CA2609653A1 - Optical microscopy with phototransformable optical labels - Google Patents

Optical microscopy with phototransformable optical labels Download PDF

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CA2609653A1
CA2609653A1 CA002609653A CA2609653A CA2609653A1 CA 2609653 A1 CA2609653 A1 CA 2609653A1 CA 002609653 A CA002609653 A CA 002609653A CA 2609653 A CA2609653 A CA 2609653A CA 2609653 A1 CA2609653 A1 CA 2609653A1
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radiation
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CA2609653C (en
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Harald F. Hess
Robert E. Betzig
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    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
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    • G01N21/64—Fluorescence; Phosphorescence
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    • G—PHYSICS
    • G02—OPTICS
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    • G02B21/00—Microscopes
    • G02B21/16—Microscopes adapted for ultraviolet illumination ; Fluorescence microscopes
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B21/00—Microscopes
    • G02B21/36—Microscopes arranged for photographic purposes or projection purposes or digital imaging or video purposes including associated control and data processing arrangements
    • G02B21/365—Control or image processing arrangements for digital or video microscopes
    • G02B21/367—Control or image processing arrangements for digital or video microscopes providing an output produced by processing a plurality of individual source images, e.g. image tiling, montage, composite images, depth sectioning, image comparison
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B27/00—Optical systems or apparatus not provided for by any of the groups G02B1/00 - G02B26/00, G02B30/00
    • G02B27/58—Optics for apodization or superresolution; Optical synthetic aperture systems
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    • 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
    • G01N2021/6417—Spectrofluorimetric devices
    • G01N2021/6419—Excitation at two or more wavelengths
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    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N2021/6417—Spectrofluorimetric devices
    • G01N2021/6421—Measuring at two or more wavelengths
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    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • G01N2021/6439—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" with indicators, stains, dyes, tags, labels, marks
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    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • G01N2021/6439—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" with indicators, stains, dyes, tags, labels, marks
    • G01N2021/6441—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" with indicators, stains, dyes, tags, labels, marks with two or more labels
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    • 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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Abstract

First activation radiation is provided to a sample that includes phototransformable optical labels ("PTOLs") to activate a first subset of th e PTOLs in the sample. First excitation radiation is provided to the first subset of PTOLs in the sample to excite at least some of the activated PTOLs , and radiation emitted from activated and excited PTOLs within the first subs et of PTOLs is detecting with imaging optics. The first activation radiation is controlled such that the mean volume per activated PTOLs in the first subset is greater than or approximately equal to a diffraction-limited resolution volume ("DLRV") of the imaging optics.

Claims (110)

1. A method comprising:
providing first activation radiation to a sample that includes phototransformable optical labels ("PTOLs") to activate a first subset of the PTOLs in the sample;
providing first excitation radiation to the first subset of PTOLs in the sample to excite at least some of the activated PTOLs;
detecting with imaging optics radiation emitted from activated and excited PTOLs within the first subset of PTOLs; and controlling the first activation radiation such that the mean volume per activated PTOLs in the first subset is greater than or approximately equal to a diffraction-limited resolution volume ("DLRV") of the imaging optics.
2. The method of claim 1, wherein a probability that two or more activated PTOLs are located within one DLRV is less than about 0.1.
3. The method of claim 1, further comprising detecting radiation emitted from the first subset of PTOLs with a position-sensitive detector located at an image plane of the PTOLs from which radiation is emitted.
4. The method of claim 1, further comprising determining the location of a plurality of individual PTOLs in the first subset of PTOLs with sub-diffraction limited accuracy based on the detected radiation.
5. The method of claim 4, further comprising generating a sub-diffraction-limited image of the sample based on the determined locations of the plurality of individual PTOLs.
6. The method of claim 1, further comprising providing deactivation radiation to the sample to deactivate PTOLs in the first subset of PTOLs.
7. The method of claim 6, wherein the deactivation radiation comprises sufficient excitation radiation to photobleach PTOLs in the first subset of PTOLs.
8. The method of claim 1, wherein the activation radiation has an activation wavelength and wherein the excitation radiation has an excitation wavelength that is longer from the activation wavelength.
9. The method of claim 1, wherein the PTOLs comprise variants of proteins derived from the Aequorea genus of jellyfish by genetic modification.
10. The method of claim 9, where the variants of proteins derived from the Aequorea genus of jellyfish by genetic modification are selected from the group consisting of PA-GFP and PS-CFP.
11. The method of claim 1, wherein the PTOLs comprise variants of proteins derived any of the corals selected from the group consisting of Discosoma striata, Trachyphyllia geoffroyi, Montastraea cavernosa, Ricordea florida, Lobophyllia hemprichii, Anemonia sulcata, and Favia favus.
12. The method of claim 11, wherein the variants of proteins derived any of the corals are selected from the group consisting of Kaede, Kikume, EosFP, and KFP.
13. The method of claim 1, wherein the PTOLs comprise variants of proteins derived from the Pectiniidae family of stony reef corals by genetic modification.
14. The method of claim 13 wherein the variants of proteins derived from the Pectiniidae family of stony reef corals by genetic modification comprise the Dronpa.
15. The method of claim 1, further comprising providing at least one of the activation radiation and the excitation radiation to the sample by total internal reflection of the at least one of the activation radiation and the excitation radiation at a sample/substrate interface.
16. The method of claim 15, wherein the substrate comprises a waveguide, and furthering comprising providing at least one of the activation radiation and the excitation radiation to the sample/substrate interface through the waveguide.
17. The method of claim 15, wherein the imaging optics comprises an objective lens and further comprising providing at least one of the activation radiation and the excitation radiation to the sample by transmitting the at least one of the activation radiation and the excitation radiation through the objective lens.
18. The method of claim 17, further comprising providing at least one of the activation radiation and the excitation radiation to the sample by reflecting at least one of the activation radiation and the excitation radiation from a region having a spatial extent that is small compared to a spatial extent of a proximal back aperture of the objective lens and that is located at a radial position relative to an optical axis of the objective lens such that at least one of the activation radiation and the excitation radiation that emerges from a distal end of the objective lens is totally internally reflected from the sample/substrate interface.
19. The method of claim 17, further comprising substantially intercepting at least one of the activation radiation and the excitation radiation emerging from a proximal back aperture of the objective lens after reflection from the sample/substrate interface with a reflective or absorptive region having a spatial extent that is small compared to a spatial extent of the back aperture of the objective lens.
20. The method of claim 1, further comprising providing at least one of the activation radiation and the excitation radiation to the sample in the form of an optical lattice.
21. The method of claim 20, further comprising creating the optical lattice by impinging at least one of the activation radiation and the excitation radiation from the substrate side of a substrate/sample interface at angles such that the at least one of the activation radiation and the excitation radiation is totally internally reflected from the interface.
22. The method of claim 20, wherein the sample spans a plurality of lattice planes and further comprising selectively detecting radiation emitted from PTOLs located in different lattice planes.
23. The method of claim 1, further comprising providing at least one of the activation radiation and the excitation radiation over a wide field.
24. The method of claim 1, further comprising focusing at least one of the activation radiation and the excitation radiation to a focal position within the sample.
25. The method of claim 1, wherein providing the first activation radiation to the sample activates PTOLs in the first subset of PTOLs in the sample through a multi-photon absorption process.
26. The method of claim 1, wherein providing the first excitation radiation to the sample excites PTOLs in the first subset of PTOLs in the sample through a multi-photon absorption process.
27 The method of claim 1, further comprising controlling a polarization of at least one of the activation radiation and the excitation radiation provided to the sample.
28. The method of claim 1, wherein detecting radiation emitted from activated and excited PTOLs within the first subset of PTOLs comprises discriminating the emitted radiation based on the polarization of the emitted radiation.
29. The method of claim 28, further comprising determining a dipole orientation for at least one of the activated and excited PTOLs that emits radiation.
30. The method of claim 29, wherein detecting radiation emitted from activated and excited PTOLs within the first subset of PTOLs comprises discriminating the emitted radiation based on the polarization of the emitted radiation, and further comprising:
determining locations of a plurality of individual PTOLs in the first subset of PTOLs with sub-diffraction limited accuracy based on the detected radiation;
determining a dipole orientation of the plurality of activated and excited PTOLs that emit radiation; and recording location and orientation data for the plurality of activated and excited PTOLs.
31. The method of claim 30, further comprising generating a sub-diffraction-limited image based on the recording location and orientation data for the plurality of activated and excited PTOLs.
32. The method of claim 1, wherein the sample comprises a thin section of material cut with a microtome from a larger block of material.
33. The method of claim 32, wherein the section is sufficiently thin to be imaged in a transmission electron microscope.
34 The method of claim 32, wherein PTOLs are bound to the selected portions of the thin section to highlight specific sample features.
35. The method of claim 1, wherein the sample comprises a section sufficiently thin to be imaged in a transmission electron microscope, and further comprising:
determining the location of a plurality of individual PTOLs in the first subset of PTOLs with sub-diffraction limited accuracy based on the detected radiation;
generating a sub-diffraction-limited image of the sample based on the determined locations of the plurality of individual PTOLs; and comparing the sub-diffraction-limited image of the sample to an image of the same section obtained by transmission electron microscopy.
36. The method of claim 1, further comprising cooling at least a portion of the sample until the portion is substantially frozen.
37 The method of claim 36, further comprising cooling the portion such that the portion is frozen in a vitreous state.
38. The method of claim 1, further comprising cooling at least a portion of the sample to a temperature sufficiently low such that the quantum efficiency of at least some of the PTOLs in the first subset are increased by about two times or more.
39. The method of claim 1, further comprising cooling the sample to a temperature sufficiently low to decrease by about two times a probability of photobleaching at least some of the PTOLs in the first subset of PTOLs.
40. A method of imaging with an optical system characterized by a diffraction-limited resolution volume, the method comprising:
in a sample comprising a plurality of phototransformable optical labels ("PTOLs") distributed in at least a portion of the sample with a density greater than an inverse of the diffraction-limited resolution volume of the optical system, activating a first subset of the PTOLs in the portion of the sample, wherein the density of PTOLs in the first subset is less than the inverse of the diffraction-limited resolution volume;
exciting a portion of the PTOLs in the first subset of PTOLs;
detecting radiation emitted from the activated and excited PTOLs in the first subset of PTOLs with the imaging optics; and determining locations of activated and excited PTOLs in the first subset of PTOLs with a sub-diffraction-limited accuracy based on the detected radiation emitted from the activated and excited PTOLs.
41. The method of claim 40, wherein activating the first subset of the PTOLs comprises providing sufficient energy to the PTOLs in the first subset to transform the PTOLs from an unactivated state to an activated state.
42. The method of claim 41, wherein providing energy to the PTOLs in the first subset comprises providing activation radiation to the sample, wherein the activating radiation has a wavelength selected to transform the PTOLs from the unactivated state to the activated state.
43. The method of claim 40, wherein exciting a portion of the first subset of PTOLs comprises providing sufficient energy to the PTOLs in the first subset to excite the PTOLs from a ground state to an excited state.
44. The method of claim 43, wherein providing energy to the PTOLs comprises providing excitation radiation to the sample, wherein the excitation radiation has a wavelength selected to transform the PTOLs from the ground state to the excited state.
45. The method of claim 40, further comprising generating an image based on the determined locations of the PTOLs in the first subset of PTOLs.
46. The method of claim 40, further comprising:
deactivating PTOLs in the first subset of PTOLs;
activating a second subset of the PTOLs in the portion of the sample, wherein a density of PTOLs in the second subset is less than the inverse of the diffraction-limited resolution volume;
exciting a portion of the PTOLs in the second subset of PTOLs;
detecting radiation emitted from the activated and excited PTOLs in the second subset of PTOLs with the imaging optics; and determining locations of activated and excited PTOLs in the second subset of PTOLs with a sub-diffraction-limited accuracy based on the detected radiation emitted from the activated and excited PTOLs in the second subset of PTOLs.
47. The method of claim 46, wherein the first and second subsets are statistically sampled subsets of the PTOLs in the portion of the sample.
48. The method of claim 46, wherein deactivating PTOLs in the first subset comprises providing sufficient excitation radiation to the sample to photobleach the activated PTOLs in the first subset.
49. The method of claim 46, wherein deactivating PTOLs in the first subset comprises providing resetting radiation to the PTOLs in the first subset.
50. The method of claim 46, wherein deactivating PTOLs in the first subset comprises allowing a period of time to elapse during which the PTOLs in the first subset decay to an unactivated state.
51. The method of claim 46, wherein deactivating PTOLs in the first subset of PTOLs occurs before activating the second subset of the PTOLs.
52. The method of claim 46, further comprising:
recording first intensity signals of radiation emitted from PTOLs in the first subset as a function of a detection location;
analyzing the first intensity signals to determine locations of the PTOLs in the first subsets to a sub-diffraction limited accuracy;
recording second intensity signals of radiation emitted from PTOLs in the second subset as a function of a detection location; and analyzing the second intensity signals to determine locations of the PTOLs in the second subsets to a sub-diffraction limited accuracy.
53. The method of claim 46, further comprising generating a sub-diffraction-limited image based on the determined locations of PTOLs in the first and second subsets.
54. The method of claim 46, wherein activating the second subset of the PTOLs comprises providing sufficient energy to the PTOLs in the second subset to transform the PTOLs from an unactivated state to an activated state.
55. The method of claim 54, wherein providing energy to the PTOLs comprises providing activation radiation to the sample, wherein the activating radiation has a wavelength selected to transform the PTOLs from the unactivated state to the activated state.
56. The method of claim 46, wherein exciting a portion of the second subset of the PTOLs comprises providing sufficient energy to the PTOLs in the second subset to excite the PTOLs from a ground state to an excited state.
57. The method of claim 56, wherein providing energy to the PTOLs in the second subset comprises providing excitation radiation to the sample, wherein the excitation radiation has a wavelength selected to transform the PTOLs from the ground state to the excited state.
58. ~The method of claim 46, further comprising repeating at least twenty times the steps of:
activating an Nth subset of the PTOLs in the portion of the sample, wherein a density of PTOLs in the Nth subset is less than the inverse of the diffraction-limited resolution volume;
exciting a portion of the PTOLs in the Nth subset of PTOLs;
detecting radiation emitted from the activated and excited PTOLs in the Nth subset of PTOLs with the imaging optics;
determining locations of activated and excited PTOLs in the Nth subset of PTOLs with a sub-diffraction-limited accuracy based on the detected radiation emitted from the activated and excited PTOLs in the Nth subset of PTOLs; and deactivating PTOLs in the Nth subset of PTOLs, wherein N is an integer that runs from 1 to 20.
59. ~A method comprising:
providing spatially-structured activation radiation having relatively high-and relatively low- intensity regions to a sample that includes phototransformable optical labels ("PTOLs") to activate a subset of the PTOLs in the sample located predominately at relatively high intensity regions of the spatially-strucured activation radiation;
providing spatially-structured excitation radiation to the subset of activated PTOLs in the sample, wherein the exciting radiation is structured so that one or more relatively high intensity regions of the excitation radiation at least partially overlap one or more relatively high intensity regions of the activating radiation;
detecting radiation emitted from the activated and excited PTOLs with imaging optics; and controlling the intensities and spatial structures of the activating radiation and the exciting radiation so that radiation emitted from PTOLs in the sample is emitted substantially from at least one volume that is comparable to or less than a diffraction-limited resolution volume ("DLRV") of the imaging optics.
60. ~The method of claim 59, further comprising detecting radiation emitted from a first region in which at least one first maximum of the spatially-structured activation radiation substantially coincides with at least one first maximum of the spatially-structured excitation radiation.
61. The method of claim 60, further comprising detecting radiation emitted from a second region in which a second maximum of the spatially-structured activation radiation substantially coincides with a second maximum of the spatially-structured excitation radiation, wherein radiation emitted from the first region and radiation from the second region are detected independently.
62. The method of claim 59, further comprising:
providing deactivation radiation to the sample to deactivate activated PTOLs in the subset of PTOLs.
63. The method of claim 62, wherein the deactivating radiation comprises excitation radiation that photobleaches the activated PTOLs.
64. The method of claim 62, wherein the deactivating radiation comprises radiation for transforming an PTOL from an activated state to an unactivated, activatable state and has a wavelength that is different from a wavelength of the excitation wavelength.
65. The method of claim 62, further comprising repeatedly:
providing the spatially-structured activation radiation to activate a subset of the PTOLs in the sample located predominately at relatively high intensity regions of the spatially-structured activation radiation;
providing the spatially-structured exciting radiation to the subset of activated PTOLs in the sample, wherein the exciting radiation is structured so that one or more relatively high intensity regions of the excitation radiation at least partially overlap one or more relatively high intensity regions of the activating radiation;
detecting radiation emitted from the activated and excited PTOLs with imaging optics; and relocating to a new location within the sample the one or more relatively high intensity regions of the excitation radiation and the one or more relatively high intensity regions of the activating radiation region that overlap.
66. The method of claim 65, further comprising generating an image based on the radiation detected when the regions of overlap are in a plurality of new positions.
67. The method of claim 66, wherein the image has sub-diffraction limited resolution.
68. The method of claim 65, further comprising controlling the intensities and spatial structures of the activating radiation and the exciting radiation so that radiation emitted from activated and excited PTOLs in at least one of the overlap regions of relatively high intensity activating radiation and relatively high excitation radiation is comparable to or less than a diffraction-limited resolution volume ("DLRV") of the imaging optics.
69. The method of claim 68, wherein the probability that two or more activated and excited PTOLs are located within one DLRV is less than about 0.1.
70. The method of claim 69, further comprising determining the location of a plurality of activated and excited PTOLs to sub-diffraction limited accuracy based on the detected emitted radiation.
71. The method of claim 70, further comprising generating a sub-diffraction-limited image based on the determined locations of the plurality of activated and excited PTOLs.
72. The method of claim 70, further comprising generating a sub-diffraction-limited image based on the determined locations and the detected intensities of the plurality of activated and excited PTOLs.
73. The method of claim 69, wherein the spatially-structured activation radiation comprises an optical lattice that is totally internally reflected at an interface between the sample and a substrate.
74. The method of claim 69, wherein the spatially-structured excitation radiation comprises an optical lattice that is totally internally reflected at a substrate/sample interface.
75. The method of claim 66, further comprising:
detecting radiation emitted from PTOLs located in multiple planes of the optical lattice; and generating a 3D image based on the detected data emitted from the PTOLs in located in the multiple image planes
76. The method of claim 69, further comprising spatially filtering radiation emitted from a activated and excited PTOL in at least one prior to detection of the emitted radiation.
77. A method comprising:
providing activation radiation to a sample that includes phototransformable optical labels ("PTOLs") to activate a first subset of the PTOLs in the sample;
providing deactivation radiation to the sample to transform activated PTOLs to an unactivated state, wherein the deactivation radiation has a spatially-structured radiation field including intensity minima, such that a second subset of PTOLs located substantially at the minima of the resetting radiation remain activated, while activated PTOLs exposed to the resetting radiation outside the minima are substantially transformed in an unactivated form;
providing excitation radiation to the sample to excite at least a portion of the activated PTOLs in the sample;
detecting radiation emitted from the activated and excited PTOLs with imaging optics; and controlling the intensity of the first activation radiation and controlling at least one of the intensity and the spatial structure of the deactivation radiation such that the mean volume per activated PTOL in the first subset is greater than or approximately equal to a diffraction-limited resolution volume ("DLRV") of the imaging optics.
78. The method of claim 77, further comprising detecting independently radiation emitted from two or more sub-diffraction limited regions in the sample.
79. The method of claim 77, further comprising transforming activated PTOLs at the intensity minima of the spatially-structured deactivating radiation field to an unactivated state.
80. The method of claim 79, wherein the activated PTOLs are transformed to an unactivated state by providing sufficient excitation radiation to the sample to photobleach the activated PTOLs at the intensity minima.
81. The method of claim 79, wherein the activated PTOLs are transformed to an unactivated state by providing deactivating radiation to the PTOLs.
82. The method of claim 79, wherein the activated PTOLs are transformed to an unactivated state by allowing a period of time to elapse during which the PTOLs decay to the unactivated state.
83. The method of claim 77, further comprising repeating the steps of:
providing activation radiation to the sample to activate the first subset of the PTOLs in the sample;
providing the spatially-structured deactivating radiation field to the sample to transform activated PTOLs to an unactivated state, such that a second subset of PTOLs located substantially at the minima of the deactivating radiation remain activated, while activated PTOLs exposed to the deactivating radiation outside the minima are substantially transformed in an unactivated form;
providing excitation radiation to the sample to excite at least a portion of the activated PTOLs; and detecting radiation emitted from the activated and excited PTOLs with imaging optics, wherein the minima of the of the deactivating radiation field are at different locations in the sample during different repetitions of the steps.
84. The method of claim 83, further comprising generating a sub-diffraction limited image based on the emitted radiation detected from a plurality of locations within the sample.
85. The method of claim 83, wherein the mean volume of activated and excited PTOLs in at least one region of remaining activation and excitation is comparable to or less than a diffraction-limited resolution volume ("DLRV") of the imaging optics.
86. The method of claim 83, wherein the probability that two or more activated and excited PTOLs are located within one DLRV is less than about 0.1.
87. The method of claim 83, further comprising determining locations of individual PTOLs to sub-diffraction limited accuracy based on the detected radiation emitted from the PTOLs.
88. The method of claim 87, further comprising generating a sub-diffraction limited resolution image based on the determined locations of a plurality of regions of localized PTOLs.
89. The method of claim 87, further comprising generating a sub-diffraction limited resolution image based on the determined locations of a plurality of regions of localized PTOLs and based on detected intensities of the plurality of activated and excited PTOLs.
90. The method of claim 77, wherein the activation radiation comprises a periodic structure, and wherein the deactivating radiation field comprises intensity minima that overlap with a periodicity of the activation field.
91. The method of claim 90, wherein the excitation radiation comprises a spatial structure that is commensurate with the intensity minima of the deactivating radiation field.
92. The method of claim 77, wherein the activation radiation comprises an optical lattice that is totally internally reflected at an interface between the sample and a substrate.
93. The method of claim 77, wherein the spatially-structured deactivating radiation field comprises an optical lattice that is totally internally reflected at an interface between the sample and a substrate.
94. The method of claim 77, wherein the excitation radiation comprises an optical lattice that is totally internally reflected at an interface between the sample and a substrate.
95. The method of claim 77, further comprising collecting radiation emitted from activated and excited PTOLs with a confocal microscope or a 4.pi.
microscope that uses the focus of a microscope to define a spatial structure of the activation radiation, the deactivating radiation field, and the exciting radiation field.
96. An apparatus comprising:
a position-sensitive detector adapted for detecting intensities of radiation as a function of position on the detector;
an optical system characterized by a diffraction-limited resolution volume, adapted for imaging light emitted from a plurality of activated and excited phototransformable optical labels ("PTOLs") in a sample onto the position sensitive-detector, wherein the PTOLs are distributed in at least a portion of the sample with a density greater than an inverse of the diffraction-limited resolution volume of the optical system;
a first light source adapted for providing first activation radiation to the sample to activate a first subset of the PTOLs in the portion of the sample;
a second light source adapted for providing first excitation radiation to the sample to excite a portion of the PTOLs in the first subset of the PTOLs; and a controller adapted for controlling the activation radiation provided to the sample such that a density of PTOLs in the first subset of activated PTOLs is less than the inverse of the diffraction-limited resolution volume.
97. The apparatus of claim 96, further comprising:
a processor for processing position-dependent intensity data about radiation emitted from activated and excited PTOLs in the first subset of PTOLs provided by the detector to determine locations of activated and excited PTOLs in the first subset of PTOLs with a sub-diffraction-limited accuracy.
98. The apparatus of claim 97, further comprising a memory adapted for storing sub-diffraction-limited positional information about PTOLs in the first subset of PTOLs.
99. The apparatus of claim 98, further comprising a processor adapted for generating a sub-diffraction-limited image based on the sub-diffraction-limited positional information about the PTOLs in the first subset of PTOLs.
100. The apparatus of claim 96, wherein the controller is further adapted for controlling the excitation radiation provided to the sample, such that PTOLs in the first subset are deactivated through photobleaching by the excitation radiation.
101. The apparatus of claim 96, wherein the controller is further adapted for controlling the activation radiation and the excitation radiation provided to the sample, such that an initial pulse of activation radiation is provided to the sample such that a density of PTOLs in an initial subset of activated PTOLs is less than the inverse of the diffraction-limited resolution volume, excitation radiation is provided to the sample to excite activated PTOLs in the initial subset, radiation emitted from activated and excited PTOLs in the initial subset of PTOLs is detected by the detector, and a subsequent pulse of activation radiation is provided to the sample after PTOLs in the initial subset have been de-activated, such that a density of PTOLs in a subsequent subset of activated PTOLs is less than the inverse of the diffraction-limited resolution volume, excitation radiation is provided to the sample to excite activated PTOLs in the subsequent subset, radiation emitted from activated and excited PTOLs in the subsequent subset of PTOLs is detected by the detector.
102. The apparatus of claim 96, further comprising a third light source adapted for providing second activation radiation to the sample to activate a second subset of the PTOLs in the portion of the sample, wherein the second activation radiation has a wavelength that is different that a wavelength of the first activation radiation, and wherein PTOLs in the first and second subsets are different species of PTOL and emit radiation having different wavelengths.
103. The apparatus of claim 102, wherein the detector is adapted for differentially detecting radiation emitted from the different species of PTOLs.
104. The apparatus of claim 96, further comprising a filter between the sample and the detector for discrimination particular wavelengths of emitted radiation.
105. The apparatus of claim 96, wherein the imaging system comprises an objective lens and, wherein the first activating radiation is provided to the sample through the objective lens.
106. The method of claim 40, wherein the sample comprises a first species and a second species of PTOL, and further comprising:
distinguishing the first species from the second species based on at least one of emission characteristics of the first and second species and excitation characteristics of the first and second species; and determining locations of activated PTOLs in the first activated subsets for the first and second species relative to one another with sub-diffraction limited accuracy.
107. The method of claim 1, wherein the sample comprises at least a first species and a second species of PTOL, and further comprising:
distinguishing the first species from the second species based on at least one of emission characteristics of the first and second species and excitation characteristics of the first and second species;
wherein a density of each species of PTOL in the sample is greater than the inverse of DLRV of the imaging optics, and wherein a density of species of PTOL in the first subset of activated PTOLs of that species is less than the inverse of the diffraction-limited resolution volume.
108. The method of claim 1, wherein the sample comprises a resist embedded with PTOLs wherein the embedded PTOLs have been subject to exposure to a spatially structured beam, such that the PTOL properties are measurably changed by such exposure.
109. The method of claim 108, further comprising generating an exposure profile for the resist from the determined locations of the detected PTOLs.
110. The method of claim 46, wherein the sample comprises a resist embedded with PTOLs wherein the embedded PTOLs have been subject to exposure to a spatially structured beam, such that the PTOL properties are measurably changed by such exposure, and further comprising generating an exposure profile for the resist from the determined locations of the detected PTOLs.
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