WO2011065195A1 - Microchip and film - Google Patents

Microchip and film Download PDF

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Publication number
WO2011065195A1
WO2011065195A1 PCT/JP2010/069576 JP2010069576W WO2011065195A1 WO 2011065195 A1 WO2011065195 A1 WO 2011065195A1 JP 2010069576 W JP2010069576 W JP 2010069576W WO 2011065195 A1 WO2011065195 A1 WO 2011065195A1
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Prior art keywords
blood
substrate
film
microchip
flow path
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PCT/JP2010/069576
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French (fr)
Japanese (ja)
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由佳 吉原
貴紀 村山
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コニカミノルタオプト株式会社
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Publication of WO2011065195A1 publication Critical patent/WO2011065195A1/en

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N11/00—Investigating flow properties of materials, e.g. viscosity, plasticity; Analysing materials by determining flow properties
    • G01N11/02—Investigating flow properties of materials, e.g. viscosity, plasticity; Analysing materials by determining flow properties by measuring flow of the material
    • G01N11/04—Investigating flow properties of materials, e.g. viscosity, plasticity; Analysing materials by determining flow properties by measuring flow of the material through a restricted passage, e.g. tube, aperture
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0627—Sensor or part of a sensor is integrated
    • B01L2300/0654—Lenses; Optical fibres
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0887—Laminated structure
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/16—Surface properties and coatings
    • B01L2300/161—Control and use of surface tension forces, e.g. hydrophobic, hydrophilic
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/08—Regulating or influencing the flow resistance
    • B01L2400/084—Passive control of flow resistance
    • B01L2400/086—Passive control of flow resistance using baffles or other fixed flow obstructions
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483—Physical analysis of biological material
    • G01N33/487—Physical analysis of biological material of liquid biological material
    • G01N33/49—Blood

Definitions

  • the present invention relates to a microchip and a film.
  • a microchip that allows blood to pass through a fine flow path is provided at the position opposite to the camera, and while the state of blood passing is observed with the camera, the captured image and passage time are analyzed and the flow is analyzed. Blood characteristics such as sex are analyzed. More specifically, the microchip is formed by bonding a transparent cover plate to a base substrate having a fine groove on the surface, and a blood flow path inside these base substrate and cover plate, A so-called microchannel array is provided.
  • An object of the present invention is to provide a microchip and a film capable of observing a pure interaction between blood and a material on the inner surface of a flow path.
  • the invention according to claim 1 is a microchip for analyzing characteristics of a liquid sample, A first substrate having fine grooves on the surface; A second substrate having a planar portion opposed to the surface of the first substrate, The first substrate and the second substrate are laminated with each other to form a liquid sample flow path inside.
  • the plane portion is Covered with film, At least the surface of the film facing the first substrate is Compared with the case where the flat portion is in contact with the liquid sample, the flat portion is formed of a predetermined material that varies the fluidity of the liquid sample in the flow path.
  • the invention according to claim 2 is the microchip according to claim 1,
  • the film covering the flat portion is replaceable.
  • the invention according to claim 3 is the microchip according to claim 1 or 2,
  • the film is transparent.
  • the invention according to claim 4 is the microchip according to any one of claims 1 to 3,
  • the liquid sample is blood;
  • the second substrate is made of glass;
  • the predetermined material is titanium, clonium, albumin, collagen or silicon.
  • the invention according to claim 5 is a film provided on a microchip for analyzing characteristics of a liquid sample
  • the microchip is A first substrate having a fine groove on the surface; and a second substrate having a planar portion opposed to the surface of the first substrate, wherein the first substrate and the second substrate are stacked on each other.
  • the film covers the flat portion of the second substrate, and at least the surface facing the first substrate is liquid in the flow path as compared with the case where the flat portion is in contact with the liquid sample. It is made of a predetermined material that makes the fluidity of the sample different, It can be exchanged.
  • the first substrate having a fine groove on the surface and the second substrate having the planar portion opposed to the surface of the first substrate are stacked on each other so as to be inside.
  • the liquid sample channel is formed, and the flat portion is covered with the film, and at least the surface of the film facing the first substrate is in the flow channel as compared with the case where the flat portion is in contact with the liquid sample.
  • the liquid sample is made of a predetermined material that has different fluidity. Since the film can be easily made uniform in thickness, it is possible to prevent variation in the inner diameter of the flow path in the observation target region. Therefore, unlike the conventional case where the coating is performed on the fine flow path, it is possible to prevent the fluidity of the liquid sample from being affected by variations in the internal diameter of the flow path. Pure interaction with the material can be easily observed.
  • the film covers the flat portion of the second substrate, the interaction between the liquid sample and the film can be made different by exchanging the second substrate with the film. Therefore, it is possible to easily generate a desired interaction between the liquid sample and the inner surface of the flow channel as compared with the conventional case in which a plurality of types of microchips configured of a base substrate with a uniform coating of grooves are prepared. it can.
  • the interaction between the liquid sample and the film can be made different simply by exchanging the film. Therefore, a desired interaction can be easily generated between the liquid sample and the inner surface of the flow path, as compared with the conventional case where a plurality of types of microchips in which grooves are uniformly coated are prepared.
  • FIG. 1 It is a block diagram which shows the whole structure of the blood characteristic analysis system which concerns on this invention. It is a figure which shows a microchip, (a) is a top view, (b) is an exploded side view, (c) is the elements on larger scale of (a). It is a figure for demonstrating the gate as a fine flow path in a microchip, the upper figure is a top view, and the lower figure is a side view.
  • FIG. 1 is a block diagram showing an overall configuration of a blood characteristic analysis system 1 in the present embodiment.
  • the blood characteristic analysis system 1 guides blood from a supply tank 10 through a microchip (filter) 2 to a discharge tank 11 and analyzes blood characteristics from information acquired in the process. is there.
  • the blood characteristic analysis system 1 is mainly based on the microchip 2, the TV camera 3 that captures the blood flow in the microchip 2, and the blood flow image captured by the TV camera 3.
  • a personal computer 7 for analyzing characteristics and a display 8 for displaying a blood flow image are provided.
  • the blood characteristic analysis system 1 according to the present embodiment further includes a mixer 12, a plurality of solution bottles 13, and the like so that a liquid such as physiological saline or a physiologically active substance can be mixed with blood and guided to the microchip 2.
  • the blood mixed with a liquid such as physiological saline or physiologically active substance (hereinafter referred to as blood) is controlled by the differential pressure control unit 14 by controlling the pump 15 to adjust the differential pressure across the microchip 2.
  • a desired amount flows through the chip 2.
  • the valve 10 a of the supply tank 10 and the like are integrated and controlled by the sequence control unit 16.
  • the microchip 2 is a flat chip disposed in the photographing region of the TV camera 3, and is formed by laminating a rectangular cover plate 20, a film 29, and a base plate 21 in this order as shown in FIG. Has been.
  • the cover plate 20 is the second substrate in the present invention, and the flat portion 200 is opposed to the inner side surface (the upper surface in FIG. 2B) of the base plate 21 with the film 29 interposed therebetween.
  • the cover plate 20 is detachably bonded to the base plate 21 via a film 29.
  • the cover plate 20 is made of glass, but may be formed of other materials.
  • the base plate 21 is a first substrate in the present invention, and has recesses 210 and 211 at both ends, and a plurality of grooves 212 and so on between the recesses 210 and 211.
  • the hollow part 210 has a through-hole 210a communicating with the supply tank 10 on the bottom surface, and an upstream storage part 22 for storing blood is formed between the cover plate 20 and the upper part.
  • the recess 211 has a through-hole 211 a communicating with the discharge tank 11 on the bottom surface, and forms a downstream storage 23 for storing blood between the cover plate 20.
  • the plurality of grooves 212 are arranged so as to extend in parallel to the direction (X direction in the drawing) connecting the recess 210 and the recess 211, and extend in the X direction described above. It is in a state of being partitioned by the portion 213.
  • the plurality of grooves 212,... Alternately communicate with the depression 210 or the depression 211, whereby the upstream blood circuit 24 that allows blood to flow from the upstream reservoir 22 and the downstream reservoir 23.
  • a downstream blood circuit 25 that allows blood to flow into the cover plate 20 is formed.
  • a plurality of hexagonal bank portions 214 are arranged in the X direction on the upper end portion of the terrace portion 213, and the top surface of the cover plate 20 is interposed through the film 29. It is in contact.
  • the plurality of bank portions 214 form a canyon portion 215 with each other, and this canyon portion 215 forms a gate 26 as a fine flow path for flowing blood in the Y direction in the figure with the cover plate 20. Formed in between.
  • the gate 26 the upstream blood circuit 24, and the downstream blood circuit 25 are cut at the positions indicated by virtual lines aa and bb in FIG.
  • the cross-sectional area is narrower than the inside of the circuit 24 and the downstream blood circuit 25.
  • the cross-sectional shape of the gate 26 is a flat rectangle in accordance with the shape of red blood cells (the shape of a disk with a hollow center and an elliptical cross-section).
  • the size of the cross-section of the gate 26 is It is smaller than the size of red blood cells.
  • the film 29 is interposed between the flat part 200 of the cover plate 20 and the flow path 28 and covers the flat part 200.
  • the film 29 is formed of a predetermined material that makes the fluidity of blood in the flow path 28 different from that of the case where the flat surface portion 200 of the cover plate 20 made of a material such as glass is in contact with blood.
  • a material such as glass
  • Examples of such materials are described in ⁇ Kurotobi, Kimi.imiet al. Short term evaluation of material blood compatibility using a microchannel array. Journal of Materials Science: As mentioned above, titanium, clonium, albumin, collagen, silicon and the like can be mentioned.
  • the blood passage time can be different by 10% or more compared to the flow path where the flat portion 200 is in contact with blood.
  • the film 29 in the present embodiment is a film of these materials, and a film selected according to the measurement content from the films formed of these materials is used. It is arranged so as to be exchangeable with respect to the surface.
  • the film 29 is formed to be transparent with a predetermined thickness so that the blood in the gate 26 can be photographed by the TV camera 3, but the blood in the gate 26 is removed by the TV camera 3.
  • the film 29 may be opaque.
  • the film 29 covers the entire lower surface of the cover plate 20, but may cover only the position facing the terrace portion 213 and further the position facing the gate 26.
  • the film 29 is formed as a predetermined material that varies the blood fluidity, but the predetermined material that varies the blood fluidity is formed on the transparent film substrate surface.
  • the film 29 may be formed by coating the surface of the substrate facing the base plate 21.
  • the film 29 may be formed by directly coating the flat portion 200 of the cover plate 20 with a predetermined material that makes blood fluidity different.
  • Pressure sensors E1 and E2 are provided before and after the microchip 2, and the pressure sensors E1 and E2 output the measured pressures P1 and P2 to the differential pressure control unit 14. (See FIG. 1).
  • the TV camera 3 is, for example, a digital CCD camera, and is a high-speed camera for color photography having a resolution sufficient for photographing moving image data of blood flow. As shown in FIG. 1, the TV camera 3 is installed so as to face the cover plate 20 in the microchip 2 and photographs the blood flow passing through the gate 26 through the film 29 and the cover plate 20.
  • the imaging range is a range including an entrance area A to an exit area C (see FIG. 3A) in the plurality of canyon portions 215. However, the imaging range may be a range including at least one of the entrance area A, the internal area B, and the exit area C in each inter-gorge portion 215.
  • the blood flow image obtained by the TV camera 3 is output to the personal computer 7 and reproduced and displayed on the display 8.
  • Such a TV camera 3 is a camera capable of shooting a moving image, although not particularly limited.
  • the personal computer 7 is connected to the TV camera 3 and calculates at least one blood characteristic from moving image data photographed by the TV camera 3.
  • the blood characteristic is a characteristic value relating to blood fluidity. For example, the shape of blood cells, the flow rate of blood flow, the direction of blood flow, the number of blood cells photographed in a predetermined number of frames, and the aggregation of blood cells Degree etc. can be mentioned.
  • the display 8 is connected to the personal computer 7 and displays a moving image photographed by the TV camera 3 and blood characteristics calculated by the personal computer 7.
  • the blood flow in the gate 26 is photographed by the TV camera 3 while flowing the blood to the microchip 2. More specifically, the sequence control unit 16 adds physiological saline or the like to the solution bottle 13 as necessary while injecting blood to be analyzed into the supply tank 10. The sequence control unit 16 causes the differential pressure control unit 14 to apply a predetermined differential pressure to the microchip 2 to flow blood through the microchip 2, while the TV camera 3 captures the blood flow in the gate 26 and takes a moving image. The image data is output to the personal computer 7.
  • the personal computer 7 calculates blood characteristics based on the moving image data, and reproduces and displays the calculated blood characteristics and blood flow in the gate 26 on the display 8.
  • the base plate 21 having fine grooves on the surface and the cover plate 20 having the flat portion 200 facing the surface of the base plate 21 are mutually connected.
  • the blood flow path 28 is formed on the inner side by being laminated, and is formed of a material that makes the blood fluidity in the flow path 28 different from that in the case where the flat portion 200 is in direct contact with blood. Since the film 29 covers the flat portion 200 and the film 29 is exchangeable, the interaction between the blood and the film 29 can be made different by exchanging the film 29. Accordingly, since it is not necessary to prepare a plurality of types of microchips in which the grooves are uniformly coated, it is possible to easily observe a desired interaction between blood and the inner surface of the flow path 28 as compared with the conventional case. .
  • the film 29 of the flat surface portion 200 that constitutes the upper side surface among the four side surfaces (upper, lower, left, right) in contact with the blood on the inner surface of the flow path 28 is provided.
  • the interaction between blood and the inner surface of the flow path 28 can be made different.
  • the flat surface portion 200 of the base plate 21 as the second substrate forms one side surface of the flow path 28, and the flat surface portion 200 is in direct contact with blood.
  • Blood is flowed into the flow path 28, and blood characteristics are calculated based on the moving image data at this time.
  • a blood characteristic for example, blood agglutination ability is measured using a blood flow velocity (passage time).
  • the same measurement is performed using the film 29 as in the present embodiment, for example, a material whose blood fluidity is lowered so that blood aggregation is likely to appear.
  • the film 29 covers the flat portion 200, it is possible to prevent the inner diameter of the flow path 28 (gate 26) from being varied in the observation target region by making the thickness of the film 29 uniform. Therefore, unlike the conventional case in which the fine channel 28 is coated, it is possible to prevent the blood fluidity from being affected by the variation in the inner diameter of the channel 28. The pure interaction with the other materials can be easily observed.
  • the microchip 2 has been described as being used for blood characteristic analysis. However, the microchip 2 may be used for characteristic analysis of other liquid samples.
  • the blood characteristic analysis system 1 may further include a known device that optically or electrically detects a chemical reaction or an antigen-antibody reaction occurring in the flow path 28.
  • examples of the device that electrically detects the reaction in the flow path 28 include a device that detects the reaction by Western blotting, and examples of the device that chemically detects the reaction include flow site.
  • An apparatus for detecting a reaction by a measurement method can be mentioned.

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Abstract

Disclosed is a microchip (2) for the analysis of liquid samples, which is for observing the pure interaction between blood and the material of the inner surface of a channel, that is provided with a base plate (21) with fine grooves on the surface thereof and a cover plate (20) with a level section (200) facing the surface of the base plate (21). A channel (28) for liquid samples is formed in the interior by stacking together the base plate (21) and the cover plate (20). The level section (200) is covered by an exchangeable film (29). The surface of the film (29) that faces the base plate (21) is formed with a prescribed material that produces a different fluidity in the liquid sample within the channel (28) in comparison to cases in which the level section (200) comes in contact with the liquid sample.

Description

マイクロチップ及びフィルムMicrochip and film
　本発明は、マイクロチップ及びフィルムに関する。 The present invention relates to a microchip and a film.
　従来、健康に対する関心の高まりとともに、健康のバロメータとして血液の流動性や血球の変形能などの血液特性が注目されるようになっており、血液特性を調べる血液特性解析装置が開発されている。 Conventionally, with increasing interest in health, blood characteristics such as blood fluidity and blood cell deformability have been attracting attention as a health barometer, and blood characteristic analysis devices for examining blood characteristics have been developed.
　この血液特性解析装置では、微細な流路に血液を通過させるマイクロチップをカメラの対向位置に備えており、血液の通過の様子をカメラで観察しつつ、撮影画像や通過時間を解析して流動性などの血液特性を解析するようになっている。より詳細には、マイクロチップは、表面に微細な溝を備えたベース基板に対して透明なカバー板を貼り合せることで形成されており、これらベース基板及びカバー板の内側に血液の流路、いわゆるマイクロチャネルアレイを有するようになっている。 In this blood characteristic analysis device, a microchip that allows blood to pass through a fine flow path is provided at the position opposite to the camera, and while the state of blood passing is observed with the camera, the captured image and passage time are analyzed and the flow is analyzed. Blood characteristics such as sex are analyzed. More specifically, the microchip is formed by bonding a transparent cover plate to a base substrate having a fine groove on the surface, and a blood flow path inside these base substrate and cover plate, A so-called microchannel array is provided.
　ところで、マイクロチップの流路内面を形成する材料の種類によっては、血液との間で相互作用が生じ、マイクロチャネルアレイにおける血液の流動性を変化させることが可能となる。そのため、近年、このような相互作用を意図的に観察する技術として、血液に対して相互作用を生じる物質をベース基板の溝にコーティングしたマイクロチップを用いて観察を行う技術が提案されている（例えば、特許文献１参照）。 By the way, depending on the type of material forming the inner surface of the flow path of the microchip, interaction with blood occurs, and the fluidity of blood in the microchannel array can be changed. Therefore, in recent years, as a technique for intentionally observing such an interaction, a technique for observing using a microchip in which a substance causing an interaction with blood is coated on a groove of a base substrate has been proposed ( For example, see Patent Document 1).
特開２００６－１４５３４５号公報JP 2006-145345 A
　しかしながら、上記特許文献１記載の技術では、微細な流路にコーティングを行うため、コーティングの厚みを均一に制御するのが難しく、コーティングのムラによって観察対象の領域で流路の内径にばらつきが生じてしまい、その内径のばらつきが血液の流れに影響を与えてしまう。そのため、血液と流路内面の材料との間の純粋な相互作用を観測することができない。 However, in the technique described in Patent Document 1, since coating is performed on a fine flow path, it is difficult to uniformly control the thickness of the coating, and unevenness in the coating causes variations in the inner diameter of the flow path in the observation target region. Therefore, the variation in the inner diameter affects the blood flow. Therefore, a pure interaction between the blood and the material on the inner surface of the flow path cannot be observed.
　また、この技術では、表面に微細な溝を備えたベース基板に対して物質をコーティングしているため、他の物質と血液との相互作用を生じさせたい場合には、当該他の物質でコーティングされたベース基板で構成されるマイクロチップを別途用意する必要があり、コストや手間がかかってしまう。そのため、血液と流路内面との間で所望の相互作用を生じさせることが困難である。 In this technique, since the substance is coated on the base substrate having a fine groove on the surface, when it is desired to cause the interaction between the other substance and the blood, the coating is performed with the other substance. Therefore, it is necessary to separately prepare a microchip composed of the manufactured base substrate, which is costly and troublesome. Therefore, it is difficult to generate a desired interaction between blood and the inner surface of the flow path.
　本発明の課題は、血液と流路内面の材料との間の純粋な相互作用を観測することのできるマイクロチップ及びフィルムを提供することである。 An object of the present invention is to provide a microchip and a film capable of observing a pure interaction between blood and a material on the inner surface of a flow path.
　請求項１記載の発明は、液体試料の特性解析用のマイクロチップであって、
　表面に微細な溝を有する第１の基板と、
　前記第１の基板の表面に平面部を対向させた第２の基板とを備え、
　前記第１の基板及び前記第２の基板は、互いに積層されることで内側に液体試料の流路を形成しており、
　前記平面部は、
　フィルムによって被覆されており、
　前記フィルムの少なくとも前記第１の基板と対向する面は、
　前記平面部が液体試料に接する場合と比較して、前記流路内での液体試料の流動性を異ならせる所定の材料で形成されていることを特徴とする。 The invention according to claim 1 is a microchip for analyzing characteristics of a liquid sample,
A first substrate having fine grooves on the surface;
A second substrate having a planar portion opposed to the surface of the first substrate,
The first substrate and the second substrate are laminated with each other to form a liquid sample flow path inside.
The plane portion is
Covered with film,
At least the surface of the film facing the first substrate is
Compared with the case where the flat portion is in contact with the liquid sample, the flat portion is formed of a predetermined material that varies the fluidity of the liquid sample in the flow path.
　請求項２記載の発明は、請求項１のマイクロチップにおいて、
　前記平面部を被覆している前記フィルムは交換可能であることを特徴とする。 The invention according to claim 2 is the microchip according to claim 1,
The film covering the flat portion is replaceable.
　請求項３記載の発明は、請求項１記載または２記載のマイクロチップにおいて、
　前記フィルムは、透明であることを特徴とする。 The invention according to claim 3 is the microchip according to claim 1 or 2,
The film is transparent.
　請求項４記載の発明は、請求項１から３のいずれか１項に記載のマイクロチップにおいて、
　前記液体試料は、血液であり、
　前記第２の基板は、ガラス製であり、
　前記所定の材料は、チタン、クロニウム、アルブミン、コラーゲンまたはシリコンであることを特徴とする。 The invention according to claim 4 is the microchip according to any one of claims 1 to 3,
The liquid sample is blood;
The second substrate is made of glass;
The predetermined material is titanium, clonium, albumin, collagen or silicon.
　請求項５記載の発明は、液体試料の特性解析用のマイクロチップに備えられるフィルムであって、
　前記マイクロチップは、
　表面に微細な溝を有する第１の基板と、前記第１の基板の表面に平面部を対向させた第２の基板とを備え、前記第１の基板及び前記第２の基板が互いに積層されることで内側に液体試料の流路を形成しており、
　当該フィルムは前記第２の基板の平面部を被覆しており、少なくとも前記第１の基板と対向する面は、前記平面部が液体試料に接する場合と比較して、前記流路内での液体試料の流動性を異ならせる所定の材料で形成され、
　交換可能であることを特徴とする。 The invention according to claim 5 is a film provided on a microchip for analyzing characteristics of a liquid sample,
The microchip is
A first substrate having a fine groove on the surface; and a second substrate having a planar portion opposed to the surface of the first substrate, wherein the first substrate and the second substrate are stacked on each other. To form a flow path for the liquid sample inside,
The film covers the flat portion of the second substrate, and at least the surface facing the first substrate is liquid in the flow path as compared with the case where the flat portion is in contact with the liquid sample. It is made of a predetermined material that makes the fluidity of the sample different,
It can be exchanged.
　請求項１記載の発明によれば、表面に微細な溝を有する第１の基板と、第１の基板の表面に平面部を対向させた第２の基板とは互いに積層されることで内側に液体試料の流路を形成しており、フィルムによって平面部は被覆されており、平面部が液体試料に接する場合と比較して、このフィルムの少なくとも第１の基板と対向する面は流路内での液体試料の流動性を異ならせる所定の材料で形成されている。フィルムは厚みを均一にすることが容易にできるので観察対象の領域で流路の内径にばらつきが生じるのを防止することができる。従って、微細な流路にコーティングを行う従来の場合と異なり、流路の内径のばらつきによって液体試料の流動性が影響を受けてしまうのを防止することができるため、液体試料と流路内面の材料との間の純粋な相互作用を、容易に観測することができる。 According to the first aspect of the present invention, the first substrate having a fine groove on the surface and the second substrate having the planar portion opposed to the surface of the first substrate are stacked on each other so as to be inside. The liquid sample channel is formed, and the flat portion is covered with the film, and at least the surface of the film facing the first substrate is in the flow channel as compared with the case where the flat portion is in contact with the liquid sample. The liquid sample is made of a predetermined material that has different fluidity. Since the film can be easily made uniform in thickness, it is possible to prevent variation in the inner diameter of the flow path in the observation target region. Therefore, unlike the conventional case where the coating is performed on the fine flow path, it is possible to prevent the fluidity of the liquid sample from being affected by variations in the internal diameter of the flow path. Pure interaction with the material can be easily observed.
　また、フィルムは第２の基板の平面部を被覆しているため、第２の基板をフィルムごと交換することにより、液体試料とフィルムとの間で生じる相互作用を異なるものにすることができる。従って、溝を均一にコーティングしたベース基板で構成されるマイクロチップを複数種類用意する従来の場合と比較して、液体試料と流路内面との間で所望の相互作用を容易に生じさせることができる。 Also, since the film covers the flat portion of the second substrate, the interaction between the liquid sample and the film can be made different by exchanging the second substrate with the film. Therefore, it is possible to easily generate a desired interaction between the liquid sample and the inner surface of the flow channel as compared with the conventional case in which a plurality of types of microchips configured of a base substrate with a uniform coating of grooves are prepared. it can.
　また、フィルムを交換可能とすれば、フィルムを交換するのみで液体試料とフィルムとの間で生じる相互作用を異なるものにすることができる。従って、溝を均一にコーティングしたマイクロチップを複数種類用意する従来の場合と比較して、液体試料と流路内面との間で所望の相互作用を容易に生じさせることができる。 Also, if the film can be exchanged, the interaction between the liquid sample and the film can be made different simply by exchanging the film. Therefore, a desired interaction can be easily generated between the liquid sample and the inner surface of the flow path, as compared with the conventional case where a plurality of types of microchips in which grooves are uniformly coated are prepared.
本発明に係る血液特性解析システムの全体構成を示すブロック図である。It is a block diagram which shows the whole structure of the blood characteristic analysis system which concerns on this invention. マイクロチップを示す図であり、（ａ）は平面図、（ｂ）は分解側面図、（ｃ）は（ａ）の部分拡大図である。It is a figure which shows a microchip, (a) is a top view, (b) is an exploded side view, (c) is the elements on larger scale of (a). マイクロチップにおける微細な流路としてのゲートを説明するための図であり、上側の図は平面図、下側の図は側面図である。It is a figure for demonstrating the gate as a fine flow path in a microchip, the upper figure is a top view, and the lower figure is a side view.
　以下、本発明の実施の形態について、図を参照して説明する。図１は、本実施の形態における血液特性解析システム１の全体構成を示すブロック図である。 Hereinafter, embodiments of the present invention will be described with reference to the drawings. FIG. 1 is a block diagram showing an overall configuration of a blood characteristic analysis system 1 in the present embodiment.
　この図に示すように、血液特性解析システム１は、血液を供給槽１０からマイクロチップ（フィルタ）２に通して排出槽１１へ導き、その過程で取得される情報から血液特性を解析するものである。 As shown in this figure, the blood characteristic analysis system 1 guides blood from a supply tank 10 through a microchip (filter) 2 to a discharge tank 11 and analyzes blood characteristics from information acquired in the process. is there.
　具体的には、血液特性解析システム１は、主に、マイクロチップ２と、マイクロチップ２内の血液の流れを撮影するＴＶカメラ３と、ＴＶカメラ３で撮影された血流画像に基づいて血液特性を解析するパソコン７と、血流画像を表示するディスプレイ８とを備えている。なお、本実施の形態における血液特性解析システム１には、生理食塩水や生理活性物質などの液体を血液と混合してマイクロチップ２に導けるよう、ミクサー１２や複数の溶液びん１３等が更に具備されている。そして、生理食塩水や生理活性物質などの液体と混合した血液（以下、血液という）は、差圧制御部１４がポンプ１５を制御してマイクロチップ２前後の差圧を調整することにより、マイクロチップ２内を所望量だけ流れるようになっている。上述のミクサー１２やポンプ１５の他，供給槽１０のバルブ１０ａ等は、シーケンス制御部１６によって統合制御されている。 Specifically, the blood characteristic analysis system 1 is mainly based on the microchip 2, the TV camera 3 that captures the blood flow in the microchip 2, and the blood flow image captured by the TV camera 3. A personal computer 7 for analyzing characteristics and a display 8 for displaying a blood flow image are provided. The blood characteristic analysis system 1 according to the present embodiment further includes a mixer 12, a plurality of solution bottles 13, and the like so that a liquid such as physiological saline or a physiologically active substance can be mixed with blood and guided to the microchip 2. Has been. The blood mixed with a liquid such as physiological saline or physiologically active substance (hereinafter referred to as blood) is controlled by the differential pressure control unit 14 by controlling the pump 15 to adjust the differential pressure across the microchip 2. A desired amount flows through the chip 2. In addition to the mixer 12 and the pump 15 described above, the valve 10 a of the supply tank 10 and the like are integrated and controlled by the sequence control unit 16.
　マイクロチップ２は、ＴＶカメラ３の撮影領域に配設された平板状のチップであり、図２に示すように、矩形状のカバー板２０、フィルム２９及びベース板２１をこの順に積層して形成されている。 The microchip 2 is a flat chip disposed in the photographing region of the TV camera 3, and is formed by laminating a rectangular cover plate 20, a film 29, and a base plate 21 in this order as shown in FIG. Has been.
　カバー板２０は、本発明における第２の基板であり、フィルム２９を介してベース板２１の内側面（図２（ｂ）では上側の面）に平面部２００を対向させている。なお、本実施の形態においては、カバー板２０は、フィルム２９を介してベース板２１に着脱可能に貼り合わされている。また、カバー板２０はガラス製となっているが、他の材料によって形成されていても良い。 The cover plate 20 is the second substrate in the present invention, and the flat portion 200 is opposed to the inner side surface (the upper surface in FIG. 2B) of the base plate 21 with the film 29 interposed therebetween. In the present embodiment, the cover plate 20 is detachably bonded to the base plate 21 via a film 29. The cover plate 20 is made of glass, but may be formed of other materials.
　ベース板２１は、本発明における第１の基板であり、両端部に窪み部２１０，２１１を、これら窪み部２１０，２１１の間に複数の溝部２１２，…を有している。 The base plate 21 is a first substrate in the present invention, and has recesses 210 and 211 at both ends, and a plurality of grooves 212 and so on between the recesses 210 and 211.
　このうち、窪み部２１０は、供給槽１０と連通する貫通口２１０ａを底面に有しており、血液を貯留する上流側貯留部２２をカバー板２０との間に形成している。 Among these, the hollow part 210 has a through-hole 210a communicating with the supply tank 10 on the bottom surface, and an upstream storage part 22 for storing blood is formed between the cover plate 20 and the upper part.
　同様に、窪み部２１１は、排出槽１１と連通する貫通口２１１ａを底面に有しており、血液を貯留する下流側貯留部２３をカバー板２０との間に形成している。 Similarly, the recess 211 has a through-hole 211 a communicating with the discharge tank 11 on the bottom surface, and forms a downstream storage 23 for storing blood between the cover plate 20.
　また、複数の溝部２１２，…は、窪み部２１０と窪み部２１１とを結ぶ方向（図中のＸ方向）に対して平行に延在するよう配設され、上述のＸ方向に延在するテラス部２１３によって仕切られた状態となっている。これら複数の溝部２１２，…は、互い違いに窪み部２１０、または窪み部２１１に連通しており、これにより、上流側貯留部２２から血液を流入させる上流側血液回路２４と、下流側貯留部２３に血液を流入させる下流側血液回路２５とを、カバー板２０との間に形成している。 Further, the plurality of grooves 212,... Are arranged so as to extend in parallel to the direction (X direction in the drawing) connecting the recess 210 and the recess 211, and extend in the X direction described above. It is in a state of being partitioned by the portion 213. The plurality of grooves 212,... Alternately communicate with the depression 210 or the depression 211, whereby the upstream blood circuit 24 that allows blood to flow from the upstream reservoir 22 and the downstream reservoir 23. A downstream blood circuit 25 that allows blood to flow into the cover plate 20 is formed.
　テラス部２１３の上端部には、図２（ｃ）や図３に示すように、六角形状の土手部２１４がＸ方向に複数配列されており、フィルム２９を介してカバー板２０に頂面で当接している。これら複数の土手部２１４は互いとの間に峡間部２１５を形成しており、この峡間部２１５は、図中のＹ方向に血液を流す微細な流路としてのゲート２６をカバー板２０との間に形成している。なお、特に限定はされないが、図２の仮想線ａ－ａ，ｂ－ｂに示す位置でゲート２６や上流側血液回路２４，下流側血液回路２５を切断した場合に、ゲート２６は上流側血液回路２４や下流側血液回路２５の内部よりも断面積が狭くなっている。より詳細には、ゲート２６の断面形状は赤血球の形状（真ん中が窪んだ円盤形状であり、断面が扁平な楕円形状）に合わせて扁平な長方形をなしており、このゲート２６の断面のサイズは赤血球のサイズより小さくなっている。これにより、毛細血管などの細い血管を赤血球が自身の形状を変形させながら通過していく状態が観察でき、また、血管中での血液のさらさら度を模擬的に再現することができる。 As shown in FIGS. 2C and 3, a plurality of hexagonal bank portions 214 are arranged in the X direction on the upper end portion of the terrace portion 213, and the top surface of the cover plate 20 is interposed through the film 29. It is in contact. The plurality of bank portions 214 form a canyon portion 215 with each other, and this canyon portion 215 forms a gate 26 as a fine flow path for flowing blood in the Y direction in the figure with the cover plate 20. Formed in between. Although not particularly limited, when the gate 26, the upstream blood circuit 24, and the downstream blood circuit 25 are cut at the positions indicated by virtual lines aa and bb in FIG. The cross-sectional area is narrower than the inside of the circuit 24 and the downstream blood circuit 25. More specifically, the cross-sectional shape of the gate 26 is a flat rectangle in accordance with the shape of red blood cells (the shape of a disk with a hollow center and an elliptical cross-section). The size of the cross-section of the gate 26 is It is smaller than the size of red blood cells. As a result, it is possible to observe a state in which red blood cells pass through a thin blood vessel such as a capillary blood vessel while deforming its own shape, and it is possible to simulate the degree of dryness of blood in the blood vessel.
　このようなマイクロチップ２においては、上流側貯留部２２、上流側血液回路２４、ゲート２６、下流側血液回路２５及び下流側貯留部２３によって、カバー板２０及びベース板２１の間に血液の流路２８が形成され、供給槽１０から導入された血液は上流側貯留部２２で貯留され、上流側血液回路２４からゲート２６、下流側血液回路２５を通過した後、下流側貯留部２３に貯留されて排出槽１１へ排出されることとなる。そして、より詳細には、図３に示すように、ゲート２６を流れる血液中の血球、例えば赤血球は、まず峡間部２１５上流の入口領域Ａを通った後、峡間部２１５の内部領域Ｂを変形しながら通過し、最後に峡間部２１５下流の出口領域Ｃを通過することとなる。なお、このようなマイクロチップ２におけるカバー板２０及びベース板２１としては、例えば特開２００５－２６５６３４号公報や特許２５３２７０７号公報、特許２６８５５４４号公報に開示のものを用いることができる。 In such a microchip 2, blood flows between the cover plate 20 and the base plate 21 by the upstream reservoir 22, the upstream blood circuit 24, the gate 26, the downstream blood circuit 25, and the downstream reservoir 23. The path 28 is formed, and the blood introduced from the supply tank 10 is stored in the upstream storage unit 22, passes from the upstream blood circuit 24 through the gate 26 and the downstream blood circuit 25, and then stored in the downstream storage unit 23. And discharged into the discharge tank 11. In more detail, as shown in FIG. 3, blood cells in blood flowing through the gate 26, for example, red blood cells, first pass through the entrance region A upstream of the canyon portion 215 and then deform the inner region B of the canyon portion 215. And finally pass through the exit area C downstream of the canyon 215. As the cover plate 20 and the base plate 21 in such a microchip 2, for example, those disclosed in Japanese Patent Application Laid-Open No. 2005-265634, Japanese Patent No. 2532707, and Japanese Patent No. 2685544 can be used.
　フィルム２９は、カバー板２０の平面部２００と流路２８との間に介在して平面部２００を被覆している。このフィルム２９は、ガラス等の材料で構成されたカバー板２０の平面部２００が血液に接する場合と比較して、流路２８内での血液の流動性を異ならせる所定の材料によって透明に形成されている。このような材料として、例えば「Kurotobi,Kimi. et al. Short term evaluation of material blood compatibility using a microchannel array. Journal of Materials Science: Materials in Medicine.2007, p.1175-1184.」に記載されているように、チタンや、クロニウム、アルブミン、コラーゲン、シリコンなどを挙げることができる。このような材料を用いたフィルム２９で形成した流路では、平面部２００が血液に接する流路と比較して血液の通過時間を１０％以上異ならせることができる。 The film 29 is interposed between the flat part 200 of the cover plate 20 and the flow path 28 and covers the flat part 200. The film 29 is formed of a predetermined material that makes the fluidity of blood in the flow path 28 different from that of the case where the flat surface portion 200 of the cover plate 20 made of a material such as glass is in contact with blood. Has been. Examples of such materials are described in `` Kurotobi, Kimi.imiet al. Short term evaluation of material blood compatibility using a microchannel array. Journal of Materials Science: As mentioned above, titanium, clonium, albumin, collagen, silicon and the like can be mentioned. In the flow path formed of the film 29 using such a material, the blood passage time can be different by 10% or more compared to the flow path where the flat portion 200 is in contact with blood.
　そして、本実施の形態におけるフィルム２９は、これらの材料をフィルム状としたもので、それら材料によって形成されたフィルムの中から測定内容に応じて選択されたフィルムが用いられており、平面部２００の表面に対して交換可能に配設されている。なお、本実施の形態においては、フィルム２９は、ＴＶカメラ３によってゲート２６内の血液が撮影されるよう、所定の厚みで透明に形成されているが、ＴＶカメラ３によってゲート２６内の血液を撮影せずに所定量の血液が流れる時間を測定する場合には、フィルム２９を不透明なものとしても良い。また、本実施の形態においては、フィルム２９はカバー板２０の下面全体を覆っているが、テラス部２１３との対向位置、更にはゲート２６との対向位置のみを覆っていても良い。さらに、本実施の形態においては、血液の流動性を異ならせる所定の材料をフィルム状としてフィルム２９形成しているが、透明のフィルム基材表面に血液の流動性を異ならせる所定の材料をフィルム基材のベース板２１と対向する面にコーティングを施してフィルム２９を形成するようにしても良い。また、カバー板２０の平面部２００に血液の流動性を異ならせる所定の材料を直接コーティングしてフィルム２９を形成するようにしてもよい。 The film 29 in the present embodiment is a film of these materials, and a film selected according to the measurement content from the films formed of these materials is used. It is arranged so as to be exchangeable with respect to the surface. In the present embodiment, the film 29 is formed to be transparent with a predetermined thickness so that the blood in the gate 26 can be photographed by the TV camera 3, but the blood in the gate 26 is removed by the TV camera 3. When measuring the time during which a predetermined amount of blood flows without taking a picture, the film 29 may be opaque. In the present embodiment, the film 29 covers the entire lower surface of the cover plate 20, but may cover only the position facing the terrace portion 213 and further the position facing the gate 26. Furthermore, in the present embodiment, the film 29 is formed as a predetermined material that varies the blood fluidity, but the predetermined material that varies the blood fluidity is formed on the transparent film substrate surface. The film 29 may be formed by coating the surface of the substrate facing the base plate 21. Alternatively, the film 29 may be formed by directly coating the flat portion 200 of the cover plate 20 with a predetermined material that makes blood fluidity different.
　以上のマイクロチップ２の前後には、圧力センサＥ１，Ｅ２が設けられており、この圧力センサＥ１，Ｅ２は、計測した各圧力Ｐ１，Ｐ２を差圧制御部１４へ出力するようになっている（図１参照）。 Pressure sensors E1 and E2 are provided before and after the microchip 2, and the pressure sensors E1 and E2 output the measured pressures P1 and P2 to the differential pressure control unit 14. (See FIG. 1).
　ＴＶカメラ３は、例えばデジタルＣＣＤカメラであり、血液の流れの動画像データを撮影するのに十分な解像度を有したカラー撮影用の高速カメラである。このＴＶカメラ３は、図１に示すように、マイクロチップ２におけるカバー板２０に対向して設置され、ゲート２６を通過する血液の流れをフィルム２９及びカバー板２０越しに撮影する。その撮影範囲は、複数の峡間部２１５における入口領域Ａ～出口領域Ｃ（図３（ａ）参照）を含む範囲となっている。但し、この撮影範囲は、各峡間部２１５における入口領域Ａ、内部領域Ｂ、出口領域Ｃのうちの少なくとも１つの領域を含む範囲であればよい。ＴＶカメラ３によって得られた血流画像は、パソコン７に出力されるとともに、ディスプレイ８で再生表示されるようになっている。なお、このようなＴＶカメラ３は、特に限定はされないが、動画が撮影可能なカメラである。 The TV camera 3 is, for example, a digital CCD camera, and is a high-speed camera for color photography having a resolution sufficient for photographing moving image data of blood flow. As shown in FIG. 1, the TV camera 3 is installed so as to face the cover plate 20 in the microchip 2 and photographs the blood flow passing through the gate 26 through the film 29 and the cover plate 20. The imaging range is a range including an entrance area A to an exit area C (see FIG. 3A) in the plurality of canyon portions 215. However, the imaging range may be a range including at least one of the entrance area A, the internal area B, and the exit area C in each inter-gorge portion 215. The blood flow image obtained by the TV camera 3 is output to the personal computer 7 and reproduced and displayed on the display 8. Such a TV camera 3 is a camera capable of shooting a moving image, although not particularly limited.
　パソコン７は、ＴＶカメラ３と接続されており、ＴＶカメラ３により撮影された動画像データから少なくとも１種類の血液特性を算出するようになっている。なお、血液特性とは、血液の流動性に関する特性値であり、例えば血球の形状と、血流の流速と、血液の流れる方向と、所定フレーム数で撮影される血球の個数と、血球の凝集度等とを挙げることができる。 The personal computer 7 is connected to the TV camera 3 and calculates at least one blood characteristic from moving image data photographed by the TV camera 3. The blood characteristic is a characteristic value relating to blood fluidity. For example, the shape of blood cells, the flow rate of blood flow, the direction of blood flow, the number of blood cells photographed in a predetermined number of frames, and the aggregation of blood cells Degree etc. can be mentioned.
　ディスプレイ８は、パソコン７と接続されており、ＴＶカメラ３により撮影された動画像や、パソコン７により算出された血液特性を表示するようになっている。 The display 8 is connected to the personal computer 7 and displays a moving image photographed by the TV camera 3 and blood characteristics calculated by the personal computer 7.
　続いて、血液特性を解析する際の血液特性解析システム１の動作について説明する。 Subsequently, the operation of the blood characteristic analysis system 1 when analyzing blood characteristics will be described.
　まずマイクロチップ２へ血液を流しつつ、ゲート２６内の血流をＴＶカメラ３で撮影する。より詳細には、シーケンス制御部１６が供給槽１０へ解析対象の血液を注入させつつ、必要に応じて溶液びん１３へ生理食塩水等を加えさせる。そして、シーケンス制御部１６が差圧制御部１４によりマイクロチップ２に所定の差圧を作用させて当該マイクロチップ２に血液を流す一方、ＴＶカメラ３がゲート２６内の血流を撮影して動画像データをパソコン７に出力する。 First, the blood flow in the gate 26 is photographed by the TV camera 3 while flowing the blood to the microchip 2. More specifically, the sequence control unit 16 adds physiological saline or the like to the solution bottle 13 as necessary while injecting blood to be analyzed into the supply tank 10. The sequence control unit 16 causes the differential pressure control unit 14 to apply a predetermined differential pressure to the microchip 2 to flow blood through the microchip 2, while the TV camera 3 captures the blood flow in the gate 26 and takes a moving image. The image data is output to the personal computer 7.
　そして、パソコン７は、動画像データに基づいて血液特性を算出し、算出された血液特性やゲート２６内の血流をディスプレイ８に再生表示させる。 The personal computer 7 calculates blood characteristics based on the moving image data, and reproduces and displays the calculated blood characteristics and blood flow in the gate 26 on the display 8.
　以上のように、本実施の形態における血液特性解析システム１によれば、表面に微細な溝を有するベース板２１と、ベース板２１の表面に平面部２００を対向させたカバー板２０とは互いに積層されることで内側に血液の流路２８を形成しており、平面部２００が直接血液に接する場合と比較して、流路２８内での血液の流動性を異ならせる材料で形成されたフィルム２９が平面部２００を被覆しており、フィルム２９は交換可能であるので、フィルム２９を交換することにより、血液とフィルム２９との間で生じる相互作用を異なるものにすることができる。従って、溝を均一にコーティングしたマイクロチップを複数種類用意する必要がないため、従来の場合と比較して、血液と流路２８内面との間で所望の相互作用を容易に観測することができる。 As described above, according to the blood characteristic analysis system 1 in the present embodiment, the base plate 21 having fine grooves on the surface and the cover plate 20 having the flat portion 200 facing the surface of the base plate 21 are mutually connected. The blood flow path 28 is formed on the inner side by being laminated, and is formed of a material that makes the blood fluidity in the flow path 28 different from that in the case where the flat portion 200 is in direct contact with blood. Since the film 29 covers the flat portion 200 and the film 29 is exchangeable, the interaction between the blood and the film 29 can be made different by exchanging the film 29. Accordingly, since it is not necessary to prepare a plurality of types of microchips in which the grooves are uniformly coated, it is possible to easily observe a desired interaction between blood and the inner surface of the flow path 28 as compared with the conventional case. .
　特に、本実施の形態における血液特性解析システム１では、流路２８内面の血液と接触する４つの側面（上、下、左、右）のうち、上側面を構成する平面部２００のフィルム２９を交換することにより、血液と流路２８内面との間の相互作用を異なるものにすることができる。 In particular, in the blood characteristic analysis system 1 according to the present embodiment, the film 29 of the flat surface portion 200 that constitutes the upper side surface among the four side surfaces (upper, lower, left, right) in contact with the blood on the inner surface of the flow path 28 is provided. By exchanging, the interaction between blood and the inner surface of the flow path 28 can be made different.
　例えば、「基準の測定」としてフィルム２９を使用せずに、第２の基板であるベース板２１の平面部２００が流路２８の一側面を形成し、平面部２００が直接血液に接する状態で血液を流路２８内に流し、このときの動画像データに基づいて血液特性を算出する。血液特性としては例えば血流の流速（通過時間）を用いて、血液の凝集能を測定する。つぎに「比較測定」として本実施形態のようなフィルム２９、例えば血液の凝集が出現しやすいように血液の流動性が低下する材料を用いて同様の測定を行う。比較測定の場合に流動性が低下するフィルム２９を用いることにより、凝集能が高い（凝集し易い）血液の場合にはより通過時間が長くなるので血液特性として検出感度が向上する。 For example, without using the film 29 as “reference measurement”, the flat surface portion 200 of the base plate 21 as the second substrate forms one side surface of the flow path 28, and the flat surface portion 200 is in direct contact with blood. Blood is flowed into the flow path 28, and blood characteristics are calculated based on the moving image data at this time. As a blood characteristic, for example, blood agglutination ability is measured using a blood flow velocity (passage time). Next, as a “comparative measurement”, the same measurement is performed using the film 29 as in the present embodiment, for example, a material whose blood fluidity is lowered so that blood aggregation is likely to appear. By using the film 29 whose fluidity is lowered in the case of comparative measurement, in the case of blood having high aggregating ability (easy to aggregate), the passage time becomes longer, so that detection sensitivity is improved as a blood characteristic.
　また、フィルム２９が平面部２００を被覆するので、フィルム２９の厚みを均一にすることで、観察対象の領域で流路２８（ゲート２６）の内径にばらつきが生じるのを防止することができる。従って、微細な流路２８にコーティングを行う従来の場合と異なり、流路２８の内径のばらつきによって血液の流動性が影響を受けてしまうのを防止することができるため、血液と流路２８内面の材料との間の純粋な相互作用を、容易に観測することができる。 Further, since the film 29 covers the flat portion 200, it is possible to prevent the inner diameter of the flow path 28 (gate 26) from being varied in the observation target region by making the thickness of the film 29 uniform. Therefore, unlike the conventional case in which the fine channel 28 is coated, it is possible to prevent the blood fluidity from being affected by the variation in the inner diameter of the channel 28. The pure interaction with the other materials can be easily observed.
　なお、上記実施の形態においては、マイクロチップ２を血液の特性解析に用いられるものとして説明したが、他の液体試料の特性解析に用いられることとしても良い。 In the above embodiment, the microchip 2 has been described as being used for blood characteristic analysis. However, the microchip 2 may be used for characteristic analysis of other liquid samples.
　また、血液特性解析システム１には、流路２８内で生じる化学反応や抗原抗体反応を光学的または電気的に検出する公知の装置が更に具備されることとしても良い。ここで、流路２８内の反応を電気的に検出する装置としては、例えば、ウェスタンブロット法により反応を検出する装置を挙げることができ、反応を化学的に検出する装置としては、例えばフローサイトメトリー法により反応を検出する装置を挙げることができる。 The blood characteristic analysis system 1 may further include a known device that optically or electrically detects a chemical reaction or an antigen-antibody reaction occurring in the flow path 28. Here, examples of the device that electrically detects the reaction in the flow path 28 include a device that detects the reaction by Western blotting, and examples of the device that chemically detects the reaction include flow site. An apparatus for detecting a reaction by a measurement method can be mentioned.
　また、その他の点についても、本発明は上記実施の形態に限定されるものではなく、適宜変更可能であるのは勿論である。 Also, regarding other points, the present invention is not limited to the above-described embodiment, and it is needless to say that it can be appropriately changed.
　２　マイクロチップ
　２０　カバー板（第２の基板）
　２１　ベース板（第１の基板）
　２８　流路
　２９　フィルム
　２００　平面部 2 Microchip 20 Cover plate (second substrate)
21 Base plate (first substrate)
28 Flow path 29 Film 200 Flat part

Claims (5)

  1. 　液体試料の特性解析用のマイクロチップであって、
    　表面に微細な溝を有する第１の基板と、
    　前記第１の基板の表面に平面部を対向させた第２の基板とを備え、
    　前記第１の基板及び前記第２の基板は、互いに積層されることで内側に液体試料の流路を形成しており、
    　前記平面部は、
    　フィルムによって被覆されており、
    　前記フィルムの少なくとも前記第１の基板と対向する面は、
    　前記平面部が液体試料に接する場合と比較して、前記流路内での液体試料の流動性を異ならせる所定の材料で形成されていることを特徴とするマイクロチップ。     A microchip for characterizing liquid samples,
    A first substrate having fine grooves on the surface;
    A second substrate having a planar portion opposed to the surface of the first substrate,
    The first substrate and the second substrate are laminated with each other to form a liquid sample flow path inside.
    The plane portion is
    Covered with film,
    At least the surface of the film facing the first substrate is
    A microchip characterized by being formed of a predetermined material that makes the fluidity of the liquid sample different in the flow path as compared with the case where the flat portion is in contact with the liquid sample.
  2. 　請求項１のマイクロチップにおいて、
    　前記平面部を被覆している前記フィルムは交換可能であることを特徴とするマイクロチップ。     The microchip of claim 1, wherein
    The microchip according to claim 1, wherein the film covering the flat portion is replaceable.
  3. 　請求項１または２記載のマイクロチップにおいて、
    　前記フィルムは、透明であることを特徴とするマイクロチップ。     The microchip according to claim 1 or 2,
    The microchip, wherein the film is transparent.
  4. 　請求項１から３のいずれか１項に記載のマイクロチップにおいて、
    　前記液体試料は、血液であり、
    　前記第２の基板は、ガラス製であり、
    　前記所定の材料は、チタン、クロニウム、アルブミン、コラーゲンまたはシリコンであることを特徴とするマイクロチップ。     The microchip according to any one of claims 1 to 3,
    The liquid sample is blood;
    The second substrate is made of glass;
    The microchip according to claim 1, wherein the predetermined material is titanium, clonium, albumin, collagen, or silicon.
  5. 　液体試料の特性解析用のマイクロチップに備えられるフィルムであって、
    　前記マイクロチップは、
    　表面に微細な溝を有する第１の基板と、前記第１の基板の表面に平面部を対向させた第２の基板とを備え、前記第１の基板及び前記第２の基板が互いに積層されることで内側に液体試料の流路を形成しており、
    　当該フィルムは前記第２の基板の平面部を被覆しており、少なくとも前記第１の基板と対向する面は、前記平面部が液体試料に接する場合と比較して、前記流路内での液体試料の流動性を異ならせる所定の材料で形成され、
    　交換可能であることを特徴とするフィルム。     A film provided on a microchip for analyzing characteristics of a liquid sample,
    The microchip is
    A first substrate having a fine groove on the surface; and a second substrate having a planar portion opposed to the surface of the first substrate, wherein the first substrate and the second substrate are stacked on each other. To form a flow path for the liquid sample inside,
    The film covers the flat portion of the second substrate, and at least the surface facing the first substrate is liquid in the flow path as compared with the case where the flat portion is in contact with the liquid sample. It is made of a predetermined material that makes the fluidity of the sample different,
    A film characterized by being exchangeable.
PCT/JP2010/069576 2009-11-30 2010-11-04 Microchip and film WO2011065195A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003302399A (en) * 2002-04-09 2003-10-24 Mitsubishi Chemicals Corp Analyzing chip
JP2006145345A (en) * 2004-11-18 2006-06-08 Yuji Kikuchi Measuring method of flowability of fluid and measuring instrument used therein
JP2008298600A (en) * 2007-05-31 2008-12-11 National Institute Of Advanced Industrial & Technology Micro-fluid element in which a plurality of recognition material are immobilized, its manufacturing method, and analytical method using the same
WO2009139407A1 (en) * 2008-05-16 2009-11-19 日本化薬株式会社 Microanalysis chip adhesive sheet, microanalysis chip, and manufacturing method thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003302399A (en) * 2002-04-09 2003-10-24 Mitsubishi Chemicals Corp Analyzing chip
JP2006145345A (en) * 2004-11-18 2006-06-08 Yuji Kikuchi Measuring method of flowability of fluid and measuring instrument used therein
JP2008298600A (en) * 2007-05-31 2008-12-11 National Institute Of Advanced Industrial & Technology Micro-fluid element in which a plurality of recognition material are immobilized, its manufacturing method, and analytical method using the same
WO2009139407A1 (en) * 2008-05-16 2009-11-19 日本化薬株式会社 Microanalysis chip adhesive sheet, microanalysis chip, and manufacturing method thereof

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