WO2008029591A1 - Procédé de réduction de la lumière de fond lors de l'observation de fluorescence avec excitation par onde évanescente, et composant pour celui-ci - Google Patents

Procédé de réduction de la lumière de fond lors de l'observation de fluorescence avec excitation par onde évanescente, et composant pour celui-ci Download PDF

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Publication number
WO2008029591A1
WO2008029591A1 PCT/JP2007/065708 JP2007065708W WO2008029591A1 WO 2008029591 A1 WO2008029591 A1 WO 2008029591A1 JP 2007065708 W JP2007065708 W JP 2007065708W WO 2008029591 A1 WO2008029591 A1 WO 2008029591A1
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Prior art keywords
light
waveguide substrate
stray light
incident
evanescent wave
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PCT/JP2007/065708
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English (en)
Japanese (ja)
Inventor
Jun Hirabayashi
Noboru Uchiyama
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National Institute Of Advanced Industrial Science And Technology
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Publication of WO2008029591A1 publication Critical patent/WO2008029591A1/fr

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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
    • G01N21/645—Specially adapted constructive features of fluorimeters
    • G01N21/648—Specially adapted constructive features of fluorimeters using evanescent coupling or surface plasmon coupling for the excitation of fluorescence
    • 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
    • G01N21/645—Specially adapted constructive features of fluorimeters
    • G01N21/6452—Individual samples arranged in a regular 2D-array, e.g. multiwell plates
    • 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
    • G01N21/7703—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 using reagent-clad optical fibres or optical waveguides
    • 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
    • G01N2021/7769—Measurement method of reaction-produced change in sensor
    • G01N2021/7786—Fluorescence
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2201/00—Features of devices classified in G01N21/00
    • G01N2201/06—Illumination; Optics
    • G01N2201/064—Stray light conditioning

Definitions

  • the present invention relates to a method for reducing background fluorescence in evanescent wave excitation fluorescence observation and a member used in the method.
  • the fluorescence observation method using the evanescent wave excitation method is a technology that has achieved high results in recent years, such as enabling single-molecule observation of proteins in the field of microscopy.
  • the fluorescence observation method based on such an evanescent wave excitation method is limited to a few hundreds of neighborhoods when light is totally reflected in a substrate in contact with a fluorescently labeled probe solution on the substrate. This is based on the fact that the fluorescently labeled probe molecules near the substrate-liquid layer interface are selectively excited by the evanescent wave. In other words, incident light is incident from the end face of the slab waveguide substrate and repeatedly reflected and totally reflected in the slide substrate to generate an evanescent wave, and the fluorescence emitted by the probe molecules excited by the evanescent wave is observed. By doing so, the interaction between the molecules immobilized on the slide substrate surface and the probe molecules can be observed (Fig. 1).
  • Such fluorescence observation by evanescent wave excitation is particularly suitable for observing the binding state between the above-mentioned molecule and a fluorescent probe in a microarray in which a large number of test molecules are immobilized.
  • Such an evanescent wave excitation method is used.
  • the microarray technology used is, for example, injecting a fluorescent probe sample solution into a reaction vessel installed on a substrate having a slab waveguide installed in a horizontal direction, thereby introducing the slab type guide into the fluorescent probe sample. It is configured to contact the wave path, and by introducing incident light at an angle in the waveguide, it is possible to selectively excite the probe molecules in the vicinity of the interface by the evanescent wave generated on the waveguide.
  • the selective excitation of the evanescent wave excitation method is theoretically a phenomenon that depends on the function of the distance from the interface, not the selectivity for the interface-bound molecules, and is far above the interface. Does not completely eliminate the excitation of non-bonded molecules present in In reality, there is stray light that deviates from the total reflection condition that occurs non-ideally in the device. In actual observation, the phenomenon that the probe solution layer above the evanescent region shines may be observed. It was known. Such stray light or light that does not satisfy the total reflection condition while traveling in the waveguide reaches the upper layer of the probe liquid and directly excites the probe molecules, resulting in increased background light intensity, resulting in a large S / N ratio. Cause a significant decline.
  • the present inventors disperse the colloid by adding a colloid solution to the probe liquid layer, and stray light.
  • the present inventors have advanced one step further, as a countermeasure against stray light entering the reaction vessel on the substrate in evanescent wave excitation fluorescence detection, by reducing the thickness of the probe solution layer extremely, A technology has been developed to reduce the absolute number of fluorescent molecules in the upper layer of the probe solution that is excited when stray light passes through the reaction chamber (Japanese Patent Application 2006-203257).
  • Japanese Patent Application 2006-203257 both of these technologies are methods that suppress the effects of stray light that does not exist in a method that deals with the source of stray light that excites fluorescent molecules in the upper layer of the probe solution. Therefore, there is a natural lower limit to the background light reduction. Also, if the existence of stray light itself is removed from the reaction tank! /, The fundamental countermeasure technology has never been reported.
  • Patent Document 1 Japanese Translation of Special Publication 2003-521684
  • An object of the present invention is that stray light generated under optically non-ideal conditions is observed in a reaction tank on a substrate when evanescent wave excitation fluorescence observation is performed using a substrate having a slab waveguide.
  • This method achieves fluorescence observation at a high S / N ratio by effectively suppressing the phenomenon of reaching the upper part of the evanescent field, and the above stray light can be suppressed easily and inexpensively.
  • it is to provide a new means for suppressing stray light that can be applied to fully automated analysis equipment.
  • the present inventor has proposed a slab-type waveguide substrate that remains in the evanescent wave excitation fluorescence observation apparatus and that is not ideal optical stray light and is totally incident upon the inside of the waveguide and repeatedly undergoes total reflection. Focusing on the fact that stray light that deviates from the total internal reflection condition reaches the upper layer of the fluorescent probe solution on the substrate and excites fluorescent molecules, this is a major cause of background light.
  • the stray light absorption region is effectively placed on the substrate as a means to suppress reaching the upper reaction vessel, thereby suppressing the amount of stray light reaching the upper layer of the probe solution layer and evanescent wave excitation fluorescence.
  • the background light during observation was greatly reduced and the present invention was completed.
  • the present invention is as follows.
  • a probe solution containing a fluorescently labeled probe molecule is introduced into a reaction vessel having a waveguide substrate with a test molecule immobilized on the bottom, and the immobilized molecule and the probe molecule are bound to each other.
  • it is a method of suppressing background light in the evanescent wave excitation fluorescence observation by suppressing the incidence of stray light into the reaction vessel, The background light described above, wherein a stray light absorption region having a width of at least 3 mm in the direction of the incident light is provided on the upper or lower surface of the waveguide substrate between the incident light incident end and the test molecule fixing position.
  • the incident light incident end face of the waveguide substrate is laser-cut! / The background light reduction method according to any one of the above (1) to (3).
  • An evanescent wave excitation characterized by a waveguide substrate used for observation of evanescent wave excited fluorescence having a reaction vessel with a test molecule fixed on the bottom, wherein the incident light incident end face is laser-cut.
  • the stray light suppressing means of the present invention can be implemented easily and inexpensively, and in addition, by adapting in combination with other methods for reducing the influence of stray light (liquid layer thickness control method), the background fluorescence can be reduced. Further reduction is possible.
  • FIG. 2 is a diagram showing a substrate and its characteristics that have been used for conventional evanescent wave excitation fluorescence observation.
  • FIG. 3 is a diagram showing the characteristics of a waveguide substrate equipped with stray light suppression means used for evanescent wave excitation fluorescence observation invented this time.
  • FIG. 4 is a diagram showing the result of observing the relationship between the width of the light absorbing member in the incident direction of incident light and the fluorescence intensity of the upper layer.
  • FIG. 5 is a diagram showing the relationship between the width of the light absorbing member in the incident direction of incident light and the fluorescence intensity of the upper layer.
  • FIG. 6 is a diagram showing the arrangement of members on a substrate provided with a light absorbing member in a stray light absorbing region on a waveguide substrate provided with the reaction vessel of the present invention.
  • FIG. 7 is a diagram showing the arrangement of members on a substrate provided with a light absorbing member in a stray light absorbing region on a waveguide substrate provided with the reaction vessel of the present invention.
  • FIG. 8 is a diagram showing dimensions of a light absorbing member designed in the practice of the present invention.
  • FIG. 9 is a diagram showing dimensions of a light absorbing member designed in the practice of the present invention.
  • FIG. 10 is a diagram showing the results of an experiment comparing the background light attenuation effect of the stray light absorption method of the present invention with the background light attenuation effect of a conventional substrate.
  • FIG. 11 is a diagram showing experimental results observing the background light reduction effect by the combination of the stray light absorption method and the liquid layer thickness control method.
  • FIG. 12 is a view showing an arrangement form of an accessory modifier on a substrate provided with a light absorbing member in a stray light absorbing region on a waveguide substrate provided with the reaction vessel of the present invention.
  • FIG. 13 is a view showing a more preferable usage form in which an accessory modifier is attached to a substrate equipped with a light absorbing member in a stray light absorbing region on a waveguide substrate provided with the reaction vessel of the present invention.
  • the present invention relates to an evanescent wave excited fluorescence observation method using a slide substrate itself as a slab type waveguide.
  • the probe solution 14 is brought into contact with the waveguide substrate 5 on which the test molecule 19 is fixed, and then the binding reaction is sufficiently advanced. After that, incident light enters from the end face of the waveguide substrate 5 and is repeatedly totally reflected in the substrate, thereby generating an evanescent wave 15 on the waveguide.
  • the fluorescently labeled probe molecule 13 bound to the test molecule 19 is excited by an evanescent wave to emit fluorescence, and the fluorescence is detected by the detector 16 to identify the test molecule bound to the probe molecule on the substrate. it can.
  • the intensity of the evanescent field that exudes from the interface has the property of exponentially decaying from the substrate interface in the vertical direction, and the region involved in the excitation of the fluorescent molecule is about several hundred nm in the vertical direction from the interface. Since it is known, even if the remaining probe solution layer is thick, in principle, the probe molecules 13 bound to the test molecules 19 on the waveguide substrate 5 are selectively detected. However, in an actual optical system, light that satisfies the total reflection condition (broken line in Fig. 2) among the light incident on the slide substrate, which is a waveguide, travels inside the substrate, whereas all light enters or reflects during the process of incidence.
  • the S / N ratio is used to generate background light by directly exciting fluorescently labeled probe molecules in the upper layer of the probe solution where a part of the light (hereinafter referred to as stray light) that no longer meets the reflection conditions (solid line in Fig. 2) remains.
  • stray light a part of the light that no longer meets the reflection conditions
  • the stray light suppressing means of the present invention is a waveguide substrate for evanescent wave excitation fluorescence observation.
  • the incident direction A stray light absorption region having a width of at least 3 mm is provided.
  • black such as carbon black
  • examples thereof include means for applying a paint containing a color pigment, or means for adhering a light absorbing member made of a molded product such as rubber or resin containing a black pigment to a waveguide substrate.
  • the form of the waveguide substrate provided with the light absorbing member of the present invention is shown in FIG.
  • Each light absorbing member is designed so as to correspond to the position of each reaction tank.
  • the upper waterproof partition member 1 and the upper light absorbing member 3 can be attached to each other with an adhesive or the like. As shown in FIG. 7, the upper waterproof partition member using the material constituting the upper light absorbing member 3 is used. And the upper light absorbing member may be integrally formed, and the reaction vessel may be formed using the light absorbing member as a constituent member of the reaction vessel side wall. This method is more advantageous in terms of cost because it can save the manufacturing cost of the upper waterproof partition member.
  • the light absorbing member of the present invention can form a stray light absorbing region 6 having a width of at least 3 mm or more in the incident light direction on the waveguide substrate between the incident light incident end and the region where the test molecule is fixed. Any shape is possible! /.
  • the background light reduction effect is not improved so much as the width of the stray light absorbing region is increased beyond 5.4 mm.
  • the thickness of the waveguide substrate used in this experimental example is the usual lmm force S, and even if it is thicker than this, it is necessary to provide a stray light absorption region at least 3 mm wide or 3 to 6.5 mm wide Background light can be effectively reduced.
  • a force S using silicon rubber 20 ° (black), or a material (resin / sealing agent, etc.) that adheres to another slide glass may be used.
  • the color is preferably black, but may be changed.
  • the adhesive shape can also be adhered by the adhesiveness of the material itself, and an adhesive having as low autofluorescence as possible in the incident light wavelength region can be used.
  • the thickness of the light-absorbing member layer is not particularly limited. However, the thickness may be increased as long as it is for the convenience of operation which is preferably 1 mm or more.
  • the reaction center disposed on the waveguide substrate has a center interval in the vertical direction of 8.4 to 9.6 mm, and is disposed between the stray light absorption regions on the left and right sides of the substrate.
  • the arrangement method of the reaction tank is not limited to one horizontal row, but may be two or more horizontal rows!
  • the reaction tank can be divided into two horizontal rows in the reaction tank area excluding the stray light absorption areas on the left and right sides of the substrate (Fig. 9). 8 and 9 are provided with 5.4 mm stray light absorption regions on both the left and right sides in the longitudinal direction of the substrate.
  • the waveguide substrate combined with the effect of reducing background light in the stray light suppression method of the present invention may be any light-transmitting substrate, but preferably has as little autofluorescence as possible and the end face shape is optical. In particular, it should be processed so that it does not generate scattered light.
  • a plate-like material include borosilicate glass, white plate glass, quartz glass, synthetic quartz, and other optical use glasses (BK7, SF03, etc.).
  • BK7, SF03, etc. optical use glasses
  • this substrate has the correspondence that can be observed with a scanner such as a confocal fluorescence observation scanner other than the evanescent wave excitation fluorescence scanner. After sufficiently reacting the probe sample solution with the immobilized molecules on the substrate, It is also possible to remove the light absorbing member and observe with a confocal fluorescence observation scanner.
  • a scanner such as a confocal fluorescence observation scanner other than the evanescent wave excitation fluorescence scanner.
  • the upper modified member and the lower modifying member may be provided so as to overlap the light absorbing member, thereby improving the strength and the convenience of operation during sample injection (FIG. 12).
  • the upper protective seal can be used to protect against physical contact from the top surface of the substrate and to prevent evaporation of the probe sample solution. Protection from contact can be achieved.
  • the role 12 serves to prevent contamination of the back surface of the waveguide in the reaction tank due to physical contact from the lower surface.
  • the upper protective seal 11 and the lower protective seal 12 are made of a light-shielding material or a wavelength-selective light-transmitting material, thereby fading the photochromic molecules in the fluorescent probe solution due to prolonged exposure to light (photo bleaching). ) Can be added.
  • Fluorescently labeled protein probes are Cy3 Mono-reactive, a fluorescent dye that has absorption maximum wavelength around 550 nm for cashier fetuin (ASF) (SIGMA) or ushi serum albumin (BSA) (SIGMA). It was prepared by fluorescent labeling using Dye (Amersham Almasia, hereinafter referred to as Cy3). The procedure is to prepare ASF and BSA in phosphate buffered saline, pH 7.4 (hereinafter PBS) to a final concentration of 1 mg / mL, and then mix 1 mL with 1.0 mg Cy 3 powder. The reaction was carried out at a certain place with timely stirring. Next, unreacted Cy3 molecules were removed by gel filtration chromatography using S-marked hadex G_25 (Amersham Pharmacia) as a carrier, and purified as a Cy3-labeled protein probe preparation.
  • PBS phosphate buffered saline, pH 7.4
  • Black silicon rubber 20 ° light-absorbing material (thickness lmm) punched to improve adhesion surface smoothness is cut and the distance between the absorbent material ends and the slide end is kept constant at 6 mm.
  • the width of the tank was changed to 3, 4, and 6 mm, and the reactor was coated with 3_glycidoxypropyltrimethoxysilane (Shin-Etsu Silicone, hereinafter GTMS). It was fabricated on a white glass slide substrate having a thickness of 25.4 mm ( ⁇ 0.05 mm) and a thickness of 1.0 mm ( ⁇ 0.05 mm). Next, add purified water with 100 ng / mL Cy3_BSA dissolved on the back of the slide substrate.
  • a spot sample for evaluating fluorescence intensity by evanescent wave excitation was prepared by spot-drying with mL. Next, fill the reaction vessel with 100% PBS solution containing 1% BSA, and leave it in a storage container kept at a humidity of 90% or more for 25 hours at 25 ° C. Probe sample on top of slide substrate in reaction vessel A blocking operation was performed to suppress nonspecific adsorption of molecules. In each reaction vessel on this substrate, 5 mg / mL Cy3_BSA was added and allowed to stand for 1 hour.
  • the probe solution in the reaction vessel was replaced with a Cy3_glycine solution, and then scanned.
  • an evanescent wave excitation type microarray scanner (GTMAS Scan IV) was used, and evanescent wave excitation fluorescence observation was performed.
  • the scanning parameters were set to Gain “4000 times”, integration number “4 times”, and exposure time “34 msec”.
  • Array-Pro Analyzer (version 4.0 for Windows Media and Ybernetics, Inc.), a commercially available microprecise angle detector for microarrays, was used to quantify the brightness of the scanned image.
  • a borosilicate glass plate is set in the reaction vessel as the liquid layer thickness control member, so that The background light intensity of the upper layer of the probe solution was observed when the liquid layer thickness control method (Japanese Patent Application No. 2006-203257), which is a background light reduction method, was applied.
  • the liquid layer thickness control method Japanese Patent Application No. 2006-203257

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Abstract

Lors de l'observation de fluorescence avec excitation par onde évanescente, la lumière parasite arrivant sur une couche de solution de sonde d'une couche supérieure d'une région de fixation de molécules en cours d'examen dans une chambre de réaction est efficacement absorbée par disposition d'une région d'absorption de la lumière parasite sur un substrat de guide d'ondes, de manière à ce que la lumière parasite ne puisse pas entrer dans la chambre de réaction et que la lumière parasite se diffusant ne puisse pas survenir au niveau d'une surface latérale du substrat de guide d'ondes formée par application d'un procédé de découpe laser à la surface latérale du substrat de guide d'ondes sur lequel la lumière est incidente. La structure permet de réduire considérablement la fluorescence de fond critique, lors de l'observation de fluorescence avec excitation par onde évanescente.
PCT/JP2007/065708 2006-09-06 2007-08-10 Procédé de réduction de la lumière de fond lors de l'observation de fluorescence avec excitation par onde évanescente, et composant pour celui-ci WO2008029591A1 (fr)

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JP2006242020A JP4883398B2 (ja) 2006-09-06 2006-09-06 エバネッセント波励起蛍光観察における背景光低減方法及び部材
JP2006-242020 2006-09-06

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Cited By (2)

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WO2011111472A1 (fr) * 2010-03-08 2011-09-15 コニカミノルタホールディングス株式会社 Dispositif de mesure de fluorescence renforcée par plasmon de surface et structure de puce
EP4020053A1 (fr) * 2020-12-25 2022-06-29 Yokogawa Electric Corporation Récipient de culture et système d'observation

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JP5487127B2 (ja) * 2011-01-14 2014-05-07 富士フイルム株式会社 測定装置およびセンサチップ
TWI585391B (zh) 2012-08-10 2017-06-01 Hamamatsu Photonics Kk Surface - enhanced Raman scattering unit and its use
CN104508466B (zh) 2012-08-10 2018-07-17 浜松光子学株式会社 表面增强拉曼散射元件
EP4033222A1 (fr) 2012-08-10 2022-07-27 Hamamatsu Photonics K.K. Unité diffusion raman à surface améliorée
WO2014025037A1 (fr) 2012-08-10 2014-02-13 浜松ホトニクス株式会社 Elément à diffusion raman exaltée par effet de surface, et son procédé de production
JP6282762B2 (ja) * 2017-01-17 2018-02-21 浜松ホトニクス株式会社 表面増強ラマン散乱ユニット
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EP4020053A1 (fr) * 2020-12-25 2022-06-29 Yokogawa Electric Corporation Récipient de culture et système d'observation

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