JPWO2007108360A1 - Substance detection method and substance detection apparatus by surface-enhanced Raman scattering using small diameter blind tube, multiple substance detection device, blind tube - Google Patents

Substance detection method and substance detection apparatus by surface-enhanced Raman scattering using small diameter blind tube, multiple substance detection device, blind tube Download PDF

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JPWO2007108360A1
JPWO2007108360A1 JP2008506250A JP2008506250A JPWO2007108360A1 JP WO2007108360 A1 JPWO2007108360 A1 JP WO2007108360A1 JP 2008506250 A JP2008506250 A JP 2008506250A JP 2008506250 A JP2008506250 A JP 2008506250A JP WO2007108360 A1 JPWO2007108360 A1 JP WO2007108360A1
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丸井智敬
保田真友子
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株式会社アイ・ピー・ビー
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    • G—PHYSICS
    • G01—MEASURING; TESTING
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    • 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
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    • G01N21/658—Raman scattering enhancement Raman, e.g. surface plasmons
    • 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
    • G01N21/65—Raman scattering
    • G01N2021/651—Cuvettes therefore

Abstract

実用性に優れ、かつ、迅速な観測が可能な表面増強ラマン散乱(ＳＥＲＳ)による微量物質の検知方法と装置の提案を課題とする。盲部に金属塊が配設された盲管にアナライトとあらかじめ用意された金属微粒子コロイドとを混合する工程と、アナライトと金属微粒子コロイドの混合物を前記の盲管に注入する工程と、注入された盲管の前記混合物が前記の盲部金属塊と接する固液界面近傍にレーザ光を照射してラマン散乱光を観測する工程を有する表面増強ラマン散乱による微量物質の検知方法、およびその方法を実現する装置である。The object is to propose a method and apparatus for detecting trace substances by surface-enhanced Raman scattering (SERS), which has excellent practicality and enables rapid observation. A step of mixing an analyte and a metal fine particle colloid prepared in advance in a blind tube having a metal lump disposed in the blind part, a step of injecting a mixture of the analyte and the metal fine particle colloid into the blind tube, and an injection A method of detecting a trace substance by surface-enhanced Raman scattering, which has a step of observing Raman scattered light by irradiating a laser beam in the vicinity of a solid-liquid interface where the mixture of the formed blind tube is in contact with the metal mass of the blind portion, and the method It is a device that realizes.

Description

本発明は、表面増強ラマン散乱(ＳＥＲＳ)による微量物質検知方法ならびに装置である。本発明では金属粒子または金属膜および金属微粒子を懸濁したコロイドを用いて、アナライト・金属粒子・金属コロイドの３者が近接混在する部位にレーザ光を照射して得られる表面増強ラマン散乱光で微量アナライトを弁別検知する方法であって、特に本発明は、パスツール管とも称される細径の盲管を用いる。 The present invention is a method and apparatus for detecting trace substances by surface enhanced Raman scattering (SERS). In the present invention, surface-enhanced Raman scattering light obtained by irradiating a laser beam to a site where analyte, metal particle, and metal colloid are close to each other using a colloid in which metal particles or metal film and metal fine particles are suspended. In particular, the present invention uses a thin blind tube also called a Pasteur tube.

金や銀など貴金属ナノ粒子群のプラズモン効果による表面増強ラマン散乱（Surface-Enhanced Raman Scattering＝ＳＥＲＳ）を観測することでアナライトをラマン分析して微量物質を弁別検知することは公知である。ナノ粒子が存在しない状態ではラマン信号が微弱な極微量の物質でも、プラズモン効果によってラマン信号が増強され、弁別検知することが可能となる。ＳＥＲＳのプラズモン効果発現メカニズムは十分解明されていないが、有害物質センサーなどへの応用を目的に研究開発が行われている。ここで、弁別検知対象物質をアナライトとも呼ぶことにする。 It is known to detect and distinguish trace substances by Raman analysis of an analyte by observing surface-enhanced Raman scattering (SERS) due to the plasmon effect of a group of noble metal nanoparticles such as gold and silver. In the absence of nanoparticles, the Raman signal is enhanced by the plasmon effect even with a very small amount of material with a weak Raman signal, and discrimination detection is possible. Although the mechanism of SERS plasmon effect expression has not been fully elucidated, research and development has been conducted for the purpose of application to harmful substance sensors. Here, the discrimination detection target substance is also called an analyte.

金や銀など貴金属ナノ粒子を含有するＳＥＲＳ基材を滴下し乾燥することでＳＥＲＳ活性のある固体基板を得る方法は公知である。たとえば特許文献１は、液体中でＳＥＲＳ基材を分散させ固体表面に定着させ、高いＳＥＲＳ活性を示す基板の簡便な作成法を開示している。 A method for obtaining a SERS-active solid substrate by dropping a SERS base material containing noble metal nanoparticles such as gold and silver and drying it is known. For example, Patent Document 1 discloses a simple method for producing a substrate exhibiting high SERS activity by dispersing a SERS base material in a liquid and fixing it on a solid surface.

ナノ粒子群をセルフアセンブル（自己整列）させ強いＳＥＲＳ活性を得る工夫も研究されている。たとえばＬＢ膜（Langmuir-Blodgett膜）の製法に準じて界面にセルフアセンブルさせた金属微粒子群を掬い取って金属微粒子が整列したＳＥＲＳ基板作成する方法も公知である（特許文献３参照）。特許文献２も、金属微粒子の含有溶液中に浸した平板を所定速度で引き上げることを繰り返して粒子を周期的に整列堆積させたＳＥＲＳ基板を形成する方法である。 A device for obtaining strong SERS activity by self-assembling nanoparticle groups has also been studied. For example, a method of forming a SERS substrate in which metal fine particles are aligned by scooping a group of metal fine particles self-assembled at the interface in accordance with a method for producing an LB film (Langmuir-Blodgett film) is also known (see Patent Document 3). Patent Document 2 is also a method of forming a SERS substrate in which particles are periodically aligned and deposited by repeatedly pulling up a flat plate immersed in a solution containing metal fine particles at a predetermined speed.

ＬＢ膜を利用したナノ粒子整列の工夫以外にも、ＳＥＲＳ基板製法が多く提案されている。たとえば、水との親和性（親水・撥水性）をもつ表面を利用したＳＥＲＳ基板の製法（特許文献５参照）がある。 Many SERS substrate manufacturing methods have been proposed other than the device for aligning nanoparticles using an LB film. For example, there is a method for producing a SERS substrate using a surface having affinity (hydrophilicity / water repellency) with water (see Patent Document 5).

以上のような固相のＳＥＲＳ活性基板ではなく、貴金属ナノ粒子を懸濁させたコロイドをＳＥＲＳ基質（液状なので基板とは言わない）として、これにアナライトを液相混合したもので表面増強ラマン散乱を観測してアナライトを弁別検知することも公知である（特許文献４参照）。 The surface-enhanced Raman is not a solid-phase SERS active substrate as described above, but a colloid in which precious metal nanoparticles are suspended as a SERS substrate (it is not called a substrate because it is liquid), and an analyte is mixed in a liquid phase. It is also known to detect analytes by observing scattering (see Patent Document 4).

コロイドＳＥＲＳ基質は、固相ＳＥＲＳ基板よりも作成が容易であるが、分離沈殿しやすく、分離沈殿状態ではＳＥＲＳ活性が消失するという欠点がある。そのため、スメクタイトのような粘土質の物質でＳＥＲＳ基質を長期間安定化する方法（特許文献４参照）などが研究されている。 A colloidal SERS substrate is easier to produce than a solid phase SERS substrate, but is easily separated and precipitated, and has the disadvantage that the SERS activity disappears in the separated and precipitated state. Therefore, a method of stabilizing the SERS substrate for a long period of time with a clay-like substance such as smectite (see Patent Document 4) has been studied.

また極微量のアナライトの分析には毛細管現象（キャピラリ）を利用することも公知である（特許文献６参照）。毛細管現象（キャピラリ）中でアナライトとコロイドＳＥＲＳ基質を混合し、ＳＥＲＳのラマン信号を分析して極微量物質を弁別検知することも公知である。 It is also known to use a capillary phenomenon (capillary) for analysis of an extremely small amount of analyte (see Patent Document 6). It is also known to mix an analyte and a colloidal SERS substrate in a capillary phenomenon (capillary) and analyze the SERS Raman signal to discriminate and detect trace amounts of substances.

同様に、マイクロリットルレベルの極微量のアナライトとコロイドＳＥＲＳ基質を公知のマイクロ流路で流動混合して、ＳＥＲＳのラマン信号を分析して極微量物質を弁別検知することも公知である（特許文献７、非特許文献３参照）。 Similarly, it is also known that a very small amount of analyte at a microliter level and a colloidal SERS substrate are fluidly mixed in a known microchannel, and a Raman signal of SERS is analyzed to detect and detect a very small amount of substance (patent). Reference 7 and Non-Patent Document 3).

一方、特許文献８にて「プラズモンミラー効果」を利用した微量物質の検知方法ならびに装置が開示されている。ここでプラズモンミラー効果とは、照射された光エネルギーで表面プラズモンポラリトンを誘起する比較的清浄な金属面の近傍にナノ粒子群をセルフアセンブル（自己整列）させ、さらに強いＳＥＲＳ活性を得ることである。プラズモンミラー効果を得るための条件やその機序は明らかでないが、比較的清浄な金属面の近傍にナノ粒子群をセルフアセンブル（自己整列）させることが重要であるとされている（特許文献８参照）。   On the other hand, Patent Document 8 discloses a method and an apparatus for detecting a trace substance using the “plasmon mirror effect”. Here, the plasmon mirror effect is to obtain a stronger SERS activity by self-assembling a group of nanoparticles in the vicinity of a relatively clean metal surface that induces surface plasmon polaritons by irradiated light energy. . Although the conditions for obtaining the plasmon mirror effect and the mechanism thereof are not clear, it is said that it is important to self-assemble the nanoparticle group in the vicinity of a relatively clean metal surface (Patent Document 8). reference).

さらに一方、金属面上にナノ粒子群をセルフアセンブル（自己整列）させ、その上部にさらに金属蒸着する、または、金属面上にナノ粒子を二段に積層することでサンドイッチとした「Sandwich Substrates」または「Sandwich architecture」も公知である。かかるサンドイッチ構成で単層よりも強いＳＥＲＳ活性が得られる場合がある（特許文献９、非特許文献４、非特許文献５参照）。 On the other hand, the “Sandwich Substrates”, in which a group of nanoparticles is self-assembled (self-aligned) on a metal surface and further metal deposited on top of it, or nanoparticles are stacked in two layers on the metal surface. Or “Sandwich architecture” is also known. In such a sandwich configuration, SERS activity stronger than that of a single layer may be obtained (see Patent Document 9, Non-Patent Document 4, and Non-Patent Document 5).

特開2005-077362号公報「表面増強ラマン散乱活性基板の作成方法」（学校法人慶應義塾）Japanese Unexamined Patent Publication No. 2005-077362 "Method for creating surface-enhanced Raman scattering active substrate" (Keio University) 特開2004-170334号公報「ラマン散乱測定センサ及びその製造方法」（科学技術振興機構ほか）Japanese Laid-Open Patent Publication No. 2004-170334 "Raman Scattering Sensor and Manufacturing Method" (Japan Science and Technology Agency, etc.) 特開2005-233637号公報「金ナノロッド薄膜によるラマン分光分析」（科学技術振興機構）Japanese Laid-Open Patent Publication No. 2005-233637 “Raman Spectroscopic Analysis with Gold Nanorod Thin Film” (Japan Science and Technology Agency) 特開2004-205435号公報「標識色素を不要とする結合性分析対象物質の分析方法ならびにそれに用いる分析キット」（福岡隆夫）Japanese Unexamined Patent Publication No. 2004-205435 “Method for Analyzing Substances to be Analyzed for Binding That Do Not Need Labeling Dye and Analytical Kits Used In It” (Takao Fukuoka) 特開2005-219184号公報「単一分子ラマン分光用金属ナノ三角柱構造アレイ基板の形成方法及びそれによる単一分子分析法」（産業技術総合研究所）JP 2005-219184 “Metal Nano-Triangular Structure Array Substrate for Single-Molecular Raman Spectroscopy and Single-Molecule Analysis Using the Same” (National Institute of Advanced Industrial Science and Technology) 特許第3462339号公報「キャピラリー電気泳動用検出器」（日本電信電話株式会社）Japanese Patent No. 3462339 “Detector for capillary electrophoresis” (Nippon Telegraph and Telephone Corporation) 特表2005-507500号公報「マイクロ流体の表面増強共鳴ラマン散乱法による検出」（ユニバーシティ オブ ストラスクライドほか）JP 2005-507500 gazette "Detection of microfluidic surface enhanced resonance Raman scattering" (University of Strathclyde et al.) 国際公開WO2005 114298公報「OPTICAL SENSOR WITH LAYERED PLASMON STRUCTURE FOR ENHANCED DETECTION OF CHEMICAL GROUPS BY SERS」VP HODLINGS,LLCInternational Publication WO2005 114298 Publication "OPTICAL SENSOR WITH LAYERED PLASMON STRUCTURE FOR ENHANCED DETECTION OF CHEMICAL GROUPS BY SERS" VP HODLINGS, LLC 米国特許US6149868公報「Surface enhanced raman scattering from metal nanoparticle-analyte-noble metal substrate sandwiches 」（Michael J. Natan）US Patent US6149868 “Surface enhanced raman scattering from metal nanoparticle-analyte-noble metal substrate sandwiches” (Michael J. Natan) 梶川浩太郎(東工大)、三井圭太「局在プラズモン共鳴を利用したバイオセンシング」応用物理、 第72巻、第12号、p.1541-1544 (2003)Kotaro Ninagawa (Tokyo Tech), Yuta Mitsui “Biosensing Using Localized Plasmon Resonance” Applied Physics, Vol. 72, No. 12, p.1541-1544 (2003) 岡本隆之(理化学研究所)「金属ナノ粒子相互作用および、バイオセンサーに関する調査研究」平成14年度科学研究費補助金（基礎研究C）「表面プラズモンの局在化とその応用に関する調査研究」研究成果報告書 個別報告Takayuki Okamoto (RIKEN) “Research on metal nanoparticle interactions and biosensors” 2002 Grant-in-Aid for Scientific Research (Basic Research C) “Research on localization of surface plasmons and their application” Report Individual report Keir R, Igata E, Arundell M, Smith WE, Graham D, McHugh C, Cooper JM.「SERRS. In situ substrate formation and improved detection using microfluidics.」Anal Chem. 2002 Apr 1;74(7):1503-8.Keir R, Igata E, Arundell M, Smith WE, Graham D, McHugh C, Cooper JM. “SERRS. In situ substrate formation and improved detection using microfluidics.” Anal Chem. 2002 Apr 1; 74 (7): 1503-8 . Jacquitta K. Daniels and George Chumanov（Clemson University）「Nanoparticle-Mirror Sandwich Substrates for Surface-Enhanced Raman Scattering 」J. Phys. Chem. B, 109 (38), 17936 -17942, 2005.Jacquitta K. Daniels and George Chumanov (Clemson University) “Nanoparticle-Mirror Sandwich Substrates for Surface-Enhanced Raman Scattering” J. Phys. Chem. B, 109 (38), 17936 -17942, 2005. Orendorff, C. J. Gole, A. Sau, T. K. Murphy, C. J.（University of South Carolina）「Surface-enhanced Raman spectroscopy of Self-assembled monolayers: Sandwich architecture and nanoparticle shape dependence」Anal Chem. 2005 May 15;77(10):3261-6.Orendorff, CJ Gole, A. Sau, TK Murphy, CJ (University of South Carolina) “Surface-enhanced Raman spectroscopy of Self-assembled monolayers: Sandwich architecture and nanoparticle shape dependence” Anal Chem. 2005 May 15; 77 (10): 3261-6.

本発明の課題は、従来のＳＥＲＳ基板やＳＥＲＳ基質による微量物質の検知方法と装置よりも実用性に優れた方法と装置を提案するものである。すなわち、金属微粒子を複雑な工程を経て整列させた基板は用いず、コロイド状ＳＥＲＳ基質を利用するが基質の分離沈殿が問題にならない方法と装置を提案する。本発明は、金属粒子（または金属膜）と金属コロイドの両方を利用した有効な方法と装置の提案を課題とする。 An object of the present invention is to propose a method and apparatus that are more practical than conventional SERS substrates and methods and apparatuses for detecting trace substances using SERS substrates. That is, the present invention proposes a method and apparatus that uses a colloidal SERS substrate without using a substrate in which metal fine particles are arranged through complicated processes, but does not cause separation and precipitation of the substrate. An object of the present invention is to propose an effective method and apparatus using both metal particles (or metal films) and metal colloids.

本発明の方法は（請求項１、図１参照）、 アナライトと金属粒子と金属コロイドの３者が近接混在する部位にレーザ光を照射して得られる表面増強ラマン散乱光で微量アナライトを弁別検知する方法であって、盲部に金属塊が配設された盲管、または盲部内面に金属膜が配設された盲管にアナライトとあらかじめ用意された金属微粒子コロイドとを混合する工程と、アナライトと金属微粒子コロイドの混合物を前記の盲管に注入する工程と、注入された盲管の前記混合物が前記の盲部金属塊と接する固液界面近傍にレーザ光を照射してラマン散乱光を観測する工程を有する表面増強ラマン散乱による微量物質の検知方法である。 According to the method of the present invention (see claim 1 and FIG. 1), a small amount of analyte is generated by surface-enhanced Raman scattering light obtained by irradiating laser light to a site where the analyte, metal particles, and metal colloid are close to each other. A method for detecting discrimination, in which an analyte is mixed with a colloid prepared in advance in a blind tube in which a metal lump is disposed in the blind portion or a blind tube in which a metal film is disposed on the inner surface of the blind portion. A step of injecting a mixture of the analyte and the metal fine particle colloid into the blind tube, and irradiating a laser beam near the solid-liquid interface where the mixture of the injected blind tube contacts the blind metal mass. This is a method for detecting a trace substance by surface-enhanced Raman scattering, which has a step of observing Raman scattered light.

本発明の盲管の内径には限定がないが、アナライトは数μリッターの少量が望ましいので、内径は１ミリメーター前後が好適である。また毛細管現象（キャピラリ）で混合物を吸引させ、吸引後に開口部を閉塞して盲部としてもよく、その場合は内径は100ミクロンメートルのオーダである。 There is no limitation on the inner diameter of the blind tube of the present invention, but since the analyte is preferably a small amount of several μL, the inner diameter is preferably around 1 mm. Alternatively, the mixture may be sucked by capillary action (capillary), and the opening may be closed after suction to form a blind portion. In this case, the inner diameter is on the order of 100 microns.

キャピラリを利用しない場合、盲部へアナライトと金属微粒子コロイドの混合物を注入するには、盲部近傍に外部から音波振動を含む機械的振動を付与すればよい。すなわち（請求項２）、アナライトと金属微粒子コロイドの混合物を盲管に注入する工程の後に、盲管に振動を与えてアナライトと金属微粒子コロイドの混合物を盲部に誘導する工程を有するとすればよい。図２の２が盲管を振動させる手段（振動によって盲管内の盲部にＡとＣの混合物を誘導する手段）である。図３は盲管を横に寝かせた状態でのラマン散乱光の観測工程、図４は盲管を立てた状態でのラマン散乱光の観測工程、図５と図６は観測実施例、図７は実施例に用いた盲管盲部写真である。 When the capillary is not used, in order to inject the mixture of the analyte and the metal fine particle colloid into the blind portion, mechanical vibration including sound wave vibration may be applied from the outside in the vicinity of the blind portion. That is, (Claim 2) having, after the step of injecting the mixture of the analyte and the metal fine particle colloid into the blind tube, the step of applying vibration to the blind tube to induce the mixture of the analyte and the metal fine particle colloid to the blind portion do it. 2 in FIG. 2 is means for vibrating the blind tube (means for guiding the mixture of A and C to the blind portion in the blind tube by vibration). 3 is an observation process of Raman scattered light in a state where the blind tube is laid sideways, FIG. 4 is an observation process of Raman scattered light in a state where the blind tube is erected, FIGS. 5 and 6 are observation examples, and FIG. These are photographs of the cecum and blind part used in the examples.

本発明の方法では（請求項３）、アナライトとあらかじめ用意された金属微粒子コロイドとを混合する工程の前に、金属塊の盲部における位置、または金属膜の盲部内面における位置を計測し、かつ、該計測位置に基く盲管の位置にマーカーを配設して盲管の観測で前記計測位置情報を読み取れるようにする工程を有するのが好ましい。あるいは、該計測位置情報を記憶した記憶媒体を盲管に配設して盲管の観測で前記計測位置情報を読み取れるようにする工程を有するのが好ましい。これらの態様は本方法によるデバイスの説明にて後述する。 In the method of the present invention (Claim 3), before the step of mixing the analyte and the metal fine particle colloid prepared in advance, the position in the blind part of the metal mass or the position in the blind part inner surface of the metal film is measured. In addition, it is preferable to include a step of arranging a marker at the position of the blind tube based on the measurement position so that the measurement position information can be read by observation of the blind tube. Alternatively, it is preferable to have a step of arranging a storage medium storing the measurement position information in the blind tube so that the measurement position information can be read by observation of the blind tube. These aspects will be described later in the description of the device according to the present method.

本発明は、従来のＳＥＲＳ基板やＳＥＲＳ基質による微量物質の検知方法と装置よりも実用性に優れる。なぜなら、ガラスなどの盲管とあらかじめ製作しておいた金属微粒子コロイドのみで検知が実施できるので、低コストである。金属微粒子を複雑な工程を経て整列させた基板は用いず、コロイド状ＳＥＲＳ基質を利用するが基質の分離沈殿が問題にならない。盲管の内面に金属薄膜を配設するにしても、費用は廉価である。大量多種のアナライトの自動分析に適する技術であるといえる。 The present invention is more practical than conventional SERS substrates and methods and devices for detecting trace substances using SERS substrates. This is because the detection can be carried out only by using a blind tube such as glass and a colloidal metal particle prepared in advance, so that the cost is low. A substrate in which metal fine particles are arranged through a complicated process is not used and a colloidal SERS substrate is used, but separation and precipitation of the substrate does not become a problem. Even if a metal thin film is disposed on the inner surface of the blind tube, the cost is low. It can be said that this technique is suitable for automatic analysis of a large amount of various analytes.

本発明の盲管説明図。（ａ）は金属塊である金属粒子Ｐを盲部に配設した例、（ｂ）は（ａ）同様であり、金属粒子の径が比較的小さい例。（ｃ）は盲部内面に金属膜Ｓを配設した例、（ｄ）は（ｃ）同様であり、盲管側面からのラマン計測に支障が出ないように金属膜Ｓの配設部位が不連続に分散している例。Explanatory drawing of the blind tube of this invention. (A) is an example in which metal particles P, which are metal lumps, are arranged in the blind portion, and (b) is an example in which the diameter of the metal particles is relatively small as in (a). (C) is an example in which the metal film S is arranged on the inner surface of the blind part, and (d) is the same as (c), and the arrangement part of the metal film S is arranged so as not to interfere with the Raman measurement from the side surface of the blind tube. An example of discontinuous dispersion. 本発明の検知方法のフロー説明図。２は振動によって盲管内の盲部にＡとＣの混合物を誘導する手段で音波を含む機械振動を盲管に与える超音波振動子または偏芯回転子を有する振動手段。Flow explanatory drawing of the detection method of this invention. 2 is a means for inducing a mixture of A and C to the blind part in the blind tube by vibration, and a vibration means having an ultrasonic vibrator or an eccentric rotor for applying mechanical vibration including sound waves to the blind tube. 混合物ACが盲部金属塊と接する固液界面近傍にレーザ光を照射してラマン散乱光を観測する工程の説明であって、盲管を水平にした例。This is an explanation of the process of observing Raman scattered light by irradiating laser light near the solid-liquid interface where mixture AC is in contact with the blind metal block, and shows an example in which the blind tube is horizontal. 図３同様にラマン散乱光を観測する工程の説明であって、盲管を垂直にした例。（ａ）は焦点位置が高く、混合物ACが盲部金属塊と接していない部位、（ｂ）は混合物ACが盲部金属塊と接している部位。It is description of the process of observing Raman scattered light similarly to FIG. 3, Comprising: The example which made the blind pipe vertical. (A) is a site where the focal position is high and the mixture AC is not in contact with the blind metal mass, and (b) is a site where the mixture AC is in contact with the blind metal mass. 本発明の実施例のデータであって、Ｐｅａｋ１はアナライトと金属コロイドの２者が近接混在する部位のラマンデータ、Ｐｅａｋ２はアナライトと金属コロイドの２者が近接混在する部位（ｄａｔａ１）のラマンデータ、Ｐｅａｋ２アナライトと金属粒子と金属コロイドの３者が近接混在する部位（ｄａｔａ２）のラマンデータである。なおアナライトはアデノシン。The data of the example of the present invention, Peak 1 is the Raman data of the site where the analyte and the metal colloid are in close proximity, and Peak 2 is the Raman data of the site where the analyte and the metal colloid are in close proximity (data 1). Data, Raman data of a site (data 2) where Peak 2 analyte, metal particle, and metal colloid are close to each other. The analyte is adenosine. 図５のＡｒｅａ１およびＡｒｅａ２の典型的なスペクトル（ｄａｔａ１とｄａｔａ２）と別測定したアナライトと金属の２者が近接混在する部位のラマンデータ（ｄａｔａ０）のスペクトルグラフ。本案の実施結果であるｄａｔａ２の優位性は明らかである。FIG. 6 is a spectrum graph of Raman data (data0) of a region where two analytes, ie, an analyte and a metal, measured separately from the typical spectra (data1 and data2) of Area1 and Area2 in FIG. The superiority of data2, which is the implementation result of this proposal, is clear. 盲管の盲部に配設した金属粒子の例図Example of metal particles placed in the blind part of the blind tube 盲部に金属塊が配設された複数本の盲管１および／または盲部内面に金属膜が配設された複数本の盲管１を並列配列したデバイスＤの説明図。ｌｅｖｅｌ_１・・ｌｅｖｅｌ_ｎは複数の盲管の第１・・第ｎの盲管盲部の金属塊または金属膜の位置含む水平面レベル、ｄ１・・ｄｎはたとえばラマン計測手段の光学系基準部位からｌｅｖｅｌ_１・・ｌｅｖｅｌ_ｎに至る距離であって、光学系の光学焦点はすべて第１・・第ｎの盲管盲部の金属塊または金属膜の位置含む水平面レベルにあるように各盲管を配設する。Explanatory drawing of the device D which arranged in parallel the multiple blind tubes 1 by which the metal lump was arrange | positioned by the blind part, and / or the multiple blind tubes 1 by which the metal film was arrange | positioned by the blind part inner surface. level_1 ·· level_n is the horizontal plane level including the position of the metal mass or metal film of the first and nth blind tube blind portions of the plurality of blind tubes, and d1 ·· dn is, for example, level_1 · Each blind tube is arranged so that it is a distance to level_n and the optical focal point of the optical system is at the level of a horizontal plane including the position of the metal mass or metal film of the first and nth blind tube blinds. 金属塊（金属膜）の盲部における位置があらかじめ計測され、金属塊（金属膜）の盲部における位置情報を記憶する記憶手段である記憶媒体が配設された盲管の例。計測位置の基準として盲管盲部に配設された光学マーカーＭに対する位置情報Ｂ１、Ｂ２、Ｂ３が符号化手段４で符号化され印字手段５でたとえばバーコードである９（盲管に印字されたＢ１、Ｂ２、Ｂ３を符号化したコード）として印字される。An example of a blind tube in which a position of a metal lump (metal film) in a blind part is measured in advance and a storage medium serving as storage means for storing position information in the blind part of the metal lump (metal film) is provided. Position information B1, B2, and B3 for the optical marker M disposed in the blind portion of the blind canal as a reference for the measurement position is encoded by the encoding means 4, and the printing means 5 is, for example, a barcode 9 (printed on the blind pipe). (B1, B2, and B3 encoded codes). 金属塊（金属膜）の盲部における位置があらかじめ計測されており、該計測位置に基く盲管の位置にマーカーが配設された盲管の例であって、図９でいうところの位置情報Ｂ１、Ｂ２、Ｂ３がマーカー配設位置自体から把握される。Ｍ１は実測によって金属塊または金属膜の位置の実測後に盲管盲部に配設された第１光学マーカー、Ｍ２は実測によって金属塊または金属膜の位置の実測後に盲管盲部に配設された第２光学マーカー、ＭＬは金属塊または金属膜の位置から離隔した所定の距離（ラマン測定の障害にならぬようマーカー位置を離隔）である。FIG. 9 shows an example of a blind tube in which the position of the metal lump (metal film) in the blind portion is measured in advance, and a marker is arranged at the position of the blind tube based on the measured position. B1, B2, and B3 are grasped from the marker arrangement position itself. M1 is a first optical marker arranged in the blind tube blind portion after the actual measurement of the position of the metal lump or metal film, and M2 is disposed in the blind tube blind portion after the actual measurement of the position of the metal lump or metal film. The second optical marker ML is a predetermined distance away from the position of the metal block or metal film (the marker position is separated so as not to obstruct Raman measurement). 盲管の端部に研削しろ７があり、その研削しろ７が盲部の金属塊または盲部内面の金属膜の位置に応じて研削され、複数の盲管が基準面に研削された面をあわせて並列配列される例。７は金属塊または金属膜位置のレベリングのための盲管底部の研削しろ、８はレベリングのため研削されたあとの盲管底部、Gは レーザ光照射焦点に対応した基準面、Hは 実際のレーザ光照射の焦点面のひとつであって、金属塊または金属膜の位置含む水平面最高位レベル、Ｊは基準面Ｇの実際の焦点面Ｈに対する一定のレベル差である。There is a grinding allowance 7 at the end of the blind tube, and the grinding allowance 7 is ground according to the position of the metal mass of the blind part or the metal film on the inner surface of the blind part, and the surface where a plurality of blind pipes are ground to the reference surface An example of parallel arrangement. 7 for grinding the bottom of the blind tube for leveling the metal block or metal film, 8 for the bottom of the blind tube after grinding for leveling, G for the reference plane corresponding to the laser irradiation focus, and H for the actual One of the focal planes of the laser beam irradiation, the highest level in the horizontal plane including the position of the metal block or metal film, J is a certain level difference between the reference plane G and the actual focal plane H. 盲管端部に円錐オス型状の基準形状物７Ａがあり、レーザ光照射焦点に対応した基準面を有するとともに該基準面に前記の円錐オス型と嵌合する円錐メス型が開口されていて、前記円錐メス型の深さは盲部の金属塊または盲部内面の金属膜の位置に応じて決定されている。それらによって、複数の盲管が前記円錐メス型開口に盲管端部の円錐オス型状基準形状物７Ａを嵌合して並列配列される。７Ａは 金属塊または金属膜位置のレベリングのための円錐オス型状の基準形状物。There is a conical male-shaped reference shape object 7A at the end of the blind tube, which has a reference surface corresponding to the focal point of laser light irradiation, and a conical female shape that fits the conical male shape is opened on the reference surface. The depth of the cone-female type is determined according to the position of the blind metal block or the metal film on the inner surface of the blind part. As a result, a plurality of blind tubes are arranged in parallel by fitting the conical male reference shape 7A at the end of the blind tube into the conical female-type opening. 7A is a conical male-shaped reference shape for leveling a metal lump or metal film position. 本案の盲管の態様例であって、（ａ）は金属材料をガラスの空盲管への投入、（ｂ）はガラスの空盲管の盲部の加熱による金属溶融、（ｃ）は盲管盲部を加圧狭窄し、金属脱落を防ぐ狭窄部形成加工、の各工程を示す。It is an example of a blind tube of the present plan, in which (a) is a method in which a metal material is charged into a glass empty blind tube, (b) is a metal melted by heating the blind portion of the glass empty blind tube, and (c) is blind. Each process of forming a constriction part for pressurizing and constricting the tube blind part and preventing metal dropout is shown.

符号の説明Explanation of symbols

１ 盲部に金属塊が配設された盲管または盲部内面に金属膜が配設された盲管
２ 盲管を振動させる手段（振動によって盲管内の盲部にＡとＣの混合物を誘導する手段）
３ Ｂ１、Ｂ２、Ｂ３データを入力し符号化手段へ出力する手段
４ 符号化手段
５ 印字手段
６ 複数の盲管１を並列配設した微量物質検知チップ
７ 金属塊または金属膜位置のレベリングのための盲管底部の研削しろ
７Ａ 金属塊または金属膜位置のレベリングのための円錐オス型状の基準形状物
８ レベリングのため研削されたあとの盲管底部
９ 盲管に印字されたＢ１、Ｂ２、Ｂ３を符号化したコード
Ａ アナライト
ＡＣ アナライトと金属コロイドの混合物
ＡＣＰ ＡＣがＰ（または金属膜）と近接する部位
Ａｒｅａ１ アナライトと金属コロイドの２者が近接混在する部位
Ａｒｅａ２ アナライトと金属粒子と金属コロイドの３者が近接混在する部位
Ｂ１ Ｍから最も近いＰの表面部位までの距離
Ｂ２ Ｍから最も遠いＰの表面部位までの距離
Ｂ３ ＭからＦまでの距離
Ｃ 金属コロイド
Ｄ 盲部に金属塊および／または金属膜が配設された複数本の盲管１を並列配列したデバイス
ｄ１ たとえばラマン計測手段の光学系基準部位からｌｅｖｅｌ_１に至る距離
ｄ２ たとえばラマン計測手段の光学系基準部位からｌｅｖｅｌ_２に至る距離
ｄ３ たとえばラマン計測手段の光学系基準部位からｌｅｖｅｌ_３に至る距離
ｄｎ たとえばラマン計測手段の光学系基準部位からｌｅｖｅｌ_４に至る距離
ｄａｔａ０ アナライトと金属の２者が近接混在する部位のラマンデータ
ｄａｔａ１ アナライトと金属コロイドの２者が近接混在する部位のラマンデータ
ｄａｔａ２ アナライトと金属粒子と金属コロイドの３者が近接混在する部位のラマンデータ
Ｆ Ｐ同士が適度に近接してＳＥＲＳ効果が顕著である部位
G レーザ光照射焦点に対応した基準面
H 実際のレーザ光照射の焦点面のひとつであって、金属塊または金属膜の位置含む水平面最高位レベル
Ｊ 基準面Ｇの実際の焦点面Ｈに対する一定のレベル差
ｌｅｖｅｌ_１ 複数の盲管の第１の盲管盲部の金属塊または金属膜の位置含む水平面レベル
ｌｅｖｅｌ_２ 複数の盲管の第２の盲管盲部の金属塊または金属膜の位置含む水平面レベル
ｌｅｖｅｌ_３ 複数の盲管の第３の盲管盲部の金属塊または金属膜の位置含む水平面レベル
ｌｅｖｅｌ_ｎ 複数の盲管の第ｎの盲管盲部の金属塊または金属膜の位置含む水平面レベル
Ｍ 計測位置の基準として盲管盲部に配設された光学マーカー
Ｍ１ 実測によって金属塊または金属膜の位置の実測後に盲管盲部に配設された第１光学マーカー
Ｍ２ 実測によって金属塊または金属膜の位置の実測後に盲管盲部に配設された第２光学マーカー
ＭＬ 金属塊または金属膜の位置から離隔した所定の距離（ラマン測定の障害にならぬようマーカー位置を離隔）
Ｐ 金属粒子
Ｐｅａｋ１ ｄａｔａ１におけるアデノシン（アナライト）の特徴ピーク
Ｐｅａｋ２ ｄａｔａ２におけるアデノシン（アナライト）の特徴ピーク
ＰＬ１ 第１の盲管盲部の金属塊または金属膜の位置含む水平面最高位レベル
ＰＬ２ 第２の盲管盲部の金属塊または金属膜の位置含む水平面最高位レベル
ＰＬ３ 第３の盲管盲部の金属塊または金属膜の位置含む水平面最高位レベル
ＰＬＵ 盲管盲部の金属塊または金属膜の位置含む水平面最高位レベル
ＰＬＬ 盲管盲部の金属塊または金属膜の位置含む水平面最低位レベル
QＬ１ ＰＬ１レベルに対応したレベル 嵌合するメス型円錐体に対応するものである。
QＬ２ ＰＬ２レベルに対応したレベル 嵌合するメス型円錐体に対応するものである。
QＬ３ ＰＬ３レベルに対応したレベル 嵌合するメス型円錐体に対応するものである。
Ｓ 盲部内面の金属膜1 A blind tube with a metal lump disposed in the blind part or a blind tube with a metal film disposed on the inner surface of the blind part 2 A means for vibrating the blind tube (vibration induces a mixture of A and C to the blind part in the blind tube Means)
3 Means for inputting B1, B2, B3 data and outputting them to encoding means 4 Encoding means 5 Printing means 6 Trace substance detection chip 7 in which a plurality of blind tubes 1 are arranged in parallel 7 For leveling of metal lump or metal film position 7A Grinding allowance at the bottom of the blind tube 7A Conical male shaped reference shape 8 for leveling the metal lump or metal film 8 Blind tube bottom 9 after grinding for leveling B1, B2, printed on the blind tube A code that encodes B3 Analyte AC A mixture of analyte and metal colloid ACP AC is in the vicinity of P (or metal film) Area 1 Area 2 where analyte and metal colloid are in close proximity Area 2 Analyte and metal particles The distance B2 M from the part B1 M where the three of the metal colloid and the metal colloid are in close proximity to the surface part of the nearest P to the surface part of the farthest P To C. Metal colloid D Device d1 in which a plurality of blind tubes 1 each having a metal lump and / or a metal film arranged in the blind portion are arranged in parallel. For example, a distance from the optical system reference portion of the Raman measuring means to level_1. d2 For example, the distance from the optical system reference part of the Raman measurement means to level_2 For example, the distance from the optical system reference part of the Raman measurement means to level_3 dn For example, the distance from the optical system reference part of the Raman measurement means to level_4 data0 Analyte and metal Raman data data1 of the site where the two of the two are closely mixed Raman data data2 of the site where the two of the analyte and the metal colloid are closely mixed Raman data FP of the site where the three of the analyte, the metal particle and the metal colloid are mixed together Sites where the SERS effect is prominent due to moderate proximity
G Reference plane corresponding to laser beam irradiation focus
H One of the focal planes of actual laser light irradiation, which is the highest level in the horizontal plane including the position of the metal lump or metal film.
level_1 horizontal plane level including the position of the metal mass or metal film of the first blind tube of the plurality of blind tubes level_2 horizontal plane level level_3 including the position of the metal tube or metal film of the second blind tube of the plurality of blind tubes Level level level_n including the position of the metal mass or metal film of the third blind tube of the cephalic tube Level level n including the position of the metal mass or metal film of the nth blind tube of the plurality of blind tubes Optical marker M1 disposed in the blind canal as a reference The first optical marker M2 disposed in the blind canal after measurement of the position of the metal lump or metal film by actual measurement of the position of the metal lump or metal film by actual measurement Second optical marker ML placed in the blind part of the blind tube after actual measurement A predetermined distance apart from the position of the metal block or metal film (the marker position is separated so as not to obstruct the Raman measurement)
P metal particle Peak 1 data 1 adenosine (analyte) feature peak Peak 2 data 2 adenosine (analyte) feature peak PL 1 first culm blind metal mass or metal film location level PL 2 second level Level 3 of the horizontal plane including the position of the metal mass or metal film of the cecum canal. 3rd level of the horizontal plane including the position of the metal mass or metal film of the 3rd culm blind PLU Horizontal plane highest level including position PLL Horizontal plane lowest level including the position of the metal mass or metal film of the blind canal
QL1 A level corresponding to the PL1 level. This corresponds to a female cone to be fitted.
QL2 Level corresponding to PL2 level Corresponds to the female cone to be fitted.
QL3 Level corresponding to PL3 level Corresponds to the female cone to be fitted.
S Metal film on the inner surface of the blind part

本発明による装置は（請求項５）、盲部に金属塊が配設された盲管、または盲部内面に金属膜が配設された盲管と、前記盲管にレーザ光を照射してラマン散乱光を観測する手段と、アナライトと金属微粒子コロイドの混合物が注入された前記盲管にて、該混合物と金属塊または金属膜とが接する固液界面近傍にレーザ光の焦点合わせをする手段とを有するものである。 The device according to the present invention (Claim 5) is a blind tube in which a metal lump is disposed in the blind part, or a blind tube in which a metal film is disposed on the inner surface of the blind part, and the blind tube is irradiated with laser light. The laser beam is focused in the vicinity of the solid-liquid interface where the mixture and the metal lump or metal film are in contact with the means for observing the Raman scattered light and the blind tube into which the mixture of the analyte and the metal fine particle colloid is injected. Means.

また本発明による装置は（請求項６）、盲管に振動を与えてアナライトと金属微粒子コロイドの混合物を盲部に誘導する手段を兼備したものでもよい。 Further, the apparatus according to the present invention (Claim 6) may be provided with means for giving vibration to the blind tube and guiding the mixture of the analyte and the metal fine particle colloid to the blind part.

また本発明による装置は（請求項７）、アナライトとあらかじめ用意された金属微粒子コロイドとを混合する工程の前に、金属塊の盲部における位置、または金属膜の盲部内面における位置があらかじめ計測されており、該計測位置に基く盲管の位置にマーカーが配設された盲管であって、その検知装置が、前記マーカー位置の読み取り手段を兼備するとともに、固液界面近傍にレーザ光の焦点合わせをする手段が、前記読み取り手段で読み取ったマーカー位置に基いて固液界面を判別し焦点合わせをするものである。（図１０および図１０の簡単な説明参照） Further, the apparatus according to the present invention (Claim 7) is arranged such that the position of the metal lump in the blind part or the position of the metal film on the inner surface of the blind part is previously set before the step of mixing the analyte and the prepared metal fine particle colloid. A blind tube in which a marker is disposed at a position of the blind tube based on the measurement position, and the detection device also has a means for reading the marker position, and a laser beam near the solid-liquid interface. The focusing means discriminates the solid-liquid interface based on the marker position read by the reading means and performs the focusing. (See the brief description of FIG. 10 and FIG. 10)

またここで、マーカーの位置は（請求項８）、盲管の管軸に直交する面で、かつ、盲部の金属塊または盲部内面の金属膜を含む面群にて、最も盲管開放端に近い面に含まれる位置（図４のＰＬＵ参照）、および／または最も盲管盲端に近い面の位置（図４のＰＬＬ参照）に対応した位置が好ましい。 In this case, the marker is located at the plane that is perpendicular to the tube axis of the blind tube and that includes the metal block of the blind portion or the metal film of the inner surface of the blind portion. The position corresponding to the position included in the surface close to the end (see PLU in FIG. 4) and / or the position of the surface closest to the blind canal end (see PLL in FIG. 4) is preferable.

また他の態様として（請求項９）、計測位置情報を記憶する記憶手段と、前記記憶手段の情報の読み取り手段を兼備するとともに、固液界面近傍にレーザ光を焦点合わせをする手段が、前記読み取り手段で読み取った金属塊の盲部における位置情報、または金属膜の盲部内面における位置情報に基づいて固液界面を判別し焦点合わせをするものでもよい。特に（請求項１０）、盲管に計測位置情報を記憶する記憶手段である記憶媒体が配設され、記憶手段の情報の読み取り手段が、盲管に配設された前記記憶媒体の情報読み取り手段であるのが好適である（図９および図９の簡単な説明参照）。 As another aspect (claim 9), the storage means for storing the measurement position information and the information reading means for the storage means, and the means for focusing the laser beam in the vicinity of the solid-liquid interface, The solid-liquid interface may be discriminated and focused based on the position information on the blind portion of the metal block read by the reading means or the position information on the inner surface of the blind portion of the metal film. In particular (claim 10), a storage medium which is storage means for storing measurement position information in the blind tube is provided, and information reading means in the storage means is information reading means in the storage medium provided in the blind tube. (Refer to the brief description of FIGS. 9 and 9).

さらに本発明は、複数のサンプリング液に潜在する微量アナライトを弁別検知する複数物質検知デバイスを構成するものであってもよい。ここで、複数本の盲管内部の金属の位置が、盲管の軸方向に概一致し、個々の固液界面近傍にレーザ光の焦点合わせを略すことができるようにすることが望ましい。 Further, the present invention may constitute a multi-substance detection device that discriminates and detects a trace amount of analyte latent in a plurality of sampling solutions. Here, it is desirable that the positions of the metals inside the plurality of blind tubes are approximately coincident with the axial direction of the blind tubes so that the focusing of the laser light can be omitted in the vicinity of each solid-liquid interface.

すなわち（請求項１１）、盲部に金属塊が配設された複数本の盲管および／または盲部内面に金属膜が配設された複数本の盲管を次の並列条件で並列配列したデバイスであり、該並列条件は；１つの盲管管軸に直交する面で、かつ、盲部の金属塊または盲部内面の金属膜を含む面群にて、最も盲管開放端に近い面または最も盲管盲端に近い面が他の盲管管軸に直交する面で、かつ、盲部の金属塊または盲部内面の金属膜を含む面群に含まれることである（図８参照）。 That is, (Claim 11), a plurality of blind tubes in which a metal lump is disposed in the blind portion and / or a plurality of blind tubes in which a metal film is disposed on the inner surface of the blind portion are arranged in parallel under the following parallel condition: The parallel condition is: a plane that is orthogonal to one blind tube axis and that is closest to the open end of the blind tube in a group of surfaces including a blind metal mass or a metal film on the blind inner surface Alternatively, the surface closest to the blind canal is included in a plane perpendicular to the axis of the other canal tube and including the blind metal mass or the metal film on the inner surface of the blind (see FIG. 8). ).

これは具体的には、以下の構造を有する複数物質検知デバイスである（請求項１２、図１１および図１１の簡単な説明参照）。すなわち、１）並列配列前の盲管の端部に研削しろがあること。２）複数物質検知デバイスが、レーザ光照射焦点に対応した基準面を有すること。３）盲管端部の研削しろが盲部の金属塊または盲部内面の金属膜の位置に応じて研削されていること。４）複数の盲管が前記基準面に研削された面をあわせて並列配列されていること。 Specifically, this is a multi-substance detection device having the following structure (see claims 12, 11 and 11). That is, 1) There must be a margin for grinding at the end of the blind tubes before the parallel arrangement. 2) The multi-substance detection device has a reference plane corresponding to the laser beam irradiation focus. 3) The margin for grinding at the end of the blind tube is ground according to the position of the metal mass of the blind portion or the metal film on the inner surface of the blind portion. 4) A plurality of blind tubes are arranged in parallel with the ground surface ground to the reference surface.

また別の具体的態様は（請求項１３、図１２および図１２の簡単な説明参照）、１）並列配列前の盲管端部に円錐オス型状の基準形状物があること。２）複数物質検知デバイスが、レーザ光照射焦点に対応した基準面を有するとともに該基準面に前記の円錐オス型と嵌合する円錐メス型が開口されていること。３）前記円錐メス型の深さは盲部の金属塊または盲部内面の金属膜の位置に応じて決定されていること。４）複数の盲管が前記円錐メス型開口に盲管端部の円錐オス型状基準形状物を嵌合して並列配列されていること。 Another specific aspect (refer to the brief description of claims 13, 12 and 12), 1) There is a conical male-shaped reference shape at the end of the blind tube before the parallel arrangement. 2) The multiple substance detection device has a reference surface corresponding to the focal point of the laser beam irradiation, and a conical female type that fits with the conical male type is opened on the reference surface. 3) The depth of the conical knife type is determined in accordance with the position of the metal block of the blind part or the metal film on the inner surface of the blind part. 4) A plurality of blind tubes are arranged in parallel by fitting a conical male-shaped reference shape at the end of the blind tube into the conical female opening.

本発明の盲管の好適な態様をその製法とともに図１３に示す。すなわち（請求項１４）、盲部に金属が配設された盲管であって、盲管に金属材を投入する工程（図１３（ａ））の後に、該盲管盲部の金属を溶融温度以上に加熱する工程（図１３（ｂ））によって、該盲管盲部内面に投入金属材が溶融固着して配設された盲管が好適である。 A preferred embodiment of the blind tube of the present invention is shown in FIG. That is, (Claim 14) is a blind tube in which metal is disposed in the blind part, and the metal in the blind part is melted after the step of introducing a metal material into the blind tube (FIG. 13 (a)). It is preferable to use a blind tube in which the metal material is melted and fixed on the inner surface of the blind portion of the blind tube by the step of heating above the temperature (FIG. 13B).

また（請求項１５）、同様の金属材投入工程と加熱工程によって、盲管盲部内面に前記投入金属材が溶融延展した薄膜が配設された盲管も好適である。 (Claim 15) A blind tube in which a thin film in which the charged metal material is melt-extended is disposed on the inner surface of the blind tube blind portion by the same metal material charging step and heating step is also suitable.

さらにまた（請求項１６）、盲部に金属が配設された盲管であって、金属材料を盲管に配設する工程の後に、該盲管金属配設部の開放端側を盲管外部から加圧狭窄する工程（図１３（ｃ））によって、盲管金属配設部の盲管内径よりも小さな内径である部位を金属配設部の開放端側に形成してもよい。この小さな内径部によって、加熱による溶融固着や溶融延展しなくても金属材が盲部から離脱しにくくなるので好適である。 Furthermore, (Claim 16) is a blind tube in which metal is disposed in the blind portion, and the open end side of the blind tube metal disposed portion is disposed in the blind tube after the step of disposing the metal material in the blind tube. A portion having an inner diameter smaller than the inner diameter of the blind tube metal placement portion may be formed on the open end side of the metal placement portion by the step of pressure constriction from the outside (FIG. 13C). This small inner diameter portion is preferable because it is difficult for the metal material to be detached from the blind portion without being melt-fixed or melt-extended by heating.

なお、盲管盲部の金属を溶融温度以上に加熱する工程にては、金属が金のような比較的溶融温度が低いものであれば盲管を外部から火炎加熱（図１３参照）すればよい。 In the process of heating the blind tube metal to the melting temperature or higher, if the metal has a relatively low melting temperature such as gold, the blind tube can be heated from outside (see FIG. 13). Good.

もちろん、盲管部材を耐熱性のもの（耐熱ガラス）にすると加熱しやすいし、盲管盲部の金属のみをレーザ加熱などの局部加熱手段で局部加熱し、盲管材溶融を回避するようにしてもよい。さらに、金属の全部または一部を溶融点の低い低融点合金として、該合金のみが溶融するようにしてもよい。 Of course, if the blind tube member is made of heat resistant material (heat resistant glass), it will be easy to heat, and only the metal in the blind tube blind region will be heated locally by local heating means such as laser heating to avoid melting the blind tube material. Also good. Furthermore, all or part of the metal may be a low melting point alloy having a low melting point, and only the alloy may be melted.

Claims (16)

アナライトと金属粒子と金属コロイドの３者が近接混在する部位にレーザ光を照射して得られる表面増強ラマン散乱光で微量アナライトを弁別検知する方法であって、盲部に金属塊が配設された盲管、または盲部内面に金属膜が配設された盲管に、アナライトとあらかじめ用意された金属微粒子コロイドとを混合する工程と、アナライトと金属微粒子コロイドの混合物を前記の盲管に注入する工程と、注入された盲管の前記混合物が前記の盲部金属塊と接する固液界面近傍にレーザ光を照射してラマン散乱光を観測する工程を有する表面増強ラマン散乱による微量物質の検知方法。   A method of discriminating and detecting a small amount of analyte by surface-enhanced Raman scattering light obtained by irradiating laser light to a site where the analyte, metal particles, and metal colloid are close to each other. A step of mixing an analyte and a metal fine particle colloid prepared in advance in a blind tube or a blind tube having a metal film disposed on the inner surface of the blind part, and a mixture of the analyte and the metal fine particle colloid By surface-enhanced Raman scattering, which includes a step of injecting into a blind tube and a step of observing Raman scattered light by irradiating a laser beam in the vicinity of the solid-liquid interface where the mixture of the injected blind tube is in contact with the blind metal mass A method for detecting trace substances. 請求項１記載の検知方法において、アナライトと金属微粒子コロイドの混合物を盲管に注入する工程の後に、盲管に振動を与えてアナライトと金属微粒子コロイドの混合物を盲部に誘導する工程をさらに有する表面増強ラマン散乱による微量物質の検知方法。 2. The detection method according to claim 1, wherein after the step of injecting the mixture of the analyte and the metal fine particle colloid into the blind tube, the step of applying vibration to the blind tube to induce the mixture of the analyte and the metal fine particle colloid to the blind portion. A method for detecting a trace substance by surface enhanced Raman scattering. 請求項１記載の検知方法において、アナライトとあらかじめ用意された金属微粒子コロイドとを混合する工程の前に、金属塊の盲部における位置、または金属膜の盲部内面における位置を計測し、かつ、該計測位置に基づく盲管の位置にマーカーを配設して盲管の観測で前記計測位置情報を読み取れるようにする工程をさらに有する表面増強ラマン散乱による微量物質の検知方法。 The detection method according to claim 1, wherein before the step of mixing the analyte and the metal fine particle colloid prepared in advance, the position in the blind part of the metal lump or the position in the blind part inner surface of the metal film is measured, and A method for detecting a trace substance by surface-enhanced Raman scattering, further comprising a step of arranging a marker at a position of the blind tube based on the measurement position so that the measurement position information can be read by observation of the blind tube. 請求項１記載の検知方法において、アナライトとあらかじめ用意された金属微粒子コロイドとを混合する工程の前に、金属塊の盲部における位置、または金属膜の盲部内面における位置を計測し、かつ、該計測位置情報を記憶した記憶媒体を盲管に配設して盲管の観測で前記計測位置情報を読み取れるようにする工程をさらに有する表面増強ラマン散乱による微量物質の検知方法。 The detection method according to claim 1, wherein before the step of mixing the analyte and the metal fine particle colloid prepared in advance, the position in the blind part of the metal lump or the position in the blind part inner surface of the metal film is measured, and A method for detecting a trace substance by surface-enhanced Raman scattering, further comprising a step of arranging a storage medium storing the measurement position information in a blind tube so that the measurement position information can be read by observation of the blind tube. 請求項１記載の方法で微量アナライトを弁別検知する装置であって、盲部に金属塊が配設された盲管、または盲部内面に金属膜が配設された盲管と、前記盲管にレーザ光を照射してラマン散乱光を観測する手段と、アナライトと金属微粒子コロイドの混合物が注入された前記盲管にて、該混合物と金属塊または金属膜とが接する固液界面近傍にレーザ光の焦点合わせをする手段を有する微量物質の検知装置。 An apparatus for discriminating and detecting a small amount of analyte by the method according to claim 1, wherein a blind tube in which a metal lump is disposed in a blind portion, or a blind tube in which a metal film is disposed on an inner surface of the blind portion; A means for observing Raman scattered light by irradiating a tube with a laser beam, and the vicinity of a solid-liquid interface where the mixture and the metal lump or metal film are in contact with the blind tube into which the mixture of analyte and metal fine particle colloid has been injected A device for detecting a trace substance having means for focusing laser light. 請求項５記載の検知装置において、盲管に振動を与えてアナライトと金属微粒子コロイドの混合物を盲部に誘導する手段を兼備した微量物質の検知装置。 6. The detection device according to claim 5, wherein the detection device is provided with means for inducing vibration to the blind tube to guide the mixture of the analyte and the metal fine particle colloid to the blind portion. 請求項５記載の検知装置の盲管が、アナライトとあらかじめ用意された金属微粒子コロイドとを混合する工程の前に、金属塊の盲部における位置、または金属膜の盲部内面における位置があらかじめ計測されており、該計測位置に基づく盲管の位置にマーカーが配設された盲管であって、
請求項５記載の検知装置が、前記マーカー位置の読み取り手段を兼備するとともに、固液界面近傍にレーザ光の焦点合わせをする手段が、前記読み取り手段で読み取ったマーカー位置に基づいて固液界面を判別し焦点合わせをするものである微量物質の検知装置。Before the step of mixing the analyte and the metal fine particle colloid prepared beforehand, the position of the position of the metal lump in the blind part or the position of the inner surface of the blind part of the metal film is previously determined. A blind tube in which a marker is disposed at a position of the blind tube based on the measurement position,
6. The detection apparatus according to claim 5, wherein the means for reading the marker position also has a means for focusing laser light in the vicinity of the solid-liquid interface based on the marker position read by the reading means. A detection device for trace substances that distinguishes and focuses. 請求項７記載のマーカーの位置が、盲管の管軸に直交する面で、かつ、盲部の金属塊または盲部内面の金属膜を含む面群にて、最も盲管開放端に近い面に含まれる位置、および／または最も盲管盲端に近い面の位置に対応した位置である検知装置。 The position of the marker according to claim 7 is a plane that is perpendicular to the tube axis of the blind tube and that is closest to the open end of the blind tube in a group of surfaces including the metal mass of the blind part or the metal film of the inner surface of the blind part. And / or a position corresponding to the position of the surface closest to the blind end of the blind canal. 請求項５記載の検知装置の盲管において、アナライトとあらかじめ用意された金属微粒子コロイドとを混合する工程の前に、金属塊の盲部における位置、または金属膜の盲部内面における位置があらかじめ計測されており、
請求項５記載の検知装置が、前記の計測位置情報を記憶する記憶手段と、前記記憶手段の情報の読み取り手段を兼備するとともに、固液界面近傍にレーザ光の焦点合わせをする手段が、前記読み取り手段で読み取った金属塊の盲部における位置情報、または金属膜の盲部内面における位置情報に基いて固液界面を判別し焦点合わせをするものである微量物質の検知装置。6. The blind tube of the detection device according to claim 5, wherein the position of the metal mass in the blind part or the position of the metal film in the blind part inner surface is previously set before the step of mixing the analyte and the metal fine particle colloid prepared in advance. Has been measured,
The detection device according to claim 5, wherein the storage unit that stores the measurement position information and the information reading unit of the storage unit are combined, and the unit that focuses the laser beam in the vicinity of the solid-liquid interface includes: An apparatus for detecting a trace substance that discriminates and focuses a solid-liquid interface based on position information in a blind portion of a metal lump read by a reading means or position information on an inner surface of a blind portion of a metal film. 請求項９記載の検知装置の盲管に、計測位置情報を記憶する記憶手段である記憶媒体が配設され、記憶手段の情報の読み取り手段が、盲管に配設された前記記憶媒体の情報読み取り手段である微量物質の検知装置。 10. A storage medium as storage means for storing measurement position information is provided in the blind tube of the detection device according to claim 9, and information reading means of the storage means is information on the storage medium provided in the blind tube. A detection device for trace substances as a reading means. 請求項１記載の方法で複数のサンプリング液に潜在する微量アナライトを弁別検知する複数物質検知デバイスであって、盲部に金属塊が配設された複数本の盲管および／または盲部内面に金属膜が配設された複数本の盲管を次の並列条件で並列配列したデバイス。
並列条件は；
１つの盲管管軸に直交する面で、かつ、盲部の金属塊または盲部内面の金属膜を含む面群にて、最も盲管開放端に近い面または最も盲管盲端に近い面が、他の盲管管軸に直交する面で、かつ、盲部の金属塊または盲部内面の金属膜を含む面群に含まれること。A multi-substance detection device for discriminating and detecting trace analytes latent in a plurality of sampling solutions by the method according to claim 1, wherein the plurality of blind tubes and / or the inner surface of the blind portion are provided with a metal block in the blind portion. A device in which a plurality of blind tubes each having a metal film disposed thereon are arranged in parallel under the following parallel conditions.
The parallel condition is:
A plane perpendicular to one blind tube axis and a surface group including a blind metal mass or a metal film on the inner surface of the blind portion, the surface closest to the open end of the blind tube or the surface closest to the blind end of the blind tube Is included in a group of planes that are perpendicular to the axis of the other canal and include a metal block of the blind part or a metal film of the inner surface of the blind part. 請求項１１記載の複数本の盲管並列条件を実現するために、以下の構成からなる複数物質検知デバイス。
１）並列配列前の盲管の端部に研削しろがあること。
２）複数物質検知デバイスが、レーザ光照射焦点に対応した基準面を有すること。
３）盲管端部の研削しろが盲部の金属塊または盲部内面の金属膜の位置に応じて研削されること。
４）複数の盲管が前記基準面に研削された面をあわせて並列配列されること。In order to realize the multiple blind tube parallel condition according to claim 11, a multiple substance detection device having the following configuration.
1) There should be a margin for grinding at the end of the blind tubes before the parallel arrangement.
2) The multi-substance detection device has a reference plane corresponding to the laser beam irradiation focus.
3) The margin for grinding at the end of the blind tube is ground in accordance with the position of the metal mass of the blind portion or the metal film on the inner surface of the blind portion.
4) A plurality of blind tubes are aligned in parallel with the ground surface ground to the reference surface. 請求項１１記載の複数本の盲管並列条件を実現するために、以下の構成からなる複数物質検知デバイス。
１）並列配列前の盲管端部に円錐オス型状の基準形状物があること。
２）複数物質検知デバイスが、レーザ光照射焦点に対応した基準面を有するとともに該基準面に前記の円錐オス型と嵌合する円錐メス型が開口されること。
３）前記円錐メス型の深さは盲部の金属塊または盲部内面の金属膜の位置に応じて決定されること。
４）複数の盲管が前記円錐メス型開口に盲管端部の円錐オス型状基準形状物を嵌合して並列配列されること。In order to realize the multiple blind tube parallel condition according to claim 11, a multiple substance detection device having the following configuration.
1) A conical male shaped reference shape is present at the end of the blind tube before the parallel arrangement.
2) The multi-substance detection device has a reference surface corresponding to the laser beam irradiation focal point, and a conical female type that fits with the male male type is opened on the reference surface.
3) The depth of the conical knife type is determined in accordance with the position of the blind metal block or the metal film on the inner surface of the blind part.
4) A plurality of blind tubes are arranged in parallel by fitting a conical male-shaped reference shape at the end of the blind tube into the conical female-type opening. 盲部に金属が配設された盲管であって、盲管に金属材を投入する工程の後に、該盲管盲部の金属を溶融温度以上に加熱する工程によって、該盲管盲部内面に前記投入金属材が溶融固着して配設された表面増強ラマン散乱による微量物質検知用盲管。 A blind tube in which a metal is disposed in the blind part, and after the step of introducing a metal material into the blind pipe, the inner surface of the blind part of the blind tube is heated by a step of heating the blind tube metal to a melting temperature or higher. A blind tube for detecting trace substances by surface-enhanced Raman scattering, in which the input metal material is melted and fixed. 盲部に金属が配設された盲管であって、盲管に金属材を投入する工程の後に、該盲管盲部の金属を溶融温度以上に加熱する工程によって、該盲管盲部内面に前記投入金属材が溶融延展した薄膜が配設された表面増強ラマン散乱による微量物質検知用盲管。 A blind tube in which a metal is disposed in the blind part, and after the step of introducing a metal material into the blind pipe, the inner surface of the blind part of the blind tube is heated by a step of heating the blind tube metal to a melting temperature or higher. A blind tube for detecting trace substances by surface-enhanced Raman scattering, in which a thin film in which the input metal material is melt-extended is disposed. 盲部に金属が配設された盲管であって、金属材料を盲管に配設する工程の後に、該盲管金属配設部の開放端側を盲管外部から加圧狭窄する工程によって、該盲管金属配設部の盲管内径よりも小さな内径である部位が金属配設部の開放端側に形成された表面増強ラマン散乱による微量物質検知用盲管。 A blind tube in which metal is disposed in the blind portion, and after the step of disposing the metal material in the blind tube, the step of pressurizing and constricting the open end side of the blind tube metal disposing portion from the outside of the blind tube A blind tube for detecting a trace substance by surface-enhanced Raman scattering, wherein a portion having an inner diameter smaller than the inner diameter of the blind tube is formed on the open end side of the metal disposed portion.
JP2008506250A 2006-03-17 2007-03-13 Substance detection method and substance detection apparatus by surface-enhanced Raman scattering using small diameter blind tube, multiple substance detection device, blind tube Pending JPWO2007108360A1 (en)

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