe pump through an inlet port, and the pressure in the flow channel was reduced by a suction pump through an outlet port for easy liquid flow. 
     The operation conditions are described below. 
     Syringe pump flow speed: 6 mL/h (=100 mL/min) 
     Suction pressure: maintained at—10 kPa (bypass tube compression amount: 0.7 mm) 
     Bead flow rate: 0.28/sec 
     Inside flow speed: 0.6 ml/h=0.167 ul/sec 
     Furthermore, as the particle-containing sample, a liquid concentrate of polystyrene bead having a diameter of 15 μm was diluted 1000 times, and a bead diluted liquid was prepared to have a bead concentration of 1.7 μl and Tween20 of 0.05%. 
     When the bead diluted liquid was flown to the single-particle capturing apparatus, a single bead stably entered the recess portion as indicated at  11 A. The reason for this is considered to be the fact that, due to presence of the flow channel side surface of the wave structure arranged in the flow channel and the recess portion arranged at the top portion of the mountain portion, even if a first bead is captured in the recess portion and a next bead is sucked to the recess portion and attempts to adhere to the captured bead, the bead that attempts to adhere contacts a subsequent bead or the liquid flow and is flown downstream because of the flow speed at the top portion which is faster by about 20% than the flow speed at the side wall. Accordingly, the captured beads hardly make doublet. 
     However, when the beads are supplied excessively, as indicated at  11 B, a phenomenon was seen in which the beads were accumulated along the wave structure. The accumulation of the beads was able to be re-dispersed when the suction pressure was released to change the flow of the bead diluted liquid. 
     (5) Embodiment 4 
     [Consideration 1 for Dispersion of Particles by Pulsation] 
       FIG. 12  illustrates the single-particle capturing apparatus including the recess portion (flat surface well) formed on the flat surface on the left side of the dotted line and the recess portion (wave-shaped well) formed on the wave structure on the right side. 
     When the bead diluted liquid was supplied to the single-particle capturing apparatus, as illustrated in the photograph “ALIGNMENT” at the top of  FIG. 12 , another particle began adhering to the captured particle in the recess portion at the flat surface well. When the bead diluted liquid was further supplied continuously, as illustrated in the photograph “ACCUMULATION” of  FIG. 12 , the beads began accumulating at the flat surface well and also accumulating at the wave-shaped well. 
     Here, when depressurization and pressurization were repeatedly applied to the flow channel of  FIG. 12  to pulsate the flow of the bead diluted liquid, as illustrated in the photograph “PULSATION” of  FIG. 12 , it was observed that the accumulated beads were moved. 
     However, although the bead dispersion function was provided by pulsation, a subsequent bead was adhered and aggregated in a bead return process at the flat surface well. Eventually, a similar accumulated state was made before and after the pulsation (photograph “WASH OUT” of  FIG. 12 ). The particle dispersion effect by pulsation gave more favorable results at the wave-shaped well than at the flat surface well. 
     (6) Embodiment 5 
     [Consideration 2 for Dispersion of Particles by Pulsation] 
     The particle dispersion effect by pulsation at a central portion and an end portion of a flow channel of a single-particle capturing apparatus including a wave structure was considered. 
     As illustrated in  FIG. 13 , when looking at the recess portion of the wave structure at a central portion of the flow channel of the single-particle capturing apparatus  100 , when the bead diluted liquid was supplied excessively, accumulation of beads was observed. When looking at the recess portion of the wave structure at an end portion of the flow channel, a great number of points where beads were not captured were observed. 
     Next, depressurization and pressurization were repeatedly applied to the flow channel to pulsate the bead diluted liquid. Then, the beads were re-dispersed and the accumulation at the bead accumulation points at the central portion was eliminated (washed out). A single bead was captured in the recess portion at the end portion where beads had not been captured (realignment). 
     From the above, it has become apparent that, although excessive bead supply results in accumulation along the shape of the flow channel, when the pressure of the particle-containing sample is periodically released, the accumulated particles can be re-dispersed, a particle can be captured in an empty recess portion during operation and particles can be flown and moved. 
     (7) Embodiment 6 
     [Example of Single-Particle Capturing Apparatus in High-Density Arrangement with Independent Suction Path and Liquid Supply Path] 
     As illustrated in  FIG. 14 , a single-particle capturing apparatus including a flow channel having a lateral U-shape, a wave structure and a recess portion on an inner side of the lateral U-shape, an outside for suction at a center on an inner side of the lateral U shape, and a draw-in passage through which the recess portion communicates with the outside was produced. The sample was flown in the direction indicated by thin arrows, and suction was conducted in the direction indicated by a bold arrow. 
     In this way, a single-particle capturing apparatus in high-density arrangement including a wave structure in which a side surface of one flow channel drawn with a single stroke of brush is a sine wave, a recess portion is arranged at the top portion of the wave structure, a draw-in passage is arranged on the bottom surface of the recess portion, the wave structure and the recess portion are formed on right and left side surfaces and upper and lower side surfaces of the flow channel can be produced. In this way, when a plurality of one-dimensional flow channels is arranged in parallel, it is possible to increase the number of particles captured. 
     Note that in the present technology, curvature or bent is not limited to a U-shape, but includes any curved or bent patterns including a C-shape, an E-shape, an H-shape, an I-shape, an L-shape, an M-shape, an N-shape, an S-shape, a T-shape, a V-shape, a W-shape, an X-shape, a Y-shape, a meandering-shape, a helical shape, and the like. 
     (8) Embodiment 7 
     [Example of Single-Particle Capturing Apparatus in Three-Dimensional High-Density Arrangement] 
     As schematically illustrated in  FIG. 15 , a three-dimensional high-density arrangement can also be produced.  15 C is an example in which the mountain portion of the wave structure has a circular truncated conical shape and the recess portion is formed at the top portion. An example in which the arrangement of the circular truncated cones densely aligned longitudinally and laterally is viewed from top and side is  15 A, and an example in which the arrangement with the rows displaced is viewed from top and side is  15 B. 
     In this way, when circular truncated cones including the recess portion at the top portion are densely arranged on the flat surface, a one-dimensional wave flow channel can be deployed on the plane surface and arranged. Then, when the flow is configured to occur from one direction on the flat surface, the effect equivalent to the one-dimensional wave flow channel can be obtained. 
     (9) Embodiment 8 
     [Example of Parallel Flow Channels] 
       FIG. 16  illustrates a single-particle capturing apparatus in which flow channels are arranged in parallel. At  16 A, flow channels are arranged in three rows. At  16 B, the structure of a left end of the flow channel is enlarged to be seen. At  16 C, the structure of a right end of the flow channel is enlarged to be seen. 
     As illustrated by the perspective views of  16 E and  16 F, each flow channel includes a wave structure, a recess portion, and a draw-in passage on both sides (upper and lower inner sides of the flow channel). 
     The particle-containing sample is supplied from an introduction portion on a left side of  16 A and passes through each flow channel. The flow is split into two at a right end and the sample liquid flows outside such that positive pressure occurs because of the presence of the draw-in passage and the particle is captured in each recess portion. The photograph before capturing of beads is  16 D, and the photograph after capturing is  16 G. It was observed that the beads were captured in the recess portions on both sides of the flow channel ( 16 G). 
     (10) Embodiment 9 
     [Example of Mounting Technology for Self-Alignment of IC Chip] 
     A single-particle capturing apparatus of the present technology was produced from an on-chip IC (SoC: System-on-Silicon) substrate. 
     As a particle to be captured, those made by cutting a high-density IC chip produced by a semiconductor process on a silicon wafer into a 100 μm square using a dicer from above the wafer were prepared. Depending on the cut-out size and the width of a cutting margin, the number of IC chips to be prepared is seven million from a 300 mm wafer. 
     Conventionally, mounting the above in an aligned matter state at equal intervals and narrow pitches by self-alignment, there is a limitation with a chip mounter (0.4 mm×0.2 mm square). 
     However, microchips at narrow pitches can be mounted along at equal intervals by utilizing a self-assembly method using a flow channel including the wave structure  31  according to the present technology. 
     The IC chip arranged in the recess portion at the top portion of the wave structure can be combined and wired with a different chip in a subsequent process. 
     Furthermore, a substrate integrated with a flow channel substrate can be produced such that a different electric circuit substrate is preliminarily made near the top portion of the wave-shaped flow channel, and wiring is performed by a wire bonder or the like when the IC chip is trapped in the recess portion for extensive arrangement. 
     Furthermore, an on-chip IC devise can be produced efficiently by cutting out. 
     (11) Embodiment 10 
     [Application to Production of Micro LED Display] 
     A single-particle capturing apparatus illustrated in  FIG. 17  was produced. Three lanes of independent flow channels including the wave structure are prepared, different micro LED chips are dispersed in the liquid of the lanes, the liquid is supplied in a direction of a left side arrow of  FIG. 17 , and a red LED, a blue LED, and a green LED are flown in the respective lanes. Thus, the LEDs can be mounted at equal intervals at 150 μm pitches. 
     The LED chips captured at the top portions of the wave structure  31  can be used as a micro LED display by being wired by a wire bonder to the capturing recess portions and global electrodes  27  arranged on a lower side of the recess portions. 
     Furthermore, similarly, in the case of an active drive-type display, e.g., an organic EL, this mounting technology can be applied and IC chips on which IC circuits, which are currently produced of polysilicon, are independently made relative to pixels can be mounted at equal interval pitches. Therefore, an active matrix polysilicon circuit that is expensive and has poor yield can be replaced by a stably operable IC chip. 
     3. SINGLE-PARTICLE CAPTURING SYSTEM 
     The single-particle capturing system of the present technology includes a liquid supply unit in the single-particle capturing apparatus. 
       FIG. 18  illustrates an example of a single-particle capturing system  101 . 
     A single-particle capturing unit  102  is coupled to a liquid supply unit  103  via the valve  21 . The liquid supply unit  103  supplies the particle-containing sample to the single-particle capturing unit  102 . The flow of the sample can be controlled by opening and closing of the valve  21 . The control can be performed by a liquid supply control unit  106 . A control program may be included in a computer to enable automatic liquid supply control. Control of liquid supply can not only flow/stop the sample, but also generate a backward flow and even a pulsatile flow that changes the flow at regular intervals. 
     Furthermore, the single-particle capturing system  101  may include a single-particle observing unit  105 . The single-particle observing unit  105  is not particularly limited. However, the flow channel and a state in which particles flow and are captured may be zoomed in under an electron microscope or the like so as to be observed by the naked eye or may be subject to data processing by an image processing apparatus or the like without the naked eye. The results of the observation in this case can be fed back to the liquid supply control unit  106 , and the flow of the sample can be further controlled. 
     Moreover, the single-particle capturing system  101  may include a waste liquid unit  104  on a downstream side. The sample liquid including a reduced particle content can be recovered as a waste liquid. A valve or pump may be further included on an upstream side or a downstream side of the waste liquid unit  104  such that a suction force is exerted on the flow channel of the single-particle capturing unit  102 . 
     4. SINGLE-PARTICLE CAPTURING METHOD 
     A single-particle capturing method of the present technology is a method in which a specimen containing a particle to be captured is supplied to the single-particle capturing apparatus and the specimen while being supplied is sucked to the outside from the recess portion via the draw-in passage such that the particle to be captured is captured. 
     As described above, the supplied liquid can be flown backward. Forward flow and backward flow are repeatedly generated to disperse the accumulated particles such that the particles enter all the recess portions. 
     Note that the present technology may adopt the configuration described below. 
     [1] A single-particle capturing apparatus including: 
     a flow channel on a substrate, 
     a wave structure with a mountain portion and a valley portion on the flow channel, and 
     a recess portion at a top portion of the mountain portion, the recess portion including a draw-in passage. 
     [2] The single-particle capturing apparatus according to [1], in which the recess portion has a depth equal to or smaller than a particle diameter of a particle to be captured. 
     [3] The single-particle capturing apparatus according to [1] or [2], in which a diameter of the recess portion is a size equal to or more than one time and less than two times of a particle diameter of a particle to be captured. 
     [4] The single-particle capturing apparatus according to any of [1] to [3], in which a height from the valley portion to the mountain portion is equal to or larger than a particle diameter of a particle to be captured. 
     [5] The single-particle capturing apparatus according to any of [1] to [4], in which a pitch between the mountain portions is a length equal to or more than 2 times and equal to or less than 20 times of a particle diameter of a particle to be captured. 
     [6] The single-particle capturing apparatus according to any of [1] to [5], in which a channel width of the flow channel is relatively small at the mountain portion and relatively large at the valley portion. 
     [7] The single-particle capturing apparatus according to any of [1] to [6], in which the draw-in passage makes communication between the recess portion and the outside. 
     [8] The single-particle capturing apparatus according to [7], in which the outside is coupled to the flow channel. 
     [9] The single-particle capturing apparatus according to any of [1] to [8], in which a plurality of the mountain portions and a plurality of the valley portions are aligned on a bottom surface of the flow channel. 
     [10] The single-particle capturing apparatus according to [1] to [9], in which the flow channel and the wave structure are curved or bent. 
     [11] The single-particle capturing apparatus according to [10], in which the flow channel and the wave structure are curved in a U-shape, and an inner side of the U-shape is the outside. 
     [12] A single-particle capturing system including: 
     a single-particle capturing unit including
         a flow channel on a substrate,   a wave structure with a mountain portion and a valley portion, on the flow channel, and   a recess portion at a top portion of the mountain portion, the recess portion including a draw-in passage; and       

     a liquid supply unit. 
     [13] The single-particle capturing system according to [12], in which the flow channel includes a valve. 
     [14] The single-particle capturing system according to [12] or [13], further including a waste liquid unit. 
     [15] The single-particle capturing system according to any of [12] to [14], further including a single-particle capturing observing unit configured to observe the single-particle capturing unit. 
     [16] The single-particle capturing system according to any of [12] to [15], further including a liquid supply control unit configured to control the liquid supply unit. 
     [17] A single-particle capturing method, in which a specimen containing a particle to be captured is supplied to a single-particle capturing apparatus including: 
     a flow channel on a substrate, 
     the flow channel including a wave structure with a mountain portion and a valley portion, and 
     a recess portion at a top portion of the mountain portion, the recess portion including a draw-in passage, and 
     the specimen is, while being supplied, sucked from the recess portion to an outside via the draw-in passage such that the particle to be captured is captured. 
     [18] The single-particle capturing method according to [17], including flowing the supplied liquid backward. 
     REFERENCE SIGNS LIST 
     
         
           11  Substrate 
           12  Flow channel 
           13  Mountain portion 
           14  Valley portion 
           15  Top portion 
           16  Recess portion 
           17  Draw-in passage 
           18  Outside 
           19  Top surface 
           21  Valve 
           22  Liquid flow direction 
           23  Draw-in by positive pressure 
           24  Bypass 
           25  Tube 
           26  Increment 
           27  Global wiring 
           31  Wave structure 
           100  Single-particle capturing apparatus 
           101  Single-particle capturing system 
           102  Bead 
           103  Liquid supply unit 
           104  Waste liquid unit 
           105  Single-particle observing unit 
           106  Liquid supply control unit