JP2017191109A - Measurement method and measurement device using array type sensor used with enhanced electromagnetic field - Google Patents
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Abstract
Description
本発明は、ラマン散乱および蛍光シグナルを増強する電磁場増強作用を持つナノ構造物を配置したアレイ型センサーを使用し、可視から近赤外帯域の波長を持つレーザーの電磁場をナノスケールに集中させ、このアレイ型センサーにレーザービームを走査し、個々のナノ構造物近傍に存在する分子のシグナルを個別に計測し識別する測定方法、及びこの測定を行う測定装置に関する。 The present invention uses an array-type sensor in which nanostructures having an electromagnetic field enhancing action that enhances Raman scattering and fluorescence signals are arranged, and concentrates the electromagnetic field of a laser having a wavelength in the visible to near-infrared band to the nanoscale, The present invention relates to a measurement method for scanning a laser beam on the array type sensor and individually measuring and identifying signals of molecules existing in the vicinity of individual nanostructures, and a measurement apparatus for performing this measurement.
表面増強ラマン散乱（Surface Enhanced Raman Scattering：ＳＥＲＳ）、表面増強赤外吸収（Surface Enhanced Infrared Absorption：ＳＥＩＲＡ）や表面プラズモン励起増強蛍光分光（Surface Plasmon-field enhanced Fluorescence Spectroscopy：ＳＰＦＳ）は、高感度かつ簡便な化学センサー・バイオセンサーに応用できる現象として、精力的な研究が行われている。特にＳＥＲＳセンサーやＳＥＩＲＡセンサーは表面プラズモン共鳴（Surface Plasmon Resonance：ＳＰＲ）センサーなどの誘電センサーや抵抗測定型のガスセンサーなどとは異なり、分子振動によるシグナルを計測でき、そのスペクトルから詳細な情報を得ることが可能である。これらのセンサーは、生体分子、環境汚染物質などの検出のみに留まらず、分子種の同定や分子構造変化のモニタリングに威力を発揮する。ＳＥＲＳ測定に可視光や近赤外光を用いる場合には、水分子による吸収が小さいため、水中でレーザー光を照射しながら「その場」で簡便に分子をモニターすることが可能である。一方ＳＥＩＲＡ効果の場合には全反射減衰光学系を用いるなどの工夫を加えることで水中にとけた微量分子の計測が可能となる（非特許文献２）。 Surface Enhanced Raman Scattering (SERS), Surface Enhanced Infrared Absorption (SEIRA), and Surface Plasmon-field enhanced Fluorescence Spectroscopy (SPFS) are highly sensitive and simple. As a phenomenon that can be applied to various chemical sensors and biosensors, energetic research has been conducted. In particular, unlike dielectric sensors such as surface plasmon resonance (SPR) sensors and resistance measurement type gas sensors, SERS sensors and SEIRA sensors can measure molecular vibration signals and obtain detailed information from their spectra. It is possible. These sensors are useful not only for detecting biomolecules and environmental pollutants, but also for identifying molecular species and monitoring molecular structural changes. When visible light or near-infrared light is used for SERS measurement, since absorption by water molecules is small, it is possible to easily monitor molecules “in place” while irradiating laser light in water. On the other hand, in the case of the SEIRA effect, it is possible to measure a trace molecule dissolved in water by adding a device such as using a total reflection attenuation optical system (Non-patent Document 2).
例えばＳＥＲＳ効果によるラマンセンサー材料の例としては、ガラスやシリコンなどの誘電体表面に金属ナノ粒子を担持させたもの、真空蒸着により島状の金属を２次元的に分布させたもの、表面粗さを意図的に持たせた２次元金属膜、ナノスケール、ミクロンスケールの構造を持った金属ナノロッドのアレイなどが存在する。これらのセンサー材料のシグナル増強効果は、表面プラズモンが金属構造物により閉じ込められて共鳴的に励起され、金属構造物表面の近接場が入射光による電磁場に比べて格段に増強される効果を利用している。ラマン散乱の強度は分子位置での電磁場強度の４乗に比例するとされ（非特許文献１）、近接場による増強効果がその感度と性能を大きく左右する。また、検出される分子は増強近接場の生じるナノスケール領域（ホットスポット、ホットサイト）に存在するごく少量の分子である。 Examples of Raman sensor materials based on the SERS effect include those in which metal nanoparticles are supported on a dielectric surface such as glass or silicon, island-shaped metals distributed two-dimensionally by vacuum deposition, and surface roughness. There are two-dimensional metal films that have been intentionally provided, arrays of metal nanorods having nanoscale and micron scale structures, and the like. The signal enhancement effect of these sensor materials utilizes the effect that the surface plasmon is confined by the metal structure and excited resonantly, and the near field on the surface of the metal structure is significantly enhanced compared to the electromagnetic field due to incident light. ing. The intensity of Raman scattering is proportional to the fourth power of the electromagnetic field intensity at the molecular position (Non-patent Document 1), and the enhancement effect by the near field greatly affects the sensitivity and performance. In addition, the molecules to be detected are a very small amount of molecules present in the nanoscale region (hot spot, hot site) where an enhanced near field occurs.
一般的なラマンセンサー材料においては、増強近接場を生じる構造物がマクロスケールにわたって高密度（光の波長以下の間隔）で分布しているため、光学的手法で計測されるシグナルもマクロスケールの平均情報となる。従って、溶液に複数の分子が存在する場合にはそれらに由来するシグナルが混ざって観測されるので、分子種の同定などは難しくなる。 In general Raman sensor materials, structures that generate enhanced near-fields are distributed at high density (interval below the wavelength of light) across the macroscale, so the signal measured by the optical method is also the average of the macroscale. Information. Therefore, when a plurality of molecules are present in the solution, signals derived from them are mixed and observed, making it difficult to identify molecular species.
また、共焦点顕微鏡等を用いて一個あるいは数個の構造物からのシグナルを計測する場合でも、センサー上に分布している複数の構造物の形状は互いに同一ではなく多形であるため、電磁場増強の度合いは場所毎に異なる。そのため、有効なホットスポットを計測しているかどうかの保証はなく、また、計測スポット毎の増強の条件が同じである保証もない。 In addition, even when measuring signals from one or several structures using a confocal microscope or the like, the shape of the structures distributed on the sensor is not the same as each other, but is polymorphic. The degree of enhancement varies from place to place. Therefore, there is no guarantee that an effective hot spot is being measured, and there is no guarantee that the enhancement conditions for each measurement spot are the same.
一般に行われるＳＥＲＳ計測では、（１）計測対象を含む溶液をＳＥＲＳセンサー材料に少量滴下し、乾燥後にＳＥＲＳ材料表面上で多層膜として堆積した分子のラマン測定を行う、（２）金属構造物上に、計測したい分子やタンパク質に対する吸着選択性を持たせた親和性分子（リンカー分子、アプタマーなど）を被覆し、溶液中で計測対象としたい分子をＳＥＲＳ材料表面へ捕捉し水中で単分子膜のＳＥＲＳ計測を行う、等の方法がある。しかし、これらのいずれの方法の場合にも、複数分子種を含む溶液の中に含まれる成分分子の同定とその定量は難しい。なぜならば前者（１）の場合には、全ての分子の振動シグナルが重畳してしまうために、上述したように分子種の同定が困難となるからである。つまり、従来技術によるＳＥＲＳ材料を用いる際には（あるいは溶液中にＳＥＲＳ増強粒子を分散したコロイド溶液などを用いることもある）、ホットスポットの形状・大きさはランダムで、その位置も偶発的に生成したものとなり、シグナル発生の位置と強度とが良く
規定されたものにはならならない。このため、溶液中に複数の分子が存在する場合、分子の同定が困難になり、計測した分子の量についての情報を得ることも難しい。また後者（２）の場合には分子種の同定はできるが、特定の一種類の特定分子の検出しかできない。
In SERS measurement that is generally performed, (1) a small amount of a solution containing a measurement target is dropped on the SERS sensor material, and after the drying, the Raman measurement of molecules deposited as a multilayer film on the surface of the SERS material is performed. (2) On the metal structure Covering the molecule to be measured and the affinity molecule (linker molecule, aptamer, etc.) that has adsorption selectivity for the protein, capture the molecule to be measured in the solution on the surface of the SERS material and form a monolayer in water. There are methods such as performing SERS measurement. However, in any of these methods, it is difficult to identify and quantify component molecules contained in a solution containing a plurality of molecular species. This is because, in the case of the former (1), the vibration signals of all the molecules are superimposed, so that it is difficult to identify the molecular species as described above. In other words, when using a SERS material according to the prior art (or a colloidal solution in which SERS enhancing particles are dispersed in a solution may be used), the shape / size of the hot spot is random and its position is also accidentally It must be generated and the location and intensity of signal generation must not be well defined. For this reason, when a plurality of molecules are present in the solution, it becomes difficult to identify the molecules, and it is also difficult to obtain information on the measured amount of molecules. In the latter case (2), the molecular species can be identified, but only one specific type of specific molecule can be detected.
本発明では、ナノスケール空間の電磁場の増幅機能を持つ構造物を並べたアレイ型センサーを使用して、例えば溶液中に存在する複数種類の分子種の同定とその定量を一回の測定で簡便に行える計測手法を提供することを目的とする。 In the present invention, using an array-type sensor in which structures having an amplification function of an electromagnetic field in a nanoscale space are arranged , for example, identification and quantification of a plurality of types of molecular species present in a solution can be easily performed by a single measurement. The purpose is to provide a measurement technique that can be performed easily.
本発明の一側面によれば、電磁場増強特性が実質的に同一であるとともに、実質的に同一の形状を有する複数のナノ構造物を、これらのナノ構造物からの光を互いに分離して観測可能な間隔で配置したアレイ型センサーを使用し、溶液中をランダムに拡散する分子または粒子が前記ナノ構造体表面に生じた増強近接場により形成されるホットスポットに入ったことによる前記光の変化を検出する分子または粒子の検出方法が与えられる。
ここで、前記複数のナノ構造物の各々は、所定の形状を有する金属のドットの対を電磁場増強特性が発現するギャップを介して対向させたものであってよい。
また、前記複数のナノ構造物は、前記ドットの形状、サイズ、及びギャップが±５ｎｍの誤差範囲内に入ってよい。
また、前記複数のナノ構造物はＡｕからなっていてよい。
また、前記複数のナノ構造物の配置の間隔は前記光の回折限界よりも大きくしてよい。
また、前記複数のナノ構造物は基板上に一次元あるいは二次元状に配置されてよい。
また、前記基板は誘電体からなっていてよい。
また、前記複数のナノ構造物は前記基板から垂直方向に離間して配置されてよい。
また、前記垂直方向の離間の距離は前記複数のナノ構造物のサイズ以上であってよい。
また、前記複数のナノ構造物は周期的に配置されていてよい。
また、前記アレイ型センサーに測定対象の試料を与えた状態で、前記複数のナノ構造物に順次光を照射し、前記複数のナノ構造物からの光信号をスペクトル計測してよい。
また、前記光はレーザー光であってよい。
本発明の他の側面によれば、前記アレイ型センサーと、前記アレイ型センサーの前記複数のナノ構造物に順次励起光を与えるレーザー光源と、前記レーザー光源からの励起光を前記複数のナノ構造物に順次照射するための位置決めを行う機構と、前記複数のナノ構造物からの光信号を受け取る光学系と、前記光学系からの前記光信号をスペクトル計測して記録する分光計測系とを設け、上記いずれかの分子または粒子の検出方法を実行する測定装置が与えられる。
According to one aspect of the present invention, a plurality of nanostructures having substantially the same electromagnetic field enhancement characteristics and substantially the same shape are observed by separating light from these nanostructures from each other. The change in light caused by molecules or particles randomly diffusing in solution entering a hot spot formed by an enhanced near field generated on the surface of the nanostructure, using an array type sensor arranged at a possible interval A method of detecting a molecule or particle is provided.
Here, each of the plurality of nanostructures may be a pair of metal dots having a predetermined shape opposed to each other through a gap that exhibits electromagnetic field enhancement characteristics.
The plurality of nanostructures may have an error range of ± 5 nm in the shape, size, and gap of the dots.
The plurality of nanostructures may be made of Au.
The interval between the arrangement of the plurality of nanostructures may be larger than the diffraction limit of the light.
The plurality of nanostructures may be arranged one-dimensionally or two-dimensionally on the substrate.
The substrate may be made of a dielectric.
Further, the plurality of nanostructures may be spaced apart from the substrate in the vertical direction.
The vertical separation distance may be greater than or equal to the size of the plurality of nanostructures.
The plurality of nanostructures may be periodically arranged.
In addition, in a state where a sample to be measured is applied to the array type sensor, the plurality of nanostructures may be sequentially irradiated with light, and optical signals from the plurality of nanostructures may be spectrum-measured.
The light may be laser light.
According to another aspect of the present invention, the array-type sensor, a laser light source that sequentially applies excitation light to the plurality of nanostructures of the array-type sensor, and the plurality of nanostructures that emit excitation light from the laser light source A positioning mechanism for sequentially irradiating an object, an optical system for receiving optical signals from the plurality of nanostructures, and a spectroscopic measurement system for spectrally measuring and recording the optical signals from the optical system , A measuring device for performing any one of the above-described molecule or particle detection methods is provided.
本発明によれば、特性の揃ったホットスポットからのシグナルを個別に観測することができる構造のアレイ型センサーを使用して、溶液中に存在する多様な分子種の同定やその定量的な測定等を容易に実現することができる。 According to the present invention, an array type sensor having a structure capable of individually observing signals from hot spots with uniform characteristics can be used to identify various molecular species present in a solution and to quantitatively measure them. Etc. can be easily realized.
上述した課題を達成するために、本発明の一実施例においては以下の様なデバイスを使用する。まず、同じ形状を持ち電磁場増強特性のそろったＳＥＲＳ活性を持つナノ構造物（以下、光学ナノアンテナと呼ぶ）を多数（数百個程度以上）２次元的に配置する。これらの光学ナノアンテナ同士の間隔は光学顕微鏡の分解能（光の回折限界）よりも十分大きな距離をもたせ（例えば２μｍ程度）、隣り合ったアンテナからのシグナルが重ならないようにする。そして、共焦点ラマン顕微鏡を用いてレーザービームを走査あるいは試料ステージを走査しながら個々の光学ナノアンテナのホットスポットにおいて個別にＳＥＲＳ測定を行う。これにより、光学ナノアンテナの増強電磁場のホットスポット（ホットサイト）に分子が入った際の分子振動のシグナルが増強ラマンシグナルとして分光器に記録される。また、ホットスポットに分子がない場合にはそこからのシグナルは計測されない。このような個々の光学ナノアンテナに対するラマン計測をアレイ内のすべてのアンテナに対して行い、それぞれのアンテナのラマンスペクトルの計測を通して、ホットスポットに滞在した分子種を同定する。本発明では光学ナノアンテナを化学修飾せずに用い、計測する分子が溶液中をランダムに拡散し、高々一個程度の分子が光学ナノアンテナのホットスポットに偶然入ることを利用する。また、ホットスポットに留まる分子は化学吸着により固定化されるのではなく、通過する、あるいは弱く吸着した状態にある。このようにして各光学ナノアンテナにて検知された分子種の情報を個々の光学ナノアンテナから集めて集計し、検出した分子種のヒストグラムを得ることができる。従って溶液中に存在する分子の種類を同定できるだけでなく、その存在比率を得ることもできる。例えば、一個のアンテナの計測時間が数秒のオーダーである場合、全てのアンテナの計測は数十分程度のオーダーで完了できる。 In order to achieve the above-mentioned problem, the following device is used in one embodiment of the present invention. First, a large number (about several hundred or more) of nanostructures (hereinafter referred to as optical nanoantennas) having the same shape and having SERS activity with uniform electromagnetic field enhancement characteristics are two-dimensionally arranged. The distance between these optical nanoantennas is set to a distance sufficiently larger than the resolution (light diffraction limit) of the optical microscope (for example, about 2 μm) so that signals from adjacent antennas do not overlap. Then, SERS measurement is individually performed at the hot spot of each optical nanoantenna while scanning the laser beam or scanning the sample stage using a confocal Raman microscope. Thereby, the signal of the molecular vibration when the molecule enters the hot spot (hot site) of the enhanced electromagnetic field of the optical nanoantenna is recorded in the spectrometer as an enhanced Raman signal. In addition, when there is no molecule in the hot spot, the signal from there is not measured. The Raman measurement for such individual optical nanoantennas is performed for all antennas in the array, and the molecular species staying at the hot spot is identified through the measurement of the Raman spectrum of each antenna. In the present invention, the optical nanoantenna is used without chemical modification, and the fact that the molecule to be measured diffuses randomly in the solution and at most about one molecule accidentally enters the hot spot of the optical nanoantenna. In addition, the molecules remaining in the hot spot are not immobilized by chemical adsorption, but pass or are weakly adsorbed. In this way, information on the molecular species detected by each optical nanoantenna can be collected from each optical nanoantenna and aggregated to obtain a histogram of the detected molecular species. Therefore, not only the type of molecules present in the solution can be identified, but also the abundance ratio can be obtained. For example, when the measurement time of one antenna is on the order of several seconds, measurement of all antennas can be completed on the order of several tens of minutes.
本発明で用いる光学ナノアンテナアレイはガラスやシリコン基板などの誘電体基板上に形成され、規則的に配列させたナノスケールの金属構造物からなる。用いるレーザー光源の周波数と構造物のアンテナ共鳴の周波数とが一致する様にその形状や大きさが設計されている。アレイの中の各構造物のサイズ及び形状は互いに実質的に同一であり、同じ共鳴周波数を持つように精密に製作されている。このように、形状及びサイズを複数の光学ナノアンテナ間で一致させることにより、単に測定対象の分子や粒子が光学ナノアンテナのホットスポットに存在する場合に得られるシグナルが光学ナノアンテナ間で同じになるだけではなく、これらの分子や粒子がホットスポットに存在する確率も光学ナノアンテナ間で同一となる。従って、分子や粒子の定量的な測定を容易に行うことが可能となる。 The optical nanoantenna array used in the present invention is formed on a dielectric substrate such as a glass or silicon substrate, and is composed of regularly arranged nanoscale metal structures. The shape and size are designed so that the frequency of the laser light source used matches the frequency of antenna resonance of the structure. The size and shape of each structure in the array are substantially identical to each other and are precisely fabricated to have the same resonant frequency. In this way, by matching the shape and size between multiple optical nanoantennas, the signal obtained when the molecule or particle to be measured is simply present at the hot spot of the optical nanoantenna is the same between the optical nanoantennas. In addition, the probability that these molecules and particles are present in the hot spot is the same between the optical nanoantennas. Therefore, it is possible to easily perform quantitative measurement of molecules and particles.
図１の例では、シリコンウエハの下地ＳｉＯ２のポストが２本形成され、その上にウエハ垂直方向から見て三角形をした厚さ２０ｎｍのＡｕのナノドットが厚さ５ｎｍのＣｒの接着層を介して形成されている。Ａｕナノ構造をシリコンから離すことでシリコンからの誘電遮蔽の効果を弱めることができ、Ａｕナノドット近傍の電場増強効果を高めることができる。つまり、誘電率の高いシリコンがＡｕの直下にある場合、Ａｕ近傍の電場の大半が下地のシリコンの中に吸い込まれるため（非特許文献３、４）、センシングに有効な上側の部分の電場の強度が弱まってしまう。Ａｕ構造物をシリコンから浮かすことで、この様なシリコンからの遮蔽効果を弱める事ができる。なお、Ａｕ構造物をシリコンから浮かせる距離（離間距離）は、この三角形のＡｕナノドット（Ａｕ構造物）がシリコン表面に対して平行な方向に広がっているサイズ程度（図１の例の場合は、好ましい離間距離は三角形の辺の長さである１００ｎｍ程度以上）であれば、当該遮蔽効果の悪影響を十分に低減することができる。一方で、Ａｕ構造物を浮かせることで、構造物から輻射される電磁場の及ぶ範囲が拡大し、構造物からの電磁場の干渉効果が生じる。この干渉効果が強めあう間隔でＡｕナノ構造を周期的に配列することにより、各光学ナノアンテナ近傍の電磁場増強効果を高めることが可能である（非特許文献４、５）。 In the example of FIG. 1, two SiO 2 posts on a silicon wafer are formed, and Au nanodots with a thickness of 20 nm that are triangular when viewed from the wafer vertical direction are interposed via a Cr adhesion layer with a thickness of 5 nm. Is formed. By separating the Au nanostructure from the silicon, the effect of dielectric shielding from silicon can be weakened, and the electric field enhancement effect in the vicinity of the Au nanodot can be enhanced. In other words, when silicon with a high dielectric constant is directly under Au, most of the electric field in the vicinity of Au is absorbed into the underlying silicon (Non-Patent Documents 3 and 4). Strength will be weakened. Such a shielding effect from silicon can be weakened by floating the Au structure from silicon. Note that the distance (separation distance) at which the Au structure floats from the silicon is about the size of the triangular Au nanodots (Au structure) spreading in a direction parallel to the silicon surface (in the case of the example in FIG. 1, If the preferable separation distance is about 100 nm or more, which is the length of the side of the triangle, the adverse effect of the shielding effect can be sufficiently reduced. On the other hand, by floating the Au structure, the range covered by the electromagnetic field radiated from the structure is expanded, and the interference effect of the electromagnetic field from the structure is generated. By periodically arranging Au nanostructures at intervals at which this interference effect strengthens, it is possible to enhance the electromagnetic field enhancement effect in the vicinity of each optical nanoantenna (Non-Patent Documents 4 and 5).
図２は、図１のＡｕナノ構造の電場分布をＦＤＴＤ法（Finite-difference time-domain method; FDTD method）を用いてシミュレーションした結果を示したものである。６４０ｎｍの平面波をＡｕドットの上側から照射した場合の電場分布を、下地基板に対して垂直方向の断面をとって示したものである。Ａｕドット対の中心部分であるナノギャップの部分に入射電場の９０倍の振幅を持つ電場が発生していることが分かる。この増強された電場の中に観測対象である有機分子等が入ることにより、ラマン散乱のシグナルやフォトルミネッセンスのシグナルの増強効果が期待できる。 FIG. 2 shows the result of simulating the electric field distribution of the Au nanostructure of FIG. 1 using the FDTD method (Finite-difference time-domain method; FDTD method). The electric field distribution when a plane wave of 640 nm is irradiated from the upper side of the Au dot is shown by taking a cross section in a direction perpendicular to the base substrate. It can be seen that an electric field having an amplitude 90 times that of the incident electric field is generated in the nanogap portion, which is the central portion of the Au dot pair. When organic molecules or the like to be observed enter this enhanced electric field, an enhancement effect of Raman scattering signal or photoluminescence signal can be expected.
なお、図１の例では光学ナノアンテナの形状はほぼ正三角形としたが、好ましい形状はこの正三角形に限定されるものではなく、多様な変形が可能である。具体的にはナノ構造物の尖った箇所同士が近接して対抗している形状が好ましい。逆に一対の三角形の辺同士が近接して向かい合っている構成では電磁場増強効果が弱い。 In the example of FIG. 1, the shape of the optical nanoantenna is almost an equilateral triangle, but the preferred shape is not limited to the equilateral triangle, and various modifications are possible. Specifically, a shape in which the pointed portions of the nanostructure are close to each other and opposed is preferable. Conversely, in a configuration in which the sides of a pair of triangles are close to each other, the electromagnetic field enhancement effect is weak.
また、ナノ構造物のサイズ、形状、配置、またナノ構造物同士の間隔について、これらが実質的に同一であるとみなせる範囲は、共鳴周波数などによっても影響を受けるが、寸法精度が±５ｎｍ以内であればよい。より好ましくはこれらの寸法精度は±３ｎｍ以内である。 In addition, regarding the size, shape, and arrangement of nanostructures, and the distance between nanostructures, the range that can be regarded as substantially the same is affected by the resonance frequency, but the dimensional accuracy is within ± 5 nm. If it is. More preferably, the dimensional accuracy is within ± 3 nm.
短時間で溶液中の複数種類の分子の検出ができれば、例えば血液の成分の分析や尿検査などに応用し、進行の早い疾病に対する早期の医療診断などへの応用が可能である。リンカ分子の親和性を用いた多くの検査チップの様に特定の分子の検出ではなく、振動スペクトルで識別可能な物質であれば原則的に検出が可能であり、光計測のみによる単純な検査チップが実現する。また、リンカ分子とターゲット分子の吸着が必要ないため、再利用可能な検査チップとしての利用も見込める。応用分野としては湖沼などの環境水中の汚染物質、化学反応時における溶液中の生成物、食品の成分のモニターなどへの応用も可能であり、溶液中の分子の計測が必要な広い分野での応用が可能である。 If a plurality of types of molecules in a solution can be detected in a short time, it can be applied to, for example, analysis of blood components and urinalysis, and can be applied to early medical diagnosis for diseases that progress quickly. It is not possible to detect specific molecules like many test chips using the affinity of linker molecules, but any substance that can be identified by vibration spectrum can be detected in principle. Is realized. In addition, since it is not necessary to adsorb the linker molecule and the target molecule, it can be used as a reusable test chip. As an application field, it can be applied to pollutants in environmental water such as lakes and marshes, products in solution during chemical reaction, monitoring of food ingredients, etc., in a wide range of fields that require measurement of molecules in solution. Application is possible.
図３は製作された三角形Ａｕナノドット対（Bowtie antennaとも呼ぶ）のアレイの走査電子顕微鏡写真である。Ａｕドット対のサイズ形状は寸法精度で±５％の誤差範囲でほぼ同じであり、ナノギャップの幅は１５ｎｍ±３ｎｍであるように、リソグラフィーを用いて作成した。このため、各ドット対の中心部における電場増強度も各Ａｕドット対間でほぼ同程度と考えて良い。この結果は、ほぼ等しい電磁場のホットスポットが規則的に配列できていることを意味する。このような電磁場ホットスポットに分子が入るとホットスポットに存在しない場合に比べてラマン散乱シグナルが増大することが期待できる。また、微粒子のフォトルミネッセンスや蛍光のシグナル増大も期待できる。このように各ホットスポットで増強されたシグナルを計測することで、溶液中に存在している分子や微粒子の種類を知ることができる。また、計測した結果を集計することで存在する分子や粒子のヒストグラムを作成することが可能であり、溶液中の成分分子や粒子の分布に関する情報を得ることができる。このような情報は湖沼などの環境水の汚染、血液成分の分析などに応用することで医療診断に利用できると考えられる。 FIG. 3 is a scanning electron micrograph of an array of fabricated triangular Au nanodot pairs (also called bowtie antennas). The size of the Au dot pair was almost the same with an error range of ± 5% in dimensional accuracy, and the width of the nanogap was created by lithography so that it was 15 nm ± 3 nm. For this reason, the electric field enhancement at the center of each dot pair may be considered to be approximately the same between the Au dot pairs. This result means that hot spots having almost equal electromagnetic fields can be regularly arranged. When molecules enter such an electromagnetic field hot spot, it can be expected that the Raman scattering signal is increased as compared with the case where the molecule does not exist in the hot spot. In addition, photoluminescence of fine particles and increase in fluorescence signal can be expected. Thus, by measuring the signal enhanced at each hot spot, the types of molecules and fine particles present in the solution can be known. Moreover, it is possible to create a histogram of existing molecules and particles by aggregating the measured results, and information on the distribution of component molecules and particles in the solution can be obtained. Such information can be used for medical diagnosis by applying it to environmental water contamination such as lakes and marshes and blood component analysis.
なお、図３の（ａ）及び（ｂ）ではＡｕナノドットが三角形ではなく、キノコに類似した形状であるかのように見える（特に図３（ｂ））。これは、これらの写真では電子線を斜め方向から照射しているためである。 In FIGS. 3A and 3B, the Au nanodots are not triangular but appear to have a shape similar to a mushroom (particularly FIG. 3B). This is because in these photographs, an electron beam is irradiated from an oblique direction.
図４（ａ）は白色光を照射した際のホットスポットからの散乱光のスペクトルである。暗視野顕微鏡を用い、白色光を図３のＡｕドット対の一つに焦点を合わせて照射し、単一Ａｕドット対からの散乱光をレンズと光ファイバーを通して分光器に導入し、スペクトルを得たものである。参照スペクトルはＡｕドット対構造の無い平坦なＳｉ下地を計測して得、その後Ａｕドット対を計測して得たスペクトルを参照スペクトルで割る（つまり、相対スペクトルを計算する）ことで、下地と光源からの情報を除外しＡｕドット対のみに起因する散乱スペクトルを抽出した。Ａｕドット対のプラズモン共鳴周波数と考えられる６４０ｎｍ近辺にピークを持つ散乱スペクトルが得られた。図４（ｂ）に各点におけるスペクトルの６４０ｎｍ近傍の部分（灰色部分）の積分強度を二次元的に描かせたマッピング測定の結果を示す。６４０ｎｍの散乱光に対応する強度は周期的に配列しており、ホットスポットの位置で強度が最大になっていることが分かる。図５は厳密結合波解析法（Rigorous Coupled Wave Analysis method）を用いて電磁場計算したＡｕドット対の消光スペクトルであり、Ａｕドット対の長手方向と短手方向のそれぞれの方向に電場成分を持つ光を照射した際のスペクトルを示している。実験では無偏向の入射光を用いており、得られたスペクトルは計算された両方のスペクトルを合わせたものに近い。計測されたスペクトルは単一Ａｕドット対からのスペクトルを良く再現している。 FIG. 4A shows a spectrum of scattered light from a hot spot when white light is irradiated. Using a dark field microscope, white light was focused on one of the Au dot pairs in FIG. 3, and the scattered light from the single Au dot pair was introduced into the spectrometer through a lens and an optical fiber to obtain a spectrum. Is. The reference spectrum is obtained by measuring a flat Si substrate without an Au dot pair structure, and then dividing the spectrum obtained by measuring the Au dot pair by the reference spectrum (that is, calculating the relative spectrum), the substrate and the light source. The scattering spectrum resulting from only the Au dot pair was extracted. A scattering spectrum having a peak around 640 nm, which is considered to be the plasmon resonance frequency of the Au dot pair, was obtained. FIG. 4B shows the result of the mapping measurement in which the integrated intensity of the portion near the 640 nm (gray portion) of the spectrum at each point is drawn two-dimensionally. It can be seen that the intensity corresponding to the scattered light of 640 nm is periodically arranged, and the intensity is maximum at the position of the hot spot. FIG. 5 is an extinction spectrum of an Au dot pair calculated by an electromagnetic field using a rigorous coupled wave analysis method. Light having an electric field component in each of the longitudinal direction and the short direction of the Au dot pair. The spectrum at the time of irradiation is shown. In the experiment, unpolarized incident light is used, and the obtained spectrum is close to the sum of both calculated spectra. The measured spectrum well reproduces the spectrum from a single Au dot pair.
このホットスポットからのラマン散乱スペクトルを計測するために、図６（ａ）の構造式で示される3,3′-Diethylthiatricarbocyanine iodide（ＤＴＴＣＩ）分子を３００ｎＭ溶液となる様にエタノールに溶解し、アレイ上に塗布した後、乾燥後にスペクトル計測を行った。ホットスポットにおける典型的なラマン散乱スペクトルを図６（ｂ）に示す。ＤＴＴＣＩ分子のラマンスペクトルが明瞭に観測されている。また、このラマンスペクトルの灰色の部分に対応する積分強度をマッピングしたものを図６（ｃ）に示す。各ホットスポットに対応する位置にラマンシグナルが明瞭に得られている。ラマンシグナルが無いホットスポットも観測されており、分子がこの部分には吸着していないと考えられる。 In order to measure the Raman scattering spectrum from this hot spot, the 3,3′-diethylthiatricarbocyanine iodide (DTTCI) molecule represented by the structural formula of FIG. 6 (a) was dissolved in ethanol so as to be a 300 nM solution, and then on the array. After coating, spectral measurement was performed after drying. A typical Raman scattering spectrum in the hot spot is shown in FIG. The Raman spectrum of the DTTCI molecule is clearly observed. Further, FIG. 6C shows the mapping of the integrated intensity corresponding to the gray portion of the Raman spectrum. A Raman signal is clearly obtained at a position corresponding to each hot spot. A hot spot without a Raman signal has also been observed, and it is thought that molecules are not adsorbed on this part.
また、検出対象をRhodamine 6G分子（構造式は図７（ａ））として行った同様な計測結果を図７に示す。ＤＴＴＣＩ分子と同様にしてRhodamine 6G分子の溶液をアレイ上に塗布し乾燥させた後、スペクトル計測を行った。図７（ｂ）は、その結果得られたところの、ホットスポットにおけるRhodamine 6G分子の振動（１３００ｃｍ−１〜１３７０ｃｍ−１）のラマン散乱強度（積分強度）を２次元表示したマッピングイメージである。また、図７（ｃ）には下地結晶シリコンの振動（５２０ｃｍ−１）のラマン散乱強度を２次元表示したマッピングイメージを示す。検出対象の分子がホットスポット上で選択的に検出できることが示されている。 In addition, FIG. 7 shows the same measurement result when the detection target is Rhodamine 6G molecule (the structural formula is FIG. 7A). In the same manner as for DTTCI molecules, a solution of Rhodamine 6G molecules was applied on the array and dried, and then spectrum measurement was performed. FIG. 7B is a mapping image obtained by two-dimensionally displaying the Raman scattering intensity (integrated intensity) of the vibration (1300 cm −1 to 1370 cm −1 ) of the Rhodamine 6G molecule at the hot spot obtained as a result. FIG. 7C shows a mapping image in which the Raman scattering intensity of the vibration (520 cm −1 ) of the underlying crystal silicon is two-dimensionally displayed. It has been shown that molecules to be detected can be selectively detected on a hot spot.
図６、図７に例示したような計測は、例えば図８に構成の概念図を示す測定装置を使用して、レーザー光源からのレーザービームを走査しながら、あるいはアレイセンサーを置いた試料ステージを走査しながら各ホットスポットに集光させたビームを照射し、そこからのラマン散乱光などの光信号を対物レンズ、フィルタ、分光器を介して検出器に導くことで、各ホットスポットにおいてスペクトル計測を行うことで実現できる。このようにして微量のターゲット分子の検出、あるいは複数分子種の同定と存在比率・ヒストグラムを得ることができると考えられる。また、分子を発光ナノ粒子などに置き換えることで、フォトルミネッセンスのスペクトルを計測し、これを粒子の種類の同定に用いることもできる。さらに進めて、（光学ナノアンテナではなく）発光粒子表面を検出したい分子を捕捉するアプタマーで修飾することなどで、ターゲット分子を捕捉した粒子の検出を通してターゲット分子を間接的に検出する方法も可能である。 The measurement as illustrated in FIG. 6 and FIG. 7 is performed by scanning a laser beam from a laser light source or a sample stage on which an array sensor is placed using, for example, a measuring device whose conceptual diagram is shown in FIG. Spectral measurement is performed at each hot spot by irradiating a focused beam to each hot spot while scanning, and guiding optical signals such as Raman scattered light to the detector through an objective lens, filter, and spectrometer. It can be realized by doing. In this way, it is considered that a small amount of target molecules can be detected, or identification of a plurality of molecular species and abundance ratio / histogram can be obtained. In addition, by replacing the molecule with a light-emitting nanoparticle or the like, the spectrum of photoluminescence can be measured and used for identifying the type of particle. It is also possible to detect the target molecule indirectly through detection of particles that have captured the target molecule, such as by modifying the surface of the luminescent particle (not an optical nanoantenna) with an aptamer that captures the molecule that you want to detect. is there.
本発明では電磁場を増強するナノ構造をアレイ化したアレイ型センサを使用することで、目的とする分子や粒子を個々のホットスポットで増強して検出することができる。よく規定されたホットスポットを周期的に配置しアレイ化し、溶液中で偶発的にホットスポットに入った際に生じる増強シグナルを識別することが可能となる。アプタマーやリンカ分子を用いて計測対象となる分子やナノ粒子を化学的に捕捉したうえで計測する方法ではなく、計測の対象物のサイズがナノギャップに入るサイズでありさえすれば良く、適用できる応用範囲は広い。低濃度の場合にターゲット分子や発光ナノ粒子一個一個を個々のホットスポットにおいて検出すれば、ターゲット分子の液体中の存在比率やヒストグラムを得ることも可能となる。この計測法を湖沼などの環境水や産業用水の排水のモニタリングなどに適用することで環境汚染や水質管理などに貢献することができる。また、血液の成分の分析を迅速に行うことで医療診断などへの応用が可能になるなど、関連する産業や社会への貢献は大きいものがある。 In the present invention, by using an array type sensor in which nanostructures that enhance electromagnetic fields are arrayed, target molecules and particles can be enhanced and detected by individual hot spots. Well defined hot spots can be periodically placed and arrayed to identify the enhancement signal that occurs when a hot spot is accidentally entered in solution. Not how to measure the molecular or nanoparticle to be measured by using the aptamer and linker molecules after having captured chemically, size of the object of measurement may be even Ri Ah size entering the nanogap, applied The range of possible applications is wide. If the target molecules and the luminescent nanoparticles are detected one by one in each hot spot at a low concentration, it is possible to obtain the abundance ratio and histogram of the target molecules in the liquid. By applying this measurement method to the monitoring of drainage of environmental water such as lakes and industrial water, it can contribute to environmental pollution and water quality management. In addition, rapid analysis of blood components can be applied to medical diagnosis and the like, and there are significant contributions to related industries and society.
Claims (13)
溶液中をランダムに拡散する分子または粒子が前記ナノ構造体表面に生じた増強近接場により形成されるホットスポットに入ったことによる前記光の変化を検出するDetecting changes in the light due to molecules or particles that diffuse randomly in solution entering a hot spot formed by an enhanced near field generated on the nanostructure surface
分子または粒子の検出方法。Method for detecting molecules or particles.
前記アレイ型センサーの前記複数のナノ構造物に順次励起光を与えるレーザー光源と、A laser light source for sequentially applying excitation light to the plurality of nanostructures of the array-type sensor;
前記レーザー光源からの励起光を前記複数のナノ構造物に順次照射するための位置決めを行う機構と、A positioning mechanism for sequentially irradiating the plurality of nanostructures with excitation light from the laser light source;
前記複数のナノ構造物からの光信号を受け取る光学系と、An optical system for receiving optical signals from the plurality of nanostructures;
前記光学系からの前記光信号をスペクトル計測して記録する分光計測系とA spectroscopic measurement system for spectrally measuring and recording the optical signal from the optical system;
を設け、Provided,
請求項１２に記載の分子または粒子の検出方法を実行するThe method for detecting molecules or particles according to claim 12 is executed.
測定装置。measuring device.
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