留言板

尊敬的读者、作者、审稿人, 关于本刊的投稿、审稿、编辑和出版的任何问题, 您可以本页添加留言。我们将尽快给您答复。谢谢您的支持!

姓名
邮箱
手机号码
标题
留言内容
验证码

Single-photon avalanche diode imagers in biophotonics: review and outlook

Claudio Bruschini Harald Homulle Ivan Michel Antolovic Samuel Burri Edoardo Charbon

Claudio Bruschini, Harald Homulle, Ivan Michel Antolovic, Samuel Burri, Edoardo Charbon. Single-photon avalanche diode imagers in biophotonics: review and outlook[J]. Rhhz Test. doi: 10.1038/s41377-019-0191-5
Citation: Claudio Bruschini, Harald Homulle, Ivan Michel Antolovic, Samuel Burri, Edoardo Charbon. Single-photon avalanche diode imagers in biophotonics: review and outlook[J]. Rhhz Test. doi: 10.1038/s41377-019-0191-5

doi: 10.1038/s41377-019-0191-5

Single-photon avalanche diode imagers in biophotonics: review and outlook

More Information
    Corresponding author: Claudio Bruschini (claudio.bruschini@epfl.ch)
  • These authors contributed equally: Claudio Bruschini, Harald Homulle
  • These authors contributed equally: Claudio Bruschini, Harald Homulle
  • Figure  1.  SPAD arrays and comparison of the SPAD pixel architectures.

    a Artist's impression of a SPAD array (top view) and b an example of the corresponding cross-section for a substrate isolated SPAD in a conventional CMOS process, depicting some of the key components (diode anode/cathode and corresponding p-n junction, multiplication region in which the avalanche is triggered, and the substrate and isolation from it)3. The SPAD fill factor can be enhanced with microlenses (c), and the inset shows an SEM image from ref. 15. The design of individual pixels ranges from d basic structures, which are only capable of generating digital pulses corresponding to individual photon arrivals on the SPAD, to e pixels including counters, which add the individual arrivals over a given time window that is possibly gated, or f more advanced electronics such as a complete TDC, which make it possible to time-stamp individual photon arrival times. The corresponding examples of pixel micrographs are displayed in gi, as reprinted from refs. 16, 81, 139

    Figure  2.  Comparison of the SPAD array architectures.

    a In linear arrays, the pixel electronics can be placed outside the pixel area, leading to an increase in the fill factor; in 2D arrays, the fill factors are generally smaller, because b electronics is needed inside the pixel itself, or at least c at the array periphery, e.g. for column-based TDCs. The related advantages and disadvantages are discussed in detail in the text, and the corresponding examples of array micrographs can be found in df, as reprinted from refs. 35, 54, 81. Finally, g provides an overview of the evolution of SPAD imagers over the last 15 years in terms of the total number of pixels (on the vertical axis), the technology node (indicated at the top of the image), and some salient architectural characteristics, such as random access or event driven (indicated at the bottom of the image). Only some representative examples, primarily targeted at biophotonics applications, are shown here (details are reported in Table 2). The diagonal lines indicate the developments along a given technology node (800, 350 and 130 nm), which are usually started by optimising the SPADs before designing full imagers. Recent years have seen a trend towards higher spatial resolutions and 3D IC solutions

    Figure  3.  Example fluorescence intensity and/or lifetime results.

    a FluoCam system used in a point-like mode for the study of monomeric ICG-c(RGDfK) injected in a mouse with a glioblastoma mouse model. A subtle lifetime shift between tumour and non-tumour tissue is observed26. b Dual-colour intensity fluorescence image of a thin slice of a plant root stained with a mixture of Safranin and Fast Green, taken with the SwissSPAD widefield time-domain gated array178. c Triple-colour intensity fluorescence image of HeLa cells labelled with DAPI, Alexa 488 and Alexa 555, taken with SwissSPAD273. d, e Label-free FLIM of an unstained liver tissue excised from a tumourigenic murine model65, imaged with a 64 × 4 SPAD array18. f, g A Convallaria FLIM measurement performed with a linear 32 × 1 SPAD array70. The images are reprinted from refs. 26, 65, 70, 73, 178

    Figure  4.  Widefield SPIM-FCS images of monomeric eGFP oligomers in HeLa cells as recorded with a SwissSPAD widefield imager.

    a Fluorescence intensity, b diffusion coefficient and c dye concentration. d Diffusion coefficients for three HeLa cells expressing different oligomers. e Particle concentration for the three HeLa cells with different oligomers. The images are reprinted from ref. 110

    Figure  5.  SPAD super-resolution images.

    a The first super-resolution image captured with SwissSPAD, compared to b EMCCD and c widefield images. The images show the microtubuli of an U2OS cell labelled with Alexa Fluor 647, in Vectashield129. d, e Comparison of the SPCImager using "smart" aggregation and microlenses with an EMCCD. The images show multiple GATTA-PAINT 40G nanoruler localisations45. f Comparison of the differences in localisation uncertainty with and without "smart" aggregation and the impact of the microlenses45, 130. g SwissSPAD super-resolution image of microtubuli labelled with Alexa 647 in OxEA buffer compared to h sCMOS and i widefield images129. The white bar indicates 1 μm. The images are reprinted from refs. 45, 129, 130

    Figure  6.  SPAD optical tomography images and applications.

    a, b NIROT camera system prototype and measurements versus simulation results for a phantom154. c, d Fluorescence molecular tomography (FMT) image as an overlap of the optical image obtained with the RadHard2 32 × 32 photon-counting sensor with the corresponding MRI image156. C51 cells (a colon cancer-derived cell line) have been implanted in the flank of a mouse. A clear spread in the protease activity, indicated by the significantly higher fluorescence intensity in some parts of the tumour, is shown. c Complete MR + FMT image, and d zoom of the cancer region. The images are reprinted from refs. 154, 156

    Figure  7.  Recent SPAD concepts for imagers revolve around 3D integration, possibly combined with microlenses to further maximise the fill factor.

    a A 3D integration concept image, b a two-tier implementation with additional microlenses179 and c, d cross-sections of different imagers using three tiers165, 172. Frontside illumination is used in c, whereas backside illumination is used in b and d. The images bd are reprinted from refs. 165, 172, 179

    Figure  8.  SPAD system complexity vs. biophotonics applications and evolution of representative SPAD sensor figures of merit.

    a Schematic overview of the SPAD-based system complexity, in terms of key functionalities (counting/gating/time-stamping) versus the main biophotonics applications. bf Overview of the representative SPAD sensor figures of merit as a function of the main target applications, based on data from Table 2: b total number of SPADs (corresponding to the effective spatial resolution in the imagers) versus time; ce total number of SPADs, PDE and DCR per unit area grouped based on the application types (dashed lines: individual sensors, top/bottom of each box: maximum/minimum); and f the DCR per unit area versus the PDE

    Table  1.   Key SPAD pixel parameters and typical values commonly found in the sensors listed in Table 2

    Value range
    SPAD pixel
      Dead time [ns] 10-100
      DCR [cps/μm2] 0.3-100
      PDP (peak) [%] 10-50
      Fill factor [%] 1-60
      Timing resolution [ps] 30-100
      Afterpulsing probability [%] 0.1-10
    下载: 导出CSV

    Table  2.   Overview of standard CMOS SPAD imagers targeting biophotonics applications, in chronological order, as published over the past 15 years

    Sensor and architecture Year SPAD array Technology [nm] SPAD diametereq. [μm] Pixel pitch [μm] Fill factor [%] PDEtop [%] DCR [cps/μm2] Timing technique Sensor specifications System features Application
    First CMOS SPAD array6 2003 8 × 4 800 6.4 < 1 0.2 1.6
    Rech112-116, 118, 119 2007 8 × 1 50.0 198 5 2.5 1.0 FRET/FCS
    Schwartz79, 80 2007 64 × 64 350HV 4.1 40 < 1 0.1 71.0 TCSPC + gating In-pixel TDC 4096 in-pixel 350 ps 10b TDCs FLIM
    Niclass (LASP)17, 41, 151 2008 128 × 128 350HV 7.0 25 6, × 2-8ml 2.1, × 2-8ml 17.0 TCSPC Column-based TDCs 32 column 98 ps 10b TDCs NIROT
    Boiko (G(2))161, 162 2009 4 × 4 350HV 3.5 36 < 1 1.0
    Niclass (FluoCAM)26, 31, 60 2009 60 × 48 350HV 8.6 85 < 1 0.1 7.0 Gating (2 ×) 2 in-pixel 8b counters 5 ns gate, 12 ps steps FLIM
    Guerrieri93, 102, 103, 104 2009 32 × 32 350HV 20.0 100 3.1 1.3 12.7 Gating In-pixel 8b counter FLIM/FCS
    MEGAFRAME3221, 50, 51, 81, 82, 85, 86, 89-92, 105 2009 32 × 32 130CIS 5.6 50 1 0.4 4.0 TCSPC In-pixel TDC 1024 in-pixel 50 ps 10b TDCs FLIM/FCS/FRET
    Pancheri18 2009 64 × 4 350HV 17.6 26 34 10.9 4.3 Gating (4×) 4 in-pixel 8b counters 4 SPADs = 1 pixel FLIM
    Carrara (RadHard2)106, 107, 156, 157 2009 32 × 32 350HV 6.0 30 3.1 1.1 5.0 - In-pixel 1b counter FCS/NIROT
    Stoppa19 2009 7 × 2 350HV 13.0 Gating In-pixel 17b counter FLIM
    Maruyama20, 140 2011 128 × 128 350HV 6.0 25 4.5, × 1.6ml 0.9, × 1.6ml 6.6 Gating In-pixel 1b counter FLIM/Raman
    MEGAFRAME12833, 83, 84 2011 160 × 128 130CIS 5.6 50 1 0.3 2.0 TCSPC In-pixel TDC 20480 in-pixel 55 ps 10b TDCs FLIM
    Pancheri76-78 2011 32 × 32 350HV 12.9 25 20.3 5.4 Gating In-pixel analogue counter 1.9 ns gate FLIM
    Durini (BackSPAD)168, 169 2012 32 × 32 3503D 94.4 50 75.4 39.7 In-pixel counters Preliminary
    Tyndall62-64 2012 32 × 32 130CIS 8.0 22 10 13.7 TCSPC Per group TDC 16 52 ps 16b TDCs, mini-SiPM FLIM
    Field34, 35 2013 64 × 64 130 5.0 48 < 1 0.3 28.0 TCSPC Column-based TDCs 4096 column 62.5 ps 10b TDCs FLIM
    Mandai22 2013 416 × 4 × 4 350HV 32.6 30/50 55.6 17.0 39.0 Majority time voting Column-based per group TDC + in-pixel 1b counter 192 column 44 ps 17b TDCs PET
    Maruyama139, 141 2013 1024 × 8 350HV 18.0 24 44.3 9.6 29.0 Gating In-pixel 1b counter 0.7 ns gate, 250 ps steps Raman
    Nissinen138, 142, 143, 145 2013 128 × 8 350HV 9.7 33 23 5.8 71.0 Gating (4×) 4-pixel gate comparators 4 SPADs = 1 pixel Raman
    Walker (SPADnet1)48, 49, 163, 164 2013 720 × 16 × 8 130CIS 16.3 19 42.9 12.0 6.2 Majority time voting In-pixel TDC + 7b counter 128 in-pixel 64 ps 12b TDCs + histogram generation PET
    Burri (SwissSPAD)15, 44, 75, 125, 129, 178 2014 512 × 128 350HV 6.0 24 5, ×8-12ml 2.3, ×8-12ml 12.0 Gating In-pixel 1b counter 4 ns gate, 20 ps steps FLIM/FCS/SRM
    Carimatto23 2015 416 × 18 × 9 350HV 33.0 30/50 57 18.6 43.0 Majority time voting Column-based per group TDC + in-pixel 1b counter 432 column 48 ps 17b TDCs PET
    Krstajic′24, 67 2015 256 × 8 130CIS 18.2 24 43.7 5.4 TCSPC + gating Per-pixel TDC + histograms 512 per-pixel 40 ps TDCs + histogram generation FLIM/Raman
    Parmesan37 2015 256 × 256 130CIS 4.2 8 19.6 4.0 TCSPC TAC pixels External 14b ADC FLIM
    Mata Pavia (3DAPS)152, 167 2015 400 × 1 1303D 6.0 11 23.3 2.8 357.0 TCSPC In-pixel TDC 3D stacked, 50 ps 12b TDCs NIROT
    Abbas173 2016 128 × 120 653D 5.9 8 45 12.4 36.2 Gating In-pixel 12b counter 3D stacked, 65 nm top-tier/45 nm bottom-tier
    Lee32 2016 72 × 60 180 15.0 35 14.4 0.4 2.3 Gating In-pixel 10b counter 10 ns gate, 72 ps steps FLIM
    Burri (LinoSPAD)54, 55 2016 256 × 1 350HV 17.1 24 40 13.6 11.0 TCSPC (External) 64 FPGA-based 25 ps TDCs FLIM/Raman
    Perenzoni38 2016 160 × 120 350HV 7.8 15 21 12.0 Gating Column analogue counter 10 ns gate, 194 ps steps FLIM
    Dutton (SPCIMAGER)25, 45, 130 2016 320 × 240 130CIS 4.7 8/16 26.8, × 1.8-2ml 10.6, × 1.8-2ml 3.0 Gating In-pixel analogue counter FLIM/SRM
    Erdogan69 2017 1024 × 16 130CIS 18.8 24 49.3 TCSPC + gating Per-pixel TDC + histograms 512 per-pixel 50 ps TDCs + histogram generation FLIM
    Holma146, 148 2017 256 × 16 350HV 18.0 35 26 TCSPC Shared TDCs Two 52 ps 3b TDCs Raman
    Kufcsák68 2017 256 × 8 130CIS 18.2 24 43.7 5.4 TCSPC + gating Per-pixel TDC + histograms Improvement of24 FLIM/FRET/Raman
    Lindner (Piccolo)46, 95, 153, 154 2017 32 × 32 180 17.0 28 28 13.4 0.6 TCSPC Column-based TDCs, dynamic reallocation 128 column 49 ps TDCs NIROT
    Ulku (SwissSPAD2)29, 73, 74 2017 512 × 512 180 6.0 16 10.5 5.2 0.3 Gating In-pixel 1b counter 5 ns gate FLIM
    Gyongy30 2018 256 × 256 130CIS 14.1 16 61 51.0 Gating In-pixel 1b counter FLIM
    All values and operating modes are reported as listed in the literature
    SPAD diametereq $2\sqrt {{\mathrm{SPAD}} \ {\mathrm{area}}/\pi}$, PDE SPAD photon detection probability at the nominal excess bias voltage, multiplied by the pixel fill factor, DCR median (or average if not indicated) dark count rate per SPAD unit area, for the same excess bias voltage as the PDE
    Operating mode definitions: TCSPC time-correlated single-photon counting, Gating use of one or multiple moving gates, Majority time voting generation of a time-stamp per event (on the first arrived photon in a pixel, in the simplest case), only if a certain photon count is reached
    mlUse of microlenses—the quoted native PDE/fill factor needs to be multiplied by a concentration factor
    CISCMOS imaging sensor process
    HVCMOS high-voltage process
    3D3D integration technology (usually backside illuminated)
    下载: 导出CSV

    Table  3.   Overview of the main biophotonics applications that have been explored with standard CMOS SPAD imagers, their conventional counterparts, advantages and disadvantages, selected experimental highlights and the predicted direction of further developments

    Application with key review papers Non-SPAD methods/sensors SPAD array architecture SPAD advantages/disadvantages Experimental highlights Technology development directions
    FLIM9, 10, 56, 66, 94 PMT, hybrid, APD point-like, linear + Increased count rate due to pixel parallelisation, on-chip histogram generation and/or lifetime estimation
    - DCR, sensitivity, system complexity
    Point-like26, 60, 64/Linear69/Spectral FLIM65/FLIM-FRET68 Increased sensitivity (especially in the red and NIR regions), shared resources such as TDCs, improved timing resolution
    FLIM - Widefield10, 56, 59 ICCD, MCP 2D + Video rate lifetime estimation (on-chip and/or on FPGA), compact all-solid-state gating, noiseless read-out
    - Fill factor, non-uniformity, large data rate, dynamic range limited by the TDC conversion rate (TCSPC) or counter bit depth (gated)
    MegaFrame51, 86/SwissSPAD273/Analogue timing37, 38 Increased sensitivity (especially in the red and NIR regions and fill factor), spatial resolution (smaller pixels) and uniformity, dedicated lifetime estimation on-chip, multi-bit counters
    FLIM - Multibeam n/a 2D + Increased count rate due to pixel parallelisation, real-time lifetime estimation on an FPGA
    - Sensor alignment
    MegaFrame91, 92/Vitali93 Optimised optical alignment setup
    FCS - Multibeam116 n/a 2D + Increased count rate due to pixel parallelisation
    - Sensor alignment, DCR, afterpulsing
    Vitali93/Kloster-Landsberg105 Optimised optical alignment setup
    Widefield FCS100, 116, 180 EMCCD, sCMOS 2D + Frame rate, noiseless read-out
    - Fill factor, sensitivity, dynamic range limited by 1-bit counters, afterpulsing
    RadHard2106/SwissSPAD110 Multi-bit counters, on-chip/on-FPGA autocorrelation and cross-correlation calculation
    Single-molecule - Multibeam112, 116 APDs [Custom SPADs] Linear, 2D (small) [Custom SPADs] + Increased count rate due to pixel parallelisation
    - DCR, non-uniformity, non-integrated electronics
    Ingargiola120, 121 [Custom SPADs] Increased sensitivity (in the red region), reduced DCR, improved non-uniformity, 3D integration with CMOS read-out chip
    SRM123, 124 EMCCD, sCMOS 2D + High-speed, noiseless read-out (→ analysis of μs blinking, precise estimation of the blink duration)
    - DCR non-uniformity, sensitivity
    SwissSPAD129/Dutton130 Increased sensitivity, decreased DCR non-uniformity and percentage of "hot" pixels by SPAD miniaturisation
    Time-resolved Raman134, 135, 138 (I)CCD Linear + Fluorescence background rejection by means of on-chip time-gating and/or time-stamping, compact systems
    - Sensitivity, spatial resolution vs. gate length/uniformity
    Maruyama139, 140, Nissinen143, Rojalin144, Krstajić67 Increased sensitivity (especially in the red and NIR regions), reduced gate length, increased time-gating uniformity, pixel miniaturisation
    NIROT149, 150 PMT, SiPM 2D + Increased count rate due to pixel parallelisation and on-chip time-stamping electronics
    - Sensitivity, data rate, dynamic range
    Piccolo95, 154 Increased sensitivity (especially in the red and NIR regions) and dynamic range (e.g. through gating), on-chip data compression
    Q-LSRM n/a 2D + On-chip timing correlations
    - Sensitivity, cross-correlations
    SPADnet163, Gasparini36 Crosstalk minimisation
    PET47 PMT SiPM + B-field insensitivity, timing resolution, on-chip time-of-arrival measurement (digital SiPM)
    - Sensitivity, DCR, data rate (multi-digital approach)
    Carimatto23, SPADnet149 Increased sensitivity and timing resolution, data compression
    APD avalanche photodiode, EMCCD electron-multiplying charge-coupled device, hybrid hybrid photomultiplier, ICCD intensified charge-coupled device, MCP microchannel plate, PMT photomultiplier tube, sCMOS scientific CMOS, custom SPADs non-standard CMOS SPADs
    下载: 导出CSV
  • [1] Zappa, F., Tisa, S., Tosi, A. & Cova, S. Principles and features of single-photon avalanche diode arrays. Sens. Actuat. A 140, 103-112 (2007). doi:  10.1016/j.sna.2007.06.021
    [2] Zappa, F., Tosi, A., Dalla Mora, A., Guerrieri, F. & Tisa, S. Single-photon avalanche diode arrays and CMOS microelectronics for counting, timing, and imaging quantum events. In Proc. SPIE, Quantum Sensing and Nanophotonic Devices VII, 76082C (SPIE, San Francisco, CA, United States, 2010). doi:  10.1117/12.840362
    [3] Charbon, E. Single-photon imaging in complementary metal oxide semiconductor processes. Philos. Trans. R. Soc. Lond. Ser. A 372, 20130100 (2014). doi:  10.1098/rsta.2013.0100
    [4] Perenzoni, M., Pancheri, L. & Stoppa, D. Compact SPAD-based pixel architectures for time-resolved image sensors. Sensors 16, 745 (2016). doi:  10.3390/s16050745
    [5] Rochas, A. et al. Single photon detector fabricated in a complementary metal-oxide-semiconductor high-voltage technology. Rev. Sci. Instrum. 74, 3263-3270 (2003). doi:  10.1063/1.1584083
    [6] Rochas, A. et al. First fully integrated 2-D array of single-photon detectors in standard CMOS technology. IEEE Photonics Technol. Lett. 15, 963-965 (2003). doi:  10.1109/LPT.2003.813387
    [7] Bronzi, D., Villa, F., Tisa, S., Tosi, A. & Zappa, F. SPAD figures of merit for photon-counting, photon-timing, and imaging applications: a review. IEEE Sens. J. 16, 3-12 (2016). doi:  10.1109/JSEN.2016.2616229
    [8] Esposito, A. Beyond range: innovating fluorescence microscopy. Remote Sens. 4, 111-119 (2012). doi:  10.3390/rs4010111
    [9] Henderson, R. K., Rae, B. R. & Li, D.-U. Complementary Metal-Oxide-Semiconductor (CMOS) Sensors for Fluorescence Lifetime Imaging (FLIM), Ch. 11, 312-347 (Elsevier, 2014). https://www.sciencedirect.com/science/article/pii/B9780857095985500117
    [10] Suhling, K. et al. Fluorescence lifetime imaging (FLIM): basic concepts and some recent developments. Med. Photonics 27, 3-40 (2015). doi:  10.1016/j.medpho.2014.12.001
    [11] Caccia, M., Nardo, L., Santoro, R. & Schaffhauser, D. Silicon photomultipliers and SPAD imagers in biophotonics: advances and perspectives. Nucl. Instrum. Methods Phys. Res. Sect. A 926, 101-117 (2019). doi:  10.1016/j.nima.2018.10.204
    [12] Niclass, C., Rochas, A., Besse, P.-A. & Charbon, E. Design and characterization of a CMOS 3-D image sensor based on single photon avalanche diodes. IEEE J. Solid-State Circuits 40, 1847-1854 (2005). doi:  10.1109/JSSC.2005.848173
    [13] Webster, E. A., Grant, L. A. & Henderson, R. K. A high-performance single-photon avalanche diode in 130-nm CMOS imaging technology. IEEE Electron Device Lett. 33, 1589-1591 (2012). doi:  10.1109/LED.2012.2214760
    [14] Fishburn, M. W., Maruyama, Y. & Charbon, E. Reduction of fixed-position noise in position-sensitive single-photon avalanche diodes. IEEE Trans. Electron Devices 58, 2354-2361 (2011). doi:  10.1109/TED.2011.2148117
    [15] Burri, S. et al. Architecture and applications of a high resolution gated SPAD image sensor. Opt. Express 22, 17573-17589 (2014). doi:  10.1364/OE.22.017573
    [16] Eisele, A. et al. 185 MHz count rate 139 dB dynamic range single-photon avalanche diode with active quenching circuit in 130 nm CMOS technology. In Proc. IISW 278-280 (IISW, Hokkaido, Japan, 2011).
    [17] Niclass, C., Favi, C., Kluter, T., Gersbach, M. & Charbon, E. A 128 × 128 single-photon image sensor with column-level 10-bit time-to-digital converter array. IEEE J. Solid-State Circuits 43, 2977-2989 (2008). doi:  10.1109/JSSC.2008.2006445
    [18] Pancheri, L. & Stoppa, D. A SPAD-based pixel linear array for high-speed time-gated fluorescence lifetime imaging. In Proc. ESSCIRC 428-431(IEEE, Athens, Greece, 2009). http://ieeexplore.ieee.org/xpls/icp.jsp?arnumber=5325948
    [19] Stoppa, D., Mosconi, D., Pancheri, L. & Gonzo, L. Single-photon avalanche diode CMOS sensor for time-resolved fluorescence measurements. IEEE Sens. J. 9, 1084-1090 (2009). doi:  10.1109/JSEN.2009.2025581
    [20] Maruyama, Y. & Charbon, E. An all-digital, time-gated 128 × 128 SPAD array for on-chip, filter-less fluorescence detection. In Solid-State Sensors Actuators and Microsystems Conference 1180-1183 (IEEE, Beijing, China, 2011). https://ieeexplore.ieee.org/document/5969324/
    [21] Gersbach, M. et al. A time-resolved, low-noise single-photon image sensor fabricated in deep-submicron CMOS technology. IEEE J. Solid-State Circuits 47, 1394-1407 (2012). doi:  10.1109/JSSC.2012.2188466
    [22] Mandai, S. & Charbon, E. A 4 × 4 × 416 digital SiPM array with 192 TDCs for multiple high-resolution timestamp acquisition. J. Instrum. 8, P05024 (2013). doi:  10.1088/1748-0221/8/05/P05024
    [23] Carimatto, A. et al. A 67, 392-SPAD PVTB-compensated multi-channel digital SiPM with 432 column-parallel 48 ps 17b TDCs for endoscopic time-of-flight PET. In IEEE ISSCC Digest of Technical Paper 1-3 (IEEE, San Francisco, CA, United States, 2015). http://ieeexplore.ieee.org/xpls/abs_all.jsp?arnumber=7062996
    [24] Krstajić, N., Levitt, J., Poland, S., Ameer-Beg, S. & Henderson, R. 256 × 2 SPAD line sensor for time resolved fluorescence spectroscopy. Opt. Express 23, 5653-5669 (2015). http://cn.bing.com/academic/profile?id=22b1060c8358882d345bf4cb93574fb7&encoded=0&v=paper_preview&mkt=zh-cn
    [25] Dutton, N. A. et al. A SPAD-based QVGA image sensor for single-photon counting and quanta imaging. IEEE Trans. Electron Devices 63, 189-196 (2016). doi:  10.1109/TED.2015.2464682
    [26] Homulle, H. et al. Compact solid-state CMOS single-photon detector array for in vivo NIR fluorescence lifetime oncology measurements. Biomed. Opt. Express 7, 1797-1814 (2016). doi:  10.1364/BOE.7.001797
    [27] Kröger, J. et al. High intensity click statistics from a 10 × 10 avalanche photodiode array. J. Phys. B Mol. Opt. Phys. 50, 214003 (2017). doi:  10.1088/1361-6455/aa8e68
    [28] Antolovic, I. M., Bruschini, C. & Charbon, E. Dynamic range extension for photon counting arrays. Opt. Express 26, 22234-22248 (2018). doi:  10.1364/OE.26.022234
    [29] Ulku, A. C., Bruschini, C., Michalet, X., Weiss, S. & Charbon, E. A 512×512 SPAD image sensor with built-in gating for phasor based real-time siFLIM. In Proc. IISW 234-237 (IISW, Hiroshima, Japan, 2017).
    [30] Gyongy, I. et al. A 256 × 256, 100 kfps, 61% fill-factor SPAD image sensor for time-resolved microscopy applications. IEEE Trans. Electron Devices 65, 547-554 (2018). doi:  10.1109/TED.2017.2779790
    [31] Niclass, C., Favi, C., Kluter, T., Monnier, F. & Charbon, E. Single-photon synchronous detection. IEEE J. Solid-State Circuits 44, 1977-1989 (2009). doi:  10.1109/JSSC.2009.2021920
    [32] Lee, C., Johnson, B., Jung, T. & Molnar, A. A 72 × 60 angle-sensitive SPAD imaging array for lens-less FLIM. Sensors 16, 1422 (2016). doi:  10.3390/s16091422
    [33] Veerappan, C. et al. A 160 × 128 single-photon image sensor with on-pixel 55 ps 10b time-to-digital converter. In IEEE ISSCC Digest in Technical Paper 312-314 (IEEE, San Francisco, CA, United States, 2011). https://ieeexplore.ieee.org/document/5746333/
    [34] Field, R. M. & Shepard, K. A 100 fps fluorescence lifetime imager in standard 0.13 μm CMOS. In IEEE Symposium on VLSI Circuits C10-C11 (IEEE, Kyoto, Japan, 2013). https://ieeexplore.ieee.org/document/6578707/
    [35] Field, R. M., Realov, S. & Shepard, K. L. A 100 fps, time-correlated single-photon-counting-based fluorescence-lifetime imager in 130 nm CMOS. IEEE J. Solid-State Circuits 49, 867-880 (2014). doi:  10.1109/JSSC.2013.2293777
    [36] Gasparini, L. et al. A 32 × 32 pixel time-resolved single-photon image sensor with 44.64 μm pitch and 19.48% fill-factor with on-chip row/frame skipping features reaching 800 kHz observation rate for quantum physics applications. In IEEE ISSCC Digest in Technical Paper 98-100 (IEEE, San Francisco, CA, United States, 2018).
    [37] Parmesan, L. et al. A 256 × 256 SPAD array with in-pixel time to amplitude conversion for fluorescence lifetime imaging microscopy. In Proc. IISW 9.04 (IISW, Vaals, Netherlands, 2015). https://www.research.ed.ac.uk/portal/en/publications/a-256-x-256-spad-array-with-inpixel-time-to-amplitude-conversion-for-fluorescence-lifetime-imaging-microscopy(be932e3d-cb12-4e14-842f-7ec504cf8bb5)/export.html
    [38] Perenzoni, M., Massari, N., Perenzoni, D., Gasparini, L. & Stoppa, D. A 160 × 120 pixel analog-counting single-photon imager with time-gating and self-referenced column-parallel A/D conversion for fluorescence lifetime imaging. IEEE J. Solid-State Circuits 51, 155-167 (2016). doi:  10.1109/JSSC.2015.2482497
    [39] Donati, S., Martini, G. & Norgia, M. Microconcentrators to recover fill-factor in image photodetectors with pixel on-board processing circuits. Opt. Express 15, 18066-18075 (2007). doi:  10.1364/OE.15.018066
    [40] Donati, S., Martini, G. & Randone, E. Improving photodetector performance by means of microoptics concentrators. J. Light. Technol. 29, 661-665 (2011). http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=7c35cd0015a6f81b01d54b97e117ef84
    [41] Pavia, J. M., Wolf, M. & Charbon, E. Measurement and modeling of microlenses fabricated on single-photon avalanche diode arrays for fill factor recovery. Opt. Express 22, 4202-4213 (2014). doi:  10.1364/OE.22.004202
    [42] Intermite, G. et al. Enhancing the fill-factor of CMOS SPAD arrays using microlens integration. In Proc. SPIE, Photon Counting Applications, 95040J (SPIE, Prague, Czech Republic, 2015). doi:  10.1117/12.2178950.short?SSO=1
    [43] Intermite, G. et al. Fill-factor improvement of Si CMOS single-photon avalanche diode detector arrays by integration of diffractive microlens arrays. Opt. Express 23, 33777-33791 (2015). doi:  10.1364/OE.23.033777
    [44] Antolovic, I. M., Burri, S., Bruschini, C., Hoebe, R. & Charbon, E. Nonuniformity analysis of a 65 kpixel CMOS SPAD imager. IEEE Trans. Electron Devices 63, 57-64 (2016). doi:  10.1109/TED.2015.2458295
    [45] Gyongy, I. et al. Cylindrical microlensing for enhanced collection efficiency of small pixel SPAD arrays in single-molecule localisation microscopy. Opt. Express 26, 2280-2291 (2018). doi:  10.1364/OE.26.002280
    [46] Zhang, C., Lindner, S., Antolovic, I., Wolf, M. & Charbon, E. A CMOS SPAD imager with collision detection and 128 dynamically reallocating TDCs for single-photon counting and 3D time-of-flight imaging. Sensors 18, 4016 (2018). doi:  10.3390/s18114016
    [47] Schaart, D. R., Charbon, E., Frach, T. & Schulz, V. Advances in digital SiPMs and their application in biomedical imaging. Nucl. Instrum. Methods Phys. Res. Sect. A 809, 31-52 (2016). doi:  10.1016/j.nima.2015.10.078
    [48] Walker, R. J. et al. A 92k SPAD time-resolved sensor in 0.13 μm CIS technology for PET/MRI applications. In Proc. IISW 1-4 (IISW, Snowbird, UT, United States, 2013).
    [49] Braga, L. H. et al. A fully digital 8 × 16 SiPM array for PET applications with per-pixel TDCs and real-time energy output. IEEE J. Solid-State Circuits 49, 301-314 (2014). doi:  10.1109/JSSC.2013.2284351
    [50] Li, D.-U. et al. Real-time fluorescence lifetime imaging system with a 32 × 32 0.13 μm CMOS low dark-count single-photon avalanche diode array. Opt. Express 18, 10257-10269 (2010). doi:  10.1364/OE.18.010257
    [51] Li, D.-U. et al. Video-rate fluorescence lifetime imaging camera with CMOS single-photon avalanche diode arrays and high-speed imaging algorithm. J. Biomed. Opt. 16, 096012-096012 (2011). doi:  10.1117/1.3625288
    [52] Li, D. & Chen, Y. Hardware-friendly bi-exponential fluorescence lifetime imaging algorithms and phasor approaches. In Proc. SPIE, Advanced Microscopy Techniques Ⅳ; and Neurophotonics Ⅲ, 95360M (SPIE, Munich, Germany, 2015).
    [53] Buchholz, J. et al. FPGA implementation of a 32 × 32 auto-correlator array for analysis of fast image series. Opt. Express 20, 17767-17782 (2012). doi:  10.1364/OE.20.017767
    [54] Burri, S., Bruschini, C. & Charbon, E. LinoSPAD: a compact linear SPAD camera system with 64 FPGA-based TDC modules for versatile 50 ps resolution time-resolved imaging. Instruments 1, 6.1-6.21 (2017). http://cn.bing.com/academic/profile?id=e35d59336b667110d3d9014c95960486&encoded=0&v=paper_preview&mkt=zh-cn
    [55] Burri, S., Homulle, H., Bruschini, C. & Charbon, E. LinoSPAD: a time-resolved 256 × 1 CMOS SPAD line sensor system featuring 64 FPGA-based TDC channels running at up to 8.5 giga-events per second. In Proc. SPIE, Optical Sensing and Detection IV, 98990D (SPIE, Brussels, Belgium, 2016). doi:  10.1117/12.2227564.short
    [56] Becker, W. Fluorescence lifetime imaging—techniques and applications. J. Microsc. 247, 119-136 (2012). doi:  10.1111/j.1365-2818.2012.03618.x
    [57] Lakowicz, J. R., Szmacinski, H., Nowaczyk, K., Berndt, K. W. & Johnson, M. Fluorescence lifetime imaging. Anal. Biochem. 202, 316-330 (1992). doi:  10.1016/0003-2697(92)90112-K
    [58] Marcu, L. Fluorescence lifetime techniques in medical applications. Ann. Biomed. Eng. 40, 304-331 (2012). doi:  10.1007/s10439-011-0495-y
    [59] Hirvonen, L. M. & Suhling, K. Wide-field TCSPC: methods and applications. Meas. Sci. Technol. 28, 012003 (2016). doi:  10.1088/1361-6501/28/1/012003
    [60] Stegehuis, P. L. et al. Fluorescence lifetime imaging to differentiate bound from unbound ICG-cRGD both in vitro and in vivo. In Proc. SPIE, Advanced Biomedical and Clinical Diagnostic and Surgical Guidance Systems XⅢ, 93130O (SPIE, San Francisco, CA, United States, 2015). https://ui.adsabs.harvard.edu/abs/2015SPIE.9313E..0OS/abstract
    [61] Léonard, J. et al. High-throughput time-correlated single photon counting. Lab a Chip 14, 4338-4343 (2014). doi:  10.1039/C4LC00780H
    [62] Arlt, J. et al. A study of pile-up in integrated time-correlated single photon counting systems. Rev. Sci. Instrum. 84, 103105 (2013). doi:  10.1063/1.4824196
    [63] Tyndall, D. et al. A 100 Mphoton/s time-resolved mini-silicon photomultiplier with on-chip fluorescence lifetime estimation in 0.13 μm CMOS imaging technology. In IEEE ISSCC Digest in Technical Paper 122-124 (IEEE, San Francisco, CA, United States, 2012).
    [64] Tyndall, D. et al. A high-throughput time-resolved mini-silicon photomultiplier with embedded fluorescence lifetime estimation in 0.13 μm CMOS. IEEE Trans. Biomed. Circuits Syst. 6, 562-570 (2012). doi:  10.1109/TBCAS.2012.2222639
    [65] Popleteeva, M. et al. Fast and simple spectral FLIM for biochemical and medical imaging. Opt. Express 23, 23511-23525 (2015). doi:  10.1364/OE.23.023511
    [66] Hanley, Q. S., Arndt-Jovin, D. J. & Jovin, T. M. Spectrally resolved fluorescence lifetime imaging microscopy. Appl. Spectrosc. 56, 155-166 (2002). doi:  10.1366/0003702021954610
    [67] Ehrlich, K. et al. Fibre optic time-resolved spectroscopy using CMOS-SPAD arrays. In Proc. SPIE, Optical Fibers and Sensors for Medical Diagnostics and Treatment Applications XVII, 10058 (SPIE, San Francisco, CA, United States, 2017).
    [68] Kufcsák, A. et al. Time-resolved spectroscopy at 19, 000 lines per second using a CMOS SPAD line array enables advanced biophotonics applications. Opt. Express 25, 11103-11123 (2017). doi:  10.1364/OE.25.011103
    [69] Erdogan, A. T. et al. A 16.5 giga events/s 1024 × 8 SPAD line sensor with per-pixel zoomable 50 ps-6.4 ns/bin histogramming TDC. In IEEE Symposium in VLSI Circuits C292-C293 (IEEE, Kyoto, Japan, 2017). https://ieeexplore.ieee.org/document/8008513
    [70] Peronio, P. et al. 32 channel time-correlated-single-photon-counting system for high-throughput lifetime imaging. Rev. Sci. Instrum. 88, 083704 (2017). doi:  10.1063/1.4986049
    [71] Tsikouras, A. et al. Characterization of SPAD array for multifocal high-content screening applications. Photonics 3, 56 (2016). doi:  10.3390/photonics3040056
    [72] Burri, S. Challenges and Solutions to Next-Generation Single-Photon Imagers. Ph.D. thesis, EPFL, Lausanne, 2016.
    [73] Ulku, A. C. et al. A 512 × 512 SPAD image sensor with integrated gating for widefield FLIM. IEEE J. Sel. Top. Quantum Electron. 25, 1-12 (2019). https://ieeexplore.ieee.org/document/8449092
    [74] Ulku, A. C. et al. Phasor-based widefield FLIM using a gated 512 × 512 single-photon SPAD imager. In Proc. SPIE, Multiphoton Microscopy in the Biomedical Sciences XIX, 10882M (SPIE, San Francisco, CA, United States, 2019).
    [75] Wargocki, P. M. et al. Imaging free and bound NADH towards cancer tissue detection using FLIM system based on SPAD array. In CLEO/Europe-EQEC 1-1 (IEEE, Munich, Germany, 2017).
    [76] Pancheri, L., Massari, N., Borghetti, F. & Stoppa, D. A 32×32 SPAD pixel array with nanosecond gating and analog readout. In Proc. IISW 1-4 (IISW, Hokkaido, Japan, 2011).
    [77] Pancheri, L. et al. Protein detection system based on 32 × 32 SPAD pixel array. In Proc. SPIE, Optical Sensing and Detection Ⅲ, 843913 (SPIE, Brussels, Belgium, 2012). https://ui.adsabs.harvard.edu/abs/2012SPIE.8439E..13P/abstract
    [78] Pancheri, L., Massari, N. & Stoppa, D. SPAD image sensor with analog counting pixel for time-resolved fluorescence detection. IEEE Trans. Electron Devices 60, 3442-3449 (2013). doi:  10.1109/TED.2013.2276752
    [79] Schwartz, D. E., Charbon, E. & Shepard, K. L. A single-photon avalanche diode imager for fluorescence lifetime applications. In IEEE Symposium in VLSI Circuits 144-145 (IEEE, Kyoto, Japan, 2007).
    [80] Schwartz, D. E., Charbon, E. & Shepard, K. L. A single-photon avalanche diode array for fluorescence lifetime imaging microscopy. IEEE J. Solid-State Circuits 43, 2546-2557 (2008). http://cn.bing.com/academic/profile?id=8386f1d3292bfa71cec638617949830d&encoded=0&v=paper_preview&mkt=zh-cn
    [81] Richardson, J. et al. A 32 × 32 50 ps resolution 10-bit time to digital converter array in 130 nm CMOS for time correlated imaging. In IEEE Custom Integrated Circuits 77-80 (IEEE, Rome, Italy, 2009).
    [82] Krstajić, N. et al. 0.5 billion events per second time correlated single photon counting using CMOS SPAD arrays. Opt. Lett. 40, 4305-4308 (2015). doi:  10.1364/OL.40.004305
    [83] Veerappan, C. et al. Characterization of large-scale non-uniformities in a 20k TDC/SPAD array integrated in a 130 nm CMOS process. In Proc. ESSDERC 331-334 (IEEE, Helsinki, Finland, 2011). https://ieeexplore.ieee.org/document/6044167
    [84] Arlt, J. et al. A fully-integrated, time-resolved 160 × 128 SPAD pixel array with micro-concentrators. In Proc. Advanced Photon Counting Techniques V, SPIE Defense and Security (SPIE, Orlando, FL, United States, 2011).
    [85] Gersbach, M. et al. High frame-rate TCSPC-FLIM using a novel SPAD-based image sensor. In Proc. SPIE, Detectors and Imaging Devices: Infrared, Focal Plane, Single Photon, 77801H (SPIE, San Diego, CA, United States, 2010). https://ui.adsabs.harvard.edu/abs/2010SPIE.7780E..1HG/abstract
    [86] Li, D.-U. et al. Time-domain fluorescence lifetime imaging techniques suitable for solid-state imaging sensor arrays. Sensors 12, 5650-5669 (2012). doi:  10.3390/s120505650
    [87] Giraud, G. et al. Fluorescence lifetime biosensing with DNA microarrays and a CMOS-SPAD imager. Biomed. Opt. Express 1, 1302-1308 (2010). doi:  10.1364/BOE.1.001302
    [88] Coelho, S. et al. Multifocal multiphoton microscopy with adaptive optical correction. In Proc. SPIE, Multiphoton Microscopy in the Biomedical Sciences XⅢI, 858817 (SPIE, San Francisco, CA, United States, 2013). https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.677125
    [89] Poland, S. P. et al. Development of a fast TCSPC FLIM-FRET imaging system. In Proc. SPIE, Multiphoton Microscopy in the Biomedical Sciences XII, 8588 (SPIE, San Francisco, CA, United States, 2013).
    [90] Poland, S. P. et al. Time-resolved multifocal multiphoton microscope for high speed FRET imaging in vivo. Opt. Lett. 39, 6013-6016 (2014). doi:  10.1364/OL.39.006013
    [91] Poland, S. P. et al. A high speed multifocal multiphoton fluorescence lifetime imaging microscope for live-cell FRET imaging. Biomed. Opt. Express 6, 277-296 (2015). doi:  10.1364/BOE.6.000277
    [92] Poland, S. P. et al. New high-speed centre of mass method incorporating background subtraction for accurate determination of fluorescence lifetime. Opt. Express 24, 6899-6915 (2016). doi:  10.1364/OE.24.006899
    [93] Vitali, M. et al. A single-photon avalanche camera for fluorescence lifetime imaging microscopy and correlation spectroscopy. IEEE J. Sel. Top. Quantum Electron. 20, 344-353 (2014). http://cn.bing.com/academic/profile?id=483b7d05839571fcbb7516f307bb52ce&encoded=0&v=paper_preview&mkt=zh-cn
    [94] Clegg, R. M. Fluorescence resonance energy transfer. Curr. Opin. Biotechnol. 6, 103-110 (1995). doi:  10.1016/0958-1669(95)80016-6
    [95] Lindner, S. et al. A novel 32 × 32, 224 Mevents/s time resolved SPAD image sensor for near-infrared optical tomography. In Optics and the Brain JTh5A-JTh56 (Optical Society of America, Hollywood, FL, United States, 2018).
    [96] Zhang, C. et al. A 30-frames/s, 252 × 144 SPAD flash LiDAR with 1728 dual-clock 48.8-ps TDCs, and pixel-wise integrated histogramming. IEEE J. Solid-State Circuits 54, 1137-1151 (2019). doi:  10.1109/JSSC.2018.2883720
    [97] Draaijer, A., Sanders, R. & Gerritsen, H. in Handbook of Biological Confocal Microscopy (ed. Pawley, J. B.) 491-505 (Springer, Boston, MA, United States, 1995).
    [98] Gyongy, I. et al. Fluorescence lifetime imaging of high-speed particles with single-photon image sensors. In Proc. SPIE, High-Speed Biomedical Imaging and Spectroscopy IV, 108890O (SPIE, San Francisco, CA, United States, 2019).
    [99] Ardelean, A., Ulku, A. C., Michalet, X., Charbon, E. & Bruschini, C. Fluorescence lifetime imaging with a single-photon SPAD array using long overlapping gates: an experimental and theoretical study. In Proc. SPIE, Multiphoton Microscopy in the Biomedical Sciences XIX, 108820Y (SPIE, San Francisco, CA, United States, 2019).
    [100] Thompson, N. L. in Topics in Fluorescence Spectroscopy (ed. Lakowicz, J. R.) 337-378 (Springer, Boston, Massachusetts, United States, 2002).
    [101] Gösch, M. et al. Parallel single molecule detection with a fully integrated single-photon 2 × 2 CMOS detector array. J. Biomed. Opt. 9, 913-921 (2004). doi:  10.1117/1.1781668
    [102] Colyer, R. A. et al. Ultra high-throughput single molecule spectroscopy with a 1024 pixel SPAD. In Proc. SPIE, Single Molecule Spectroscopy and Imaging IV, 790503 (SPIE, San Francisco, CA, United States, 2011). https://www.ncbi.nlm.nih.gov/pubmed/24386535
    [103] Guerrieri, F., Tisa, S. & Zappa, F. Fast single-photon imager acquires 1024 pixels at 100 kframe/s. In Proc. SPIE, Sensors, Cameras, and Systems for Industrial/Scientific Applications X, 72490U (SPIE, San Jose, CA, United States, 2009). https://ui.adsabs.harvard.edu/abs/2009SPIE.7249E..0UG/abstract
    [104] Guerrieri, F., Tisa, S., Tosi, A. & Zappa, F. Two-dimensional SPAD imaging camera for photon counting. IEEE Photonics J. 2, 759-774 (2010). doi:  10.1109/JPHOT.2010.2066554
    [105] Kloster-Landsberg, M. et al. Multi-confocal fluorescence correlation spectroscopy in living cells using a complementary metal oxide semiconductor-single photon avalanche diode array. Rev. Sci. Instrum. 84, 076105 (2013). doi:  10.1063/1.4816156
    [106] Singh, A. P. et al. The performance of 2D array detectors for light sheet based fluorescence correlation spectroscopy. Opt. Express 21, 8652-8668 (2013). doi:  10.1364/OE.21.008652
    [107] Carrara, L., Niclass, C., Scheidegger, N., Shea, H. & Charbon, E. A gamma, X-ray and high energy proton radiation-tolerant CIS for space applications. In IEEE ISSCC Digest in Technical Paper 40-41 (IEEE, San Francisco, CA, United States, 2009). https://ieeexplore.ieee.org/document/4977297
    [108] Krieger, J. W. Mapping Diffusion Properties in Living Cells. Ph.D. thesis, Heidelberg Universität, Heidelberg, 2014.
    [109] Krieger, J. W. et al. Imaging fluorescence correlation: Novel results on new image sensors (SPAD arrays) and a comprehensive new software package (QUICKFIT 3.0). In Proc. Focus on Microscopy (FOM, Göttingen, Germany, 2015).
    [110] Buchholz, J. et al. Widefield high frame rate single-photon SPAD imagers for SPIM-FCS. Biophys. J. 114, 2455-2464 (2018). doi:  10.1016/j.bpj.2018.04.029
    [111] Buchholz, J. Evaluation of Single Photon Avalanche Diode Arrays for Imaging Fluorescence Correlation Spectroscopy: FPGA-Based Data Readout and Fast Correlation Analysis on CPUs, GPUs and FPGAs. Ph.D. thesis, Heidelberg Universität, Heidelberg, 2016.
    [112] Michalet, X. et al. Silicon photon-counting avalanche diodes for single-molecule fluorescence spectroscopy. IEEE J. Sel. Top. Quantum Electron. 20, 248-267 (2014).
    [113] Rech, I., Resnati, D., Marangoni, S., Ghioni, M. & Cova, S. Compact eight-channel photon counting module with monolithic array detector. In Proc. SPIE, Advanced Photon Counting Techniques II, 677113 (SPIE, Boston, MA, United States, 2007).
    [114] Rech, I., Marangoni, S., Resnati, D., Ghioni, M. & Cova, S. Multipixel single-photon avalanche diode array for parallel photon counting applications. J. Mod. Opt. 56, 326-333 (2009). doi:  10.1080/09500340802318309
    [115] Michalet, X. et al. High-throughput single-molecule fluorescence spectroscopy using parallel detection. In Proc. SPIE, Quantum Sensing and Nanophotonic Devices VII, 76082D (SPIE, San Francisco, CA, United States, 2010).
    [116] Michalet, X. et al. Development of new photon-counting detectors for single-molecule fluorescence microscopy. Philos. Trans. R. Soc. Lond. Ser. B 368, 20120035 (2013). doi:  10.1098/rstb.2012.0035
    [117] Gulinatti, A., Ceccarelli, F., Rech, I. & Ghioni, M. Silicon technologies for arrays of single photon avalanche diodes. In Proc. SPIE, Advanced Photon Counting Techniques X, 98580A (SPIE, Baltimore, MD, United States, 2016). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5061057/?report=reader
    [118] Ingargiola, A. et al. Parallel multispot smFRET analysis using an 8 pixel SPAD array. In Proc. SPIE, Single Molecule Spectroscopy and Superresolution Imaging V, 82280B (SPIE, San Francisco, CA, United States, 2012). https://www.spiedigitallibrary.org/page-not-found?aspxerrorpath=%2fredirect%2fproceedings%2fmobile%2fproceeding
    [119] Ingargiola, A. et al. 8-spot smFRET analysis using two 8 pixel SPAD arrays. In Proc. SPIE, Single Molecule Spectroscopy and Superresolution Imaging Ⅵ, 85900E (SPIE, San Francisco, CA, United States, 2013). https://www.ncbi.nlm.nih.gov/pubmed/24386541
    [120] Ingargiola, A. et al. Multispot single-molecule FRET: high-throughput analysis of freely diffusing molecules. PLoS ONE 12, e0175766 (2017). doi:  10.1371/journal.pone.0175766
    [121] Ingargiola, A. et al. 48-spot single-molecule FRET setup with periodic acceptor excitation. J. Chem. Phys. 148, 123304 (2018). doi:  10.1063/1.5000742
    [122] Abbe, E. Beiträge zur Theorie des Mikroskops und der mikroskopischen Wahrnehmung. Arch. für Mikrosk. Anat. 9, 413-418 (1873). doi:  10.1007/BF02956173
    [123] Hell, S. W. Microscopy and its focal switch. Nat. Methods 6, 24-32 (2009). doi:  10.1038/nmeth.1291
    [124] Fölling, J. et al. Fluorescence nanoscopy by ground-state depletion and single-molecule return. Nat. Methods 5, 943 (2008). doi:  10.1038/nmeth.1257
    [125] Antolovic, I. M., Burri, S., Bruschini, C., Hoebe, R. & Charbon, E. Analyzing blinking effects in super resolution localization microscopy with single-photon SPAD imagers. In Proc. SPIE, Single Molecule Spectroscopy and Superresolution Imaging Ⅸ, 971406 (SPIE, San Francisco, CA, United States, 2016).
    [126] Nieuwenhuizen, R. P. J. et al. Measuring image resolution in optical nanoscopy. Nat. Methods 10, 557-562 (2013). doi:  10.1038/nmeth.2448
    [127] Thompson, R. E., Larson, D. R. & Webb, W. W. Precise nanometer localization analysis for individual fluorescent probes. Biophys. J. 82, 2775-2783 (2002). doi:  10.1016/S0006-3495(02)75618-X
    [128] Nahidiazar, L., Agronskaia, A. V., Broertjes, J., van den Broek, B. & Jalink, K. Optimizing imaging conditions for demanding multi-color super resolution localization microscopy. PLoS ONE 11, e0158884 (2016). doi:  10.1371/journal.pone.0158884
    [129] Antolovic, I. M., Burri, S., Bruschini, C., Hoebe, R. A. & Charbon, E. SPAD imagers for super resolution localization microscopy enable analysis of fast fluorophore blinking. Sci. Rep. 7, 44108 (2017). doi:  10.1038/srep44108
    [130] Gyongy, I. et al. Smart-aggregation imaging for single molecule localization with SPAD cameras. Sci. Rep. 6, 1-10 (2016). doi:  10.1038/s41598-016-0001-8
    [131] Krishnaswami, V., Van Noorden, C. J., Manders, E. M. & Hoebe, R. A. Towards digital photon counting cameras for single-molecule optical nanoscopy. Opt. Nanosc. 3, 1 (2014). doi:  10.1186/2192-2853-3-1
    [132] Huang, F. et al. Video-rate nanoscopy using sCMOS camera-specific single-molecule localization algorithms. Nat. Methods 10, 653 (2013). doi:  10.1038/nmeth.2488
    [133] Colthup, N. B., Daly, L. H. & Wiberly, S. E. Introduction to Infrared and Raman Spectroscopy 2nd edn (Academic Press, Boston, MA, United States, 1975).
    [134] Krafft, C., Dietzek, B., Schmitt, M. & Popp, J. Raman and coherent anti-Stokes Raman scattering microspectroscopy for biomedical applications. J. Biomed. Opt. 17, 040801 (2012). doi:  10.1117/1.JBO.17.4.040801
    [135] Shipp, D., Sinjab, F. & Notingher, I. Raman spectroscopy: techniques and applications in the life sciences. Adv. Opt. Photonics 9, 315-428 (2017). doi:  10.1364/AOP.9.000315
    [136] Matousek, P. & Stone, N. Development of deep subsurface Raman spectroscopy for medical diagnosis and disease monitoring. Chem. Soc. Rev. 45, 1794-1802 (2016). doi:  10.1039/C5CS00466G
    [137] Nissinen, I. et al. A sub-ns time-gated CMOS single photon avalanche diode detector for Raman spectroscopy. In Proc. ESSDERC 375-378 (IEEE, Helsinki, Finland, 2011). https://ieeexplore.ieee.org/document/6044156
    [138] Kostamovaara, J. et al. Fluorescence suppression in Raman spectroscopy using a time-gated CMOS SPAD. Opt. Express 21, 31632-31645 (2013). doi:  10.1364/OE.21.031632
    [139] Maruyama, Y., Blacksberg, J. & Charbon, E. A 1024 × 8, 700 ps time-gated SPAD line sensor for planetary surface exploration with laser Raman spectroscopy and LIBS. IEEE J. Solid-State Circuits 49, 179-189 (2014). doi:  10.1109/JSSC.2013.2282091
    [140] Blacksberg, J., Maruyama, Y., Charbon, E. & Rossman, G. R. Fast single-photon avalanche diode arrays for laser Raman spectroscopy. Opt. Lett. 36, 3672-3674 (2011). doi:  10.1364/OL.36.003672
    [141] Maruyama, Y., Blacksberg, J. & Charbon, E. A 1024 × 8 700 ps time-gated SPAD line sensor for laser Raman spectroscopy and LIBS in space and rover-based planetary exploration. In IEEE ISSCC Digest in Technical Paper 110-111 (IEEE, San Francisco, CA, United States, 2013). https://ieeexplore.ieee.org/document/6487659
    [142] Nissinen, I., Lansman, A.-K., Nissinen, J., Holma, J. & Kostamovaara, J. 2×(4×)128 time-gated CMOS single photon avalanche diode line detector with 100 ps resolution for Raman spectroscopy. In Proc. ESSCIRC 291-294 (IEEE, Bucharest, Romania, 2013). https://ieeexplore.ieee.org/document/6649130
    [143] Nissinen, I. et al. A 2 × (4) × 128 multitime-gated SPAD line detector for pulsed Raman spectroscopy. IEEE Sens. J. 15, 1358-1365 (2015). doi:  10.1109/JSEN.2014.2361610
    [144] Rojalin, T. et al. Fluorescence-suppressed time-resolved Raman spectroscopy of pharmaceuticals using complementary metal-oxide semiconductor (CMOS) single-photon avalanche diode (SPAD) detector. Anal. Bioanal. Chem. 408, 761-774 (2016). doi:  10.1007/s00216-015-9156-6
    [145] Nissinen, I., Nissinen, J., Holma, J. & Kostamovaara, J. A 4 × 128 SPAD array with a 78 ps 512 channel TDC for time-gated pulsed Raman spectroscopy. Analog Integr. Circuits Signal Process. 84, 353-362 (2015). doi:  10.1007/s10470-015-0592-1
    [146] Holma, J., Nissinen, I., Nissinen, J. & Kostamovaara, J. Characterization of the timing homogeneity in a CMOS SPAD array designed for time-gated Raman spectroscopy. IEEE Trans. Instrum. Meas. 66, 1837-1844 (2017). doi:  10.1109/TIM.2017.2673002
    [147] Nissinen, I., Nissinen, J. & Kostamovaara, J. Effects of the inhomogeneity of the time resolving CMOS single-photon avalanche diode array on time-gated Raman spectroscopy. In Proc. I2MTC 1-6 (IEEE, Turin, Italy, 2017). https://ieeexplore.ieee.org/document/7969713/
    [148] Nissinen, I., Nissinen, J., Keränen, P., Stoppa, D. & Kostamovaara, J. A 16 × 256 SPAD line detector with a 50-ps, 3-bit, 256-channel time-to-digital converter for Raman spectroscopy. IEEE Sens. J. 18, 3789-3798 (2018). doi:  10.1109/JSEN.2018.2813531
    [149] Alayed, M. & Deen, M. Time-resolved diffuse optical spectroscopy and imaging using solid-state detectors: characteristics, present status, and research challenges. Sensors 17, 2115 (2017). doi:  10.3390/s17092115
    [150] Ferocino, E. et al. High throughput detection chain for time domain optical mammography. Biomed. Opt. Express 9, 755-770 (2018). doi:  10.1364/BOE.9.000755
    [151] Pavia, J. M., Wolf, M. & Charbon, E. Single-photon avalanche diode imagers applied to near-infrared imaging. IEEE J. Sel. Top. Quantum Electron. 20, 291-298 (2014). doi:  10.1109/JSTQE.2014.2313983
    [152] Pavia, J. M. Near-Infrared Optical Tomography with Single-Photon Avalanche Diode Image Sensors. Ph.D. thesis, EPFL, Lausanne, 2015.
    [153] Lindner, S. et al. Column-parallel dynamic TDC reallocation in SPAD sensor module fabricated in 180 nm CMOS for near infrared optical tomography. In Proc. IISW 86-89 (IISW, Hiroshima, Japan, 2017).
    [154] Kalyanov, A. et al. Time domain near-infrared optical tomography with time-of-flight SPAD camera: The new generation. In Proc. Biophotonics Congress: Biomedical Optics Congress OF4D-OF45 (Optical Society of America, Hollywood, FL, United States, 2018).
    [155] Mora, A. D. et al. Towards next-generation time-domain diffuse optics for extreme depth penetration and sensitivity. Biomed. Opt. Express 6, 1749-1760 (2015). doi:  10.1364/BOE.6.001749
    [156] Stuker, F. et al. Hybrid small animal imaging system combining magnetic resonance imaging with fluorescence tomography using single photon avalanche diode detectors. IEEE Trans. Med. Imaging 30, 1265-1273 (2011). doi:  10.1109/TMI.2011.2112669
    [157] Stuker, F. et al. A novel hybrid imaging system for simultaneous fluorescence molecular tomography and magnetic resonance imaging. In Proc. Biomedical Optics and 3-D Imaging BTuD1 (Optical Society of America, Miami, FL, United States, 2010). https://www.osapublishing.org/abstract.cfm?URI=BIOMED-2010-BTuD1
    [158] Tanner, M. et al. Ballistic and snake photon imaging for locating optical endomicroscopy fibres. Biomed. Opt. Express 8, 4077-4095 (2017). doi:  10.1364/BOE.8.004077
    [159] Muntean, A., Venialgo, E., Gnecchi, S., Jackson, C. & Charbon, E. Towards a fully digital state-of-the-art analog SiPM. In Proc. NSS/MIC (IEEE, Atlanta, GA, United States, 2017).
    [160] Venialgo, E., Lusardi, N., Garzetti, F., Geraci, A. & Charbon, E. A network-enabled PET detector module based on TDCs on FPGA. In Proc. NSS/MIC (IEEE, Atlanta, GA, United States, 2017).
    [161] Boiko, D. et al. A quantum imager for intensity correlated photons. New J. Phys. 11, 013001 (2009). doi:  10.1088/1367-2630/11/1/013001
    [162] Boiko, D. et al. On the application of a monolithic array for detecting intensity-correlated photons emitted by different source types. Opt. Express 17, 15087-15103 (2009). doi:  10.1364/OE.17.015087
    [163] Unternährer, M., Bessire, B., Gasparini, L., Stoppa, D. & Stefanov, A. Coincidence detection of spatially correlated photon pairs with a monolithic time-resolving detector array. Opt. Express 24, 28829-28841 (2016). doi:  10.1364/OE.24.028829
    [164] Gasparini, L. et al. SUPERTWIN: towards 100 kpixel CMOS quantum image sensors for quantum optics applications. In Proc. SPIE, Quantum Sensing and Nano Electronics and Photonics XIV, 101112L (SPIE, San Francisco, CA, United States, 2017).
    [165] Aull, B. Geiger-mode avalanche photodiode arrays integrated to all-digital CMOS circuits. Sensors 16, 495 (2016). doi:  10.3390/s16040495
    [166] Aull, B. F. et al. A study of crosstalk in a 256 × 256 photon counting imager based on silicon Geiger-mode avalanche photodiodes. IEEE Sens. J. 15, 2123-2132 (2015). doi:  10.1109/JSEN.2014.2368456
    [167] Pavia, J. M., Scandini, M., Lindner, S., Wolf, M. & Charbon, E. A 1 × 400 backside-illuminated SPAD sensor with 49.7 ps resolution, 30 pJ/sample TDCs fabricated in 3D CMOS technology for near-infrared optical tomography. IEEE J. Solid-State Circuits 50, 2406-2418 (2015). doi:  10.1109/JSSC.2015.2467170
    [168] Durini, D. et al. BackSPAD - back-side illuminated single-photon avalanche diodes: concept and preliminary performances. In Proc. NSS/MIC 1-2 (IEEE, Anaheim, CA, United States, 2012).
    [169] Zou, Y., Bronzi, D., Villa, F. & Weyers, S. Backside Illuminated Wafer-to-Wafer Bonding Single Photon Avalanche Diode Array. In Proc. PRIME 1-4 (IEEE, Grenoble, France, 2014).
    [170] Nolet, F. et al. A 2D proof of principle towards a 3D digital SiPM in HV CMOS with low output capacitance. IEEE Trans. Nucl. Sci. 63, 2293-2299 (2016). doi:  10.1109/TNS.2016.2582686
    [171] Nolet, F. et al. Digital SiPM channel integrated in CMOS 65 nm with 17.5 ps FWHM single photon timing resolution. Nucl. Instrum. Methods Phys. Res. Sect. A 912, 29-32 (2018). doi:  10.1016/j.nima.2017.10.022
    [172] Bérubé, B.-L. et al. Implementation study of single photon avalanche diodes (SPAD) in 0.8 μm HV CMOS technology. IEEE Trans. Nucl. Sci. 62, 710-718 (2015). doi:  10.1109/TNS.2015.2424852
    [173] Al Abbas, T. et al. Backside illuminated SPAD image sensor with 7.83 μm pitch in 3D-Stacked CMOS technology. In Proc. IEDM 8.1.1-8.1.4 (IEEE, San Francisco, CA, United States, 2016).
    [174] Lindner, S. et al. A high-PDE, backside-illuminated SPAD in 65/40 nm 3D IC CMOS pixel with cascoded passive quenching and active recharge. IEEE Electron Device Lett. 38, 1547-1550 (2017). doi:  10.1109/LED.2017.2755989
    [175] Lee, M.-J. et al. A back-illuminated 3D-stacked single-photon avalanche diode in 45 nm CMOS technology. In Proc. IEDM 16.6.1-16.6.4 (IEEE, San Francisco, CA, United States, 2017).
    [176] You, Z., Parmesan, L., Pellegrini, S. & Henderson, R. K. 3 μm pitch, 1 μm active diameter SPAD arrays in 130 nm CMOS imaging technology. In Proc. IISW 238-241 (IISW, Hiroshima, Japan, 2017).
    [177] Pellegrini, S. & Rae, B. Fully industrialised single photon avalanche diodes. In Proc. SPIE, Advanced Photon Counting Techniques XI, 102120D (SPIE, Anaheim, CA, United States, 2017).
    [178] Antolovic, I. M. et al. Photon-counting arrays for time-resolved imaging. Sensors 16, 1005 (2016). doi:  10.3390/s16071005
    [179] Ximenes, A. R. et al. A 256 × 256 45/65 nm 3D-stacked SPAD-based direct TOF image sensor for LiDAR applications with optical polar modulation for up to 18.6 dB interference suppression. In IEEE ISSCC Digest in Technical Paper 96-98 (IEEE, San Francisco, CA, United States, 2018).
    [180] Krieger, J. W. et al. Imaging fluorescence (cross-)correlation spectroscopy in live cells and organisms. Nat. Protoc. 10, 1948-1974 (2015). doi:  10.1038/nprot.2015.100
  • 加载中
图(8) / 表(3)
计量
  • 文章访问数:  106
  • HTML全文浏览量:  52
  • PDF下载量:  0
  • 被引次数: 0
出版历程
  • 收稿日期:  2018-11-28
  • 录用日期:  2019-08-07
  • 修回日期:  2019-07-30
  • 网络出版日期:  2019-09-18

目录

    /

    返回文章
    返回