JPH0989780A - Optical measuring apparatus - Google Patents
Optical measuring apparatusInfo
- Publication number
- JPH0989780A JPH0989780A JP7239510A JP23951095A JPH0989780A JP H0989780 A JPH0989780 A JP H0989780A JP 7239510 A JP7239510 A JP 7239510A JP 23951095 A JP23951095 A JP 23951095A JP H0989780 A JPH0989780 A JP H0989780A
- Authority
- JP
- Japan
- Prior art keywords
- fine particles
- solution
- fluorescent
- fluorescent dye
- sample
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 230000003287 optical effect Effects 0.000 title claims abstract description 21
- 239000010419 fine particle Substances 0.000 claims abstract description 36
- 239000007850 fluorescent dye Substances 0.000 claims description 31
- 230000004907 flux Effects 0.000 claims 3
- 239000000523 sample Substances 0.000 description 20
- 239000000975 dye Substances 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 239000012488 sample solution Substances 0.000 description 5
- 239000004793 Polystyrene Substances 0.000 description 4
- 229920002223 polystyrene Polymers 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000005284 excitation Effects 0.000 description 3
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 2
- 229910001424 calcium ion Inorganic materials 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 210000001908 sarcoplasmic reticulum Anatomy 0.000 description 2
- 230000005653 Brownian motion process Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000005537 brownian motion Methods 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000006059 cover glass Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000000651 laser trapping Methods 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 239000003068 molecular probe Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
Landscapes
- Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、光学トラップを用いた
光学測定装置に関する。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an optical measuring device using an optical trap.
【０００２】[0002]
【従来の技術】試料が引き起こす溶液状態の変化を観察
する手法として、溶液中に蛍光色素を分散させ、その蛍
光色素の強度変化を観察する手法が実用化されている。
たとえば、筋小胞体からのカルシウムの放出は、インド
ー・ワンなどのカルシウムの濃度の変化に応じて蛍光強
度が変化する蛍光色素を用い、溶液中に分散させたその
蛍光色素の強度変化を経時観察することで筋小胞体から
放出されたカルシウムイオンを測定することができる。
溶液中に分散している蛍光色素の強度変化を空間分解能
をもって観察するためには、共焦点顕微鏡を用いてμm
オーダーの空間分解能を持った観察が可能である。ま
た、試料が蛋白質等の固形物である場合には、試料に蛍
光色素を付着させてこの蛍光色素の強度変化を観察する
ことで試料表面の蛍光色素の強度を選択的に観察するこ
とができる。2. Description of the Related Art As a method for observing a change in a solution state caused by a sample, a method in which a fluorescent dye is dispersed in a solution and an intensity change of the fluorescent dye is observed has been put into practical use.
For example, for the release of calcium from the sarcoplasmic reticulum, a fluorescent dye whose fluorescence intensity changes in response to changes in calcium concentration, such as Indo-One, is used, and the intensity change of the fluorescent dye dispersed in the solution is observed over time. By doing so, the calcium ion released from the sarcoplasmic reticulum can be measured.
In order to observe the intensity change of the fluorescent dye dispersed in the solution with spatial resolution, use a confocal microscope to
Observation with a spatial resolution of the order is possible. When the sample is a solid such as protein, the intensity of the fluorescent dye on the sample surface can be selectively observed by attaching the fluorescent dye to the sample and observing the intensity change of the fluorescent dye. .
【０００３】蛍光色素には、米国のモレキュラープロー
ブ社のｐＨ感受性色素、カルシウム感受性色素など、溶
液状態の変化に応じて蛍光強度が変化する様々な蛍光色
素が実用化されている。As fluorescent dyes, various fluorescent dyes such as pH-sensitive dyes and calcium-sensitive dyes manufactured by Molecular Probes, Inc. in the United States, whose fluorescence intensity changes according to changes in the solution state, have been put to practical use.
【０００４】集束光を用いた微粒子の捕獲技術はアーサ
ー・アシュキンらによって提案され、光学トラップ装置
として特許出願されている（特開平２−９１５４５）。
光学トラップでは、ポリスチレン球等の微粒子を光の集
束点に捕獲し、この集束点を移動させることで溶液中で
特定の微粒子を移動させることが可能となっている。ま
た、蛍光色素を付加したポリスチレン球なども実用化さ
れており、特に、表面にカルボキシル基あるいはアミノ
基を付加したポリスチレン球の表面に、反応残基を持つ
蛍光色素を共有結合させることで、任意の蛍光色素を付
けたポリスチレン球を作ることができる。A technique for capturing fine particles using focused light has been proposed by Arthur Ashkin et al. And has been applied for a patent as an optical trap device (Japanese Patent Laid-Open No. 2-91545).
In an optical trap, fine particles such as polystyrene spheres are captured at a light focusing point, and by moving this focusing point, it is possible to move specific fine particles in a solution. In addition, polystyrene spheres to which fluorescent dyes have been added have also been put to practical use, and in particular, the surface of polystyrene spheres to which carboxyl groups or amino groups have been added can be used by covalently bonding a fluorescent dye having a reactive residue You can make polystyrene spheres with the fluorescent dyes.
【０００５】[0005]
【発明が解決しようとする課題】従来の技術では、蛍光
色素を用いて溶液中のpＨ、あるいは特定のイオンの空
間中での分布を観察する手法として、溶液中に溶質とし
て分散させる場合と、蛋白質等の試料に蛍光色素を共有
結合させ、試料の近傍に色素を局在させる手法があった
が、溶液中に分散させた場合は、共焦点顕微鏡を用いた
場合であっても、その蛍光物質の発光の空間分解能はμ
mオーダー程度までしか高くできなかった。また、試料
に直接蛍光物質を付着させた場合は、蛍光色素の局在に
よってその発光の空間分解能は向上するが、蛍光色素の
付着による試料の活性の低下、あるいは試料と蛍光物質
との付着の手法の開発の必要などの問題点があった。In the prior art, as a method of observing the pH in a solution or the distribution of specific ions in a space using a fluorescent dye, a method of dispersing as a solute in a solution, There was a method of covalently binding a fluorescent dye to a sample such as protein and localizing the dye in the vicinity of the sample.However, when dispersed in a solution, even when a confocal microscope was used, the fluorescence The spatial resolution of the emission of a substance is μ
I could only raise it to about m orders. Further, when the fluorescent substance is directly attached to the sample, the spatial resolution of the light emission is improved by the localization of the fluorescent dye, but the activity of the sample is reduced due to the attachment of the fluorescent dye, or the adhesion of the sample and the fluorescent substance is prevented. There were problems such as the need to develop methods.
【０００６】本発明は、溶液状態の変化に応じて蛍光強
度が変化する蛍光色素を用い、試料に蛍光色素を付着す
ることなく、空間分解能を持った形で試料が引き起こす
溶液状態の変化を観察する手段を有する装置を提供する
ことを目的とする。The present invention uses a fluorescent dye whose fluorescence intensity changes according to the change of the solution state, and observes the change of the solution state caused by the sample with a spatial resolution without attaching the fluorescent dye to the sample. It is an object of the present invention to provide a device having means for doing so.
【０００７】[0007]
【課題を解決するための手段】上記課題を解決するため
には、溶液状態の変化に応じて蛍光強度が変化する蛍光
色素を微粒子の表面に付着し、集束光を用いた光学トラ
ップ装置を用いてこの微粒子を捕獲し、また、この集束
点を移動させることでこの微粒子の位置を移動させ、溶
液中の任意の位置における蛍光微粒子の蛍光強度を測定
解析すればよい。また、光学トラップ装置で用いる集束
光の波長として、蛍光色素の励起波長の２倍波長を用い
ることで、光学トラップで捕獲した蛍光微粒子の蛍光色
素のみを選択的に励起すればよい。In order to solve the above-mentioned problems, an optical trap device using focused light is used, in which a fluorescent dye whose fluorescence intensity changes according to the change in solution state is attached to the surface of fine particles. The fine particles are captured, and the position of the fine particles is moved by moving the focusing point, and the fluorescence intensity of the fluorescent fine particles at an arbitrary position in the solution may be measured and analyzed. Further, by using the wavelength of the focused light used in the optical trap device that is twice the excitation wavelength of the fluorescent dye, only the fluorescent dye of the fluorescent fine particles captured by the optical trap may be selectively excited.
【０００８】[0008]
【作用】溶液状態の変化に応じて蛍光強度が変化する蛍
光色素を付加した微粒子を光学トラップによって捕獲
し、この光学トラップの集光点を移動させることで、微
粒子を溶液中で自在に移動させることができる。このと
き、微粒子を測定したい溶液中で移動させ、そのときの
蛍光強度の変化を観測、解析することによって、溶液状
態の変化を空間分解能をもったかたちで見積もることが
できる。[Function] The fine particles to which the fluorescent dye is added whose fluorescence intensity changes according to the change of the solution state are captured by the optical trap, and the condensing point of the optical trap is moved to freely move the fine particles in the solution. be able to. At this time, by moving the fine particles in the solution to be measured and observing and analyzing the change in the fluorescence intensity at that time, the change in the solution state can be estimated with a spatial resolution.
【０００９】[0009]
【実施例】図１に、本発明の代表的な実施例の装置構成
図を示す。本装置は、集束光を試料溶液中に作り出す機
構と、試料観察、解析のための機構からなる。集束光を
試料溶液中に作り出す機構は、以下のような構成になっ
ている。レーザー光源６で発生させた単色の平行光は、
半透鏡７で対物レンズ５に導入される。レーザー光はレ
ンズ５で試料を含む溶液４中に集束される。また、この
レーザー光の集束点の位置は半透鏡７の方向を走査機構
１５によって制御することで移動させることができる。
あるいは、試料を載せた台を移動させることで同様な効
果を与えることができる。DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS FIG. 1 shows an apparatus configuration diagram of a typical embodiment of the present invention. This device consists of a mechanism for producing focused light in the sample solution and a mechanism for observing and analyzing the sample. The mechanism for producing the focused light in the sample solution has the following configuration. The monochromatic parallel light generated by the laser light source 6 is
It is introduced into the objective lens 5 by the semi-transparent mirror 7. The laser light is focused by the lens 5 into the solution 4 containing the sample. Further, the position of the focal point of the laser light can be moved by controlling the direction of the semitransparent mirror 7 by the scanning mechanism 15.
Alternatively, the same effect can be obtained by moving the table on which the sample is placed.
【００１０】この集束光を試料溶液中に作り出す機構の
レーザー光源６の波長を蛍光物質の励起波長の２倍波長
で用いれば２光子吸収の原理によって、試料溶液中の光
の集束点近傍のみの蛍光色素を選択的に励起させること
ができる。If the wavelength of the laser light source 6 that creates the focused light in the sample solution is twice the excitation wavelength of the fluorescent material, the principle of two-photon absorption causes only the vicinity of the focusing point of the light in the sample solution. The fluorescent dye can be selectively excited.
【００１１】また、この集束光を試料溶液中に作り出す
機構を用いることで微粒子の光トラップを行うことがで
きる。すなわち、その集束点の近傍に集束レーザー光が
生み出す勾配力場が発生することから、この勾配力場に
よって溶液中に浮遊する蛍光微粒子１８は捕獲される。
図２に、このような集束光によって蛍光微粒子１８が捕
獲される様子を示す。溶液４中での蛍光微粒子１８の位
置は、対物レンズ５を通じて集束したレーザー光の位置
を移動させることで移動することができる。Further, by using a mechanism for producing this focused light in the sample solution, it is possible to perform optical trapping of fine particles. That is, since a gradient force field generated by the focused laser light is generated in the vicinity of the focusing point, the fluorescent fine particles 18 floating in the solution are captured by this gradient force field.
FIG. 2 shows how the fluorescent fine particles 18 are captured by such focused light. The position of the fluorescent fine particles 18 in the solution 4 can be moved by moving the position of the laser beam focused through the objective lens 5.
【００１２】試料観察、解析の機構は以下のような構成
になっている。水銀ランプ、ハロゲンランプ等の照射光
源１より照射された白色光は反射鏡２でコンデンサー３
に導入される。コンデンサー３を通過した光は試料を含
む溶液４に入射し、対物レンズ５を通過して半透鏡７を
通過して半透鏡８に達する。半透鏡８で分割された光の
一方は、レーザー光源の波長の光を遮断するフィルター
８１を通して、試料面からの散乱光を除去した上でテレ
ビカメラ９に送られる。テレビカメラ９で撮られた試料
を含む溶液の全体像は、そのまま、画像記憶部１２、画
像処理解析部１３、モニター１４に送られる。半透鏡８
で分割された光のもう一方は、反射鏡１０を経て、蛍光
微粒子が発する蛍光のみを透過するフィルター１０１通
過後にテレビカメラ１１で、蛍光微粒子の蛍光強度を計
測することができる。また、レーザー光源６の波長を蛍
光物質の励起波長の２倍波長で用いれば、このレーザー
光の集束点で捕獲された蛍光微粒子１８の蛍光色素を、
２光子吸収の機構で選択的に励起させることができる。
この集束点における２光子吸収によって、蛍光微粒子の
一部、光の集束点近傍のみを選択的に励起させることが
でき、この結果、蛍光微粒子の発光点の空間分解能を高
めることができる。The sample observation and analysis mechanism has the following structure. White light emitted from an irradiation light source 1 such as a mercury lamp or a halogen lamp is reflected by a reflecting mirror 2 to a condenser 3
Will be introduced. The light passing through the condenser 3 enters the solution 4 containing the sample, passes through the objective lens 5, passes through the semitransparent mirror 7, and reaches the semitransparent mirror 8. One of the lights split by the semi-transparent mirror 8 is sent to the television camera 9 after removing scattered light from the sample surface through a filter 81 that blocks light of the wavelength of the laser light source. The entire image of the solution containing the sample taken by the television camera 9 is sent to the image storage unit 12, the image processing analysis unit 13, and the monitor 14 as it is. Semi-transparent mirror 8
The other part of the light divided by is passed through the reflecting mirror 10, and after passing through the filter 101 that transmits only the fluorescence emitted by the fluorescent fine particles, the television camera 11 can measure the fluorescence intensity of the fluorescent fine particles. Further, if the wavelength of the laser light source 6 is set to be twice the excitation wavelength of the fluorescent substance, the fluorescent dye of the fluorescent fine particles 18 captured at the focusing point of the laser light is
It can be selectively excited by a two-photon absorption mechanism.
Due to the two-photon absorption at the focus point, only a part of the fluorescent fine particles and the vicinity of the light focus point can be selectively excited, and as a result, the spatial resolution of the emission point of the fluorescent fine particles can be improved.
【００１３】蛍光微粒子１８は、光学トラップによって
捕獲され、その光の集束点を走査機構１５をもちいて移
動させることで、溶液中を移動させることができるが、
このとき、微粒子１８を溶液中で移動させながら微粒子
の蛍光強度を連続的に測定することで、微粒子が移動し
た軌跡上の溶液の状態を連続的に測定することができ
る。このときの空間分解能はｎｍオーダーに達する。ま
た、光学トラップによって蛍光微粒子を捕獲するのみの
場合には、集束点を一点に固定して微粒子のブラウン運
動を抑制し、この結果、一点での蛍光微粒子の蛍光強度
の経時変化を連続測定することもできる。このとき、微
粒子に付加する蛍光色素としては、ｐＨ感受性色素、カ
ルシウムイオン感受性色素、電位感受性色素、その他イ
オン感受性色素等がある。また、画像処理解析部１３に
よって微粒子の蛍光強度の変化に応じて半透鏡７を走査
機構１５によって制御し、光学トラップの位置を移動さ
せることもできる。これによって、等イオン濃度曲線を
求めることもできる。The fluorescent fine particles 18 are trapped by the optical trap, and the focusing point of the light can be moved in the solution by moving it using the scanning mechanism 15.
At this time, by continuously measuring the fluorescence intensity of the fine particles while moving the fine particles 18 in the solution, the state of the solution on the locus of movement of the fine particles can be continuously measured. The spatial resolution at this time reaches the nm order. Further, in the case of only capturing the fluorescent fine particles by the optical trap, the focusing point is fixed to one point to suppress the Brownian motion of the fine particles, and as a result, the temporal change of the fluorescence intensity of the fluorescent fine particles at one point is continuously measured. You can also At this time, examples of fluorescent dyes added to the fine particles include pH-sensitive dyes, calcium ion-sensitive dyes, voltage-sensitive dyes, and other ion-sensitive dyes. Further, the position of the optical trap can be moved by controlling the semi-transparent mirror 7 by the scanning mechanism 15 according to the change in the fluorescence intensity of the fine particles by the image processing analysis unit 13. With this, the iso-ion concentration curve can also be obtained.
【００１４】[0014]
【発明の効果】本発明は、以上説明したように構成され
ているので、空間分解能を持った形で試料が引き起こす
溶液状態の変化を観察することができるという効果を奏
する。EFFECTS OF THE INVENTION Since the present invention is configured as described above, it is possible to observe the change in the solution state caused by the sample with a spatial resolution.
【図１】本発明の実施例の装置構成図。FIG. 1 is an apparatus configuration diagram of an embodiment of the present invention.
【図２】光学トラップによる蛍光微粒子の捕獲を説明す
る模式図。FIG. 2 is a schematic diagram illustrating capture of fluorescent fine particles by an optical trap.
１…照射光源、２、１０…反射鏡、３…コンデンサー、
４…試料を含む溶液、５…対物レンズ、６…レーザー光
源、７、８…半透鏡、８１、１０１…フィルター、９、
１１…テレビカメラ、１２…画像記憶部、１３…画像処
理解析部、１４…モニター、１５…走査機構、１７…カ
バーグラス、１８…蛍光微粒子。1 ... Irradiation light source, 2, 10 ... Reflector, 3 ... Condenser,
4 ... Solution containing sample, 5 ... Objective lens, 6 ... Laser light source, 7, 8 ... Semi-transparent mirror, 81, 101 ... Filter, 9,
11 ... Television camera, 12 ... Image storage unit, 13 ... Image processing analysis unit, 14 ... Monitor, 15 ... Scanning mechanism, 17 ... Cover glass, 18 ... Fluorescent fine particles.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 石渡 信一 東京都大田区西嶺町32−12 (72)発明者 木下 一彦 神奈川県横浜市都筑区茅ヶ崎南４−12−12 −503 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Shinichi Ishiwata 32-12 Nishimine-cho, Ota-ku, Tokyo (72) Inventor Kazuhiko Kinoshita 4-12-12-503 Chigasaki Minami, Tsuzuki-ku, Yokohama-shi, Kanagawa
Claims (2)
所定の領域に前記光束を集光させる手段および前記集光
点を移動させる手段とよりなる光学トラップを形成する
機構と、溶液の状態の変化に応じて蛍光強度を変える蛍
光色素を含む微粒子と、その微粒子の蛍光色素を励起す
る所定の波長領域の光源と、蛍光色素の発光を検出する
手段と、その蛍光色素の蛍光強度を解析する手段とを具
有することを特徴とする光学測定装置。1. A light source for generating a light flux in a predetermined wavelength range,
A mechanism for forming an optical trap consisting of a means for condensing the light flux and a means for moving the condensing point in a predetermined region, and fine particles containing a fluorescent dye that changes the fluorescence intensity according to the change in the state of the solution, An optical measuring device comprising: a light source in a predetermined wavelength region for exciting a fluorescent dye of the fine particles; a means for detecting the emission of the fluorescent dye; and a means for analyzing the fluorescence intensity of the fluorescent dye.
源が蛍光色素を励起する波長の２倍の波長とされた請求
項１記載の光学測定装置。2. The optical measuring device according to claim 1, wherein the light source for generating the light flux in the predetermined wavelength region has a wavelength twice as long as the wavelength for exciting the fluorescent dye.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7239510A JPH0989780A (en) | 1995-09-19 | 1995-09-19 | Optical measuring apparatus |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7239510A JPH0989780A (en) | 1995-09-19 | 1995-09-19 | Optical measuring apparatus |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0989780A true JPH0989780A (en) | 1997-04-04 |
Family
ID=17045872
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7239510A Pending JPH0989780A (en) | 1995-09-19 | 1995-09-19 | Optical measuring apparatus |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0989780A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6624940B1 (en) * | 1998-02-03 | 2003-09-23 | Arch Development Corporation | Method for applying optical gradient forces and moving material |
| US6718083B2 (en) | 2001-06-20 | 2004-04-06 | Arryx, Inc. | Optical switch and router |
-
1995
- 1995-09-19 JP JP7239510A patent/JPH0989780A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6624940B1 (en) * | 1998-02-03 | 2003-09-23 | Arch Development Corporation | Method for applying optical gradient forces and moving material |
| US7227688B2 (en) | 1998-02-03 | 2007-06-05 | National Science Foundation | Apparatus for applying optical gradient forces |
| US6718083B2 (en) | 2001-06-20 | 2004-04-06 | Arryx, Inc. | Optical switch and router |
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