CN101949849B - Light-activated positioning microscopic imaging system based on optical fiber evanescent field illuminator - Google Patents
Light-activated positioning microscopic imaging system based on optical fiber evanescent field illuminator Download PDFInfo
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- CN101949849B CN101949849B CN2010102755277A CN201010275527A CN101949849B CN 101949849 B CN101949849 B CN 101949849B CN 2010102755277 A CN2010102755277 A CN 2010102755277A CN 201010275527 A CN201010275527 A CN 201010275527A CN 101949849 B CN101949849 B CN 101949849B
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- G—PHYSICS
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- 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
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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
- G01N21/6456—Spatial resolved fluorescence measurements; Imaging
- G01N21/6458—Fluorescence microscopy
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Abstract
The invention relates to a light-activated positioning microscopic imaging system based on an optical fiber evanescent field illuminator. Activation lasers emitted by an activation laser sequentially pass through a neutral filter, a shutter and a controller thereof, a reflective mirror, a dichroscope and a lens and then enter the optical fiber evanescent field illuminator; imaging lasers emitted by an imaging laser sequentially pass through the neutral filter, the shutter and the controller thereof, the dichroscope and the lens and then enter the optical fiber evanescent field illuminator; the optical fiber evanescent field illuminator is fixed on a controlling device and is arranged in a sample pool of an inverted fluorescence microscope, and a detector EMCCD (Electron Multiplying Charge-Coupled Device) collects fluorescence signals collected by an objective of the inverted fluorescence microscope. According to the invention, the illuminating light path is separated from the imaging light path so as to simplify the light path, the illumination is carried out by using the optical fiber evanescent field illuminator without an objective with high numerical aperture so as to reduce the system cost; meanwhile each surface of a cell sample is imaged by controlling the position, the depth and the angle of the optical fiber evanescent field illuminator.
Description
Technical field
The present invention relates to a kind of photoactivation location micro imaging system, especially a kind of photoactivation location micro imaging system that can carry out multi-faceted illumination imaging to sample based on illuminator in fiber-optical evanescent field.
Background technology
In the bio-science field, accurately locating specific protein has vital role to position and the function of studying albumen.Electron microscope and non-optical class Scanning Probe Microscopy can reach nano level resolution, but it can't study single protein molecular by specific marker, also can't be used for the observational study live body simultaneously.
The optical microphotograph imaging can be carried out the non-invasi live body and detect and Single Molecule Detection, and important optical information such as polarization state, spectrum can be provided, and these advantages are imaged in the biological study optical microphotograph and have a wide range of applications.But common far-field optics micro-imaging is owing to be subjected to the restriction of the Rayleigh diffraction limit of Abbe, and the resolution of wide field and Laser Scanning Confocal Microscope can only reach about 200nm.Because be subjected to the restriction of limited spatial resolution, common far-field optics micro-imaging can't be used for the research of micro-structure such as the research of protein function etc.In recent years, along with the appearance of novel fluorescence probe and the innovation of imaging mode, the resolution of photoactivation location microtechnic has reached about 20nm.
Photoactivation location microtechnic is utilized the photoactivation characteristic of photoactivation albumen, light intensity by the control exciting light is activated with sparse photoactivation fluorescin molecule in the realization visual field, use imaging to excite the fluorescin of activated state to send fluorescence then, other fluorescins that are not activated then can't send fluorescence, realize occurring at the most in each diffraction-limited zone the fluorescin of an activated state like this.At last the unimolecule spatial light intensity information that collects is handled, calculated the accurate positional information of unimolecule.Through repeatedly repeating, nearly all bleached until fluorescin like this, all locating information are stacked up can obtain to break through the super-resolution imaging of diffraction limit.A major issue that exists is, what it need be surveyed is monomolecular intensity signal, because the unimolecule signal is very weak, and be easy to be subjected to the influence of ground unrest, so general photoactivation location microtechnic utilization is that the evanscent field that total internal reflection produces throws light on.
The evanscent field that TOTAL INTERNAL REFLECTION FLUORESCENCE MICROSCOPY utilizes total internal reflection the to produce sample that throws light on, because evanscent field only is present in the thin layer of hundred nano-scale, so only being in the fluorescence molecule of this layer is subjected to exciting and sends fluorescence, can well suppress ground unrest, obtain the very fluorescence imaging of high s/n ratio.
Yet, evanscent field only be present in adherent 100nm of sample about scope in, so photoactivation location microtechnic generally can only be used for the shallow-layer information of adherent of observation of cell, and can't observe the cell upper surface and the side that may have biological function; The object lens of the high-NA that uses in order to obtain the better effects evanscent field have simultaneously increased the cost of system.
Summary of the invention
The present invention is directed to the deficiency that above-mentioned prior art exists, utilize the illumination of optical fiber evanscent field, designed a kind of photoactivation location micro imaging system based on illuminator in fiber-optical evanescent field, the present invention separates illumination path and imaging optical path on the basis of traditional photoactivation location micro imaging system, has simplified light path; Utilize illuminator in fiber-optical evanescent field to throw light on, do not need the object lens of high-NA, reduced system cost; By position, the degree of depth and the angle of control illuminator in fiber-optical evanescent field, carry out imaging simultaneously to realize each surface of pair cell sample.
Technical solution of the present invention is:
Photoactivation location micro imaging system based on illuminator in fiber-optical evanescent field, mainly by activating laser instrument 11, imaging laser instrument 12, neutral colour filter (9,10), shutter and controller thereof (7,8), catoptron 6, dichroscope 5, lens 4, illuminator in fiber-optical evanescent field 1, control device 3, inverted fluorescence microscope 14, detector electron multiplication EMCCD13 form; The activation laser that activates laser instrument 11 emissions incides illuminator in fiber-optical evanescent field 1 through neutral colour filter 9, shutter and controller 7 thereof, catoptron 6, dichroscope 5, lens 4 successively; The imaging laser of imaging laser instrument 12 emissions incides illuminator in fiber-optical evanescent field 1 through neutral colour filter 10, shutter and controller 8 thereof, dichroscope 5, lens 4 successively; Illuminator in fiber-optical evanescent field 1 is fixed on the control device 3, and illuminator in fiber-optical evanescent field 1 is placed in the sample cell of inverted fluorescence microscope 14, and detector electron multiplication EMCCD13 gathers the object lens of inverted fluorescence microscope 14 and collects fluorescence signal.Activate laser instrument 11 and be used for emission activation laser, the light intensity of neutral colour filter 9 control exciting lights, shutter and controller 7 thereof are used to control the irradiation time that activates laser; Imaging laser instrument 12 is used to launch imaging laser, and neutral colour filter 10 is used to be controlled to the light intensity of picture laser, and shutter and controller 8 thereof are used to be controlled to the irradiation time of picture laser; Catoptron 6 is used to change the exciting light direction; Dichroscope 5 energy catoptric imaging laser, and to activating laser-transmitting, the optical axis coincidence of the imaging laser of the activation laser of process catoptron 6 and dichroscope 5 and process dichroscope 5; Lens 4 are used for activation laser and imaging laser coupled are gone into illuminator in fiber-optical evanescent field; Illuminator in fiber-optical evanescent field 1 is used to sample that the evanscent field illumination is provided; Control device 3 can carry out three-dimensional position to illuminator in fiber-optical evanescent field to be regulated, and the position of illuminator in fiber-optical evanescent field, the degree of depth and angle can freely change like this; Detector EMCCD13 is used to receive the object lens of inverted fluorescence microscope 14 and collects fluorescence signal.
The described illuminator in fiber-optical evanescent field 1 employing patent No. is 200810237414.0 " illuminator in fiber-optical evanescent field ".
Characteristics of the present invention are: (1) separates illumination path and imaging optical path, has simplified system light path; (2) do not need the large-numerical aperture object lens, reduced system cost; (3) carry out imaging by each surface of position pair cell of control illuminator in fiber-optical evanescent field, and easy to adjust.
Description of drawings
Fig. 1 is the system architecture synoptic diagram based on the photoactivation location micro imaging system of illuminator in fiber-optical evanescent field.
Fig. 2 is the illuminator in fiber-optical evanescent field fundamental diagram.
Fig. 3 is for activating the imaging sequential chart in the photoactivation positioning and imaging process.
Embodiment
The present invention will be described in detail below in conjunction with accompanying drawing:
As shown in Figure 1, the present invention is mainly by activating laser instrument 11, imaging laser instrument 12, neutral colour filter (9,10), shutter and controller thereof (7,8), catoptron 6, dichroscope 5, lens 4, illuminator in fiber-optical evanescent field 1, control device 3, inverted fluorescence microscope 14, detector electron multiplication EMCCD13 form; The activation laser that activates laser instrument 11 emissions incides illuminator in fiber-optical evanescent field 1 through neutral colour filter 9, shutter and controller 7 thereof, catoptron 6, dichroscope 5, lens 4 successively; The imaging laser of imaging laser instrument 12 emissions incides illuminator in fiber-optical evanescent field 1 through neutral colour filter 10, shutter and controller 8 thereof, dichroscope 5, lens 4 successively; Illuminator in fiber-optical evanescent field 1 is fixed on the control device 3, and illuminator in fiber-optical evanescent field 1 is placed in the sample cell of inverted fluorescence microscope 14, and detector electron multiplication EMCCD13 gathers the object lens of inverted fluorescence microscope 14 and collects fluorescence signal.Activate laser instrument 11 and be used for emission activation laser, the light intensity of neutral colour filter 9 control exciting lights, shutter and controller 7 thereof are used to control the irradiation time that activates laser; Imaging laser instrument 12 is used to launch imaging laser, and neutral colour filter 10 is used to be controlled to the light intensity of picture laser, and shutter and controller 8 thereof are used to be controlled to the irradiation time of picture laser; Catoptron 6 is used to change the exciting light direction; Dichroscope 5 energy catoptric imaging laser, and to activating laser-transmitting, the optical axis coincidence of the imaging laser of the activation laser of process catoptron 6 and dichroscope 5 and process dichroscope 5; Lens 4 are used for activation laser and imaging laser coupled are gone into illuminator in fiber-optical evanescent field; Illuminator in fiber-optical evanescent field 1 is used to sample that the evanscent field illumination is provided; Control device 3 can carry out three-dimensional position to illuminator in fiber-optical evanescent field to be regulated, and the position of illuminator in fiber-optical evanescent field, the degree of depth and angle can freely change like this; Detector EMCCD13 is used to receive the object lens of inverted fluorescence microscope 14 and collects fluorescence signal.
The described illuminator in fiber-optical evanescent field 1 employing patent No. is 200810237414.0 " illuminator in fiber-optical evanescent field ".
Embodiment one: utilize the super-resolution micro-imaging of realizing biological cell based on the photoactivation location micro imaging system of illuminator in fiber-optical evanescent field.Fig. 1 is the system architecture synoptic diagram based on the photoactivation location micro imaging system of illuminator in fiber-optical evanescent field.Experimental cell is the hek293 cell BK passage of mEosFP light conversion fluorescence protein labeling.Activate laser and use the laser of wavelength as 405nm, imaging laser uses the laser of wavelength as 561nm.The optical axis that utilizes catoptron 6 and dichroscope 5 will activate laser and imaging laser is adjusted to coincidence.Utilize lens 4 will activate laser and the imaging laser coupled is gone in the illuminator in fiber-optical evanescent field.Control device 3 can be regulated the three-dimensional position of illuminator in fiber-optical evanescent field, with position, the degree of depth and the angle of control illuminator in fiber-optical evanescent field.
Fig. 2 is the illuminator in fiber-optical evanescent field fundamental diagram.One end of optical fiber is worn into the inclined-plane, reflects when light is incident to the inclined-plane from fiber cores 2, and light reflexes to the fiber end face place, and produces evanscent field in the fiber end face experiences total internal reflection.
At first sample is placed on the microscopical objective table, moving stage moves into cell sample in the visual field, and the cell compartment that then illuminator in fiber-optical evanescent field is moved into the visual field and press close to need to observe utilizes evanscent field to activate and excite the mEosFP fluorescin.Actual conditions are chosen suitable exciting light light intensity per sample, the exciting light irradiation time, and the exciting light light intensity, the excitation light irradiation time, and pass through the control that neutral colour filter (9,10) and shutter and controller (7,8) thereof are realized above-mentioned parameter.Imaging process activates the imaging sequential as shown in Figure 3.Actual conditions are chosen suitable EMCCD and are adopted graph parameter per sample, as time shutter and gain etc., begin to gather a series of images then.Pass through the data processing in later stage at last, the accurate unimolecule that collects of location, and superpose and obtain final super-resolution micro-imaging restructuring graph.
Claims (1)
1. based on the photoactivation location micro imaging system of illuminator in fiber-optical evanescent field, mainly become by activation laser instrument, imaging laser instrument, first neutral colour filter, second neutral colour filter, first shutter and controller, second shutter and controller thereof, catoptron, dichroscope, lens, illuminator in fiber-optical evanescent field, control device, inverted fluorescence microscope, electron multiplication inductive coupling device detector set; The activation laser that activates the laser instrument emission incides illuminator in fiber-optical evanescent field through first neutral colour filter, first shutter and controller thereof, catoptron, dichroscope, lens successively; The imaging laser of imaging laser instrument emission incides illuminator in fiber-optical evanescent field through second neutral colour filter, second shutter and controller thereof, dichroscope, lens successively; Illuminator in fiber-optical evanescent field is fixed on the control device, and illuminator in fiber-optical evanescent field is placed in the sample cell of inverted fluorescence microscope, and electron multiplication inductive coupling device detector is gathered the object lens of inverted fluorescence microscope and collected fluorescence signal; The structure of this illuminator in fiber-optical evanescent field is set to: the part of optical fiber one end grinds to form the inclined-plane, and fiber cores position 1-10 micron is crossed on the inclined-plane, when light from fiber cores incident, be reflected onto the fiber end face place at the place, inclined-plane, and in the fiber end face experiences total internal reflection, it is on 125 microns the simple optical fiber that the evanscent field luminaire is produced on diameter, and the inclined-plane can make the light in the fiber cores that total reflection takes place at the place, inclined-plane, perhaps utilizes coating technique plating total reflection film on the inclined-plane.
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| US9512985B2 (en) | 2013-02-22 | 2016-12-06 | Kla-Tencor Corporation | Systems for providing illumination in optical metrology |
| CN103235406B (en) * | 2013-04-27 | 2015-01-07 | 中国科学院化学研究所 | Total internal reflection illumination and semi-total internal reflection illumination dual optical path fluorescence microscope system |
| CN104568857B (en) * | 2015-01-29 | 2017-10-17 | 山东大学 | A kind of two-dimentional light scattering quiescence cells instrument method and device |
| WO2017200907A1 (en) * | 2016-05-20 | 2017-11-23 | Instrumentation Laboratory Company | Evanescent hemolysis detection |
| CN107014788A (en) * | 2017-02-24 | 2017-08-04 | 浙江大学 | The caliberating device and scaling method of the incident depth of new utilizing total internal reflection fluorescence microscope |
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