Source: http://www.google.com/patents/US7864314?dq=patent:6144888
Timestamp: 2017-10-22 14:20:12
Document Index: 471568423

Matched Legal Cases: ['Application No. 06784461', 'Application No. 06784461', 'Application No. 06784461', 'Application No. 2008', 'Application No. 2008', 'Application No. 06784461', 'Application No. 2008']

Patent US7864314 - Optical microscopy with phototransformable optical labels - Google Patents
An apparatus includes a position-sensitive detector to detect intensities of radiation as a function of position on the detector, and an optical system, characterized by a diffraction-limited resolution volume, adapted for imaging light emitted from activated and excited phototransformable optical labels...http://www.google.com/patents/US7864314?utm_source=gb-gplus-sharePatent US7864314 - Optical microscopy with phototransformable optical labels
Publication number US7864314 B2
Application number US 12/645,019
Also published as CA2609653A1, CA2609653C, EP1894010A2, EP1894010A4, EP1894010B1, EP1894010B2, EP2453237A1, EP2453237B1, EP2453238A1, EP2453238B1, EP2453239A1, EP2453239B1, EP2453240A1, EP2453240B1, EP2453241A1, EP2453241B1, EP3203235A1, US7535012, US7626694, US7626695, US7626703, US7710563, US7782457, US8462336, US8599376, US9360426, US20080068588, US20080068589, US20080070322, US20080070323, US20080111086, US20090206251, US20100181497, US20110102787, US20130126759, US20140287941, US20170115221, WO2006127692A2, WO2006127692A3
Publication number 12645019, 645019, US 7864314 B2, US 7864314B2, US-B2-7864314, US7864314 B2, US7864314B2
Original Assignee Hestzig Llc
Patent Citations (53), Non-Patent Citations (66), Referenced by (15), Classifications (15), Legal Events (1)
US 7864314 B2
n i = N 2 πσ ⅇ - ( x i x c ) 2 2 σ 2 ,
FIGS. 9 a and 9 b are schematic diagrams of a system that can use through-the-objective TIRF excitation radiation to excite sparsely-populated activated PTOLs in a sample, such that radiation emitted from the activated, excited PTOLs can be imaged to produce superresolution images of the sample via phototransformation, isolation, and localization of multiple subsets of discrete PTOLs within the sample. For continuous excitation of activated PTOLs, light having a wavelength of 561 nm emitted from a 10 mW diode-pumped solid-state laser (available from Lasos GmbH, Jena, Germany) is fiber-coupled to an excitation collimator 900 and provides an excitation input beam 901 that can be focused at the rear pupil plane internal to a 60×, 1.45 NA total internal reflection fluorescence (“TIRF”) oil immersion objective 902 (available from Olympus America, Melville, N.Y.). A narrow bandwidth laser line filter 903 (available from Semrock, Inc., Rochester, N.Y.) is used to reject both emission noise from the laser and autofluorescence generated in the optical path prior to the objective 902. For pulsed activation of the PTOLs, a second diode laser (available form Coherent Inc., Santa Clara, Calif.) that can yield about 50 mW of power at an activation wavelength, λact, of about 405 nm can be fiber-coupled through an intermediate galvanometer-based switch (not shown) to an activation collimator 904 to create a focused activation input beam 905 that is similarly filtered by a bandpass filter 906 (available from CVI Optical, Covina, Calif.) before being combined with the excitation input beam 901 at a dichroic minor 907 (available from Semrock, Inc.). This combined input beam 908 then can be reflected from an elliptical spot on a custom-patterned, aluminized mirror 909 (available from Reynard Corp., San Clemente, Calif.) into the objective 902. The radius, ρ, at which the combined beam 908 enters objective 902 can be controlled to be (nsample/NA)*4.35≈4.14 mm≦ρ≦4.35 mm (for nsample≈1.38), such that the resulting refracted ray transverses a low autofluorescence immersion oil (e.g., Cargille type FF, available from Structure Probe Inc., West Chester, Pa.) and is incident at the interface between the sample and a cover slip 913 (e.g., a #2 thickness cover slip available from Fisher Scientific, Hampton, N.H.) at greater than the critical angle, θc≈sin−1(nsample/ncoverlip), for which total internal reflection (“TIR”) occurs. An evanescent field can be thereby established within the sample, exciting only those molecules within the short decay length of the evanescent field. A substantial proportion of the incident energy of the excitation and activation beams, however, can be reflected at the interface to yield a combined output beam 910 that emerges from the objective 902, and that is then reflected from a second elliptical spot on mirror 909 diagonally opposite the first elliptical spot on the mirror. This beam 910 is then divided at dichroic mirror 907 into an excitation output beam 911 and a separate activation output beam 912 that are finally directed to respective beam dumps.
For typical molecular cross-sections (e.g., approximately 10−16 cm2), the reflected excitation beam energy may be 1015-fold more intense than a PTOL signal beam 914 that emerges from the objective 902, as shown in FIG. 9 b. Therefore, a challenge in this through-the-objective TIRF geometry is the isolation of the molecular signal from both the interface-reflected excitation beam and any autofluorescence generated by this beam in the optics encountered thereafter. The mirror 909 aids in this isolation because the mirror has an elliptical, anti-reflection coated, transmissive aperture whose projection perpendicular to the objective axis matches the 8.7 mm diameter of the rear pupil, and therefore passes signal beam 914 to the detection optics with high efficiency. Also, for an elliptical reflective spot D times larger than the gaussian width of the reflected beam at the spot, only about erfc(D) of the excitation energy is passed onto the detection optics, or ˜2.10−5 to ˜2.10−8 for D=3 or 4, respectively. Furthermore, since the spots occlude only a small fraction of the periphery of the rear pupil, they do not substantially degrade the detection numerical aperture. Consequently, the PSF standard deviation, s, that factors into sub-diffraction limited localization of PTOLs is not substantially degraded. Furthermore, the mirror 909 is wavelength insensitive, and therefore can be used with different excitation lasers and different PTOLs without replacement. The minor 909 can include multiple spots to support multi-angle, multi-polarization and/or standing wave TIRF excitation.
Because the activation wavelength is typically short (e.g., about 400 nm) for Dronpa, the activation PSF can provide most of the resolution benefit in the overall PSF. If cellular damage from this short of a wavelength is a concern, multiphoton activation can be used, at the cost of a slightly larger activation PSF than is possible with linear (i.e., single photon) activation. In addition, because the density of emitting molecules is given by PSF PSFactivation×PSFexcitation, the emitting molecules will be confined to at least as tight a focal region as in conventional two-photon excitation, thereby leading to greatly reduced out-of-plane photobleaching and background, even using linear, confocal excitation. Of course, further gains in both spatial and temporal resolution are possible if sparse composite lattices of the same or commensurate periods are used for both the activation radiation (as shown in FIG. 13 a, and in the close up view of FIG. 13 a shown in FIG. 13 d) and for the excitation radiation (as shown in FIG. 13 b, and in the close up of FIG. 13 b in FIG. 13 e), leading to an overall lattice (shown in FIG. 13 c) that achieves activation and excitation of PTOLs and that has having sharper maxima (shown in FIG. 130 than the maxima in the lattices for the activation and excitation radiation. Point spread function engineering and relative displacement of the activation and excitation PSFs might be used to further increase the resolution by reducing the region of their effective overlap. If the contribution of the detection PSF to the overall resolution is negligible, it might be advantageous to simply omit pinhole filtering (as in most embodiments of multiphoton microscopy) in order to maximize the collected signal. Finally, we note that this method of superresolution, is well suited to dynamic superresolution imaging in living cells (particularly with lattice microscopy), because potentially many more molecules would be emitting photons at a given time from each focus (when confocal radiation is used for activation and excitation) or excitation maximum (when radiation patterned in a lattice is used for activation and excitation).
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US20080068588 Nov 21, 2007 Mar 20, 2008 Hess Harald F Optical microscopy with phototransformable optical labels
US20080068589 Nov 21, 2007 Mar 20, 2008 Robert Betzig Optical microscopy with phototransformable optical labels
US20080070322 Nov 21, 2007 Mar 20, 2008 Robert Betzig Optical microscopy with phototransformable optical labels
US20080070323 Nov 21, 2007 Mar 20, 2008 Robert Betzig Optical microscopy with phototransformable optical labels
US20080111086 Nov 21, 2007 May 15, 2008 Robert Eric Betzig Optical microscopy with phototransformable optical labels
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US20090135432 May 22, 2007 May 28, 2009 Robert Eric Betzig Optical lattice microscopy
US20090206251 Nov 21, 2007 Aug 20, 2009 Robert Eric Betzig Optical microscopy with phototransformable optical labels
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WO2004090950A2 Apr 8, 2004 Oct 21, 2004 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Creation of a permanent structure with high three-dimensional resolution
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Cooperative Classification G02B27/58, G02B21/367, G02B21/16, G01N2021/6441, G01N2021/6421, G01N2021/6419, G01N21/648, G01N21/6458, G01N21/6428, G01N2021/6439, G01N21/64, G01N33/582