Light microscopy: an ongoing contemporary revolution

The optical microscope is one of the oldest scientific instruments that is still used in forefront research. Ernst Abbe’s nineteenth century formulation of the resolution limit in microscopy let generations of scientists believe that optical studies of individual molecules and resolving subwavelength structures were not feasible. The Nobel Prize in 2014 for super-resolution fluorescence microscopy marks a clear recognition that the old beliefs have to be revisited. In this article, we present a critical overview of various recent developments in optical microscopy. In addition to the popular super-resolution fluorescence methods, we discuss the prospects of various other techniques and imaging contrasts and consider some of the fundamental and practical challenges that lie ahead.

[1]  Dan Oron,et al.  Superresolution microscopy with quantum emitters. , 2013, Nano letters.

[2]  Jean-Jacques Greffet,et al.  Stimulated emission depletion microscopy resolves individual nitrogen vacancy centers in diamond nanocrystals. , 2013, ACS nano.

[3]  Mike Heilemann,et al.  Multicolor photoswitching microscopy for subdiffraction-resolution fluorescence imaging , 2009, Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology.

[4]  E. Betzig,et al.  Proposed method for molecular optical imaging. , 1995, Optics letters.

[5]  Anne Sentenac,et al.  Influence of multiple scattering on three-dimensional imaging with optical diffraction tomography. , 2006, Journal of the Optical Society of America. A, Optics, image science, and vision.

[6]  Alois Renn,et al.  Fluorescence Microscopy of Single Molecules , 1994 .

[7]  M. Orrit,et al.  Laser-driven microsecond temperature cycles analyzed by fluorescence polarization microscopy. , 2006, Biophysical journal.

[8]  W. Denk,et al.  Two-photon laser scanning fluorescence microscopy. , 1990, Science.

[9]  G Leuchs,et al.  Sharper focus for a radially polarized light beam. , 2003, Physical review letters.

[10]  Alois Renn,et al.  Aligned terrylene molecules in a spin-coated ultrathin crystalline film of p-terphenyl , 2004 .

[11]  V. Veselago.  The Electrodynamics of Substances with Simultaneously Negative Values of ∊ and μ , 1968 .

[12]  S. Hell,et al.  Simultaneous multi-lifetime multi-color STED imaging for colocalization analyses. , 2011, Optics express.

[13]  K. Jacobson,et al.  Single-particle tracking: applications to membrane dynamics. , 1997, Annual review of biophysics and biomolecular structure.

[14]  Mark Bates,et al.  Three-Dimensional Super-Resolution Imaging by Stochastic Optical Reconstruction Microscopy , 2008, Science.

[15]  U Valentin Nägerl,et al.  Two-color STED microscopy of living synapses using a single laser-beam pair. , 2011, Biophysical journal.

[16]  M. Chalfie.  GREEN FLUORESCENT PROTEIN , 1995, Photochemistry and photobiology.

[17]  Vahid Sandoghdar,et al.  Reflection scanning near-field optical microscopy with uncoated fiber tips: How good is the resolution really? , 1997 .

[18]  C Cremer,et al.  Considerations on a laser-scanning-microscope with high resolution and depth of field. , 1978, Microscopica acta.

[19]  Stefan W. Hell,et al.  Protein localization in electron micrographs using fluorescence nanoscopy , 2010, Nature Methods.

[20]  Vahid Sandoghdar,et al.  Direct optical sensing of single unlabelled proteins and super-resolution imaging of their binding sites. , 2014, Nature communications.

[21]  W. Denk,et al.  Optical stethoscopy: Image recording with resolution λ/20 , 1984 .

[22]  V. Sandoghdar,et al.  Diamond colour centres as a nanoscopic light source for scanning near‐field optical microscopy , 2001, Journal of microscopy.

[23]  E. Betzig,et al.  Near-field spectroscopy of single molecules at room temperature , 1994, Nature.

[24]  J. Pawley,et al.  Handbook of Biological Confocal Microscopy , 1990, Springer US.

[25]  Keith A. Lidke,et al.  Simultaneous multiple-emitter fitting for single molecule super-resolution imaging , 2011, Biomedical optics express.

[26]  P. Barber.  Absorption and scattering of light by small particles , 1984 .

[27]  S. Hell,et al.  Ground-state-depletion fluorscence microscopy: A concept for breaking the diffraction resolution limit , 1995 .

[28]  Fu-Jen Kao,et al.  Optical Imaging and Microscopy , 2003 .

[29]  Alper D Ozkan,et al.  Label-Free Nanometer-Resolution Imaging of Biological Architectures through Surface Enhanced Raman Scattering , 2013, Scientific Reports.

[30]  M. Garcia-Parajo,et al.  Power-law-distributed dark states are the main pathway for photobleaching of single organic molecules. , 2005, Physical review letters.

[31]  Y. Martin,et al.  Scanning Interferometric Apertureless Microscopy: Optical Imaging at 10 Angstrom Resolution , 1995, Science.

[32]  Lord Rayleigh F.R.S..  LVI. Investigations in optics, with special reference to the spectroscope , 1879 .

[33]  J. Popp,et al.  Surface-enhanced Raman spectroscopy , 2009, Analytical and bioanalytical chemistry.

[34]  E. Ulin-Avila,et al.  Three-dimensional optical metamaterial with a negative refractive index , 2008, Nature.

[35]  G Maire,et al.  Full-polarized tomographic diffraction microscopy achieves a resolution about one-fourth of the wavelength. , 2013, Physical review letters.

[36]  Erin A. Riley,et al.  Temperature-dependent fluorescence intermittency for single molecules of violamine R in poly(vinyl alcohol) , 2009 .

[37]  S. Holden,et al.  DAOSTORM: an algorithm for high- density super-resolution microscopy , 2011, Nature Methods.

[38]  C. Sheppard.  Super-resolution in confocal imaging , 1988 .

[39]  F. Keilmann,et al.  Near-field probing of vibrational absorption for chemical microscopy , 1999, Nature.

[40]  S. Habuchi,et al.  Blinking of single dye molecules in a polymer matrix is correlated with free volume in polymers , 2011 .

[41]  Jeremy L O'Brien,et al.  Solid Immersion Facilitates Fluorescence Microscopy with Nanometer Resolution and Sub-Ångström Emitter Localization , 2012, Advanced materials.

[42]  Nadine Gottschalk,et al.  Fundamentals Of Photonics , 2016 .

[43]  M. H. Kaplan,et al.  LOCALIZATION OF A N T I G E N I N TISSUE CELLS I I . IMPROVEMENTS IN A METHOD FOR THE DETECTION OF ANTIGEN BY MEANS OF FLUORESCENT ANTIBODY*' , 2003 .

[44]  Paul R. Selvin,et al.  Myosin V Walks Hand-Over-Hand: Single Fluorophore Imaging with 1.5-nm Localization , 2003, Science.

[45]  T. J. Watson,et al.  Apertureless near-field optical microscope , 1999 .

[46]  H. F. Talbot.  XLIV. Experiments on light , 1834 .

[47]  Akihiro Kusumi,et al.  Paradigm shift of the plasma membrane concept from the two-dimensional continuum fluid to the partitioned fluid: high-speed single-molecule tracking of membrane molecules. , 2005, Annual review of biophysics and biomolecular structure.

[48]  Barry R. Masters,et al.  Resolution enhancement techniques in microscopy , 2013 .

[49]  Rainer Heintzmann,et al.  Resolving a misconception about structured illumination , 2014, Nature Photonics.

[50]  M. Garcia-Parajo,et al.  Power-law blinking in the fluorescence of single organic molecules. , 2007, Chemphyschem : a European journal of chemical physics and physical chemistry.

[51]  Mike Heilemann,et al.  A reducing and oxidizing system minimizes photobleaching and blinking of fluorescent dyes. , 2008, Angewandte Chemie.

[52]  G. G. Stokes.  "J." , 1890, The New Yale Book of Quotations.

[53]  L. Kador,et al.  Spectrally resolved analysis of fluorescence blinking of single dye molecules in polymers at low temperatures. , 2012, The Journal of chemical physics.

[54]  Alberto Diaspro,et al.  Probing Cytoskeletal Structures by Coupling Optical Superresolution and AFM Techniques for a Correlative Approach , 2013, Cytoskeleton.

[55]  M Celebrano,et al.  Imaging a single quantum dot when it is dark. , 2009, Nano letters.

[56]  M. Davidson,et al.  Rapid three-dimensional isotropic imaging of living cells using Bessel beam plane illumination , 2011, Nature Methods.

[57]  Michael J Rust,et al.  Sub-diffraction-limit imaging by stochastic optical reconstruction microscopy (STORM) , 2006, Nature Methods.

[58]  R N Zare,et al.  Probing individual molecules with confocal fluorescence microscopy. , 1994, Science.

[59]  X. Zhuang,et al.  Isotropic 3D Super-resolution Imaging with a Self-bending Point Spread Function , 2014, Nature photonics.

[60]  J. Spudich,et al.  Movement of myosin-coated fluorescent beads on actin cables in vitro , 1983, Nature.

[61]  H. Flyvbjerg,et al.  Optimized localization-analysis for single-molecule tracking and super-resolution microscopy , 2010, Nature Methods.

[62]  Robert M. Dickson,et al.  Imaging Three-Dimensional Single Molecule Orientations , 1999 .

[63]  C.E. Shannon,et al.  Communication in the Presence of Noise , 1949, Proceedings of the IRE.

[64]  J. Schuster,et al.  Influence of self-trapped states on the fluorescence intermittency of single molecules , 2005 .

[65]  F. Pinaud,et al.  Ultrahigh-resolution multicolor colocalization of single fluorescent probes. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[66]  L. Mets,et al.  Nanometer-localized multiple single-molecule fluorescence microscopy. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[67]  Toby D M Bell,et al.  Characterizing the fluorescence intermittency and photobleaching kinetics of dye molecules immobilized on a glass surface. , 2006, The journal of physical chemistry. A.

[68]  H Schindler,et al.  Single-molecule microscopy on model membranes reveals anomalous diffusion. , 1997, Biophysical journal.

[69]  Zygmunt Gryczynski,et al.  Single molecule studies of multiple-fluorophore labeled antibodies. Effect of homo-FRET on the number of photons available before photobleaching. , 2008, Current pharmaceutical biotechnology.

[70]  A. V Narlikar,et al.  Oxford Handbook of Nanoscience and Technology, Volume 1 , 2010 .

[71]  W. Webb,et al.  Precise nanometer localization analysis for individual fluorescent probes. , 2002, Biophysical journal.

[72]  George Biddell Airy,et al.  On the diffraction of an object-glass with circular aperture , 1835 .

[73]  R. Sec..  XV. On the theory of optical images, with special reference to the microscope , 2009 .

[74]  Viola Vogel,et al.  Binding-activated localization microscopy of DNA structures. , 2011, Nano letters.

[75]  R. Tsien,et al.  On/off blinking and switching behaviour of single molecules of green fluorescent protein , 1997, Nature.

[76]  M. Chial,et al.  in simple , 2003 .

[77]  M. Orrit,et al.  Photoblinking of Rhodamine 6G in Poly(vinyl alcohol): Radical Dark State Formed through the Triplet , 2003 .

[78]  V. Sandoghdar,et al.  Spectroscopic detection and state preparation of a single praseodymium ion in a crystal , 2013, Nature Communications.

[79]  Satoshi Kawata,et al.  Measurement of a saturated emission of optical radiation from gold nanoparticles: application to an ultrahigh resolution microscope. , 2014, Physical review letters.

[80]  W. Heisenberg.  The Physical Principles of the Quantum Theory , 1930 .

[81]  C. Sheppard,et al.  Image Formation in the Scanning Microscope , 1977 .

[82]  M. Gustafsson,et al.  S: Widefield Light Microscopy with 100-nm-scale Resolution in Three Dimensions , 2007 .

[83]  Taekjip Ha,et al.  Photophysics of fluorescent probes for single-molecule biophysics and super-resolution imaging. , 2012, Annual review of physical chemistry.

[84]  J. Haseloff,et al.  Molecular Characterization of Recombinant Green Fluorescent Protein by Fluorescence Correlation Microscopy , 1995 .

[85]  Ian M. Dobbie,et al.  Super-Resolution Microscopy Using Standard Fluorescent Proteins in Intact Cells under Cryo-Conditions , 2014, Nano letters.

[86]  O. Bisi.  Experiments with Light , 2015 .

[87]  Johann Engelhardt,et al.  Parallelized STED fluorescence nanoscopy. , 2011, Optics express.

[88]  Kristin L. Hazelwood,et al.  A bright and photostable photoconvertible fluorescent protein for fusion tags , 2009, Nature Methods.

[89]  E. Abbe.  Beiträge zur Theorie des Mikroskops und der mikroskopischen Wahrnehmung , 1873 .

[90]  W. P. Ambrose,et al.  Fluorescence spectroscopy and spectral diffusion of single impurity molecules in a crystal , 1991, Nature.

[91]  V. Sandoghdar,et al.  Nanometer Resolution and Coherent Optical Dipole Coupling of Two Individual Molecules , 2002, Science.

[92]  Shu Jia,et al.  Ultra-bright Photoactivatable Fluorophores Created by Reductive Caging , 2012, Nature Methods.

[93]  W. P. Ambrose,et al.  Alterations of Single Molecule Fluorescence Lifetimes in Near-Field Optical Microscopy , 1994, Science.

[94]  T. Ha,et al.  Single-molecule high-resolution imaging with photobleaching. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[95]  Andrew D Ellington,et al.  Aptamers as potential tools for super-resolution microscopy , 2012, Nature Methods.

[96]  Michael Unser,et al.  Super-resolution orientation estimation and localization of fluorescent dipoles using 3-D steerable filters. , 2009, Optics express.

[97]  S. Hell,et al.  Subdiffraction resolution in far-field fluorescence microscopy. , 1999, Optics letters.

[98]  Roger Y. Tsien,et al.  Fluorophores for Confocal Microscopy: Photophysics and Photochemistry , 2006 .

[99]  D. Pohl,et al.  Scanning near-field optical probe with ultrasmall spot size. , 1995, Optics letters.

[100]  H. Ewers,et al.  A simple, versatile method for GFP-based super-resolution microscopy via nanobodies , 2012, Nature Methods.

[101]  Akihiro Kusumi,et al.  Phospholipids undergo hop diffusion in compartmentalized cell membrane , 2002, The Journal of cell biology.

[102]  Ram Dixit,et al.  Cell damage and reactive oxygen species production induced by fluorescence microscopy: effect on mitosis and guidelines for non-invasive fluorescence microscopy. , 2003, The Plant journal : for cell and molecular biology.

[103]  N. Fang,et al.  Sub–Diffraction-Limited Optical Imaging with a Silver Superlens , 2005, Science.

[104]  Stephan J Sigrist,et al.  Multi‐colour direct STORM with red emitting carbocyanines , 2012, Biology of the cell.

[105]  G. A. Blab,et al.  Single nanoparticle photothermal tracking (SNaPT) of 5-nm gold beads in live cells. , 2006, Biophysical journal.

[106]  Guang-Can Guo,et al.  Quantum statistical imaging of particles without restriction of the diffraction limit. , 2012, Physical review letters.

[107]  Christian Eggeling,et al.  Breaking the diffraction barrier in fluorescence microscopy by optical shelving. , 2007, Physical review letters.

[108]  V. Sandoghdar,et al.  A single gold particle as a probe for apertureless scanning near‐field optical microscopy , 2001, Journal of microscopy.

[109]  Samuel J. Lord,et al.  Three-dimensional, single-molecule fluorescence imaging beyond the diffraction limit by using a double-helix point spread function , 2009, Proceedings of the National Academy of Sciences.

[110]  Lukas Novotny,et al.  Facts and artifacts in near-field optical microscopy , 1997 .

[111]  Jan Renger,et al.  Strong antenna-enhanced fluorescence of a single light-harvesting complex shows photon antibunching , 2014, Nature Communications.

[112]  Ji-Xin Cheng,et al.  Far-field Imaging of Non-fluorescent Species with Sub-diffraction Resolution , 2013, Nature Photonics.

[113]  R. Hochstrasser,et al.  Wide-field subdiffraction imaging by accumulated binding of diffusing probes , 2006, Proceedings of the National Academy of Sciences.

[114]  Steven Chu,et al.  Subnanometre single-molecule localization, registration and distance measurements , 2010, Nature.

[115]  Steven R. Emory,et al.  Probing Single Molecules and Single Nanoparticles by Surface-Enhanced Raman Scattering , 1997, Science.

[116]  T. Hirschfeld.  Optical microscopic observation of single small molecules. , 1976, Applied optics.

[117]  F. Keilmann,et al.  Near-field microscopy by elastic light scattering from a tip , 2004, Philosophical Transactions of the Royal Society of London. Series A: Mathematical, Physical and Engineering Sciences.

[118]  Markus Greiner,et al.  A quantum gas microscope for detecting single atoms in a Hubbard-regime optical lattice , 2009, Nature.

[119]  P. Zoller,et al.  Coherent quantum optical control with subwavelength resolution. , 2007, Physical review letters.

[120]  Xue-Wen Chen,et al.  Resolution and enhancement in nanoantenna-based fluorescence microscopy. , 2009, Nano letters.

[121]  Santiago Casado,et al.  Correlative atomic force microscopy and localization-based super-resolution microscopy: revealing labelling and image reconstruction artefacts. , 2014, Chemphyschem : a European journal of chemical physics and physical chemistry.

[122]  F. Simmel,et al.  Single-molecule kinetics and super-resolution microscopy by fluorescence imaging of transient binding on DNA origami. , 2010, Nano letters.

[123]  W. Moerner,et al.  Optical detection and spectroscopy of single molecules in a solid. , 1989, Physical review letters.

[124]  S. Hell,et al.  Two-color far-field fluorescence nanoscopy. , 2007, Biophysical journal.

[125]  Byoungho Lee,et al.  Vector field microscopic imaging of light , 2007 .

[126]  Th. Förster.  Zwischenmolekulare Energiewanderung und Fluoreszenz , 1948 .

[127]  Jörg Enderlein,et al.  Image scanning microscopy. , 2010, Physical review letters.

[128]  Christian Eggeling,et al.  Nanoscopy with more than 100,000 'doughnuts' , 2013, Nature Methods.

[129]  Paul R Selvin,et al.  Polarization effect on position accuracy of fluorophore localization. , 2006, Optics express.

[130]  J. Goodman.  Introduction to Fourier optics , 1969 .

[131]  V. Sandoghdar,et al.  Optical microscopy using a single-molecule light source , 2000, Nature.

[132]  Lukas Novotny,et al.  Antenna-based optical imaging of single Ca2+ transmembrane proteins in liquids. , 2008, Nano letters.

[133]  Harald F Hess,et al.  Correlative 3D superresolution fluorescence and electron microscopy reveal the relationship of mitochondrial nucleoids to membranes , 2012, Proceedings of the National Academy of Sciences.

[134]  Lars Hufnagel,et al.  Multiview light-sheet microscope for rapid in toto imaging , 2012, Nature Methods.

[135]  Alf Honigmann,et al.  Coaligned dual-channel STED nanoscopy and molecular diffusion analysis at 20 nm resolution. , 2013, Biophysical journal.

[136]  F. Del Bene,et al.  Optical Sectioning Deep Inside Live Embryos by Selective Plane Illumination Microscopy , 2004, Science.

[137]  Peter Dedecker,et al.  Spectroscopic rationale for efficient stimulated-emission depletion microscopy fluorophores. , 2010, Journal of the American Chemical Society.

[138]  M. Sheetz,et al.  Tracking kinesin-driven movements with nanometre-scale precision , 1988, Nature.

[139]  M. Orrit,et al.  Single pentacene molecules detected by fluorescence excitation in a p-terphenyl crystal. , 1990, Physical review letters.

[140]  S. Hell.  Far-Field Optical Nanoscopy , 2007, Science.

[141]  Daniel F Gilbert,et al.  Performance of scientific cameras with different sensor types in measuring dynamic processes in fluorescence microscopy , 2013, Microscopy research and technique.

[142]  X. Zhuang,et al.  Whole cell 3D STORM reveals interactions between cellular structures with nanometer-scale resolution , 2008, Nature Methods.

[143]  Martin J Booth,et al.  Adaptive optics enables 3D STED microscopy in aberrating specimens. , 2012, Optics express.

[144]  Alexander Y Katsov,et al.  fast multicolor 3 d imaging using aberration-corrected multifocus microscopy , 2012 .

[145]  M. Gustafsson.  Nonlinear structured-illumination microscopy: wide-field fluorescence imaging with theoretically unlimited resolution. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[146]  J. Lippincott-Schwartz,et al.  Imaging Intracellular Fluorescent Proteins at Nanometer Resolution , 2006, Science.

[147]  M. Delhaye,et al.  Raman microprobe and microscope with laser excitation , 1975 .

[148]  S. Ram,et al.  Localization accuracy in single-molecule microscopy. , 2004, Biophysical journal.

[149]  Vahid Sandoghdar,et al.  Enhancement of single-molecule fluorescence using a gold nanoparticle as an optical nanoantenna. , 2006, Physical review letters.

[150]  Randy Wayne.  Light and video microscopy , 2008 .

[151]  Michel Orrit,et al.  Single-molecule optics. , 2004, Annual review of physical chemistry.

[152]  Zhaowei Liu,et al.  Far-Field Optical Hyperlens Magnifying Sub-Diffraction-Limited Objects , 2007, Science.

[153]  Brahim Lounis,et al.  Large parallelization of STED nanoscopy using optical lattices. , 2013, Optics express.

[154]  M Deutsch,et al.  Connective tissue polarity. Optical second-harmonic microscopy, crossed-beam summation, and small-angle scattering in rat-tail tendon. , 1986, Biophysical journal.

[155]  D. Baylor,et al.  Single-photon detection by rod cells of the retina , 1998 .

[156]  Alois Renn,et al.  Cryogenic colocalization microscopy for nanometer-distance measurements. , 2014, Chemphyschem : a European journal of chemical physics and physical chemistry.

[157]  Alberto Diaspro,et al.  A novel nanoscopic tool by combining AFM with STED microscopy , 2012, Optical Nanoscopy.

[158]  Bo Jing,et al.  Cryogenic localization of single molecules with angstrom precision , 2013, Optics & Photonics - NanoScience + Engineering.

[159]  David J. Nesbitt,et al.  ``On''/``off'' fluorescence intermittency of single semiconductor quantum dots , 2001 .

[160]  Satoshi Kawata,et al.  Plasmon saturation induced super-resolution imaging , 2013, Photonics West - Biomedical Optics.

[161]  M El Sayed,et al.  SHAPE AND SIZE DEPENDENCE OF RADIATIVE, NON-RADIATIVE AND PHOTOTHERMAL PROPERTIES OF GOLD NANOCRYSTALS , 2000 .

[162]  Tracking single particles on supported lipid membranes: multimobility diffusion and nanoscopic confinement. , 2013, The journal of physical chemistry. B.

[163]  S. Kawata,et al.  Near-field scanning optical microscope with a metallic probe tip. , 1994, Optics letters.

[164]  M. Bertolaccini,et al.  The measurement of luminescence waveforms by single‐photon techniques , 1973 .

[165]  Michael D. Mason,et al.  Ultra-high resolution imaging by fluorescence photoactivation localization microscopy. , 2006, Biophysical journal.

[166]  Zhaowei Liu,et al.  Spherical hyperlens for two-dimensional sub-diffractional imaging at visible frequencies. , 2010, Nature communications.

[167]  Alois Renn,et al.  Single-molecule imaging by optical absorption , 2011 .

[168]  Robert Neuhauser,et al.  Blinking statistics in single semiconductor nanocrystal quantum dots , 2001 .

[169]  Mike Heilemann,et al.  The effect of photoswitching kinetics and labeling densities on super-resolution fluorescence imaging. , 2010, Journal of biotechnology.

[170]  J. Pendry,et al.  Negative refraction makes a perfect lens , 2000, Physical review letters.

[171]  Roger Y. Tsien,et al.  Fluorophores for Confocal Microscopy , 1995 .

[172]  Anne Sentenac,et al.  Beyond the Rayleigh criterion: grating assisted far-field optical diffraction tomography. , 2006, Physical review letters.

[173]  L. Rayleigh.  Investigations in optics, with special reference to the spectroscope , 1880 .

[174]  Magnetic field dependence of the exciton energy in a quantum disk , 2000, cond-mat/0002405.

[175]  Alexander Y Katsov,et al.  Fast and sensitive multi-color 3D imaging using aberration-corrected multi-focus microscopy , 2012, Nature Methods.

[176]  Christian Eggeling,et al.  Breaking the diffraction barrier in fluorescence microscopy at low light intensities by using reversibly photoswitchable proteins. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[177]  Viola Vogel,et al.  Interferometric optical detection and tracking of very small gold nanoparticles at a water-glass interface. , 2006, Optics express.

[178]  S Fine,et al.  Optical second harmonic generation in biological systems. , 1971, Applied optics.

[179]  Christian Eggeling,et al.  Multicolor far-field fluorescence nanoscopy through isolated detection of distinct molecular species. , 2008, Nano letters.

[180]  Robert J. Chichester,et al.  Single Molecules Observed by Near-Field Scanning Optical Microscopy , 1993, Science.

[181]  Benjamin Schmid,et al.  High-resolution reconstruction of the beating zebrafish heart , 2014, Nature Methods.

[182]  Alois Renn,et al.  Single-Molecule Sensitivity in Optical Absorption at Room Temperature , 2010 .

[183]  F. Zernike.  How I discovered phase contrast. , 1955, Science.

[184]  Satoru Shoji,et al.  Saturation and Reverse Saturation of Scattering in a Single Plasmonic Nanoparticle , 2014 .

[185]  T. Yanagida,et al.  Single molecule nanobioscience. , 2001, Trends in biochemical sciences.

[186]  S. Hess,et al.  Three-dimensional sub–100 nm resolution fluorescence microscopy of thick samples , 2008, Nature Methods.

[187]  Agard,et al.  I5M: 3D widefield light microscopy with better than 100 nm axial resolution , 1999, Journal of microscopy.

[188]  Mortazavi,et al.  Supporting Online Material Materials and Methods Figs. S1 to S13 Tables S1 to S3 References Label-free Biomedical Imaging with High Sensitivity by Stimulated Raman Scattering Microscopy , 2022 .

[189]  V. Adam,et al.  Reversible photoswitching in fluorescent proteins: A mechanistic view , 2012, IUBMB life.

[190]  V. Sandoghdar,et al.  Detection and spectroscopy of gold nanoparticles using supercontinuum white light confocal microscopy. , 2004, Physical review letters.

[191]  Lars Meyer,et al.  Dual-color STED microscopy at 30-nm focal-plane resolution. , 2008, Small.

[192]  L. Novotný,et al.  Enhancement and quenching of single-molecule fluorescence. , 2006, Physical review letters.

[193]  Wesley R. Legant,et al.  Lattice light-sheet microscopy: Imaging molecules to embryos at high spatiotemporal resolution , 2014, Science.

[194]  E. Synge.  XXXVIII. A suggested method for extending microscopic resolution into the ultra-microscopic region , 1928 .

[195]  Philipp J. Keller,et al.  Quantitative high-speed imaging of entire developing embryos with simultaneous multiview light-sheet microscopy , 2012, Nature Methods.

[196]  R Hoffman,et al.  Modulation contrast microscope. , 1975, Applied optics.

[197]  S. Hell,et al.  Breaking the diffraction resolution limit by stimulated emission: stimulated-emission-depletion fluorescence microscopy. , 1994, Optics letters.

[198]  S. Hell,et al.  Nanoscale resolution in GFP-based microscopy , 2006, Nature Methods.

[199]  M. Gustafsson.  Surpassing the lateral resolution limit by a factor of two using structured illumination microscopy , 2000, Journal of microscopy.

[200]  Steven F. Lee,et al.  Improved super-resolution microscopy with oxazine fluorophores in heavy water. , 2013, Angewandte Chemie.

[201]  R. W. Terhune,et al.  Study of Optical Effects Due to an Induced Polarization Third Order in the Electric Field Strength , 1965 .

[202]  R. Heintzmann,et al.  Saturated patterned excitation microscopy--a concept for optical resolution improvement. , 2002, Journal of the Optical Society of America. A, Optics, image science, and vision.

[203]  Christian L. Müller,et al.  High-speed nanoscopic tracking of the position and orientation of a single virus , 2009, Nature Methods.

[204]  Immanuel Bloch,et al.  Single-atom-resolved fluorescence imaging of an atomic Mott insulator , 2010, Nature.

[205]  Renaud Bachelot,et al.  Near field optical microscopy using a metallic vibrating tip , 1995 .

[206]  Mark Bates,et al.  Multicolor Super-Resolution Imaging with Photo-Switchable Fluorescent Probes , 2007, Science.

[207]  Christian Eggeling,et al.  Macromolecular-scale resolution in biological fluorescence microscopy. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[208]  S. Stallinga,et al.  Position and orientation estimation of fixed dipole emitters using an effective Hermite point spread function model. , 2012, Optics express.