WO2018105538A1 - Fluorescence observation device - Google Patents

Fluorescence observation device Download PDF

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Publication number
WO2018105538A1
WO2018105538A1 PCT/JP2017/043394 JP2017043394W WO2018105538A1 WO 2018105538 A1 WO2018105538 A1 WO 2018105538A1 JP 2017043394 W JP2017043394 W JP 2017043394W WO 2018105538 A1 WO2018105538 A1 WO 2018105538A1
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Prior art keywords
substrate
excitation light
fluorescence
fluorescence observation
observation apparatus
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PCT/JP2017/043394
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French (fr)
Japanese (ja)
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博行 野地
博史 上野
慶嘉 皆川
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国立大学法人東京大学
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Publication of WO2018105538A1 publication Critical patent/WO2018105538A1/en

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • G01N21/78—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator producing a change of colour

Definitions

  • the present invention relates to an apparatus for observing fluorescence excited by excitation light.
  • the present inventors have proposed a high-sensitivity detection device for low-concentration target molecules (see Patent Documents 1 and 2 below) using a microchamber array in which holes with a diameter of several micrometers are arranged.
  • an enzyme-linked immunosorbent assay ELISA
  • ELISA enzyme-linked immunosorbent assay
  • a molecular marker such as PSA (prostate specific antigen)
  • PSA prote specific antigen
  • the present invention has been made based on the above situation.
  • the main object of the present invention is to provide a technique capable of observing fluorescence in a microchamber array with simple and inexpensive equipment.
  • a fluorescence observation apparatus comprising a microchamber array, a substrate, and a light source
  • the microchamber array includes a storage unit for storing droplets
  • the substrate is a waveguide through which excitation light for exciting the fluorescence of the fluorescent substance present in the housing portion passes.
  • the distance between the substrate and the housing portion is set to a distance at which near-field light leaking from the excitation light passing through the substrate reaches the housing portion,
  • the light source is configured to make the excitation light incident on the substrate.
  • the observation unit includes a camera for observing the fluorescence, an optical system for transmitting the fluorescence to the camera, and a filter for reducing the incident amount of the excitation light to the camera.
  • the fluorescence observation apparatus according to Item 1.
  • the light source is configured to make the excitation light incident on the substrate from an end surface of the substrate,
  • the stopper is installed in the vicinity of the end face of the substrate with the end face exposed, and extended in a direction intersecting the incident direction of the excitation light to reduce stray light from the excitation light;
  • the fluorescence observation apparatus according to any one of items 1 to 3.
  • the light source is movable in a direction that intersects the emission direction of the excitation light and that extends along the extension direction of the substrate, and thereby scans the excitation light along the extension direction of the substrate.
  • the fluorescence observation apparatus according to any one of items 1 to 7, wherein the fluorescence observation apparatus is configured to be capable of performing the above-described configuration.
  • (Item 9) A fluorescence observation method using the fluorescence observation apparatus according to any one of items 1 to 8, Containing the droplets in the containing part; Making the excitation light incident on the substrate from the light source; The substrate passing the excitation light as a waveguide; And a step of exciting near-field light leaking from excitation light passing through the inside of the substrate to excite fluorescence of a fluorescent substance present in the housing portion.
  • the portable terminal includes application software capable of analyzing fluorescence captured by the camera.
  • the fluorescence of the fluorescent substance in the microchamber array can be observed with simple and inexpensive equipment. Thereby, it becomes easy to introduce a fluorescence observation apparatus using a microchamber array into a general medical facility such as a hospital.
  • the fluorescence observation apparatus of this embodiment includes a microchamber array 1, a substrate 2, and a light source 3. Furthermore, this apparatus further includes an observation unit 4 and a stopper 5.
  • the microchamber array 1 includes a plurality of storage portions 11 that store the droplets 7. More specifically, the microchamber array 1 of this example includes a lower main body 12, an upper main body 13, a hydrophobic layer 14, and a side wall 15.
  • the lower main body 12 is formed in a substantially plate shape extending in a direction intersecting with the paper surface in FIG.
  • the accommodating portion 11 is formed by a through hole that penetrates the lower main body 12 in the thickness direction.
  • the size of the accommodating portion 11 can be, for example, 1 to 10 ⁇ m in diameter.
  • the upper body 13 is formed in a substantially plate shape, and is arranged in parallel with and spaced from the lower body 12.
  • the hydrophobic layer 14 is disposed on the inner surface (the lower surface in FIG. 1) of the upper body 13.
  • the side wall 15 is disposed so as to connect the hydrophobic layer 14 or the side of the upper body 13 and the side of the lower body 12. Thereby, in the present embodiment, a closed space 17 is formed between the hydrophobic layer 14 and the lower main body 12.
  • Fluorescent material 18 is arranged inside the accommodating portion 11 of this example.
  • the fluorescent material 18 emits fluorescence when irradiated with excitation light.
  • the fluorescent substance for example, fluorescein, resorufin, 4MU can be used.
  • the capacity of the accommodating portion 11 of the present embodiment is 1000 fL or less.
  • the substrate 2 is a waveguide through which excitation light for exciting the fluorescence of the fluorescent substance present in the accommodating portion 11 passes.
  • the distance between the substrate 2 and the accommodating portion 11 is set to a distance at which the near-field light leaking from the excitation light passing through the substrate 2 reaches the accommodating portion 11. This distance can be, for example, about 0 to 100 nm.
  • the refractive index of the substrate 2 is higher than the refractive index around the substrate 2 at least in the portion constituting the waveguide.
  • the material of the substrate for example, glass can be used.
  • the light source 3 is configured to make excitation light incident on the substrate 2.
  • the light source 3 of the present embodiment is configured such that excitation light enters the substrate 2 from the end face of the substrate 2.
  • a laser capable of emitting the wavelength of the excitation light is used.
  • other light-emitting elements such as LEDs can be used as long as they include the wavelength of the excitation light and have the necessary light emission intensity.
  • the incident angle of the light source 3 on the substrate 2 is set to an angle that satisfies the total reflection condition of the excitation light traveling inside the substrate 2. This angle can be, for example, about 40 to 60 degrees.
  • the observation unit 4 includes a camera 41 for observing fluorescence, an optical system 42 for transmitting fluorescence to the camera 41, and a filter 43 for reducing the amount of incident excitation light to the camera 41. .
  • the camera 41 of the present embodiment is a camera built in a smartphone or other portable terminal. Specifically, the camera 41 includes an imaging lens 411 and an image sensor 412.
  • the stopper 5 is installed near the end face of the substrate 2 with the end face exposed.
  • the stopper 5 is extended in a direction intersecting with the incident direction of the excitation light to reduce stray light from the excitation light.
  • the stopper 5 of the present embodiment includes a lower stopper 51 that extends downward in FIG. 1 and an upper stopper 52 that extends upward in FIG. 1.
  • Step SA-1 in FIG. 2 First, a droplet is accommodated in each accommodating part.
  • this accommodation method for example, the method described in Patent Document 2 can be used, and detailed description thereof will be omitted.
  • Steps SA-2 and SA-3 in FIG. 2 Next, the light source 3 is driven and laser light is incident on the end face of the substrate 2 (see FIG. 1).
  • the incident laser light enters the inside from the end face of the substrate 2 and travels along the extending direction of the substrate 2. That is, the substrate 2 of this embodiment exhibits the function of an optical waveguide.
  • the incident angle of the excitation light from the light source 3 to the substrate 2 is set to an angle that satisfies the total reflection condition of the excitation light traveling inside the substrate 2. It can be efficiently introduced inside and transmitted by the substrate 2.
  • the stopper 5 since the stopper 5 is installed in the vicinity of the end portion of the substrate 2, the light emitted from the light source 3 toward the end portion of the substrate 2 proceeds toward the microchamber array 1 and the camera 41. Can inhibit. For this reason, according to this embodiment, there is also an advantage that stray light (excitation light) incident on the camera 41 can be reduced.
  • Step SA-4 in FIG. 2 When the excitation light travels inside the substrate 2, near-field light oozes out of the substrate 2 near the surface of the substrate 2. It is known that the reach distance of near-field light is very small (several tens of nanometers or less).
  • the distance between the substrate 2 and the accommodating portion 11 is a distance at which the near-field light leaking from the excitation light passing through the substrate 2 can reach the accommodating portion 11.
  • the fluorescent material 18 can be irradiated with light. That is, in this embodiment, fluorescence can be excited by near-field light.
  • Step SA-5 in FIG. 2 The excited fluorescence passes through the optical system 42 and is received by the image sensor 412 of the camera 41. That is, in this embodiment, fluorescence can be captured by the camera 41. In this way, fluorescence observation becomes possible. Video captured by the camera 41 can be analyzed by an appropriate analysis method.
  • the conventional fluorescence observation apparatus requires an expensive filter because strong excitation light enters the camera as background light.
  • the fluorescence is excited using near-field light, the excitation light incident on the camera 41 is small enough to be ignored. That is, in the present embodiment, it is possible to use an inexpensive and lightweight filter 43 that can remove ambient light and slightly leaked excitation light. As such a filter 43, for example, an inexpensive film filter can be used. Therefore, according to the present embodiment, there is an advantage that the fluorescence observation apparatus can be reduced in size and weight, and further, the manufacturing and operation costs of the apparatus can be reduced.
  • the light source device is placed on a large scale because the light source is arranged facing the microchamber array.
  • the configuration of the light source 3 can be simplified. That is, in this embodiment, the device can be reduced in size and weight from this point, and the manufacturing and operating costs of the device can be reduced.
  • the light source 3 may be movable in a direction that intersects the emission direction of the excitation light and extends along the extending direction of the substrate (that is, the thickness direction of the paper surface in FIG. 1). If comprised in this way, it will become possible to scan excitation light along the extension direction of the board
  • FIG. According to the configuration of the first modification, even when near-field light is used as the excitation light, the excitation light is radiated without leakage to the fluorescent substance in the accommodating portion 11 that is two-dimensionally distributed and arranged. There is an advantage that it becomes possible.
  • a mobile terminal for example, a smartphone
  • the camera 41 may be provided with application software that can analyze fluorescence captured by the camera 41.
  • fluorescence observation and sample analysis can be performed with simpler equipment, and there is an advantage that versatility increases.
  • the observation result can be used as so-called big data for various purposes.
  • the upper part and the lower part are merely terms for distinction, and do not limit the arrangement state in mounting.
  • the arrangement of the filter 43 can be omitted depending on the fluorescent photographing conditions.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Physics & Mathematics (AREA)
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  • Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)

Abstract

The present invention is for observation of fluorescence in a microchamber array by means of simplified and inexpensive equipment. A microchamber array 1 is provided with a storage 11 for storing liquid droplets 7. A substrate 2 serves as a waveguide for allowing transmission of excitation light for exciting fluorescence in a fluorescent substance 18 present in the storage 11. The distance between the substrate 2 and the storage 11 is set to a distance in which near-field light leaking from the excitation light passing through the substrate 2 reaches the storage 11. A light source 3 causes the excitation light to enter the substrate 2.

Description

蛍光観察装置Fluorescence observation equipment
　本発明は、励起光によって励起される蛍光を観察するための装置に関するものである。 The present invention relates to an apparatus for observing fluorescence excited by excitation light.
　本発明者らは、数マイクロメートルの直径の穴が並んでいるマイクロチャンバアレイを用いた、低濃度ターゲット分子の高感度検出装置（下記特許文献１及び２参照）を提案している。この技術を用いると、マイクロチャンバアレイに封入されたフェムトリットル体積の微小液滴中で酵素結合免疫吸着アッセイ（ＥＬＩＳＡ）を行い、酵素１分子の反応によって生成される蛍光色素を検出することができる。すると、例えばＰＳＡ（前立腺特異抗原）のような分子マーカーを、従来の約１００万倍という超高感度で検出することが可能になる。 The present inventors have proposed a high-sensitivity detection device for low-concentration target molecules (see Patent Documents 1 and 2 below) using a microchamber array in which holes with a diameter of several micrometers are arranged. Using this technology, an enzyme-linked immunosorbent assay (ELISA) can be performed in a femtoliter volume microdroplet enclosed in a microchamber array, and the fluorescent dye produced by the reaction of one enzyme molecule can be detected. . Then, for example, it becomes possible to detect a molecular marker such as PSA (prostate specific antigen) with an ultra-high sensitivity of about 1 million times the conventional one.
　ところで、この技術においては、蛍光を励起するための励起光を、マイクロチャンバアレイに照射する必要がある。マイクロチャンバアレイに照射された励起光（透過光又は反射光）は、蛍光を観察するためのカメラに、強い背景光（ノイズ）として入射する。そこで、従来の蛍光観察装置では、強い背景光を除去するための高性能なフィルタをカメラの手前に配置する必要があった。さらに、従来の装置では、マイクロチャンバアレイ全体に励起光を照射するための設備も大がかりとなっていた。このため、従来の蛍光観察装置は、大型でかつ高価であるという問題があった。一方、医療の現場では、小型かつ安価な装置が求められており、従来の蛍光観察装置を病院などの医療施設に配置することには困難があった。 By the way, in this technique, it is necessary to irradiate the microchamber array with excitation light for exciting fluorescence. Excitation light (transmitted light or reflected light) irradiated on the microchamber array enters a camera for observing fluorescence as strong background light (noise). Therefore, in the conventional fluorescence observation apparatus, it is necessary to arrange a high-performance filter for removing strong background light in front of the camera. Furthermore, in the conventional apparatus, the equipment for irradiating the entire micro chamber array with the excitation light has been large. For this reason, the conventional fluorescence observation apparatus has a problem that it is large and expensive. On the other hand, in the medical field, a small and inexpensive apparatus has been demanded, and it has been difficult to arrange a conventional fluorescence observation apparatus in a medical facility such as a hospital.
特開２００４－３０９４０５号公報JP 2004-309405 A 国際公開２０１２／１２１３１０号公報International Publication No. 2012/121310
　本発明は、前記した状況に基づいてなされたものである。本発明の主な目的は、マイクロチャンバアレイにおける蛍光を、簡易でかつ安価な設備により観察できる技術を提供することである。 The present invention has been made based on the above situation. The main object of the present invention is to provide a technique capable of observing fluorescence in a microchamber array with simple and inexpensive equipment.
　前記した課題を解決する手段は、以下の項目のように記載できる。 The means for solving the above-described problems can be described as the following items.
　（項目１）
　マイクロチャンバアレイと、基板と、光源とを備える蛍光観察装置であって、
　前記マイクロチャンバアレイは、液滴を収容する収容部を備えており、
　前記基板は、前記収容部に存在する蛍光物質の蛍光を励起するための励起光を通過させる導波路となっており、
　前記基板と前記収容部との距離は、前記基板を通過する励起光から漏れ出す近接場光が前記収容部に到達する距離に設定されており、
　前記光源は、前記励起光を前記基板に入射する構成となっている
　蛍光観察装置。 (Item 1)
A fluorescence observation apparatus comprising a microchamber array, a substrate, and a light source,
The microchamber array includes a storage unit for storing droplets,
The substrate is a waveguide through which excitation light for exciting the fluorescence of the fluorescent substance present in the housing portion passes.
The distance between the substrate and the housing portion is set to a distance at which near-field light leaking from the excitation light passing through the substrate reaches the housing portion,
The light source is configured to make the excitation light incident on the substrate.
　（項目２）
　さらに観察部を備えており、
　前記観察部は、前記蛍光を観察するためのカメラと、前記カメラに前記蛍光を伝送するための光学系と、前記カメラへの前記励起光の入射量を低減させるためのフィルタとを備えている
　項目１に記載の蛍光観察装置。 (Item 2)
Furthermore, it has an observation part,
The observation unit includes a camera for observing the fluorescence, an optical system for transmitting the fluorescence to the camera, and a filter for reducing the incident amount of the excitation light to the camera. Item 2. The fluorescence observation apparatus according to Item 1.
　（項目３）
　前記カメラは、スマートフォンその他の携帯端末に内蔵されたカメラである
　項目２に記載の蛍光観察装置。 (Item 3)
The fluorescence observation apparatus according to Item 2, wherein the camera is a camera built in a mobile terminal such as a smartphone.
　（項目４）
　さらにストッパを備えており、
　前記光源は、前記基板の端面から前記励起光を前記基板に入射する構成となっており、
　前記ストッパは、前記基板の端面近傍に、前記端面を露出させた状態で設置され、かつ、前記励起光の入射方向と交差する方向に延長されて、前記励起光からの迷光を低減させる構成となっている
　項目１～３のいずれか１項に記載の蛍光観察装置。 (Item 4)
It also has a stopper,
The light source is configured to make the excitation light incident on the substrate from an end surface of the substrate,
The stopper is installed in the vicinity of the end face of the substrate with the end face exposed, and extended in a direction intersecting the incident direction of the excitation light to reduce stray light from the excitation light; The fluorescence observation apparatus according to any one of items 1 to 3.
　（項目５）
　前記収容部の容量は１０００ｆＬ以下とされている
　項目１～４のいずれか１項に記載の蛍光観察装置。 (Item 5)
Item 5. The fluorescence observation apparatus according to any one of Items 1 to 4, wherein a capacity of the housing portion is 1000 fL or less.
　（項目６）
　前記基板への前記光源の入射角度は、前記基板の内部を進む前記励起光の全反射条件を満たす角度に設定されている
　項目１～５のいずれか１項に記載の蛍光観察装置。 (Item 6)
6. The fluorescence observation apparatus according to claim 1, wherein an incident angle of the light source on the substrate is set to an angle that satisfies a total reflection condition of the excitation light traveling inside the substrate.
　（項目７）
　前記基板の屈折率は、少なくとも前記導波路を構成する部分においては、前記基板の周囲の屈折率よりも高いものとされている
　項目１～６のいずれか１項に記載の蛍光観察装置。 (Item 7)
Item 7. The fluorescence observation apparatus according to any one of Items 1 to 6, wherein a refractive index of the substrate is higher than a refractive index around the substrate at least in a portion constituting the waveguide.
　（項目８）
　前記光源は、前記励起光の出射方向に交差し、かつ、前記基板の延長方向に沿う方向に移動可能とされており、これによって、前記励起光を、前記基板の延長方向に沿って走査させることができる構成となっている
　項目１～７のいずれか１項に記載の蛍光観察装置。 (Item 8)
The light source is movable in a direction that intersects the emission direction of the excitation light and that extends along the extension direction of the substrate, and thereby scans the excitation light along the extension direction of the substrate. 8. The fluorescence observation apparatus according to any one of items 1 to 7, wherein the fluorescence observation apparatus is configured to be capable of performing the above-described configuration.
　（項目９）
　項目１～８のいずれか１項に記載の蛍光観察装置を用いた蛍光観察方法であって、
　前記収容部に前記液滴を収容するステップと、
　前記光源から、前記励起光を前記基板に入射するステップと、
　前記基板が、導波路として、前記励起光を通過させるステップと、
　前記基板の内部を通過する励起光から漏れ出す近接場光が、前記収容部に存在する蛍光物質の蛍光を励起するステップと
　を備える蛍光観察方法。 (Item 9)
A fluorescence observation method using the fluorescence observation apparatus according to any one of items 1 to 8,
Containing the droplets in the containing part;
Making the excitation light incident on the substrate from the light source;
The substrate passing the excitation light as a waveguide;
And a step of exciting near-field light leaking from excitation light passing through the inside of the substrate to excite fluorescence of a fluorescent substance present in the housing portion.
　（項目１０）
　項目３に記載の蛍光観察装置を用いた試料分析方法であって、
　前記携帯端末は、前記カメラで撮影された蛍光を解析可能なアプリケーションソフトウエアを備えている
　試料分析方法。 (Item 10)
A sample analysis method using the fluorescence observation apparatus according to Item 3,
The portable terminal includes application software capable of analyzing fluorescence captured by the camera.
　本発明によれば、マイクロチャンバアレイ中の蛍光物質の蛍光を、簡易かつ安価な設備により観察することが可能になる。これにより、マイクロチャンバアレイを用いた蛍光観察装置を、病院などの一般的な医療施設に導入することが容易となる。 According to the present invention, the fluorescence of the fluorescent substance in the microchamber array can be observed with simple and inexpensive equipment. Thereby, it becomes easy to introduce a fluorescence observation apparatus using a microchamber array into a general medical facility such as a hospital.
本発明の一実施形態における蛍光観察装置の概略的な構成を示すための要部断面図である。It is principal part sectional drawing for showing the schematic structure of the fluorescence observation apparatus in one Embodiment of this invention. 図１の装置を用いた蛍光観察方法を説明するためのフローチャートである。It is a flowchart for demonstrating the fluorescence observation method using the apparatus of FIG.
　以下、本発明の一実施形態に係る蛍光観察装置を、図１を参照しながら説明する。 Hereinafter, a fluorescence observation apparatus according to an embodiment of the present invention will be described with reference to FIG.
　（本実施形態の構成）
　本実施形態の蛍光観察装置は、マイクロチャンバアレイ１と、基板２と、光源３とを備えている。さらに、この装置は、観察部４とストッパ５とを追加的に備えている。 (Configuration of this embodiment)
The fluorescence observation apparatus of this embodiment includes a microchamber array 1, a substrate 2, and a light source 3. Furthermore, this apparatus further includes an observation unit 4 and a stopper 5.
　（マイクロチャンバアレイ）
　マイクロチャンバアレイ１は、液滴７を収容する複数の収容部１１を備えている。より具体的には、本例のマイクロチャンバアレイ１は、下部本体１２と、上部本体１３と、疎水性層１４と、側壁１５とを備えている。 (Microchamber array)
The microchamber array 1 includes a plurality of storage portions 11 that store the droplets 7. More specifically, the microchamber array 1 of this example includes a lower main body 12, an upper main body 13, a hydrophobic layer 14, and a side wall 15.
　下部本体１２は、図１における紙面に交差する方向に延長された略板状に形成されている。収容部１１は、下部本体１２をその厚さ方向に貫通する貫通孔により形成されている。収容部１１の大きさとしては、たとえば直径１～１０μｍとすることができる。 The lower main body 12 is formed in a substantially plate shape extending in a direction intersecting with the paper surface in FIG. The accommodating portion 11 is formed by a through hole that penetrates the lower main body 12 in the thickness direction. The size of the accommodating portion 11 can be, for example, 1 to 10 μm in diameter.
　上部本体１３は、略板状に形成されており、下部本体１２と平行に、かつ離間して配置されている。疎水性層１４は、上部本体１３の内面（図１における下面）に配置されている。側壁１５は、疎水性層１４あるいは上部本体１３の側部と下部本体１２との側部とを接続するように配置されている。これにより、本実施形態では、疎水性層１４と下部本体１２との間に閉鎖された空間１７が形成されるようになっている。 The upper body 13 is formed in a substantially plate shape, and is arranged in parallel with and spaced from the lower body 12. The hydrophobic layer 14 is disposed on the inner surface (the lower surface in FIG. 1) of the upper body 13. The side wall 15 is disposed so as to connect the hydrophobic layer 14 or the side of the upper body 13 and the side of the lower body 12. Thereby, in the present embodiment, a closed space 17 is formed between the hydrophobic layer 14 and the lower main body 12.
　本例の収容部１１の内部には、蛍光物質１８が配置されている。この蛍光物質１８は、励起光の照射によって蛍光を発するものとなっている。具体的には、蛍光物質としては、例えば、フルオレセイン、レゾルフィン、４ＭＵを用いることができる。 Fluorescent material 18 is arranged inside the accommodating portion 11 of this example. The fluorescent material 18 emits fluorescence when irradiated with excitation light. Specifically, as the fluorescent substance, for example, fluorescein, resorufin, 4MU can be used.
　本実施形態の収容部１１の容量は、１０００ｆＬ以下とされている。 The capacity of the accommodating portion 11 of the present embodiment is 1000 fL or less.
　前記以外の点におけるマイクロチャンバアレイの構成は、例えば前記特許文献２に記載のものと同様とすることができるので、これ以上詳しい説明は省略する。 Since the configuration of the microchamber array other than the above can be the same as that described in Patent Document 2, for example, detailed description thereof is omitted.
　（基板）
　基板２は、収容部１１に存在する蛍光物質の蛍光を励起するための励起光を通過させる導波路となっている。 (substrate)
The substrate 2 is a waveguide through which excitation light for exciting the fluorescence of the fluorescent substance present in the accommodating portion 11 passes.
　基板２と収容部１１との距離は、基板２を通過する励起光から漏れ出す近接場光が収容部１１に到達する距離に設定されている。この距離としては、例えば、０～１００ｎｍ程度とすることができる。 The distance between the substrate 2 and the accommodating portion 11 is set to a distance at which the near-field light leaking from the excitation light passing through the substrate 2 reaches the accommodating portion 11. This distance can be, for example, about 0 to 100 nm.
　基板２の屈折率は、少なくとも導波路を構成する部分においては、基板２の周囲の屈折率よりも高いものとされている。具体的には、基板２の材質としては例えば、ガラスを用いることができる。 The refractive index of the substrate 2 is higher than the refractive index around the substrate 2 at least in the portion constituting the waveguide. Specifically, as the material of the substrate 2, for example, glass can be used.
　（光源）
　光源３は、励起光を基板２に入射する構成となっている。本実施形態の光源３は、基板２の端面から励起光を基板２に入射する構成となっている。本実施形態の光源３としては、励起光の波長を発光可能なレーザが用いられている。ただし、励起光の波長を含み、かつ必要な発光強度を持つものであれば、他の発光素子、例えばＬＥＤを用いることも可能である。 (light source)
The light source 3 is configured to make excitation light incident on the substrate 2. The light source 3 of the present embodiment is configured such that excitation light enters the substrate 2 from the end face of the substrate 2. As the light source 3 of the present embodiment, a laser capable of emitting the wavelength of the excitation light is used. However, other light-emitting elements such as LEDs can be used as long as they include the wavelength of the excitation light and have the necessary light emission intensity.
　基板２への光源３の入射角度は、基板２の内部を進む励起光の全反射条件を満たす角度に設定されている。この角度としては、例えば、４０度～６０度程度とすることができる。 The incident angle of the light source 3 on the substrate 2 is set to an angle that satisfies the total reflection condition of the excitation light traveling inside the substrate 2. This angle can be, for example, about 40 to 60 degrees.
　（観察部）
　観察部４は、蛍光を観察するためのカメラ４１と、カメラ４１に蛍光を伝送するための光学系４２と、カメラ４１への励起光の入射量を低減させるためのフィルタ４３とを備えている。 (Observation part)
The observation unit 4 includes a camera 41 for observing fluorescence, an optical system 42 for transmitting fluorescence to the camera 41, and a filter 43 for reducing the amount of incident excitation light to the camera 41. .
　本実施形態のカメラ４１は、スマートフォンその他の携帯端末に内蔵されたカメラである。具体的には、このカメラ４１は、結像レンズ４１１とイメージセンサ４１２とを備えている。 The camera 41 of the present embodiment is a camera built in a smartphone or other portable terminal. Specifically, the camera 41 includes an imaging lens 411 and an image sensor 412.
　（ストッパ）
　ストッパ５は、基板２の端面近傍に、この端面を露出させた状態で設置されている。かつ、ストッパ５は、励起光の入射方向と交差する方向に延長されて、励起光からの迷光を低減させる構成となっている。具体的には、本実施形態のストッパ５は、図１において下向きに延長された下部ストッパ５１と、図１において上向きに延長された上部ストッパ５２とを備えている。 (Stopper)
The stopper 5 is installed near the end face of the substrate 2 with the end face exposed. The stopper 5 is extended in a direction intersecting with the incident direction of the excitation light to reduce stray light from the excitation light. Specifically, the stopper 5 of the present embodiment includes a lower stopper 51 that extends downward in FIG. 1 and an upper stopper 52 that extends upward in FIG. 1.
　（本実施形態の動作）
　つぎに、図２をさらに参照して、本実施形態の装置を用いた蛍光観察方法について説明する。 (Operation of this embodiment)
Next, with reference to FIG. 2 further, a fluorescence observation method using the apparatus of the present embodiment will be described.
　（図２のステップＳＡ－１）
　まず、各収容部に液滴を収容する。この収容方法としては、例えば前記した特許文献２に記載の方法を用いることができるので、これについての詳しい説明は省略する。 (Step SA-1 in FIG. 2)
First, a droplet is accommodated in each accommodating part. As this accommodation method, for example, the method described in Patent Document 2 can be used, and detailed description thereof will be omitted.
　（図２のステップＳＡ－２及びＳＡ－３）
　次に、光源３を駆動して、レーザ光を基板２の端面に入射する（図１参照）。入射されたレーザ光は、基板２の端面からその内部に入り、基板２の延長方向に沿って進行する。すなわち、本実施形態の基板２は、光導波路の機能を発揮する。 (Steps SA-2 and SA-3 in FIG. 2)
Next, the light source 3 is driven and laser light is incident on the end face of the substrate 2 (see FIG. 1). The incident laser light enters the inside from the end face of the substrate 2 and travels along the extending direction of the substrate 2. That is, the substrate 2 of this embodiment exhibits the function of an optical waveguide.
　ここで、本実施形態では、光源３から基板２への励起光の入射角度を、基板２の内部を進む励起光の全反射条件を満たす角度に設定しているので、励起光を基板２の内部に効率よく導入して、基板２により伝送することができる。 Here, in the present embodiment, the incident angle of the excitation light from the light source 3 to the substrate 2 is set to an angle that satisfies the total reflection condition of the excitation light traveling inside the substrate 2. It can be efficiently introduced inside and transmitted by the substrate 2.
　さらに、本実施形態では、基板２の端部近傍にストッパ５を設置したので、光源３から基板２の端部に向けて照射された光がマイクロチャンバアレイ１やカメラ４１の方向に進むことを阻害できる。このため、本実施形態によれば、カメラ４１に入射する迷光（励起光）を低減させることができるという利点もある。 Furthermore, in this embodiment, since the stopper 5 is installed in the vicinity of the end portion of the substrate 2, the light emitted from the light source 3 toward the end portion of the substrate 2 proceeds toward the microchamber array 1 and the camera 41. Can inhibit. For this reason, according to this embodiment, there is also an advantage that stray light (excitation light) incident on the camera 41 can be reduced.
　さらに、本実施形態では、光源３からの励起光を、マイクロチャンバアレイ１の方向に向けて（図１では斜め上向きに）照射しているので、カメラ４１に入り込む迷光をさらに減らすことができるという利点もある。 Furthermore, in this embodiment, since the excitation light from the light source 3 is irradiated toward the microchamber array 1 (inclined upward in FIG. 1), stray light entering the camera 41 can be further reduced. There are also advantages.
　（図２のステップＳＡ－４）
　励起光が基板２の内部を進むと、基板２の表面近傍においては、近接場光が基板２の外側にしみ出す。近接場光の到達距離は、ごくわずか（数十ナノメートル以下）であることが知られている。 (Step SA-4 in FIG. 2)
When the excitation light travels inside the substrate 2, near-field light oozes out of the substrate 2 near the surface of the substrate 2. It is known that the reach distance of near-field light is very small (several tens of nanometers or less).
　本実施形態では、基板２と収容部１１との距離を、基板２を通過する励起光から漏れ出す近接場光が収容部１１に到達できる距離としているので、本実施形態によれば、近接場光を蛍光物質１８に照射することができる。すなわち、本実施形態では、近接場光により蛍光を励起することができる。 In the present embodiment, the distance between the substrate 2 and the accommodating portion 11 is a distance at which the near-field light leaking from the excitation light passing through the substrate 2 can reach the accommodating portion 11. The fluorescent material 18 can be irradiated with light. That is, in this embodiment, fluorescence can be excited by near-field light.
　（図２のステップＳＡ－５）
　励起された蛍光は、光学系４２を通り、カメラ４１のイメージセンサ４１２により受光される。すなわち、本実施形態では、蛍光をカメラ４１により撮影することができる。このようにして蛍光観察が可能になる。カメラ４１で撮影された映像は、適宜な解析手法により解析可能である。 (Step SA-5 in FIG. 2)
The excited fluorescence passes through the optical system 42 and is received by the image sensor 412 of the camera 41. That is, in this embodiment, fluorescence can be captured by the camera 41. In this way, fluorescence observation becomes possible. Video captured by the camera 41 can be analyzed by an appropriate analysis method.
　ここで、従来の蛍光観察装置では、強い励起光が背景光としてカメラに入射してしまうため、高価なフィルタが必要であった。これに対して、本実施形態では、近接場光を用いて蛍光を励起しているので、カメラ４１に入射する励起光はほとんど無視できるほどに小さい。すなわち、本実施形態では、環境光やわずかに漏れ出た励起光を除去できるような安価で軽量なフィルタ４３を用いることができる。このようなフィルタ４３としては、例えば安価なフィルム状フィルタを用いることができる。したがって、本実施形態によれば、蛍光観察装置を小型化及び軽量化でき、さらには、装置の製造及び運用コストを低減できるという利点がある。 Here, the conventional fluorescence observation apparatus requires an expensive filter because strong excitation light enters the camera as background light. On the other hand, in this embodiment, since the fluorescence is excited using near-field light, the excitation light incident on the camera 41 is small enough to be ignored. That is, in the present embodiment, it is possible to use an inexpensive and lightweight filter 43 that can remove ambient light and slightly leaked excitation light. As such a filter 43, for example, an inexpensive film filter can be used. Therefore, according to the present embodiment, there is an advantage that the fluorescence observation apparatus can be reduced in size and weight, and further, the manufacturing and operation costs of the apparatus can be reduced.
　また、従来の蛍光観察装置では、光源をマイクロチャンバアレイに対向して配置しているために、光源装置も大がかりになっていた。これに対して、本実施形態では、基板２の側面に励起光を照射することで蛍光を励起できるので、光源３の構成を簡略化することができる。すなわち、本実施形態では、この点からも、装置の小型化及び軽量化を図ることができ、さらには、装置の製造及び運用コストを低減することができる。 Also, in the conventional fluorescence observation apparatus, the light source device is placed on a large scale because the light source is arranged facing the microchamber array. On the other hand, in this embodiment, since the fluorescence can be excited by irradiating the side surface of the substrate 2 with excitation light, the configuration of the light source 3 can be simplified. That is, in this embodiment, the device can be reduced in size and weight from this point, and the manufacturing and operating costs of the device can be reduced.
　（変形例１）
　光源３は、励起光の出射方向に交差し、かつ、基板の延長方向に沿う方向（すなわち、図１における紙面の厚さ方向）に移動可能であってもよい。このように構成すれば、励起光を、基板２の延長方向に沿って走査させることが可能となる。この変形例１の構成によれば、励起光として近接場光を用いた場合においても、２次元的に分散配置されている収容部１１内の蛍光物質に対して、漏れなく励起光を照射することが可能になるという利点がある。 (Modification 1)
The light source 3 may be movable in a direction that intersects the emission direction of the excitation light and extends along the extending direction of the substrate (that is, the thickness direction of the paper surface in FIG. 1). If comprised in this way, it will become possible to scan excitation light along the extension direction of the board | substrate 2. FIG. According to the configuration of the first modification, even when near-field light is used as the excitation light, the excitation light is radiated without leakage to the fluorescent substance in the accommodating portion 11 that is two-dimensionally distributed and arranged. There is an advantage that it becomes possible.
　（変形例２）
　カメラ４１を内蔵した携帯端末（例えばスマートフォン）は、カメラ４１で撮影された蛍光を解析可能なアプリケーションソフトウエアを備えたものであってもよい。このようにすると、より簡易な設備により蛍光観察及び試料分析を行うことが可能になり、汎用性が増すという利点がある。あるいは、携帯端末からサーバあるいはクラウドにデータを送ることにより、観察結果をいわゆるビッグデータとして用いて、各種用途に活用することも可能である。 (Modification 2)
A mobile terminal (for example, a smartphone) incorporating the camera 41 may be provided with application software that can analyze fluorescence captured by the camera 41. In this way, fluorescence observation and sample analysis can be performed with simpler equipment, and there is an advantage that versatility increases. Alternatively, by sending data from a mobile terminal to a server or cloud, the observation result can be used as so-called big data for various purposes.
　なお、本発明の内容は、前記実施形態に限定されるものではない。本発明は、特許請求の範囲に記載された範囲内において、具体的な構成に対して種々の変更を加えうるものである。 Note that the content of the present invention is not limited to the above embodiment. In the present invention, various modifications can be made to the specific configuration within the scope of the claims.
　例えば、前記説明において上部や下部とは、区別のための用語に過ぎず、実装における配置状態を限定するものではない。 For example, in the above description, the upper part and the lower part are merely terms for distinction, and do not limit the arrangement state in mounting.
　また、蛍光の撮影条件によっては、フィルタ４３の配置を省略することも可能である。 Also, the arrangement of the filter 43 can be omitted depending on the fluorescent photographing conditions.
　１　マイクロチャンバアレイ
　１１　収容部
　１２　下部本体
　１３　上部本体
　１４　疎水性層
　１５　側壁
　１７　空間
　１８　蛍光物質
　２　基板
　３　光源
　４　観察部
　４１　カメラ
　４１１　結像レンズ
　４１２　イメージセンサ
　４２　光学系
　４３　フィルタ
　５　ストッパ
　５１　下部ストッパ
　５２　上部ストッパ
　７　液滴 DESCRIPTION OF SYMBOLS 1 Microchamber array 11 Housing | casing part 12 Lower main body 13 Upper main body 14 Hydrophobic layer 15 Side wall 17 Space 18 Fluorescent substance 2 Substrate 3 Light source 4 Observation part 41 Camera 411 Imaging lens 412 Image sensor 42 Optical system 43 Filter 5 Stopper 51 Lower stopper 52 Upper stopper 7 Droplet

Claims (10)

  1. 　マイクロチャンバアレイと、基板と、光源とを備える蛍光観察装置であって、
    　前記マイクロチャンバアレイは、液滴を収容する収容部を備えており、
    　前記基板は、前記収容部に存在する蛍光物質の蛍光を励起するための励起光を通過させる導波路となっており、
    　前記基板と前記収容部との距離は、前記基板を通過する励起光から漏れ出す近接場光が前記収容部に到達する距離に設定されており、
    　前記光源は、前記励起光を前記基板に入射する構成となっている
    　蛍光観察装置。     A fluorescence observation apparatus comprising a microchamber array, a substrate, and a light source,
    The microchamber array includes a storage unit for storing droplets,
    The substrate is a waveguide through which excitation light for exciting the fluorescence of the fluorescent substance present in the housing portion passes.
    The distance between the substrate and the housing portion is set to a distance at which near-field light leaking from the excitation light passing through the substrate reaches the housing portion,
    The light source is configured to make the excitation light incident on the substrate.
  2. 　さらに観察部を備えており、
    　前記観察部は、前記蛍光を観察するためのカメラと、前記カメラに前記蛍光を伝送するための光学系と、前記カメラへの前記励起光の入射量を低減させるためのフィルタとを備えている
    　請求項１に記載の蛍光観察装置。     Furthermore, it has an observation part,
    The observation unit includes a camera for observing the fluorescence, an optical system for transmitting the fluorescence to the camera, and a filter for reducing the incident amount of the excitation light to the camera. The fluorescence observation apparatus according to claim 1.
  3. 　前記カメラは、スマートフォンその他の携帯端末に内蔵されたカメラである
    　請求項２に記載の蛍光観察装置。     The fluorescence observation apparatus according to claim 2, wherein the camera is a camera built in a smartphone or other portable terminal.
  4. 　さらにストッパを備えており、
    　前記光源は、前記基板の端面から前記励起光を前記基板に入射する構成となっており、
    　前記ストッパは、前記基板の端面近傍に、前記端面を露出させた状態で設置され、かつ、前記励起光の入射方向と交差する方向に延長されて、前記励起光からの迷光を低減させる構成となっている
    　請求項１～３のいずれか１項に記載の蛍光観察装置。     It also has a stopper,
    The light source is configured to make the excitation light incident on the substrate from an end surface of the substrate,
    The stopper is installed in the vicinity of the end face of the substrate with the end face exposed, and extended in a direction intersecting the incident direction of the excitation light to reduce stray light from the excitation light; The fluorescence observation apparatus according to any one of claims 1 to 3.
  5. 　前記収容部の容量は１０００ｆＬ以下とされている
    　請求項１～４のいずれか１項に記載の蛍光観察装置。     The fluorescence observation apparatus according to any one of claims 1 to 4, wherein a capacity of the housing portion is 1000 fL or less.
  6. 　前記基板への前記光源の入射角度は、前記基板の内部を進む前記励起光の全反射条件を満たす角度に設定されている
    　請求項１～５のいずれか１項に記載の蛍光観察装置。     The fluorescence observation apparatus according to any one of claims 1 to 5, wherein an incident angle of the light source to the substrate is set to an angle that satisfies a total reflection condition of the excitation light traveling inside the substrate.
  7. 　前記基板の屈折率は、少なくとも前記導波路を構成する部分においては、前記基板の周囲の屈折率よりも高いものとされている
    　請求項１～６のいずれか１項に記載の蛍光観察装置。     The fluorescence observation apparatus according to any one of claims 1 to 6, wherein a refractive index of the substrate is higher than a refractive index around the substrate at least in a portion constituting the waveguide.
  8. 　前記光源は、前記励起光の出射方向に交差し、かつ、前記基板の延長方向に沿う方向に移動可能とされており、これによって、前記励起光を、前記基板の延長方向に沿って走査させることができる構成となっている
    　請求項１～７のいずれか１項に記載の蛍光観察装置。     The light source is movable in a direction that intersects the emission direction of the excitation light and that extends along the extension direction of the substrate, and thereby scans the excitation light along the extension direction of the substrate. The fluorescence observation apparatus according to any one of Claims 1 to 7, wherein the fluorescence observation apparatus is configured to be capable of performing the following.
  9. 　請求項１～８のいずれか１項に記載の蛍光観察装置を用いた蛍光観察方法であって、
    　前記収容部に前記液滴を収容するステップと、
    　前記光源から、前記励起光を前記基板に入射するステップと、
    　前記基板が、導波路として、前記励起光を通過させるステップと、
    　前記基板の内部を通過する励起光から漏れ出す近接場光が、前記収容部に存在する蛍光物質の蛍光を励起するステップと
    　を備える蛍光観察方法。     A fluorescence observation method using the fluorescence observation apparatus according to any one of claims 1 to 8,
    Containing the droplets in the containing part;
    Making the excitation light incident on the substrate from the light source;
    The substrate passing the excitation light as a waveguide;
    And a step of exciting near-field light leaking from excitation light passing through the inside of the substrate to excite fluorescence of a fluorescent substance present in the housing portion.
  10. 　請求項３に記載の蛍光観察装置を用いた試料分析方法であって、
    　前記携帯端末は、前記カメラで撮影された蛍光を解析可能なアプリケーションソフトウエアを備えている
    　試料分析方法。     A sample analysis method using the fluorescence observation apparatus according to claim 3,
    The portable terminal includes application software capable of analyzing fluorescence captured by the camera.
PCT/JP2017/043394 2016-12-05 2017-12-04 Fluorescence observation device WO2018105538A1 (en)

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