Advertisement

Fluorescence Lifetime Imaging

  • Klaus SuhlingEmail author
  • Liisa M. Hirvonen
  • James A. Levitt
  • Pei-Hua Chung
  • Carolyn Tregidgo
  • Dmitri Rusakov
  • Kaiyu Zheng
  • Simon Ameer-Beg
  • Simon Poland
  • Simon Coelho
  • Robert Henderson
  • Nikola Krstajic
Living reference work entry

Later version available View entry history

Abstract

Fluorescence lifetime imaging (FLIM) is a key fluorescence microscopy technique to map the environment and interaction of fluorescent probes. It can report on photophysical events that are difficult or impossible to observe by fluorescence intensity imaging, because FLIM is largely independent of the local fluorophore concentration and excitation intensity. Many FLIM applications relevant for biology concern the identification of Förster resonance energy transfer (FRET) to study protein interactions and conformational changes. In addition, FLIM has been used to image viscosity, temperature, pH, refractive index, and ion and oxygen concentrations, all at the cellular level. The basic principles and recent advances in the application of FLIM, FLIM instrumentation, molecular probe, and FLIM detector development will be discussed.

Keywords

Time-correlated single-photon counting (TCSPC) Fluorescence microscopy Fluorescence spectroscopy Anisotropy Förster resonance energy transfer (FRET) Fluorescence anisotropy imaging (FAIM) Time-resolved fluorescence anisotropy imaging (TR-FAIM) Total internal reflection fluorescence (TIRF) Fluorescence enhancement Plasmonics 

Notes

Acknowledgments

We would like to thank the UK’s MRC, BBSRC, and EPSRC for funding.

References

  1. 1.
    Borst JW, Visser AJWG (2010) Fluorescence lifetime imaging microscopy in life sciences. Meas Sci Technol 21(10):102002Google Scholar
  2. 2.
    Berezin MY, Achilefu S (2010) Fluorescence lifetime measurements and biological imaging. Chem Rev 110(5):2641–2684Google Scholar
  3. 3.
    Becker W (2012) Fluorescence lifetime imaging – techniques and applications. J Microsc 247(2):119–136Google Scholar
  4. 4.
    Wallrabe H, Periasamy A (2005) Imaging protein molecules using FRET and FLIM microscopy. Curr Opin Biotechnol 16(1):19–27Google Scholar
  5. 5.
    Chen Y, Mills JD, Periasamy A (2003) Protein localization in living cells and tissues using FRET and FLIM. Differentiation 71(9–10):528–541Google Scholar
  6. 6.
    Peter M, Ameer-Beg SM (2004) Imaging molecular interactions by multiphoton FLIM. Biol Cell 96(3):231–236Google Scholar
  7. 7.
    Jares-Erijman EA, Jovin TM (2003) FRET imaging. Nat Biotechnol 21(11):1387–1396Google Scholar
  8. 8.
    Duncan RR (2006) Fluorescence lifetime imaging microscopy (FLIM) to quantify protein-protein interactions inside cells. Biochem Soc Trans 34(5):679–682Google Scholar
  9. 9.
    Festy F, Ameer-Beg SM, Ng T, Suhling K (2007) Imaging proteins in vivo using fluorescence lifetime microscopy. Mol Biosyst 3(6):381–391Google Scholar
  10. 10.
    Pietraszewska-Bogiel A, Gadella TWJ (2011) FRET microscopy: from principle to routine technology in cell biology. J Microsc 241(2):111–118Google Scholar
  11. 11.
    Bird DK, Agg KM, Barnett NW, Smith TA (2007) Time-resolved fluorescence microscopy of gunshot residue: an application to forensic science. J Microsc Oxf 226(1):18–25MathSciNetGoogle Scholar
  12. 12.
    Ni T, Melton LA (1996) Two-dimensional gas-phase temperature measurements using fluorescence lifetime imaging. Appl Spectrosc 50(9):1112–1116Google Scholar
  13. 13.
    Ehn A, Johansson O, Bood J, Arvidsson A, Li B, Alden M (2011) Fluorescence lifetime imaging in a flame. Proc Combust Inst 33:807–813Google Scholar
  14. 14.
    Liaugaudas G, Collins AT, Suhling K, Davies G, Heintzmann R (2009) Luminescence-lifetime mapping in diamond. J Phys Condens Matter 21:364210, (7 pp)Google Scholar
  15. 15.
    Liaugaudas G, Davies G, Suhling K, Khan RUA, Evans DJF (2012) Luminescence lifetimes of neutral nitrogen-vacancy centres in synthetic diamond containing nitrogen. J Phys Condens Matter 24:435503 (5pp)Google Scholar
  16. 16.
    Magennis SW, Graham EM, Jones AC (2005) Quantitative spatial mapping of mixing in microfluidic systems. Angew Chem Int Ed 44(40):6512–6516Google Scholar
  17. 17.
    Benninger RKP, Koc Y, Hofmann O, Requejo-Isidro J, Neil MAA, French PMW, deMello AJ (2006) Quantitative 3D Mapping of Fluidic Temperatures within Microchannel Networks Using Fluorescence Lifetime Imaging. Anal Chem 78:2272–2278Google Scholar
  18. 18.
    Robinson T, Valluri P, Manning HB, Owen DM, Munro I, Talbot CB, Dunsby C, Eccleston JF, Baldwin GS, Neil MAA, de Mello AJ, French PMW (2008) Three-dimensional molecular mapping in a microfluidic mixing device using fluorescence lifetime imaging. Opt Lett 33(16):1887–1889Google Scholar
  19. 19.
    Benninger RKP, Hofmann O, McGinty J, Requejo-Isidro J, Munro I, Neil MAA, deMello AJ, French PMW (2005) Time-resolved fluorescence imaging of solvent interactions in microfluidic devices. Opt Express 13(16):6275–6285Google Scholar
  20. 20.
    Elder AD, Matthews SM, Swartling J, Yunus K, Frank JH, Brennan CM, Fisher AC, Kaminski CF (2006) The application of frequency-domain Fluorescence Lifetime Imaging Microscopy as a quantitative analytical tool for microfluidic devices. Opt Express 14(12):5456–5467Google Scholar
  21. 21.
    Graham EM, Iwai K, Uchiyama S, de Silva AP, Magennis SW, Jones AC (2010) Quantitative mapping of aqueous microfluidic temperature with sub-degree resolution using fluorescence lifetime imaging microscopy. Lab Chip 10(10):1267–1273Google Scholar
  22. 22.
    Redford GI, Majumdar ZK, Sutin JDB, Clegg RM (2005) Properties of microfluidic turbulent mixing revealed by fluorescence lifetime imaging. J Chem Phys 123(22):224504Google Scholar
  23. 23.
    Comelli D, D’Andrea C, Valentini G, Cubeddu R, Colombo C, Toniolo L (2004) Fluorescence lifetime imaging and spectroscopy as tools for nondestructive analysis of works of art. Appl Optics 43(10):2175–2183Google Scholar
  24. 24.
    Comelli D, Valentini G, Cubeddu R, Toniolo L (2005) Fluorescence lifetime imaging and Fourier transform infrared spectroscopy of Michelangelo’s David. Appl Spectrosc 59(9):1174–1181Google Scholar
  25. 25.
    Ge JH, Kuang CF, Lee SS, Kao FJ (2012) Fluorescence lifetime imaging with pulsed diode laser enabled stimulated emission. Opt Express 20(27):28216–28221Google Scholar
  26. 26.
    Lin PY, Lee SS, Chang CS, Kao FJ (2012) Long working distance fluorescence lifetime imaging with stimulated emission and electronic time delay. Opt Express 20(10):11445–11450Google Scholar
  27. 27.
    Esposito A (2012) Beyond range: innovating fluorescence microscopy. Remote Sens 4(1):111–119Google Scholar
  28. 28.
    Togashi DM, Romao RIS, da Silva AMG, Sobral AJFN, Costa SMB (2005) Self-organization of a sulfonamido-porphyrin in Langmuir monolayers and Langmuir-Blodgett films. Phys Chem Chem Phys 7:3875–3884Google Scholar
  29. 29.
    Okabe K, Inada N, Gota C, Harada Y, Funatsu T, Uchiyama S (2012) Intracellular temperature mapping with a fluorescent polymeric thermometer and fluorescence lifetime imaging microscopy. Nat Commun 3:705Google Scholar
  30. 30.
    Bennet MA, Richardson PR, Arlt J, McCarthy A, Buller GS, Jones AC (2011) Optically trapped microsensors for microfluidic temperature measurement by fluorescence lifetime imaging microscopy. Lab Chip 11(22):3821–3828Google Scholar
  31. 31.
    Li Q, Ruckstuhl T, Seeger S (2004) Deep-UV laser-based fluorescence lifetime imaging microscopy of single molecules. J Phys Chem B 108(24):8324–8329Google Scholar
  32. 32.
    Suhling K (2006) Fluorescence Lifetime Imaging. In: Stephens D (ed) Cell Imaging. Scion, Bloxham, pp 219–245Google Scholar
  33. 33.
    Harris H (1999) The Birth of the Cell. Yale University Press, New Haven, p 212ppGoogle Scholar
  34. 34.
    Wouters FS (2006) The physics and biology of fluorescence microscopy in the life sciences. Contemp Phys 47(5):239–255Google Scholar
  35. 35.
    Amos WB, White JG (2003) How the confocal laser scanning microscope entered biological research. Biol Cell 95(6):335–342Google Scholar
  36. 36.
    Michalet X, Siegmund OHW, Vallerga J, Jelinsky P, Millaud JE, Weiss S (2007) Detectors for single-molecule fluorescence imaging and spectroscopy. J Mod Opt 54(2–3):239–281Google Scholar
  37. 37.
    Hadfield RH (2009) Single-photon detectors for optical quantum information applications. Nat Photonics 3(12):696–705Google Scholar
  38. 38.
    Buller GS, Collins RJ (2010) Single-photon generation and detection. Meas Sci Technol 21(1):012002Google Scholar
  39. 39.
    Hungerford G, Birch DJS (1996) Single-photon timing detectors for fluorescence lifetime spectroscopy. Meas Sci Technol 7(2):121–135Google Scholar
  40. 40.
    Eisaman MD, Fan J, Migdall A, Polyakov SV (2011) Invited review article: single-photon sources and detectors. Rev Sci Instrum 82(7):071101Google Scholar
  41. 41.
    Shaner NC, Patterson GH, Davidson MW (2007) Advances in fluorescent protein technology. J Cell Sci 120(24):4247–4260Google Scholar
  42. 42.
    Smith GE (2009) The invention and early history of the CCD. Nucl Instrum Methods Phys Res A 607(1):1–6Google Scholar
  43. 43.
    Hirvonen LM, Smith TA (2011) Imaging on the nanoscale: super-resolution fluorescence microscopy. Aust J Chem 64(1):41–45Google Scholar
  44. 44.
    Heintzmann R, Ficz G (2006) Breaking the resolution limit in light microscopy. Brief Funct Genomic Proteomic 5:289–301Google Scholar
  45. 45.
    Galbraith CG, Galbraith JA (2011) Super-resolution microscopy at a glance. J Cell Sci 124(10):1607–1611Google Scholar
  46. 46.
    Venetta BD (1959) Microscope phase fluorometer for determining the fluorescence lifetimes of fluorochromes. Rev Sci Instrum 30(6):450–457Google Scholar
  47. 47.
    Bugiel I, König K, Wabnitz H (1989) Investigation of cells by fluorescence laser scanning microscopy with subnanosecond time resolution. Lasers Life Sci 3(1):47–53Google Scholar
  48. 48.
    Wang XF, Uchida T, Minami S (1989) A fluorescence lifetime distribution measurement system based on phase-resolved detection using an image dissector tube. Appl Spectrosc 43(5):840–845Google Scholar
  49. 49.
    Breusegem SY, Levi M, Barry NP (2006) Fluorescence correlation spectroscopy and fluorescence lifetime imaging microscopy. Nephron J 103(2):e41–e49Google Scholar
  50. 50.
    Becker W, Bergmann A, Haustein E, Petrasek Z, Schwille P, Biskup C, Kelbauskas L, Benndorf K, Klöcker N, Anhut T, Riemann I, König K (2006) Fluorescence lifetime images and correlation spectra obtained by multidimensional time-correlated single photon counting. Microsc Res Tech 69(3):186–195Google Scholar
  51. 51.
    Nguyen TA, Sarkar P, Veetil JV, Koushik SV, Vogel SS (2012) Fluorescence polarization and fluctuation analysis monitors subunit proximity, stoichiometry, and protein complex hydrodynamics. Plos One 7(5):e38209Google Scholar
  52. 52.
    Kwak ES, Kang TJ, Bout DAV (2001) Fluorescence lifetime imaging with near-field scanning optical microscopy. Anal Chem 73(14):3257–3262Google Scholar
  53. 53.
    Micic M, Hu DH, Suh YD, Newton G, Romine M, Lu HP (2004) Correlated atomic force microscopy and fluorescence lifetime imaging of live bacterial cells. Colloids Surf B Biointerfaces 34(4):205–212Google Scholar
  54. 54.
    Levitt JA, Chung PH, Alibhai DR, Suhling K (2011) Simultaneous measurements of fluorescence lifetimes, anisotropy and FRAP recovery curves. In: SPIE Proc 7902:79020Y.Google Scholar
  55. 55.
    Roberti MJ, Jovin TM, Jares-Erijman E (2011) Confocal Fluorescence anisotropy and FRAP imaging of alpha-synuclein amyloid aggregates in living cells. Plos One 6(8):e23338Google Scholar
  56. 56.
    Vitali M, Reis M, Friedrich T, Eckert H-J (2010) A wide-field multi-parameter FLIM and FRAP setup to investigate the fluorescence emission of individual living cyanobacteria. SPIE Proc 7376:737610Google Scholar
  57. 57.
    Devauges V, Marquer C, Lecart S, Cossec JC, Potier MC, Fort E, Suhling K, Leveque-Fort S (2012) Homodimerization of amyloid precursor protein at the plasma membrane: a homoFRET study by time-resolved fluorescence anisotropy imaging. Plos One 7(9):e44434Google Scholar
  58. 58.
    Bruns T, Strauss WSL, Schneckenburger H (2008) Total internal reflection fluorescence lifetime and anisotropy screening of cell membrane dynamics. J Biomed Opt 13(4):041317Google Scholar
  59. 59.
    Auksorius E, Boruah BR, Dunsby C, Lanigan PMP, Kennedy G, Neil MAA, French PMW (2008) Stimulated emission depletion microscopy with a supercontinuum source and fluorescence lifetime imaging. Opt Lett 33(2):113–115Google Scholar
  60. 60.
    Lin PY, Lin YC, Chang CS, Kao FJ (2013) Fluorescence lifetime imaging microscopy with subdiffraction-limited resolution. Jpn J Appl Phys 52(2):028004Google Scholar
  61. 61.
    Slepkov AD, Ridsdale A, Wan HN, Wang MH, Pegoraro AF, Moffatt DJ, Pezacki JP, Kao FJ, Stolow A (2011) Forward-collected simultaneous fluorescence lifetime imaging and coherent anti-Stokes Raman scattering microscopy. J Biomed Opt 16(2):021103Google Scholar
  62. 62.
    McGinty J, Stuckey DW, Soloviev VY, Laine R, Wylezinska-Arridge M, Wells DJ, Arridge SR, French PMW, Hajnal JV, Sardini A (2011) In vivo fluorescence lifetime tomography of a FRET probe expressed in mouse. Biomed Opt Express 2(7):1907–1917Google Scholar
  63. 63.
    Valeur B, Berberan-Santos M (2011) A brief history of fluorescence and phosphorescence before the emergence of quantum theory. J Chem Educ 88:731–738Google Scholar
  64. 64.
    Stokes GG (1852) On the change of refrangibility of light. Philos Trans R Soc Lond 142:463–562Google Scholar
  65. 65.
    Stokes GG (1853) On the change of refrangibility of light II. Phil Trans R Soc London 143:385–396Google Scholar
  66. 66.
    Malley M (1991) A heated controversy on cold light. Arch Hist Exact Sci 42(2):173–186MathSciNetGoogle Scholar
  67. 67.
    Stern O, Volmer M (1919) Über die Abklingungszeit der Fluoreszenz. Phys Z 20:183–188Google Scholar
  68. 68.
    Gaviola E (1926) Die Abklingungszeiten der Fluoreszenz von Farbstofflösungen. Ann Phys 386(23):681–710Google Scholar
  69. 69.
    Lakowicz JR (2006) Principles of fluorescence spectroscopy, 3rd edn. Springer, New YorkGoogle Scholar
  70. 70.
    Valeur B, Berberan-Santos MN (2012) Molecular fluorescence. Principles and applications, 2nd edn. Wiley, WeinheimGoogle Scholar
  71. 71.
    Sauer M, Hofkens J, Enderlein J (2011) Handbook of fluorescence spectroscopy and imaging. Wiley-VCH, WeinheimGoogle Scholar
  72. 72.
    Goldys EM (2009) Fluorescence applications in biotechnology and life sciences. Wiley-Blackwell, HobokenGoogle Scholar
  73. 73.
    Jablonski A (1935) Über den Mechanismus der Photolumineszenz von Farbstoffphosphoren. Z Phys 94:38–46Google Scholar
  74. 74.
    Kasha M (1950) Characterization of electronic transitions in complex molecules. Discuss Faraday Soc 9:14–19Google Scholar
  75. 75.
    Strickler SJ, Berg RA (1962) Relationship between absorption intensity and fluorescence lifetime of molecules. J Chem Phys 37(4):814–820Google Scholar
  76. 76.
    Einstein A (1917) Zur Quantentheorie der Strahlung. Phys Z 18:121–128Google Scholar
  77. 77.
    Einstein A (1916) Strahlungsemission und -absorption nach der Quantentheorie. Ber Deutsch Phys Ges 13–14:3128–3323Google Scholar
  78. 78.
    Toptygin D, Savtchenko RS, Meadow ND, Roseman S, Brand L (2002) Effect of the solvent refractive index on the excited-state lifetime of a single tryptophan residue in a protein. J Phys Chem B 106(14):3724–3734Google Scholar
  79. 79.
    Toptygin D (2003) Effects of the solvent refractive index and its dispersion on the radiative decay rate and extinction coefficient of a fluorescent solute. J Fluoresc 13(3):201–219Google Scholar
  80. 80.
    Istratov AA, Vyvenko OF (1999) Exponential analysis in physical phenomena. Rev Sci Instrum 70(2):1233–1257Google Scholar
  81. 81.
    Zollinger H (2003) Color chemistry: syntheses, properties, and applications of organic dyes and pigments. Helvetica Chimica Acta, ZurichGoogle Scholar
  82. 82.
    Resch-Genger U, Grabolle M, Cavaliere-Jaricot S, Nitschke R, Nann T (2008) Quantum dots versus organic dyes as fluorescent labels. Nat Methods 5(9):763–775Google Scholar
  83. 83.
    Howes P, Green M, Levitt J, Suhling K, Hughes M (2010) Phospholipid encapsulated semiconducting polymer nanoparticles: their use in cell imaging and protein attachment. J Am Chem Soc 132(11):3989–3996Google Scholar
  84. 84.
    Green M, Howes P, Berry C, Argyros O, Thanou M (2009) Simple conjugated polymer nanoparticles as biological labels. Proc R Soc Math Phys Eng Sci 465(2109):2751–2759Google Scholar
  85. 85.
    Faklaris O, Joshi V, Irinopoulou T, Tauc P, Sennour M, Girard H, Gesset C, Arnault JC, Thorel A, Boudou JP, Curmi PA, Treussart F (2009) Photoluminescent diamond nanoparticles for cell labeling: study of the uptake mechanism in mammalian cells. ACS Nano 3(12):3955–3962Google Scholar
  86. 86.
    Neugart F, Zappe A, Jelezko F, Tietz C, Boudou JP, Krueger A, Wrachtrup J (2007) Dynamics of diamond nanoparticles in solution and cells. Nano Lett 7(12):3588–3591Google Scholar
  87. 87.
    Mohan N, Chen CS, Hsieh HH, Wu YC, Chang HC (2010) In vivo imaging and toxicity assessments of fluorescent nanodiamonds in Caenorhabditis elegans. Nano Lett 10(9):3692–3699Google Scholar
  88. 88.
    Kuo Y, Hsu T-Y, Wu Y-C, Hsu J-H, Chang H-C (2013) Fluorescence lifetime imaging microscopy of nanodiamonds in vivo. In: SPIE Proc 8635:863503Google Scholar
  89. 89.
    Edmonds AM, Sobhan MA, Sreenivasan VKA, Grebenik EA, Rabeau JR, Goldys EM, Zvyagin AV (2013) Nano-ruby: a promising fluorescent probe for background-free cellular imaging. Part Part Syst Charact 30(6):506–513Google Scholar
  90. 90.
    Sreenivasan VKA, Zvyagin AV, Goldys EM (2013) Luminescent nanoparticles and their applications in the life sciences. J Phys Condens Matter 25(19)Google Scholar
  91. 91.
    Green M (2004) Semiconductor quantum dots as biological imaging agents. Angew Chem 43(32):4129–4131Google Scholar
  92. 92.
    Grecco HE, Lidke KA, Heintzmann R, Lidke DS, Spagnuolo C, Martinez OE, Jares-Erijman EA, Jovin TM (2004) Ensemble and single particle photophysical proper-ties (Two-photon excitation, anisotropy, FRET, lifetime, spectral conversion) of commercial quantum dots in solution and in live cells. Microsc Res Tech 65(4–5):169–179Google Scholar
  93. 93.
    Michalet X, Pinaud FF, Bentolila LA, Tsay JM, Doose S, Li JJ, Sundaresan G, Wu AM, Gambhir SS, Weiss S (2005) Quantum dots for live cells, in vivo imaging, and diagnostics. Science 307(5709):538–544Google Scholar
  94. 94.
    Chudakov DM, Matz MV, Lukyanov S, Lukyanov KA (2010) Fluorescent proteins and their applications in imaging living cells and tissues. Physiol Rev 90(3):1103–1163Google Scholar
  95. 95.
    Elson D et al (2004) Time-domain fluorescence lifetime imaging applied to biological tissue. Photochem Photobiol Sci 3(8):795–801Google Scholar
  96. 96.
    Urayama P, Mycek M-A (2003) Fluorescence lifetime imaging microscopy of endogenous biological fluorescence. In: Mycek M-A, Pogue BW (eds) Handbook of biomedical fluorescence. Marcel Dekker, New YorkGoogle Scholar
  97. 97.
    Ahmed Z, Lin CC, Suen KM, Melo FA, Levitt JA, Suhling K, Ladbury JE (2013) Grb2 controls phosphorylation of FGFR2 by inhibiting receptor kinase and Shp2 phosphatase activity. J Cell Biol 200(4):493–504Google Scholar
  98. 98.
    Förster T (1946) Energiewanderung und Fluoreszenz. Naturwissenschaften 33(6):167–175, translated into English by Suhling K (2012) J Biomed Opt 17(1):011002Google Scholar
  99. 99.
    Ogilby PR (2010) Singlet oxygen: there is indeed something new under the sun. Chem Soc Rev 39(8):3181–3209Google Scholar
  100. 100.
    Dixon JM, Taniguchi M, Lindsey JS (2005) PhotochemCAD 2: a refined program with accompanying spectral databases for photochemical calculations. Photochem Photobiol 81(1):212–213Google Scholar
  101. 101.
    Du H, Fuh RCA, Li J, Corkan LA, Lindsey JS (1998) PhotochemCAD: a computer-aided design and research tool in photochemistry. Photochem Photobiol 68(2):141–142Google Scholar
  102. 102.
    Stryer L (1978) Fluorescence energy transfer as a spectroscopic ruler. Annu Rev Biochem 47:819–846Google Scholar
  103. 103.
    Stryer L, Haugland RP (1967) Energy transfer: a spectroscopic ruler. Proc Natl Acad Sci U S A 58:719–726Google Scholar
  104. 104.
    Dos Remedios CG, Moens PDJ (1995) Fluorescence resonance energy transfer spectroscopy is a reliable “Ruler” for measuring structural changes in proteins. Dispelling the problem of the unknown orientation factor. J Struct Biol 115(2):175–185Google Scholar
  105. 105.
    Hunt J, Keeble AH, Dale RE, Corbett MK, Beavil RL, Levitt J, Swann MJ, Suhling K, Ameer-Beg S, Sutton BJ, Beavil AJ (2012) A fluorescent biosensor reveals conformational changes in human immunoglobulin E Fc. Implications for mechanisms of receptor binding, inhibition and allergen recognition. J Biol Chem 287(21):17459–17470Google Scholar
  106. 106.
    Hötzer B, Ivanov R, Altmeier S, Kappl R, Jung G (2011) Determination of copper(II) ion concentration by lifetime measurements of green fluorescent protein. J Fluoresc 21(6):2143–2153Google Scholar
  107. 107.
    Miyawaki A, Llopis J, Helm R, McCaffery JM, Adams JA, Ikura M, Tsien RY (1997) Fluorescent indicators for Ca2+ based on green fluorescent proteins and calmodulin. Nature 388(6645):882–887Google Scholar
  108. 108.
    Pelet S, Previte MJR, So PTC (2006) Comparing the quantification of Förster resonance energy transfer measurement accuracies based on intensity, spectral, and lifetime imaging. J Biomed Opt 11(3):034017Google Scholar
  109. 109.
    Thaler C, Koushik SV, Blank PS, Vogel SS (2005) Quantitative multiphoton spectral imaging and its use for measuring resonance energy transfer. Biophys J 89:2736–2749Google Scholar
  110. 110.
    Fiserova E, Kubala M (2012) Mean fluorescence lifetime and its error. J Luminescence 132(8):2059–2064Google Scholar
  111. 111.
    Sillen A, Engelborghs Y (1998) The correct use of “average” fluorescence parameters. Photochem Photobiol 67(5):475–486Google Scholar
  112. 112.
    Suhling K, Siegel J, Phillips D, French PMW, Lévêque-Fort S, Webb SED, Davis DM (2002) Imaging the environment of green fluorescent protein. Biophys J 83(6):3589–3595Google Scholar
  113. 113.
    Uskova MA, Borst J, Hink MA, van Hoek A, Schots A, Klyachko AL, Visser AJWG (2000) Fluorescence dynamics of green fluorescent protein in AOT reversed micelles. Biophys Chem 87:73–84Google Scholar
  114. 114.
    Heikal AA, Hess ST, Webb WW (2001) Multiphoton molecular spectroscopy and excited-state dynamics of enhanced green fluorescent protein (EGFP): acid–base specificity. Chem Phys 274(1):37–55Google Scholar
  115. 115.
    Cotlet M, Hofkens J, Maus M, Gensch T, van der Auweraer M, Michiels J, Dirix G, van Guyse M, Vanderleyden J, Visser AJWG, de Schryver FC (2001) Excited state dynamics in the enhanced green fluorescent protein mutant probed by picosecond time-resolved single photon counting spectroscopy. J Phys Chem B 105(21):4999–5006Google Scholar
  116. 116.
    Jovin TM, Arndt-Jovin DJ (1989) FRET microscopy: digital imaging of fluorescence resonance energy transfer. In: Kohen E, Hirschberg JG, Ploem JS (eds) Cell structure and function by microspectrofluorometry. Academic, London, pp 99–117Google Scholar
  117. 117.
    Fernandez SM, Berlin RD (1976) Cell-surface distribution of lectin receptors determined by resonance energy-transfer. Nature 264(5585):411–415Google Scholar
  118. 118.
    Suhling K, French PMW, Phillips D (2005) Time-resolved fluorescence microscopy. Photochem Photobiol Sci 4:13–22Google Scholar
  119. 119.
    Shaner NC, Steinbach PA, Tsien RY (2005) A guide to choosing fluorescent proteins. Nat Methods 2(12):905–909Google Scholar
  120. 120.
    Zimmer M (2002) Green fluorescent protein (GFP): applications, structure, and related photophysical behavior. Chem Rev 102(3):759–781Google Scholar
  121. 121.
    Haidekker MA, Nipper M, Mustafic A, Lichlyter D, Dakanali M, Theodorakis EA (2010) Dyes with segmental mobility: molecular rotors. In: Demchenko AP (ed) Advanced fluorescence reporters in chemistry and biology I. Fundamentals and molecular design. Springer, Berlin/Heidelberg, pp 267–308Google Scholar
  122. 122.
    Haidekker MA, Theodorakis EA (2007) Molecular rotors-fluorescent biosensors for viscosity and flow. Org Biomol Chem 5(11):1669–1678Google Scholar
  123. 123.
    Kuimova MK (2012) Molecular rotors image intracellular viscosity. Chimia 66(4):159–165Google Scholar
  124. 124.
    Kuimova MK (2012) Mapping viscosity in cells using molecular rotors. Phys Chem Chem Phys 14(37):12671–12686Google Scholar
  125. 125.
    Uzhinov BM, Ivanov VL, Melnikov MY (2011) Molecular rotors as luminescence sensors of local viscosity and viscous flow in solutions and organized systems. Russ Chem Rev 80(12):1179–1190Google Scholar
  126. 126.
    Förster T, Hoffmann G (1971) Die Viskositätsabhängigkeit der Fluoreszenzquantenausbeuten einiger Farbstoffsysteme. Z Phys Chem Neue Folge 75:63–76Google Scholar
  127. 127.
    Loutfy RO (1986) Fluorescence probes for polymer free-volume. Pure Appl Chem 58(9):1239–1248Google Scholar
  128. 128.
    Rei A, Hungerford G, Ferreira MIC (2008) Probing local effects in silica sol–gel media by fluorescence spectroscopy of p-DASPMI. J Phys Chem B 112(29):8832–8839Google Scholar
  129. 129.
    Hungerford G, Allison A, McLoskey D, Kuimova MK, Yahioglu G, Suhling K (2009) Monitoring sol-to-gel transitions via fluorescence lifetime determination using viscosity sensitive fluorescent probes. J Phys Chem B 113(35):12067–12074Google Scholar
  130. 130.
    Law KY (1981) Fluorescence probe for micro-environments – a new probe for micelle solvent parameters and premicellar aggregates. Photochem Photobiol 33(6):799–806Google Scholar
  131. 131.
    Lu J, Liotta CL, Eckert CA (2003) Spectroscopically probing microscopic solvent properties of room-temperature ionic liquids with the addition of carbon dioxide. J Phys Chem A 107(19):3995–4000Google Scholar
  132. 132.
    Gutkowski KI, Japas ML, Aramendia PF (2006) Fluorescence of dicyanovinyl julolidine in a room-temperature ionic liquid. Chem Phys Lett 426(4–6):329–333Google Scholar
  133. 133.
    Paul A, Samanta A (2008) Free volume dependence of the internal rotation of a molecular rotor probe in room temperature ionic liquids. J Phys Chem B 112(51):16626–16632Google Scholar
  134. 134.
    Haidekker MA, Tsai AG, Brady T, Stevens HY, Frangos JA, Theodorakis E, Intaglietta M (2002) A novel approach to blood plasma viscosity measurement using fluorescent molecular rotors. Am J Phys Heart Circ Physiol 282(5):H1609–H1614Google Scholar
  135. 135.
    Kung CE, Reed JK (1986) Microviscosity measurements of phospholipid bilayers using fluorescent dyes that undergo torsional relaxation. Biochemistry 25:6114–6121Google Scholar
  136. 136.
    Nipper ME, Dakanali M, Theodorakis EA, Haidekker MA (2010) Detection of liposome membrane viscosity perturbations with ratiometric molecular rotors. Biochimie 93:988–994Google Scholar
  137. 137.
    Kung CE, Reed JK (1989) Fluorescent molecular rotors – a new class of probes for tubulin structure and assembly. Biochemistry 28(16):6678–6686Google Scholar
  138. 138.
    Kuimova MK, Yahioglu G, Levitt JA, Suhling K (2008) Molecular rotor measures viscosity of live cells via fluorescence lifetime imaging. J Am Chem Soc 130(21):6672–6673Google Scholar
  139. 139.
    Levitt JA, Kuimova MK, Yahioglu G, Chung PH, Suhling K, Phillips D (2009) Membrane-bound molecular rotors measure viscosity in live cells via fluorescence lifetime imaging. J Phys Chem C 113(27):11634–11642Google Scholar
  140. 140.
    Peng X, Yang Z, Wang J, Fan J, He Y, Song F, Wang B, Sun S, Qu J, Qi J, Yan M (2011) Fluorescence ratiometry and fluorescence lifetime imaging: using a single molecular sensor for dual mode imaging of cellular viscosity. J Am Chem Soc 133:6626–6635Google Scholar
  141. 141.
    Wandelt B, Cywinski P, Darling GD, Stranix BR (2005) Single cell measurement of micro-viscosity by ratio imaging of fluorescence of styrylpyridinium probe. Biosens Bioelectron 20(9):1728–1736Google Scholar
  142. 142.
    Haidekker MA, Ling T, Anglo M, Stevens HY, Frangos JA, Theodorakis EA (2001) New fluorescent probes for the measurement of cell membrane viscosity. Chem Biol 8(2):123–131Google Scholar
  143. 143.
    Luby-Phelps K, Mujumdar S, Mujumdar R, Ernst LA, Galbraith W, Waggoner AS (1993) A novel fluorescence ratiometric method confirms the low solvent viscosity of the cytoplasm. Biophys J 65(1):236–242Google Scholar
  144. 144.
    Battisti A, Panettieri S, Abbandonato G, Jacchetti E, Cardarelli F, Signore G, Beltram F, Bizzarri R (2013) Imaging intracellular viscosity by a new molecular rotor suitable for phasor analysis of fluorescence lifetime. Anal Bioanal Chem 405(19):6223–6233Google Scholar
  145. 145.
    Kuimova MK, Botchway SW, Parker AW, Balaz M, Collins HA, Anderson HL, Suhling K, Ogilby PR (2009) Imaging intracellular viscosity of a single cell during photoinduced cell death. Nat Chem 1:69–73Google Scholar
  146. 146.
    Haidekker M, Brady TP, Lichlyter D, Theodorakis EA (2006) A ratiometric fluorescent viscosity sensor. J Am Chem Soc 128:398–399Google Scholar
  147. 147.
    Wandelt B, Mielniczak A, Turkewitsch P, Darling GD, Stranix BR (2003) Substituted 4-[4-(dimethylamino)styryl] pyridinium salt as a fluorescent probe for cell microviscosity. Biosens Bioelectron 18(4):465–471Google Scholar
  148. 148.
    Ghiggino KP, Hutchison JA, Langford SJ, Latter MJ, Lee MAP, Lowenstern PR, Scholes C, Takezaki M, Wilman BE (2007) Porphyrin-based molecular rotors as fluorescent probes of nanoscale environments. Adv Funct Mater 17(5):805–813Google Scholar
  149. 149.
    Hosny NA, Mohamedi G, Rademeyer P, Owen J, Wu Y, Tang MX, Eckersley RJ, Stride E, Kuimova MK (2013) Mapping microbubble viscosity using fluorescence lifetime imaging of molecular rotors. Proc Natl Acad Sci U S A 110(23):9225–9230Google Scholar
  150. 150.
    Loison P, Hosny NA, Gervais P, Champion D, Kuimova MK, Perrier-Cornet JM (2013) Direct investigation of viscosity of an atypical inner membrane of Bacillus spores: a molecular rotor/FLIM study. Biochim Biophys Acta 1828(11):2436–2443Google Scholar
  151. 151.
    Mendels DA, Graham EM, Magennis SW, Jones AC, Mendels F (2008) Quantitative comparison of thermal and solutal transport in a T-mixer by FLIM and CFD. Microfluid Nanofluid 5(5):603–617Google Scholar
  152. 152.
    Treanor B, Lanigan PM, Suhling K, Schreiber T, Munro I, Neil MA, Phillips D, Davis DM, French PMW (2005) Imaging fluorescence lifetime heterogeneity applied to GFP-tagged MHC protein at an immunological synapse. J Microsc 217(1):36–43MathSciNetGoogle Scholar
  153. 153.
    Tregidgo C, Levitt JA, Suhling K (2008) Effect of refractive index on the fluorescence lifetime of green fluorescent protein. J Biomed Opt 13:031218Google Scholar
  154. 154.
    Ma YJ, Rajendran P, Blum C, Cesa Y, Gartmann N, Bruhwiler D, Subramaniam V (2011) Microspectroscopic analysis of green fluorescent proteins infiltrated into mesoporous silica nanochannels. J Colloid Interface Sci 356(1):123–130Google Scholar
  155. 155.
    van Manen HJ, Verkuijlen P, Wittendorp P, Subramaniam V, van den Berg TK, Roos D, Otto C (2008) Refractive index sensing of green fluorescent proteins in living cells using fluorescence lifetime imaging microscopy. Biophys J 94:L67–L69Google Scholar
  156. 156.
    Pliss A, Zhao LL, Ohulchanskyy TY, Qu JL, Prasad PN (2012) Fluorescence lifetime of fluorescent proteins as an intracellular environment probe sensing the cell cycle progression. ACS Chem Biol 7(8):1385–1392Google Scholar
  157. 157.
    Nakabayashi T, Nagao I, Kinjo M, Aoki Y, Tanaka M, Ohta N (2008) Stress-induced environmental changes in a single cell as revealed by fluorescence lifetime imaging. Photochem Photobiol Sci 7(6):671–674Google Scholar
  158. 158.
    Fort E, Gresillon S (2008) Surface enhanced fluorescence. J Phys D Appl Phys 41(1):013001Google Scholar
  159. 159.
    Lakowicz JR (2005) Radiative decay engineering 5: metal-enhanced fluorescence and plasmon emission. Anal Biochem 337(2):171–194Google Scholar
  160. 160.
    Barnes WL (1998) Fluorescence near interfaces: the role of photonic mode density. J Mod Opt 45(4):661–699Google Scholar
  161. 161.
    Teixeira R, Paulo PMR, Viana AS, Costa SMB (2011) Plasmon-enhanced emission of a phthalocyanine in polyelectrolyte films induced by gold nanoparticles. J Phys Chem C 115(50):24674–24680Google Scholar
  162. 162.
    Cade NI, Fruhwirth G, Archibald SJ, Ng T, Richards D (2010) A cellular screening assay using analysis of metal-modified fluorescence lifetime. Biophys J 98(11):2752–2757Google Scholar
  163. 163.
    Kawata S, Inouye Y, Ichimura T (2004) Near-field optics and spectroscopy for molecular nano-imaging. Sci Prog 87(1):25–49Google Scholar
  164. 164.
    Cade NI, Fruhwirth GO, Ng T, Richards D (2013) Plasmon-assisted super-resolution axial distance sensitivity in fluorescence cell imaging. J Phys Chem Lett 4(20):3402–3406Google Scholar
  165. 165.
    Berndt M, Lorenz M, Enderlein J, Diez S (2010) Axial nanometer distances measured by fluorescence lifetime imaging microscopy. Nano Lett 10(4):1497–1500Google Scholar
  166. 166.
    Pickup JC, Zhi ZL, Khan F, Saxl T, Birch DJS (2008) Nanomedicine and its potential in diabetes research and practice. Diabetes Metab Res Rev 24(8):604–610Google Scholar
  167. 167.
    Saxl T, Khan F, Matthews DR, Zhi ZL, Rolinski O, Ameer-Beg S, Pickup J (2009) Fluorescence lifetime spectroscopy and imaging of nano-engineered glucose sensor microcapsules based on glucose/galactose-binding protein. Biosens Bioelectron 24(11):3229–3234Google Scholar
  168. 168.
    Saxl T, Khan F, Ferla M, Birch D, Pickup J (2011) A fluorescence lifetime-based fibre-optic glucose sensor using glucose/galactose-binding protein. Analyst 136(5):968–972Google Scholar
  169. 169.
    Biskup C, Gensch T (2014) Fluorescence lifetime imaging of ions in biological tissues. In: Elson D, French PWM, Marcu L (eds) Fluorescence lifetime spectroscopy and imaging. Principles and applications in biomedical diagnostics. Taylor & Francis, Boca RatonGoogle Scholar
  170. 170.
    Lakowicz JR, Szmacinski H, Nowaczyk K, Lederer WJ (1994) Fluorescence lifetime imaging of intracellular calcium in COS cells using Quin-2. Cell Calcium 15(1):7–27Google Scholar
  171. 171.
    Lakowicz JR, Szmacinski H, Nowaczyk K, Johnson ML (1992) Fluorescence lifetime imaging of calcium using Quin-2. Cell Calcium 13(3):131–147Google Scholar
  172. 172.
    Herman B, Wodnicki P, Kwon S, Periasamy A, Gordon GW, Mahajan N, Xue Feng W (1997) Recent developments in monitoring calcium and protein interactions in cells using fluorescence lifetime microscopy. J Fluoresc 7(1):85–92Google Scholar
  173. 173.
    Celli A, Sanchez S, Behne M, Hazlett T, Gratton E, Mauro T (2010) The epidermal Ca2+ gradient: measurement using the phasor representation of fluorescent lifetime imaging. Biophys J 98(5):911–921Google Scholar
  174. 174.
    Sanders R, Gerritsen HC, Draaijer A, Houpt PM, Levine YK (1994) Fluorescence lifetime imaging of free calcium in single cells. Bioimaging 2:131–138Google Scholar
  175. 175.
    Lahn M, Dosche C, Hille C (2011) Two-photon microscopy and fluorescence lifetime imaging reveal stimulus-induced intracellular Na+ and Cl changes in cockroach salivary acinar cells. Am J Physiol Cell Physiol 300(6):C1323–C1336Google Scholar
  176. 176.
    Kaneko H, Putzier I, Frings S, Kaupp UB, Gensch T (2004) Chloride accumulation in mammalian olfactory sensory neurons. J Neurosci 24(36):7931–7938Google Scholar
  177. 177.
    Gilbert D, Franjic-Wurtz C, Funk K, Gensch T, Frings S, Mohrlen F (2007) Differential maturation of chloride homeostasis in primary afferent neurons of the somatosensory system. Int J Dev Neurosci 25(7):479–489Google Scholar
  178. 178.
    Hötzer B, Ivanov R, Brumbarova T, Bauer P, Jung G (2012) Visualization of Cu2+uptake and release in plant cells by fluorescence lifetime imaging microscopy. FEBS J 279(3):410–419Google Scholar
  179. 179.
    Szmacinski H, Lakowicz JR (1999) Potassium and sodium measurements at clinical concentrations using phase-modulation fluorometry. Sensors Actuators B Chem 60(1):8–18Google Scholar
  180. 180.
    Szmacinski H, Lakowicz JR (1996) Fluorescence lifetime characterization of magnesium probes: improvement of Mg2+ dynamic range and sensitivity using phase-modulation fluorometry. J Fluoresc 6:83–85Google Scholar
  181. 181.
    Carlsson K, Liljeborg A, Andersson RM, Brismar H (2000) Confocal pH imaging of microscopic specimens using fluorescence lifetimes and phase fluorometry: influence of parameter choice on system performance. J Microsc 199(2):106–114Google Scholar
  182. 182.
    Sanders R, Draaijer A, Gerritsen HC, Houpt PM, Levine YK (1995) Quantitative pH imaging in cells using confocal fluorescence lifetime imaging microscopy. Anal Biochem 227:302–308Google Scholar
  183. 183.
    Lin HJ, Herman P, Lakowicz JR (2003) Fluorescence lifetime-resolved pH imaging of living cells. Cytometry 52A:77–89Google Scholar
  184. 184.
    Behne MJ, Meyer JW, Hanson KM, Barry NP, Murata S, Crumrine D, Clegg RW, Gratton E, Holleran WM, Elias PM (2002) NHE1 regulates the stratum corneum permeability barrier homeostasis. Microenvironment acidification assessed with fluorescence lifetime imaging. J Biol Chem 277(49):47399–47406Google Scholar
  185. 185.
    Hanson KM, Behne MJ, Barry NP, Mauro TM, Gratton E, Clegg RM (2002) Two-photon fluorescence lifetime imaging of the skin stratum corneum pH gradient. Biophys J 83(3):1682–1690Google Scholar
  186. 186.
    Nakabayashi T, Wang HP, Kinjo M, Ohta N (2008) Application of fluorescence lifetime imaging of enhanced green fluorescent protein to intracellular pH measurements. Photochem Photobiol Sci 7(6):668–670Google Scholar
  187. 187.
    Ogikubo S, Nakabayashi T, Adachi T, Islam MS, Yoshizawa T, Kinjo M, Ohta N (2011) Intracellular pH sensing using autofluorescence lifetime microscopy. J Phys Chem B 115(34):10385–10390Google Scholar
  188. 188.
    Estrada AD, Ponticorvo A, Ford TN, Dunn AK (2008) Microvascular oxygen quantification using two-photon microscopy. Opt Lett 33(10):1038–1040Google Scholar
  189. 189.
    Finikova OS, Lebedev AY, Aprelev A, Troxler T, Gao F, Garnacho C, Muro S, Hochstrasser RM, Vinogradov SA (2008) Oxygen microscopy by two-photon-excited phosphorescence. Chemphyschem 9(12):1673–1679Google Scholar
  190. 190.
    Hosny NA, Lee DA, Knight MM (2012) Single photon counting fluorescence lifetime detection of pericellular oxygen concentrations. J Biomed Opt 17:016007Google Scholar
  191. 191.
    Gerritsen HC, Sanders R, Draaijer A, Ince C, Levine YK (1997) Fluorescence lifetime imaging of oxygen in living cells. J Fluoresc 7(1):11–16Google Scholar
  192. 192.
    Choi H, Tzeranis DS, Cha JW, Clemenceau P, de Jong SJG, van Geest LK, Moon JH, Yannas IV, So PTC (2012) 3D-resolved fluorescence and phosphorescence lifetime imaging using temporal focusing wide-field two-photon excitation. Opt Express 20(24):26219–26235Google Scholar
  193. 193.
    Cicchi R, Pavone FS (2011) Non-linear fluorescence lifetime imaging of biological tissues. Anal Bioanal Chem 400(9):2687–2697Google Scholar
  194. 194.
    Ghukasyan VV, Kao FJ (2009) Monitoring cellular metabolism with fluorescence lifetime of reduced nicotinamide adenine dinucleotide. J Phys Chem C 113(27):11532–11540Google Scholar
  195. 195.
    Lakowicz JR, Szmacinski H, Nowaczyk K, Johnson ML (1992) Fluorescence lifetime imaging of free and protein-bound NADH. Proc Natl Acad Sci U S A 89(4):1271–1275Google Scholar
  196. 196.
    Mayevsky A, Chance B (2007) Oxidation-reduction states of NADH in vivo: From animals to clinical use. Mitochondrion 7(5):330–339Google Scholar
  197. 197.
    Bird DK, Yan L, Vrotsos KM, Eliceiri KW, Vaughan EM, Keely PJ, White JG, Ramanujam N (2005) Metabolic mapping of MCF10A human breast cells via multiphoton fluorescence lifetime imaging of the coenzyme NADH. Cancer Res 65(19):8766–8773Google Scholar
  198. 198.
    Yu QR, Heikal AA (2009) Two-photon autofluorescence dynamics imaging reveals sensitivity of intracellular NADH concentration and conformation to cell physiology at the single-cell level. J Photochem Photobiol B Biol 95(1):46–57Google Scholar
  199. 199.
    Tadrous PJ, Siegel J, French PMW, Shousha S, Lalani EN, Stamp GW (2003) Fluorescence lifetime imaging of unstained tissues: early results in human breast cancer. J Pathol 199(3):309–317Google Scholar
  200. 200.
    Provenzano PP, Eliceiri KW, Keely PJ (2009) Multiphoton microscopy and fluorescence lifetime imaging microscopy (FLIM) to monitor metastasis and the tumor microenvironment. Clin Exp Metastasis 26(4):357–370Google Scholar
  201. 201.
    Conklin MW, Provenzano PP, Eliceiri KW, Sullivan R, Keely PJ (2009) Fluorescence lifetime imaging of endogenous fluorophores in histopathology sections reveals differences between normal and tumor epithelium in carcinoma in situ of the breast. Cell Biochem Biophys 53(3):145–157Google Scholar
  202. 202.
    Skala MC, Riching KM, Gendron-Fitzpatrick A, Eickhoff J, Eliceiri KW, White JG, Ramanujam N (2007) In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia. Proc Natl Acad Sci U S A 104(49):19494–19499Google Scholar
  203. 203.
    Skala MC, Riching KM, Bird DK, Gendron-Fitzpatrick A, Eickhoff J, Eliceiri KW, Keely PJ, Ramanujam N (2007) In vivo multiphoton fluorescence lifetime imaging of protein-bound and free nicotinamide adenine dinucleotide in normal and precancerous epithelia. J Biomed Opt 12(2)Google Scholar
  204. 204.
    Chorvat D, Chorvatova A (2006) Spectrally resolved time-correlated single photon counting: a novel approach for characterization of endogenous fluorescence in isolated cardiac myocytes. Eur Biophys J Biophys Lett 36(1):73–83Google Scholar
  205. 205.
    Chorvat D, Chorvatova A (2009) Multi-wavelength fluorescence lifetime spectroscopy: a new approach to the study of endogenous fluorescence in living cells and tissues. Laser Phys Lett 6(3):175–193Google Scholar
  206. 206.
    Wang HW, Gukassyan V, Chen CT, Wei YH, Guo HW, Yu JS, Kao FJ (2008) Differentiation of apoptosis from necrosis by dynamic changes of reduced nicotinamide adenine dinucleotide fluorescence lifetime in live cells. J Biomed Opt 13(5):054011Google Scholar
  207. 207.
    Torno K, Wright BK, Jones MR, Digman MA, Gratton E, Phillips M (2013) Real-time analysis of metabolic activity within lactobacillus acidophilus by phasor fluorescence lifetime imaging microscopy of NADH. Curr Microbiol 66(4):365–367Google Scholar
  208. 208.
    Stringari C, Edwards RA, Pate KT, Waterman ML, Donovan PJ, Gratton E (2012) Metabolic trajectory of cellular differentiation in small intestine by Phasor Fluorescence Lifetime Microscopy of NADH. Sci Rep 2:568Google Scholar
  209. 209.
    Stringari C, Cinquin A, Cinquin O, Digman MA, Donovan PJ, Gratton E (2011) Phasor approach to fluorescence lifetime microscopy distinguishes different metabolic states of germ cells in a live tissue. Proc Natl Acad Sci U S A 108(33):13582–13587Google Scholar
  210. 210.
    Galletly NP, McGinty J, Dunsby C, Teixeira F, Requejo-Isidro J, Munro I, Elson DS, Neil MAA, Chu AC, French PMW, Stamp GW (2008) Fluorescence lifetime imaging distinguishes basal cell carcinoma from surrounding uninvolved skin. Br J Dermatol 159(1):152–161Google Scholar
  211. 211.
    Seidenari S, Arginelli F, Dunsby C, French P, König K, Magnoni C, Manfredini M, Talbot C, Ponti G (2012) Multiphoton laser tomography and fluorescence lifetime imaging of basal cell carcinoma: morphologic features for non-invasive diagnostics. Exp Dermatol 21(11):831–836Google Scholar
  212. 212.
    Patalay R, Talbot C, Alexandrov Y, Lenz MO, Kumar S, Warren S, Munro I, Neil MAA, König K, French PMW, Chu A, Stamp GWH, Dunsby C (2012) Multiphoton multispectral fluorescence lifetime tomography for the evaluation of basal cell carcinomas. Plos One 7(9):e43460Google Scholar
  213. 213.
    Dancik Y, Favre A, Loy CJ, Zvyagin AV, Roberts MS (2013) Use of multiphoton tomography and fluorescence lifetime imaging to investigate skin pigmentation in vivo. J Biomed Opt 18(2)Google Scholar
  214. 214.
    Sanchez WY, Prow TW, Sanchez WH, Grice JE, Roberts MS (2010) Analysis of the metabolic deterioration of ex vivo skin from ischemic necrosis through the imaging of intracellular NAD(P)H by multiphoton tomography and fluorescence lifetime imaging microscopy. J Biomed Opt 15(4):046008-1–046008-11Google Scholar
  215. 215.
    Sanchez WY, Obispo C, Ryan E, Grice JE, Roberts MS (2012) Changes in the redox state and endogenous fluorescence of in vivo human skin due to intrinsic and photo-aging, measured by multiphoton tomography with fluorescence lifetime imaging. J Biomed Opt 18(6)Google Scholar
  216. 216.
    Arginelli F, Manfredini M, Bassoli S, Dunsby C, French P, König K, Magnoni C, Ponti G, Talbot C, Seidenari S (2013) High resolution diagnosis of common nevi by multiphoton laser tomography and fluorescence lifetime imaging. Skin Res Technol 19(2):194–204Google Scholar
  217. 217.
    Breunig HG, Weinigel M, Buckle R, Kellner-Hofer M, Lademann J, Darvin ME, Sterry W, König K (2013) Clinical coherent anti-Stokes Raman scattering and multiphoton tomography of human skin with a femtosecond laser and photonic crystal fiber. Laser Phys Lett 10(2)Google Scholar
  218. 218.
    Lin LL, Grice JE, Butler MK, Zvyagin AV, Becker W, Robertson TA, Soyer HP, Roberts MS, Prow TW (2011) Time-correlated single photon counting for simultaneous monitoring of zinc oxide nanoparticles and NAD(P)H in intact and barrier-disrupted volunteer skin. Pharm Res 28(11):2920–2930Google Scholar
  219. 219.
    Schweitzer D, Schenke S, Hammer M, Schweitzer F, Jentsch S, Birckner E, Becker W, Bergmann A (2007) Towards metabolic mapping of the human retina. Microsc Res Tech 70(5):410–419Google Scholar
  220. 220.
    Schweitzer D, Hammer M, Schweitzer F, Anders R, Doebbecke T, Schenke S, Gaillard ER, Gaillard ER (2004) In vivo measurement of time-resolved autofluorescence at the human fundus. J Biomed Opt 9(6):1214–1222Google Scholar
  221. 221.
    König K, Schneckenburger H, Hibst R (1999) Time-gated in vivo autofluorescence imaging of dental caries. Cell Mol Biol 45(2):233–239Google Scholar
  222. 222.
    Siegel J, Elson DS, Webb SED, Lee KCB, Vlandas A, Gambaruto GL, Lévêque-Fort S, Lever MJ, Tadrous PJ, Stamp GWH (2003) Studying biological tissue with fluorescence lifetime imaging: microscopy, endoscopy, and complex decay profiles. Appl Optics 42(16):2995–3004Google Scholar
  223. 223.
    McConnell G, Girkin JM, Ameer-Beg SM, Barber PR, Vojnovic B, Ng T, Banerjee A, Watson TF, Cook RJ (2007) Time-correlated single-photon counting fluorescence lifetime confocal imaging of decayed and sound dental structures with a white-light supercontinuum source. J Microsc Oxf 225(2):126–136MathSciNetGoogle Scholar
  224. 224.
    Requejo-Isidro J, McGinty J, Munro I, Elson DS, Galletly NP, Lever MJ, Neil MAA, Stamp GWH, French PMW, Kellett PA, Hares JD, Dymoke-Bradshaw AKL (2004) High-speed wide-field time-gated endoscopic fluorescence-lifetime imaging. Opt Lett 29(19):2249–2251Google Scholar
  225. 225.
    Fruhwirth GO, Ameer-Beg S, Cook R, Watson T, Ng T, Festy F (2010) Fluorescence lifetime endoscopy using TCSPC for the measurement of FRET in live cells. Opt Express 18(11):11148–11158Google Scholar
  226. 226.
    Sun YH, Hatami N, Yee M, Phipps J, Elson DS, Gorin F, Schrot RJ, Marcu L (2010) Fluorescence lifetime imaging microscopy for brain tumor image-guided surgery. J Biomed Opt 15(5):056022Google Scholar
  227. 227.
    Zeng Y, Wu Y, Li D, Zheng W, Wang WX, Qu JNY (2012) Two-photon excitation chlorophyll fluorescence lifetime imaging: a rapid and noninvasive method for in vivo assessment of cadmium toxicity in a marine diatom Thalassiosira weissflogii. Planta 236(5):1653–1663Google Scholar
  228. 228.
    Murata S, Herman P, Lakowicz JR (2001) Texture analysis of fluorescence lifetime images of AT- and GC- rich regions in nuclei. J Histochem Cytochem 49(11):1443–1451Google Scholar
  229. 229.
    Murata S, Herman P, Lakowicz JR (2001) Texture analysis of fluorescence lifetime images of nuclear DNA with effect of fluorescence resonance energy transfer. Cytometry 43(2):94–100Google Scholar
  230. 230.
    Murata S, Herman P, Lin HJ, Lakowicz JR (2000) Fluorescence lifetime imaging of nuclear DNA: effect of fluorescence resonance energy transfer. Cytometry 41(3):178–185Google Scholar
  231. 231.
    van Zandvoort M, de Grauw CJ, Gerritsen HC, Broers JLV, Egbrink M, Ramaekers FCS, Slaaf DW (2002) Discrimination of DNA and RNA in cells by a vital fluorescent probe: lifetime imaging of SYTO13 in healthy and apoptotic cells. Cytometry 47(4):226–235Google Scholar
  232. 232.
    Bacskai BJ, Skoch J, Hickey GA, Allen R, Hyman BT (2003) Fluorescence resonance energy transfer determinations using multiphoton fluorescence lifetime imaging microscopy to characterize amyloid-beta plaques. J Biomed Opt 8(3):368–375Google Scholar
  233. 233.
    Berezovska O, Ramdya P, Skoch J, Wolfe MS, Bacskai BJ, Hyman BT (2003) Amyloid precursor protein associates with a nicastrin-dependent docking site on the presenilin 1-gamma-secretase complex in cells demonstrated by fluorescence lifetime imaging. J Neurosci 23(11):4560–4566Google Scholar
  234. 234.
    Kaminski-Schierle GS, Bertoncini CW, Chan FTS, van der Goot AT, Schwedler S, Skepper J, Schlachter S, van Ham T, Esposito A, Kumita JR, Nollen EAA, Dobson CM, Kaminski CF (2011) A FRET sensor for non-invasive imaging of amyloid formation in vivo. Chemphyschem 12(3):673–680Google Scholar
  235. 235.
    Gu J, Fu CY, Ng BK, Gulam Razul S, Lim SK (2013) Quantitative diagnosis of cervical neoplasia using fluorescence lifetime imaging on haematoxylin and eosin stained tissue sections. J Biophotonics 7(7):483–491Google Scholar
  236. 236.
    Valeur B (2005) Pulse and phase fluorometries: an objective comparison. In: Hof M, Hutterer R, Fidler V (eds) Fluorescence spectroscopy in biology. Springer, Berlin, pp 30–48Google Scholar
  237. 237.
    Becker W, Bergmann A, Hink MA, Konig K, Benndorf K, Biskup C (2004) Fluorescence lifetime imaging by time-correlated single-photon counting. Microsc Res Tech 63(1):58–66Google Scholar
  238. 238.
    Buurman EP, Sanders R, Draaijer A, Gerritsen HC, van Ween JJF, Houpt PM, Levine YK (1992) Fluorescence lifetime imaging using a confocal laser scanning microscope. Scanning 14:155–159Google Scholar
  239. 239.
    Gerritsen HC, Asselbergs NAH, Agronskaia AV, Van Sark WGJHM (2002) Fluorescence lifetime imaging in scanning microscopes: acquisition speed, photon economy and lifetime resolution. J Microsc 206(3):218–224MathSciNetGoogle Scholar
  240. 240.
    Krishnan RV, Masuda A, Centonze VE, Herman B (2003) Quantitative imaging of protein-protein interactions by multiphoton fluorescence lifetime imaging microscopy using a streak camera. J Biomed Opt 8(3):362–367Google Scholar
  241. 241.
    Biskup C, Zimmer T, Benndorf K (2004) FRET between cardiac Na+ channel subunits measured with a confocal microscope and a streak camera. Nat Biotechnol 22(2):220–224Google Scholar
  242. 242.
    Minami T, Hirayama S (1990) High quality fluorescence decay curves and lifetime imaging using an elliptical scan streak camera. J Photochem Photobiol A 53:11–21Google Scholar
  243. 243.
    Booth MJ, Wilson T (2004) Low-cost, frequency-domain, fluorescence lifetime confocal microscopy. J Microsc 214(1):36–42MathSciNetGoogle Scholar
  244. 244.
    Carlsson K, Liljeborg A (1998) Simultaneous confocal lifetime imaging of multiple fluorophores using the intensity-modulated multiple-wavelength scanning (IMS) technique. J Microsc 191(2):119–127Google Scholar
  245. 245.
    French T, So PTC, Weaver DJ, Coelho-Sampaio T, Gratton E, Voss EW, Carrero J (1997) Two-photon fluorescence lifetime imaging microscopy of macrophage-mediated antigen processing. J Microsc 185:339–353Google Scholar
  246. 246.
    Becker W (2005) Advanced time-correlated single photon counting techniques. Springer series in chemical physics, vol 81. Springer: New YorkGoogle Scholar
  247. 247.
    O’Connor DV, Phillips D (1984) Time-correlated single-photon counting. Academic, New YorkGoogle Scholar
  248. 248.
    Esposito A, Gerritsen HC, Wouters FS (2007) Optimizing frequency-domain fluorescence lifetime sensing for high-throughput applications: photon economy and acquisition speed. J Opt Soc Am A 24:3261Google Scholar
  249. 249.
    Philip J, Carlsson K (2003) Theoretical investigation of the signal-to-noise ratio in fluorescence lifetime imaging. J Opt Soc Am A 20(2):368–379Google Scholar
  250. 250.
    Gratton E, Breusegem S, Sutin J, Ruan Q, Barry N (2003) Fluorescence lifetime imaging for the two-photon microscope: time-domain and frequency-domain methods. J Biomed Opt 8(3):381–390Google Scholar
  251. 251.
    Birch DJS, Imhof RE (1991) Time-domain fluorescence spectroscopy using time-correlated single photon counting. In: Lakowicz JR (ed) Topics in fluorescence spectroscopy: techniques. Plenum Press, New YorkGoogle Scholar
  252. 252.
    Lévêque-Fort S, Papadopoulos DN, Forget S, Balembois F, Georges P (2005) Fluorescence lifetime imaging with a low-repetition-rate passively mode-locked diode-pumped Nd:YVO4 oscillator. Opt Lett 30:168–170Google Scholar
  253. 253.
    Dunsby C, Lanigan PMP, McGinty J, Elson DS, Requejo-Isidro J, Munro I, Galletly N, McCann F, Treanor B, Önfelt B, Davis DM, Neil MAA, French PMW (2004) An electronically tunable ultrafast laser source applied to fluorescence imaging and fluorescence lifetime imaging microscopy. J Phys D Appl Phys 37:3296–3303Google Scholar
  254. 254.
    Esposito A, Bader AN, Schlachter SC, van den Heuvel DJ, Schierle GSK, Venkitaraman AR, Kaminski CF, Gerritsen HC (2011) Design and application of a confocal microscope for spectrally resolved anisotropy imaging. Opt Express 19(3):2546–2555Google Scholar
  255. 255.
    Michalet X et al (2013) Development of new photon-counting detectors for single-molecule fluorescence microscopy. Philos Trans R Soc B Biol Sci 368(1611):20120035Google Scholar
  256. 256.
    Becker W, Su B, Holub O, Weisshart K (2011) FLIM and FCS detection in laser-scanning microscopes: increased efficiency by GaAsP hybrid detectors. Microsc Res Tech 74(9):804–811Google Scholar
  257. 257.
    Michalet X, Cheng A, Antelman J, Suyama M, Arisaka K, Weiss S (2008) Hybrid photodetector for single-molecule spectroscopy and microscopy. In: SPIE Proc 6862:68620FGoogle Scholar
  258. 258.
    Walther KA, Papke B, Sinn MB, Michel K, Kinkhabwala A (2011) Precise measurement of protein interacting fractions with fluorescence lifetime imaging microscopy. Mol Biosyst 7(2):322–336Google Scholar
  259. 259.
    Haugen GR, Wallin BW, Lytle FE (1979) Optimization of data-acquisition rates in time-correlated single-photon fluorimetry. Rev Sci Instrum 50(1):64–79Google Scholar
  260. 260.
    Wang XF, Periasamy A, Herman B, Coleman DM (1992) Fluorescence lifetime imaging microscopy (FLIM): instrumentation and applications. Crit Rev Anal Chem 23(5):369–395Google Scholar
  261. 261.
    Wang XF, Uchida T, Coleman DM, Minami S (1991) A 2-dimensional fluorescence lifetime imaging system using a gated image intensifier. Appl Spectrosc 45(3):360–366Google Scholar
  262. 262.
    Dowling K, Hyde SCW, Dainty JC, French PMW, Hares JD (1997) 2-D fluorescence lifetime imaging using a time-gated image intensifier. Opt Commun 135(1–3):27–31Google Scholar
  263. 263.
    Scully AD, Mac Robert AJ, Botchway S, O’Neill P, Parker AW, Ostler RB, Phillips D (1996) Development of a laser-based fluorescence microscope with subnanosecond time resolution. J Fluoresc 6(2):119–125Google Scholar
  264. 264.
    Agronskaia AV, Tertoolen L, Gerritsen HC (2003) High frame rate fluorescence lifetime imaging. J Phys D Appl Phys 36(14):1655–1662Google Scholar
  265. 265.
    Dowling K, Dayel MJ, Lever MJ, French PMW, Hares JD, Dymoke-Bradshaw AKL (1998) Fluorescence lifetime imaging with picosecond resolution for biomedical applications. Opt Lett 23(10):810–812Google Scholar
  266. 266.
    Elson DS, Munro I, Requejo-Isidro J, McGinty J, Dunsby C, Galletly N, Stamp GW, Neil MAA, Lever MJ, Kellett PA, Dymoke-Bradshaw A, Hares J, French PMW (2004) Real-time time-domain fluorescence lifetime imaging including single-shot acquisition with a segmented optical image intensifier. New J Phys 6:180Google Scholar
  267. 267.
    Mitchell AC, Wall JE, Murray JG, Morgan CG (2002) Direct modulation of the effective sensitivity of a CCD detector: a new approach to time-resolved fluorescence imaging. J Microsc 206(3):225–232MathSciNetGoogle Scholar
  268. 268.
    Mitchell AC, Wall JE, Murray JG, Morgan CG (2002) Measurement of nanosecond time-resolved fluorescence with a directly gated interline CCD camera. J Microsc 206(3):233–238MathSciNetGoogle Scholar
  269. 269.
    Morgan CG, Mitchell AC, Murray JG (1990) Nanosecond time-resolved fluorescence microscopy: principles and practice. Proc R Microsc Soc 1:463–466Google Scholar
  270. 270.
    Pepperkok R, Squire A, Geley S, Bastiaens PIH (1999) Simultaneous detection of multiple green fluorescent proteins in live cells by fluorescence lifetime imaging microscopy. Curr Biol 9(5):269–272Google Scholar
  271. 271.
    Lakowicz JR, Szmacinski H, Nowaczyk K, Berndt KW, Johnson M (1992) Fluorescence lifetime imaging. Anal Biochem 202(2):316–330Google Scholar
  272. 272.
    Gadella TWJ, Jovin TM, Clegg RM (1993) Fluorescence lifetime imaging microscopy (FLIM) – spatial resolution of structures on the nanosecond timescale. Biophys Chem 48:221–239Google Scholar
  273. 273.
    Ng T, Squire A, Hansra G, Bornancin F, Prevostel C, Hanby A, Harris W, Barnes D, Schmidt S, Mellor H, Bastiaens PI, Parker PJ (1999) Imaging protein kinase C alpha activation in cells. Science 283(5410):2085–2089Google Scholar
  274. 274.
    Squire A, Verveer PJ, Bastiaens PIH (2000) Multiple frequency fluorescence lifetime imaging microscopy. J Microsc 197(2):136–149Google Scholar
  275. 275.
    Schneider PC, Clegg RM (1997) Rapid acquisition analysis and display of fluorescence lifetime-resolved images for real-time applications. Rev Sci Instrum 68(11):4107–4119Google Scholar
  276. 276.
    Mizeret J, Stepinac T, Hansroul M, Studzinski A, van den Bergh H, Wagnieres G (1999) Instrumentation for real-time fluorescence lifetime imaging in endoscopy. Rev Sci Instrum 70(12):4689–4701Google Scholar
  277. 277.
    Mizeret J, Wagnieres G, Stepinac T, Van Den Bergh H (1997) Endoscopic tissue characterization by frequency-domain fluorescence lifetime imaging (FD-FLIM). Lasers Med Sci 12:209–217Google Scholar
  278. 278.
    Hedstrom J, Sedarus S, Prendergast FG (1988) Measurements of fluorescence lifetimes by use of a hybrid time-correlated and multifrequency phase fluorometer. Biochemistry 27:6203–6208Google Scholar
  279. 279.
    Lee KCB, Siegel J, Webb SED, Lévêque-Fort S, Cole MJ, Jones R, Dowling K, Lever MJ, French PMW (2001) Application of the stretched exponential function to fluorescence lifetime imaging. Biophys J 81(3):1265–1274Google Scholar
  280. 280.
    Kress M, Meier T, Steiner R, Dolp F, Erdmann R, Ortmann U, Rück A (2003) Time-resolved microspectrofluorometry and fluorescence lifetime imaging of photosensitizers using picosecond pulsed diode lasers in laser scanning microscopes. J Biomed Opt 8(1):26–32Google Scholar
  281. 281.
    Elson DS, Siegel J, Webb SED, Lévêque-Fort S, Lever MJ, French PMW, Lauritsen K, Wahl M, Erdmann R (2002) Fluorescence lifetime system for microscopy and multi-well plate imaging with a blue picosecond diode laser. Opt Lett 27(16):1409–1411Google Scholar
  282. 282.
    Ryder AG, Glynn TJ, Przyjalgowski M, Szczupak B (2002) A compact violet diode laser-based fluorescence lifetime microscope. J Fluoresc 12(2):177–180Google Scholar
  283. 283.
    Sakai Y, Hirayama S (1988) A fast deconvolution method to analyze fluorescence decays when the excitation pulse repetition period is less than the decay times. J Luminescence 39(3):145–151Google Scholar
  284. 284.
    van Munster EB, Gadella TWJ (2004) phi-FLIM: a new method to avoid aliasing in frequency-domain fluorescence lifetime imaging microscopy. J Microsc 213(1):29–38MathSciNetGoogle Scholar
  285. 285.
    van Munster EB, Gadella TWJ (2004) Suppression of photobleaching-induced artifacts in frequency-domain FLIM by permutation of the recording order. Cytometry A 58(2):185–194Google Scholar
  286. 286.
    Schuermann KC, Grecco HE (2012) flatFLIM: enhancing the dynamic range of frequency domain FLIM. Opt Express 20(18):20730–20741Google Scholar
  287. 287.
    Becker W, Bergmann A, Biskup C, Zimmer T, Klöcker N, Benndorf K (2002) Multiwavelength TCSPC lifetime imaging (Invited Paper) [4620–19]. In: SPIE Proc: 4620:79–84Google Scholar
  288. 288.
    Tinnefeld P, Herten DP, Sauer M (2001) Photophysical dynamics of single molecules studied by spectrally-resolved fluorescence lifetime imaging microscopy (SFLIM). J Phys Chem A 105(34):7989–8003Google Scholar
  289. 289.
    Hanley QS, Arndt-Jovin DJ, Jovin TM (2002) Spectrally resolved fluorescence lifetime imaging microscopy. Appl Spectrosc 56(2):155–166Google Scholar
  290. 290.
    Bird DK, Eliceiri KW, Fan CH, White JG (2004) Simultaneous two-photon spectral and lifetime fluorescence microscopy. Appl Optics 43:5173–5182Google Scholar
  291. 291.
    Levitt JA, Matthews DR, Ameer-Beg SM, Suhling K (2009) Fluorescence lifetime and polarization-resolved imaging in cell biology. Curr Opin Biotechnol 20:28–36Google Scholar
  292. 292.
    Jameson DM, Ross JA (2010) Fluorescence polarization/anisotropy in diagnostics and imaging. Chem Rev 110(5):2685–2708Google Scholar
  293. 293.
    Gradinaru CC, Marushchak DO, Samim M, Krull UJ (2010) Fluorescence anisotropy: from single molecules to live cells. Analyst 135(3):452–459Google Scholar
  294. 294.
    Yengo CM, Berger CL (2010) Fluorescence anisotropy and resonance energy transfer: powerful tools for measuring real time protein dynamics in a physiological environment. Curr Opin Pharmacol 10(6):731–737Google Scholar
  295. 295.
    Chan FTS, Kaminski CF, Schierle GSK (2011) HomoFRET fluorescence anisotropy imaging as a tool to study molecular self-assembly in live cells. Chemphyschem 12(3):500–509Google Scholar
  296. 296.
    Vogel SS, Thaler C, Blank PS, Koushik SV (2010) Time-resolved fluorescence anisotropy. In: Ammasi Periasamy RMC (ed) FLIM microscopy in biology and medicine. Chapman & Hall/Taylor & Francis Group, Boca Raton, pp 245–288Google Scholar
  297. 297.
    Tramier M, Coppey-Moisan M (2008) Fluorescence anisotropy imaging microscopy for homo-FRET in living cells. In: Kevin FS (ed) Methods in cell biology. Academic, Amsterdam, pp 395–414Google Scholar
  298. 298.
    Birch DJS (2011) Fluorescence detections and directions. Meas Sci Technol 22(5):052002Google Scholar
  299. 299.
    Piston DW (2010) Fluorescence anisotropy of protein complexes in living cells. Biophys J 99(6):1685–1686Google Scholar
  300. 300.
    Axelrod D (1979) Carbocyanine dye orientation in red cell membrane studied by microscopic fluorescence polarization. Biophys J 26(3):557–573Google Scholar
  301. 301.
    Ha T, Laurence TA, Chemla DS, Weiss S (1999) Polarization spectroscopy of single fluorescent molecules. J Phys Chem B 103(33):6839–6850Google Scholar
  302. 302.
    Yan YL, Marriott G (2003) Fluorescence resonance energy transfer imaging microscopy and fluorescence polarization imaging microscopy. Methods in Enzymology, Biophotonics Pt A 360:561–580Google Scholar
  303. 303.
    Fisz JJ (2009) Another treatment of fluorescence polarization microspectroscopy and imaging. J Phys Chem A 113(15):3505–3516Google Scholar
  304. 304.
    Fisz JJ (2007) Another look at magic-angle-detected fluorescence and emission anisotropy decays in fluorescence microscopy. J Phys Chem A 111(50):12867–12870Google Scholar
  305. 305.
    Fisz JJ (2007) Fluorescence polarization spectroscopy at combined high-aperture excitation and detection: application to one-photon-excitation fluorescence microscopy. J Phys Chem A 111(35):8606–8621Google Scholar
  306. 306.
    Koshioka M, Sasaki K, Masuhara H (1995) Time-dependent fluorescence depolarization analysis in 3-dimensional microspectroscopy. Appl Spectrosc 49(2):224–228Google Scholar
  307. 307.
    Fixler D, Namer Y, Yishay Y, Deutsch M (2006) Influence of fluorescence anisotropy on fluorescence intensity and lifetime measurement: theory, simulations and experiments. IEEE Trans Biomed Eng 53(6):1141–1152Google Scholar
  308. 308.
    Axelrod D (1989) Fluorescence polarization microscopy. Methods Cell Biol 30:333–352Google Scholar
  309. 309.
    Suhling K, Siegel J, Lanigan PMP, Leveque-Fort S, Webb SED, Phillips D, Davis DM, French PMW (2004) Time-resolved fluorescence anisotropy imaging applied to live cells. Opt Lett 29(6):584–586Google Scholar
  310. 310.
    Birch DJS (2001) Multiphoton excited fluorescence spectroscopy of biomolecular systems. Spectrochim Acta A Mol Biomol Spectrosc 57(11):2313–2336Google Scholar
  311. 311.
    Lidke DS, Nagy P, Barisas BG, Heintzmann R, Post JN, Lidke KA, Clayton AHA, Arndt-Jovin DJ, Jovin TM (2003) Imaging molecular interactions in cells by dynamic and static fluorescence anisotropy (rFLIM and emFRET). Biochem Soc Trans 31(5):1020–1027Google Scholar
  312. 312.
    Dix JA, Verkman AS (1990) Mapping of fluorescence anisotropy in living cells by ratio imaging. Applications to cytoplasmic viscosity. Biophys J 57:231–240Google Scholar
  313. 313.
    Swaminathan R, Hoang CP, Verkman AS (1997) Photobleaching recovery and anisotropy decay of green fluorescent protein GFP-S65T in solution and cells: Cytoplasmic viscosity probed by green fluorescent protein translational and rotational diffusion. Biophys J 72:1900–1907Google Scholar
  314. 314.
    Gough AH, Taylor DL (1993) Fluorescence anisotropy imaging microscopy maps calmodulin-binding during cellular contraction and locomotion. J Cell Biol 121(5):1095–1107Google Scholar
  315. 315.
    Levitt JA, Chung PH, Kuimova MK, Yahioglu G, Wang Y, Qu JL, Suhling K (2011) Fluorescence anisotropy of molecular rotors. Chemphyschem 12(3):662–672Google Scholar
  316. 316.
    Bigelow CE, Conover DL, Foster TH (2003) Confocal fluorescence spectroscopy and anisotropy imaging system. Opt Lett 28(9):695–697Google Scholar
  317. 317.
    Foster TH, Pearson BD, Mitra S, Bigelow CE (2005) Fluorescence anisotropy imaging reveals localization of meso-tetrahydroxyphenyl chlorin in the nuclear envelope. Photochem Photobiol 81(6):1544–1547Google Scholar
  318. 318.
    Bigelow CE, Vishwasrao HD, Frelinger JG, Foster TH (2004) Imaging enzyme activity with polarization-sensitive confocal fluorescence microscopy. J Microsc Oxf 215:24–33MathSciNetGoogle Scholar
  319. 319.
    Li W, Wang Y, Shao HR, He YH, Ma H (2007) Probing rotation dynamics of biomolecules using polarization based fluorescence microscopy. Microsc Res Tech 70(4):390–395Google Scholar
  320. 320.
    Cao Z, Huang CC, Tan W (2006) Nuclease resistance of telomere-like oligonucleotides monitored in live cells by fluorescence anisotropy imaging. Anal Chem 78:1478–1484Google Scholar
  321. 321.
    Mattheyses AL, Hoppe AD, Axelrod D (2004) Polarized fluorescence resonance energy transfer microscopy. Biophys J 87(4):2787–2797Google Scholar
  322. 322.
    Rizzo MA, Piston DW (2005) High-contrast imaging of fluorescent protein FRET by fluorescence polarization microscopy. Biophys J 88(2):L14–L16Google Scholar
  323. 323.
    Matthews DR, Carlin LM, Ofo E, Barber PR, Vojnovic B, Irving M, Ng T, Ameer-Beg SM (2010) Time-lapse FRET microscopy using fluorescence anisotropy. J Microsc Oxf 237(1):51–62MathSciNetGoogle Scholar
  324. 324.
    Mao S, Benninger RKP, Yan YL, Petchprayoon C, Jackson D, Easley CJ, Piston DW, Marriott G (2008) Optical lock-in detection of FRET using synthetic and genetically encoded optical switches. Biophys J 94(11):4515–4524Google Scholar
  325. 325.
    Squire A, Verveer PJ, Rocks O, Bastiaens PI (2004) Red-edge anisotropy microscopy enables dynamic imaging of homo-FRET between green fluorescent proteins in cells. J Struct Biol 147(1):62–69Google Scholar
  326. 326.
    Keating SM, Wensel TG (1991) Nanosecond fluorescence microscopy. Emission kinetics of fura-2 in single cells. Biophys J 59(1):186–202Google Scholar
  327. 327.
    Spitz JA, Polard V, Maksimenko A, Subra F, Baratti-Elbaz C, Meallet-Renault R, Pansu RB, Tauc P, Auclair C (2007) Assessment of cellular actin dynamics by measurement of fluorescence anisotropy. Anal Biochem 367(1):95–103Google Scholar
  328. 328.
    Tramier M, Kemnitz K, Durieux C, Coppey J, Denjean P, Pansu RB, Coppey-Moisan M (2000) Restrained torsional dynamics of nuclear DNA in living proliferative mammalian cells. Biophys J 78(5):2614–2627Google Scholar
  329. 329.
    Clayton AHA, Hanley QS, Arndt-Jovin DJ, Subramaniam V, Jovin TM (2002) Dynamic fluorescence anisotropy imaging microscopy in the frequency domain (rFLIM). Biophys J 83:1631–1649Google Scholar
  330. 330.
    Botchway SW, Lewis AM, Stubbs CD (2011) Development of fluorophore dynamics imaging as a probe for lipid domains in model vesicles and cell membranes. Eur Biophys J Biophys Lett 40(2):131–141Google Scholar
  331. 331.
    Min MY, Rusakov DA, Kullmann DM (1998) Activation of AMPA, kainate, and metabotropic receptors at hippocampal mossy fiber synapses: role of glutamate diffusion. Neuron 21(3):561–570Google Scholar
  332. 332.
    Perrais D, Ropert N (2000) Altering the concentration of GABA in the synaptic cleft potentiates miniature IPSCs in rat occipital cortex. Eur J Neurosci 12(1):400–404Google Scholar
  333. 333.
    Savtchenko LP, Sylantyev S, Rusakov DA (2013) Central synapses release a resource-efficient amount of glutamate. Nat Neurosci 16(1):10–16Google Scholar
  334. 334.
    Nielsen TA, DiGregorio DA, Silver RA (2004) Modulation of glutamate mobility reveals the mechanism underlying slow-rising AMPAR EPSCs and the diffusion coefficient in the synaptic cleft. Neuron 42(5):757–771Google Scholar
  335. 335.
    Piet R, Vargova L, Sykova E, Poulain DA, Oliet SHR (2004) Physiological contribution of the astrocytic environment of neurons to intersynaptic crosstalk. Proc Natl Acad Sci U S A 101(7):2151–2155Google Scholar
  336. 336.
    Savtchenko LP, Rusakov DA (2005) Extracellular diffusivity determines contribution of high-versus low-affinity receptors to neural signaling. Neuroimage 25(1):101–111Google Scholar
  337. 337.
    Kukita F (2000) Solvent effects on squid sodium channels are attributable to movements of a flexible protein structure in gating currents and to hydration in a pore. J Physiol Lond 522(3):357–373Google Scholar
  338. 338.
    Svoboda K, Tank DW, Denk W (1996) Direct measurement of coupling between dendritic spines and shafts. Science 272(5262):716–719Google Scholar
  339. 339.
    Santamaria F, Wils S, De Schutter E, Augustine GJ (2006) Anomalous diffusion in Purkinje cell dendrites caused by spines. Neuron 52(4):635–648Google Scholar
  340. 340.
    Biess A, Korkotian E, Holcman D (2011) Barriers to diffusion in dendrites and estimation of calcium spread following synaptic inputs. Plos Comput Biol 7(10):e1002182Google Scholar
  341. 341.
    Murakoshi H, Wang H, Yasuda R (2011) Local, persistent activation of Rho GTPases during plasticity of single dendritic spines. Nature 472(7341):100–104Google Scholar
  342. 342.
    Nicholson C, Phillips JM, Gardner-Medwin AR (1979) Diffusion from an iontophoretic point source in the brain – role of tortuosity and volume fraction. Brain Res 169(3):580–584Google Scholar
  343. 343.
    Sykova E, Nicholson C (2008) Diffusion in brain extracellular space. Physiol Rev 88(4):1277–1340Google Scholar
  344. 344.
    Nicholson C, Tao L (1993) Hindered diffusion of high-molecular-weight compounds in brain extracellular microenvironment measured with integrative optical imaging. Biophys J 65(6):2277–2290Google Scholar
  345. 345.
    Hrabetova S (2005) Extracellular diffusion is fast and isotropic in the stratum radiatum of hippocampal CA1 region in rat brain slices. Hippocampus 15(4):441–450Google Scholar
  346. 346.
    Xiao FR, Nicholson C, Hrabe J, Hrabetova S (2008) Diffusion of flexible random-coil dextran polymers measured in anisotropic brain extracellular space by integrative optical Imaging. Biophys J 95(3):1382–1392Google Scholar
  347. 347.
    Zheng KY, Scimemi A, Rusakov DA (2008) Receptor actions of synaptically released glutamate: the role of transporters on the scale from nanometers to microns. Biophys J 95(10):4584–4596Google Scholar
  348. 348.
    Thorne RG, Nicholson C (2006) In vivo diffusion analysis with quantum dots and dextrans predicts the width of brain extracellular space. Proc Natl Acad Sci U S A 103(14):5567–5572Google Scholar
  349. 349.
    Magzoub M, Zhang H, Dix JA, Verkman AS (2009) Extracellular space volume measured by two-color pulsed dye infusion with microfiberoptic fluorescence photodetection. Biophys J 96(6):2382–2390Google Scholar
  350. 350.
    Zhang H, Verkman AS (2010) Microfiberoptic measurement of extracellular space volume in brain and tumor slices based on fluorescent dye partitioning. Biophys J 99(4):1284–1291Google Scholar
  351. 351.
    Reits EAJ, Neefjes JJ (2001) From fixed to FRAP: measuring protein mobility and activity in living cells. Nat Cell Biol 3(6):E145–E147Google Scholar
  352. 352.
    Cui-Wang TT, Hanus C, Cui T, Helton T, Bourne J, Watson D, Harris KM, Ehlers MD (2012) Local zones of endoplasmic reticulum complexity confine cargo in neuronal dendrites. Cell 148(1–2):309–321Google Scholar
  353. 353.
    Benninger RKP, Önfelt B, Neil MAA, Davis DM, French PMW (2005) Fluorescence imaging of two-photon linear dichroism: cholesterol depletion disrupts molecular orientation in cell membranes. Biophys J 88:609–622Google Scholar
  354. 354.
    Reeve JE, Corbett AD, Boczarow I, Wilson T, Bayley H, Anderson HL (2012) Probing the orientational distribution of dyes in membranes through multiphoton microscopy. Biophys J 103(5):907–917Google Scholar
  355. 355.
    Brack AS, Brandmeier BD, Ferguson RE, Criddle S, Dale RE, Irving M (2004) Bifunctional rhodamine probes of myosin regulatory light chain orientation in relaxed skeletal muscle fibers. Biophys J 86(4):2329–2341Google Scholar
  356. 356.
    Mojzisova H, Olesiak J, Zielinski M, Matczyszyn K, Chauvat D, Zyss J (2009) Polarization-sensitive two-photon microscopy study of the organization of liquid-crystalline DNA. Biophys J 97(8):2348–2357Google Scholar
  357. 357.
    Dale RE, Eisinger J, Blumberg WE (1979) The orientational freedom of molecular probes. Biophys J 26:161–194Google Scholar
  358. 358.
    van der Meer BW (2002) Kappa-squared: from nuisance to new sense. J Biotechnol 82(3):181–196Google Scholar
  359. 359.
    Varma R, Mayor S (1998) GPI-anchored proteins are organized in submicron domains at the cell surface. Nature 394:798–801Google Scholar
  360. 360.
    Sharma P, Varma R, Sarasij RC, Ira GK, Krishnamoorthy G, Rao M, Mayor S (2004) Nanoscale organization of multiple GPI-anchored proteins in living cell membranes. Cell 116(4):577–589Google Scholar
  361. 361.
    Vishwasrao HD, Trifilieff P, Kandel ER (2012) In vivo imaging of the actin polymerization state with two-photon fluorescence anisotropy. Biophys J 102(5):1204–1214Google Scholar
  362. 362.
    van Ham TJ, Esposito A, Kumita JR, Hsu S-TD, Kaminski Schierle GS, Kaminski CF, Dobson CM, Nollen EAA, Bertoncini CW (2010) Towards multiparametric fluorescent imaging of amyloid formation: studies of a YFP model of α-synuclein aggregation. J Mol Biol 395(3):627–642Google Scholar
  363. 363.
    Steinmeyer R, Harms GS (2009) Fluorescence resonance energy transfer and anisotropy reveals both hetero- and homo-energy transfer in the pleckstrin homology-domain and the parathyroid hormone-receptor. Microsc Res Tech 72(1):12–21Google Scholar
  364. 364.
    Gautier I, Tramier M, Durieux C, Coppey J, Pansu RB, Nicolas JC, Kemnitz K, Coppey-Moisan M (2001) Homo-FRET microscopy in living cells to measure monomer-dimer transition of GFP-tagged proteins. Biophys J 80(6):3000–3008Google Scholar
  365. 365.
    Bader AN, Hofman EG, Voortman J, Henegouwen PMPVE, Gerritsen HC (2009) Homo-FRET imaging enables quantification of protein cluster sizes with subcellular resolution. Biophys J 97(9):2613–2622Google Scholar
  366. 366.
    Bader AN, Hofman EG, Henegouwen PMPVE, Gerritsen HC (2007) Imaging of protein cluster sizes by means of confocal time-gated fluorescence anisotropy microscopy. Opt Express 15(11):6934–6945Google Scholar
  367. 367.
    Bader AN, Hoetzl S, Hofman EG, Voortman J, Henegouwen PMPVE, van Meer G, Gerritsen HC (2011) Homo-FRET imaging as a tool to quantify protein and lipid clustering. Chemphyschem 12(3):475–483Google Scholar
  368. 368.
    Yeow EKL, Clayton AHA (2007) Enumeration of oligomerization states of membrane proteins in living cells by homo-FRET spectroscopy and microscopy: theory and application. Biophys J 92(9):3098–3104Google Scholar
  369. 369.
    Thaler C, Koushik SV, Puhl HL, Blank PS, Vogel SS (2009) Structural rearrangement of CaMKII alpha catalytic domains encodes activation. Proc Natl Acad Sci U S A 106(15):6369–6374Google Scholar
  370. 370.
    Woolley P, Steinhäuser KG, Epe B (1987) Förster-type energy-transfer – simultaneous forward and reverse transfer between unlike fluorophores. Biophys Chem 26(2–3):367–374Google Scholar
  371. 371.
    Porter GB (1972) Reversible energy-transfer. Theor Chim Acta 24(2–3):265–270Google Scholar
  372. 372.
    Willaert K, Loewenthal R, Sancho J, Froeyen M, Fersht A, Engelborghs Y (1992) Determination of the excited-state lifetimes of the tryptophan residues in barnase, via multifrequency phase fluorometry of tryptophan mutants. Biochemistry 31(3):711–716Google Scholar
  373. 373.
    Jung G, Ma YZ, Prall BS, Fleming GR (2005) Ultrafast fluorescence depolarisation in the yellow fluorescent protein due to its dimerisation. Chemphyschem 6(8):1628–1632Google Scholar
  374. 374.
    Koushik SV, Vogel SS (2008) Energy migration alters the fluorescence lifetime of Cerulean: implications for fluorescence lifetime imaging Forster resonance energy transfer measurements. J Biomed Opt 13(3):031204Google Scholar
  375. 375.
    Gee ML, Lensun L, Smith TA, Scholes CA (2004) Time-resolved evanescent wave-induced fluorescence anisotropy for the determination of molecular conformational changes of proteins at an interface. Eur Biophys J Biophys Lett 33(2):130–139Google Scholar
  376. 376.
    Smith TA, Gee ML, Scholes CA (2005) Time-resolved evanescent wave-induced fluorescence anisotropy measurements. In: Lakowicz CDGJR (ed) Reviews in fluorescence. Springer, New York, pp 245–271Google Scholar
  377. 377.
    Digman MA, Caiolfa VR, Zamai M, Gratton E (2008) The phasor approach to fluorescence lifetime imaging analysis. Biophys J 94(2):L14–L16Google Scholar
  378. 378.
    Barber PR, Ameer-Beg SM, Pathmananthan S, Rowley M, Coolen ACC (2010) A Bayesian method for single molecule, fluorescence burst analysis. Biomed Opt Express 1(4):1148–1158Google Scholar
  379. 379.
    Kröger HW, Schmidt GK, Pailer N (1992) Faint object camera: European contribution to the Hubble Space Telescope. Acta Astronaut 26(11):827–834Google Scholar
  380. 380.
    Mason KO, Breeveld A, Much R, Carter M, Cordova FA, Cropper MS, Fordham J, Huckle H, Ho C, Kawakami H (2001) The XMM-Newton optical/UV monitor telescope. Astron Astrophys 365(1):L36–L44Google Scholar
  381. 381.
    Tarhoni MH, Vigneswara V, Smith M, Anderson S, Wigmore P, Lees JE, Ray DE, Carter WG (2011) Detection, quantification, and microlocalisation of targets of pesticides using microchannel plate autoradiographic imagers. Molecules 16(10):8535–8551Google Scholar
  382. 382.
    Rembold CM, Kendall JM, Campbell AK (1997) Measurement of changes in sarcoplasmic reticulum Ca2+ in rat tail artery with targeted apoaequorin delivered by an adenoviral vector. Cell Calcium 21(1):69–79Google Scholar
  383. 383.
    Read PD, Carter MK, Pike CD, Harrison RA, Kent BJ, Swinyard BM, Patchett BE, Redfern RM, Shearer A, Colhoun M (1997) Uses of microchannel plate intensified detectors for imaging applications in the X-ray, EUV and visible wavelength regions. Nucl Instrum Methods A392:359–363Google Scholar
  384. 384.
    Sergent N, Levitt JA, Green M, Suhling K (2010) Rapid wide-field photon counting imaging with microsecond time resolution. Opt Express 18(24):25292–25298Google Scholar
  385. 385.
    Suhling K, Hungerford G, Airey RW, Morgan BL (2001) A position-sensitive photon event counting detector applied to fluorescence imaging of dyes in sol–gel matrices. Meas Sci Technol 12:131–141Google Scholar
  386. 386.
    Sharp NA (1992) Millisecond time resolution with the Kitt Peak photon-counting array. Publ Astron Soc Pac 104:263–269Google Scholar
  387. 387.
    Kemnitz K, Pfeifer L, Ainbund MR (1997) Detector for multichannel spectroscopy and fluorescence lifetime imaging on the picosecond timescale. Nucl Instrum Methods Phys Res A 387(1/2):86–87Google Scholar
  388. 388.
    Michalet X, Colyer RA, Antelman J, Siegmund OHW, Tremsin A, Vallerga JV, Weiss S (2009) Single-quantum dot imaging with a photon counting camera. Curr Pharm Biotechnol 10:543–558Google Scholar
  389. 389.
    Esposito A, Gerritsen HC, Oggier T, Lustenberger F, Wouters FS (2006) Innovating lifetime microscopy: a compact and simple tool for life sciences, screening, and diagnostics. J Biomed Opt 11:034016Google Scholar
  390. 390.
    Zhao QL, Schelen B, Schouten R, van den Oever R, Leenen R, van Kuijk H, Peters I, Polderdijk F, Bosiers J, Raspe M, Jalink K, de Jong JGS, van Geest B, Stoop K, Young IT (2012) Modulated electron-multiplied fluorescence lifetime imaging microscope: all-solid-state camera for fluorescence lifetime imaging. J Biomed Opt 17(12):126020Google Scholar
  391. 391.
    Lange R, Seitz P (2001) Solid-state time-of-flight range camera. IEEE J Quantum Electron 37(3):390–397Google Scholar
  392. 392.
    Kawahito S, Halin IA, Ushinaga T, Sawada T, Homma M, Maeda Y (2007) A CMOS time-of-flight range image sensor with gates-on-field-oxide structure. IEEE Sens J 7(11–12):1578–1586Google Scholar
  393. 393.
    Oggier T, Lehmann M, Kaufmann R, Schweizer M, Richter M, Metzler P, Lang G, Lustenberger F, Blanc N. (2004) An all-solid-state optical range camera for 3D real-time imaging with sub-centimeter depth resolution (SwissRanger). In: Proc SPIE: 5249, 534–545Google Scholar
  394. 394.
    Rochas A, Gani M, Furrer B, Besse PA, Popovic RS, Ribordy G, Gisin N (2003) Single photon detector fabricated in a complementary metal-oxide-semiconductor high-voltage technology. Rev Sci Instrum 74(7):3263–3270Google Scholar
  395. 395.
    Schwartz DE, Charbon E, Shepard KL (2008) A single-photon avalanche diode array for fluorescence lifetime imaging microscopy. IEEE J Solid State Circuits 43(11):2546–2557Google Scholar
  396. 396.
    Pancheri L, Stoppa D (2009) A SPAD-based Pixel Linear Array for High-Speed Time-Gated Fluorescence Lifetime Imaging. In: 2009 Proceedings of Esscirc IEEE, New York, pp 429–432Google Scholar
  397. 397.
    Blacksberg J, Maruyama Y, Charbon E, Rossman GR (2011) Fast single-photon avalanche diode arrays for laser Raman spectroscopy. Opt Lett 36(18):3672–3674Google Scholar
  398. 398.
    Niclass C, Favi C, Kluter T, Gersbach M, Charbon E (2008) A 128 × 128 single-photon image sensor with column-level 10-Bit time-to-digital converter array. IEEE J Solid State Circuits 43(12):2977–2989Google Scholar
  399. 399.
    Niclass C, Rochas A, Besse PA, Charbon E (2005) Design and characterization of a CMOS 3-D image sensor based on single photon avalanche diodes. IEEE J Solid State Circuits 40(9):1847–1854Google Scholar
  400. 400.
    Richardson J, Walker R, Grant L, Stoppa D, Borghetti F, Charbon E, Gersbach M, Henderson RK (2009) A 32x32 50ps resolution 10 bit time to digital converter array in 130 nm CMOS for time correlated imaging. In: Proceedings of the IEEE 2009 custom integrated circuits conference, New York, pp 77–80Google Scholar
  401. 401.
    Gersbach M, Maruyama Y, Trimananda R, Fishburn MW, Stoppa D, Richardson JA, Walker R, Henderson R, Charbon E (2012) A time-resolved, low-noise single-photon image sensor fabricated in deep-submicron CMOS technology. IEEE J Solid State Circuits 47(6):1394–1407Google Scholar
  402. 402.
    Stoppa D, Borghetti F, Richardson J, Walker R, Grant L, Henderson RK, Gersbach M, Charbon E (2009) A 32x32-pixel array with in-pixel photon counting and arrival time measurement in the analog domain. In: 2009 Proceedings of Esscirc, Athens, pp 205–208Google Scholar
  403. 403.
    Veerappan C, Richardson J, Walker R, Day-Uey L, Fishburn MW, Maruyama Y, Stoppa D, Borghetti F, Gersbach M, Henderson RK, Charbon E (2011) A 160x128 single-photon image sensor with on-pixel 55 ps 10b time-to-digital converter. In: Solid-state circuits conference digest of technical papers (ISSCC), San Francisco, 312–314Google Scholar
  404. 404.
    Field R, Shepard KL (2013) A 100-fps fluorescence lifetime imager in standard 0.13-μm CMOS. In 2013 Symposium on VLSI Circuits. VLSI Circuits (VLSIC): KyotoGoogle Scholar
  405. 405.
    Arlt J, Tyndall D, Rae BR, Li DDU, Richardson JA, Henderson RK (2013) A study of pile-up in integrated time-correlated single photon counting systems. Rev Sci Instrum 84(10):103105Google Scholar
  406. 406.
    Pancheri L, Massari N, Stoppa D (2013) SPAD image sensor with analog counting pixel for time-resolved fluorescence detection. IEEE Trans Electron Devices 60(10):3442–3449Google Scholar
  407. 407.
    Dutton N, Grant L, Henderson R (2013) 9.8μm SPAD-based analogue single photon counting pixel with bias controlled sensitivity. In: International image sensor workshop. Snowbird, UtahGoogle Scholar
  408. 408.
    Antonioli S, Cuccato A, Miari L, Labanca I, Rech I, Ghioni M (2013) Ultra-compact 32-channel system for time-correlated single-photon counting measurements. In: SPIE Proc 8773: 87730DGoogle Scholar
  409. 409.
    Colyer RA, Scalia G, Rech I, Gulinatti A, Ghioni M, Cova S, Weiss S, Michalet X (2010) High-throughput FCS using an LCOS spatial light modulator and an 8 x 1 SPAD array. Biomed Opt Express 1(5):1408–1431Google Scholar
  410. 410.
    Poland SP, Krstajić N, Coelho S, Tyndall D, Walker RJ, Devauges V, Morton PE, Nicholas NS, Richardson J, Li DD-U, Suhling K, Wells CM, Parsons M, Henderson RK, Ameer-Beg SM (2014) Time-resolved multifocal multiphoton microscope for high speed FRET imaging in vivo. Optics Letters, 39(20):6013–6016Google Scholar
  411. 411.
    Fraser GW, Heslop-Harrison JS, Schwarzacher T, Holland AD, Verhoeve P, Peacock A (2003) Detection of multiple fluorescent labels using superconducting tunnel junction detectors. Rev Sci Instrum 74(9):4140–4144Google Scholar
  412. 412.
    Fraser GW, Heslop-Harrison JS, Schwarzacher T, Verhoeve P, Peacock A, Smith SJ (2006) Optical fluorescence of biological samples using STJs. Nucl Instrum Methods Phys Res A 559(2):782–784Google Scholar
  413. 413.
    Verhoeve P, Martin D, van Dordrecht A, Verveer J, den Hartog R, Peacock A (2003) 120-pixel array of superconducting tunnel junctions as spectrophotometer for optical astronomy. Nucl Instrum Methods Phys Res A 513(1–2):206–210Google Scholar
  414. 414.
    Stevens MJ, Hadfield RH, Schwall RE, Nam SW, Mirin RP, Gupta JA (2006) Fast lifetime measurements of infrared emitters using a low-jitter superconducting single-photon detector. Appl Phys Lett 89:031109Google Scholar
  415. 415.
    Marsili F, Verma VB, Stern JA, Harrington S, Lita AE, Gerrits T, Vayshenker I, Baek B, Shaw MD, Mirin RP, Nam SW (2013) Detecting single infrared photons with 93 % system efficiency. Nat Photonics 7(3):210–214Google Scholar
  416. 416.
    Natarajan CM, Tanner MG, Hadfield RH (2012) Superconducting nanowire single-photon detectors: physics and applications. Supercond Sci Technol 25(6):063001Google Scholar
  417. 417.
    Gemmell NR, McCarthy A, Liu BC, Tanner MG, Dorenbos SD, Zwiller V, Patterson MS, Buller GS, Wilson BC, Hadfield RH (2013) Singlet oxygen luminescence detection with a fiber-coupled superconducting nanowire single-photon detector. Opt Express 21(4):5005–5013Google Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Klaus Suhling
    • 1
    Email author
  • Liisa M. Hirvonen
    • 1
  • James A. Levitt
    • 1
  • Pei-Hua Chung
    • 1
  • Carolyn Tregidgo
    • 1
  • Dmitri Rusakov
    • 2
  • Kaiyu Zheng
    • 2
  • Simon Ameer-Beg
    • 3
    • 4
  • Simon Poland
    • 3
    • 4
  • Simon Coelho
    • 3
    • 4
  • Robert Henderson
    • 5
  • Nikola Krstajic
    • 5
    • 6
  1. 1.Department of PhysicsKing’s College LondonLondonUK
  2. 2.Laboratory of Synaptic Imaging, Department of Clinical and Experimental EpilepsyUniversity College LondonLondonUK
  3. 3.Randall Division of Cell and Molecular BiophysicsKing’s College LondonLondonUK
  4. 4.Richard Dimbleby Department of Cancer Research, Division of Cancer Studies, New Hunt’s HouseKing’s College LondonLondonUK
  5. 5.CMOS Sensors & Systems Group, Integrated Micro & Nano Systems, School of EngineeringUniversity of EdinburghEdinburghUK
  6. 6.EPSRC IRC “Hub” in Optical Molecular Sensing & Imaging, MRC Centre for Inflammation Research, Queen’s Medical Research InstituteUniversity of EdinburghEdinburghUK

Personalised recommendations