{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T23:31:52Z","timestamp":1780356712482,"version":"3.54.1"},"reference-count":51,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2024,9,4]],"date-time":"2024-09-04T00:00:00Z","timestamp":1725408000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"MICIU\/AEI\/10.13039\/501100011033","award":["PID2019-105714RB-I00"],"award-info":[{"award-number":["PID2019-105714RB-I00"]}]},{"name":"MICIU\/AEI\/10.13039\/501100011033","award":["PID2022-136833OB-C21"],"award-info":[{"award-number":["PID2022-136833OB-C21"]}]},{"name":"MICIU\/AEI\/10.13039\/501100011033","award":["PDC2023-145805-I00"],"award-info":[{"award-number":["PDC2023-145805-I00"]}]},{"name":"European Regional Development Fund","award":["PID2019-105714RB-I00"],"award-info":[{"award-number":["PID2019-105714RB-I00"]}]},{"name":"European Regional Development Fund","award":["PID2022-136833OB-C21"],"award-info":[{"award-number":["PID2022-136833OB-C21"]}]},{"name":"European Regional Development Fund","award":["PDC2023-145805-I00"],"award-info":[{"award-number":["PDC2023-145805-I00"]}]},{"name":"European Union NextGenerationEU\/PRTR","award":["PID2019-105714RB-I00"],"award-info":[{"award-number":["PID2019-105714RB-I00"]}]},{"name":"European Union NextGenerationEU\/PRTR","award":["PID2022-136833OB-C21"],"award-info":[{"award-number":["PID2022-136833OB-C21"]}]},{"name":"European Union NextGenerationEU\/PRTR","award":["PDC2023-145805-I00"],"award-info":[{"award-number":["PDC2023-145805-I00"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Sensors"],"abstract":"<jats:p>Digital histogram generation for time-resolved measurements with single-photon avalanche diode (SPAD) sensors requires the storage of many timestamp signals. This work presents a mixed-signal time-to-digital converter (TDC) that uses analog storage to achieve an area-efficient design that can be integrated in large SPAD arrays. Fabricated using a 150 nm CMOS process, the prototype occupies an area of only 18.3 \u00b5m \u00d7 36.5 \u00b5m, a notable size reduction compared to conventional designs. The experimental results demonstrated high performance, with an integral nonlinearity (INL) of 0.35\/0.14 least significant bit (LSB) and a differential nonlinearity (DNL) of 0.14\/\u22120.12 LSB. In addition, the proposed TDC can support the construction of histograms comprising up to 512 bins, making it an effective solution to accommodate a wide range of resolution requirements. Validated in a point-of-care (PoC) device for fluorescence lifetime measurements, it distinguished between lifetimes of approximately 4.1 ns, 3.6 ns and 80 ns with the Alexa Fluor (AF) 546 and 568 dyes and Quantum Dot (QD) 705, respectively. The analog storage design and area-efficient architecture offer a novel approach to integrating TDCs in SPAD-based systems, with potential applications in medical diagnostics and beyond.<\/jats:p>","DOI":"10.3390\/s24175763","type":"journal-article","created":{"date-parts":[[2024,9,5]],"date-time":"2024-09-05T02:34:06Z","timestamp":1725503646000},"page":"5763","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Area-Efficient Mixed-Signal Time-to-Digital Converter Integration for Time-Resolved Photon Counting"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4471-1555","authenticated-orcid":false,"given":"Sergio","family":"Moreno","sequence":"first","affiliation":[{"name":"Department of Electronic and Biomedical Engineering, Faculty of Physics, University of Barcelona, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6950-0981","authenticated-orcid":false,"given":"Victor","family":"Moro","sequence":"additional","affiliation":[{"name":"Department of Electronic and Biomedical Engineering, Faculty of Physics, University of Barcelona, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5431-8554","authenticated-orcid":false,"given":"Joan","family":"Canals","sequence":"additional","affiliation":[{"name":"Department of Electronic and Biomedical Engineering, Faculty of Physics, University of Barcelona, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6721-7245","authenticated-orcid":false,"given":"Angel","family":"Di\u00e9guez","sequence":"additional","affiliation":[{"name":"Department of Electronic and Biomedical Engineering, Faculty of Physics, University of Barcelona, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Yokota, H., Fukasawa, A., Hirano, M., and Ide, T. (2021). Low-Light Photodetectors for Fluorescence Microscopy. Appl. Sci., 11.","DOI":"10.3390\/app11062773"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1364\/OL.419381","article-title":"Multispectral Compressive Fluorescence Lifetime Imaging Microscopy with a SPAD Array Detector","volume":"46","author":"Ghezzi","year":"2021","journal-title":"Opt. Lett."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Zickus, V., Wu, M.-L., Morimoto, K., Kapitany, V., Fatima, A., Turpin, A., Insall, R., Whitelaw, J., Machesky, L., and Bruschini, C. (2020). Fluorescence Lifetime Imaging with a Megapixel SPAD Camera and Neural Network Lifetime Estimation. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-77737-0"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1364\/OPTICA.454790","article-title":"In Vitro and In Vivo NIR Fluorescence Lifetime Imaging with a Time-Gated SPAD Camera","volume":"9","author":"Smith","year":"2022","journal-title":"Optica"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Xiao, D., Zang, Z., Wang, Q., Jiao, Z., Della Rocca, F.M., Chen, Y., and Li, D.D.U. (2022, January 11\u201315). Smart Wide-Field Fluorescence Lifetime Imaging System with CMOS Single-Photon Avalanche Diode Arrays. Proceedings of the 2022 44th Annual International Conference of the IEEE Engineering in Medicine & Biology Society (EMBC), Glasgow, Scotland.","DOI":"10.1109\/EMBC48229.2022.9870996"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.1109\/JSSC.2022.3150721","article-title":"A High Dynamic Range 128 \u00d7 120 3-D Stacked CMOS SPAD Image Sensor SoC for Fluorescence Microendoscopy","volume":"57","author":"Erdogan","year":"2022","journal-title":"IEEE J. Solid-State Circuits"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"6004110","DOI":"10.1109\/TIM.2021.3054679","article-title":"Time-Resolved Raman Spectrometer With High Fluorescence Rejection Based on a CMOS SPAD Line Sensor and a 573-Nm Pulsed Laser","volume":"70","author":"Talala","year":"2021","journal-title":"IEEE Trans. Instrum. Meas."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1109\/JSSC.2022.3212549","article-title":"CMOS SPAD Line Sensor With Fine-Tunable Parallel Connected Time-to-Digital Converters for Raman Spectroscopy","volume":"58","author":"Talala","year":"2023","journal-title":"IEEE J. Solid-State Circuits"},{"key":"ref_9","unstructured":"Raghavachari, R., and Berezin, M.Y. (2024, January 30\u201331). A Review of Recent Developments on CMOS Single-Photon Avalanche Diode-Based Cameras for Biomedical Time-Resolved Applications. Proceedings of the Reporters, Markers, Dyes, Nanoparticles, and Molecular Probes for Biomedical Applications XV, San Francisco, CA, USA."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1109\/JSTQE.2009.2035823","article-title":"Fast-Gated Single-Photon Avalanche Diode for Wide Dynamic Range Near Infrared Spectroscopy","volume":"16","author":"Tosi","year":"2010","journal-title":"IEEE J. Sel. Top. Quantum Electron."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1038\/s41377-019-0191-5","article-title":"Single-Photon Avalanche Diode Imagers in Biophotonics: Review and Outlook","volume":"8","author":"Bruschini","year":"2019","journal-title":"Light. Sci. Appl."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2401","DOI":"10.1109\/JSEN.2011.2123090","article-title":"High-Speed, Single-Photon Avalanche-Photodiode Imager for Biomedical Applications","volume":"11","author":"Palubiak","year":"2011","journal-title":"IEEE Sens. J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"012003","DOI":"10.1088\/1361-6501\/28\/1\/012003","article-title":"Wide-Field TCSPC: Methods and Applications","volume":"28","author":"Hirvonen","year":"2017","journal-title":"Meas. Sci. Technol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1430001","DOI":"10.1142\/S0218126614300013","article-title":"A review of cmos time-to-digital converter","volume":"23","author":"Wang","year":"2014","journal-title":"J. Circuits Syst. Comput."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1109\/JSTQE.2014.2342197","article-title":"CMOS Imager with 1024 SPADs and TDCs for Single-Photon Timing and 3-D Time-of-Flight","volume":"20","author":"Villa","year":"2014","journal-title":"IEEE J. Sel. Top. Quantum Electron."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2977","DOI":"10.1109\/JSSC.2008.2006445","article-title":"A 128 \u00d7 128 Single-Photon Image Sensor With Column-Level 10-Bit Time-to-Digital Converter Array","volume":"43","author":"Niclass","year":"2008","journal-title":"IEEE J. Solid-State Circuits"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3406","DOI":"10.1109\/TIM.2019.2936717","article-title":"A Review of New Time-to-Digital Conversion Techniques","volume":"68","author":"Tancock","year":"2019","journal-title":"IEEE Trans. Instrum. Meas."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1002\/cta.2936","article-title":"Time-to-digital Converters\u2014A Comprehensive Review","volume":"49","author":"Mattada","year":"2021","journal-title":"Int. J. Circuit Theory Appl."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4205","DOI":"10.1109\/TIM.2019.2938436","article-title":"Recent Developments and Challenges in FPGA-Based Time-to-Digital Converters","volume":"68","author":"Machado","year":"2019","journal-title":"IEEE Trans. Instrum. Meas."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1109\/JSSC.2018.2883720","article-title":"A 30-Frames\/s, 252 \u00d7 144 SPAD Flash LiDAR With 1728 Dual-Clock 48.8-Ps TDCs, and Pixel-Wise Integrated Histogramming","volume":"54","author":"Zhang","year":"2019","journal-title":"IEEE J. Solid-State Circuits"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Arvani, F., Carusone, T.C., and Rogers, E.S. (2019, January 26\u201329). TDC Sharing in SPAD-Based Direct Time-of-Flight 3D Imaging Applications. Proceedings of the 2019 IEEE International Symposium on Circuits and Systems (ISCAS), Sapporo, Japan.","DOI":"10.1109\/ISCAS.2019.8702586"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1109\/JSSC.2013.2293777","article-title":"A 100 Fps, Time-Correlated Single-Photon-Counting-Based Fluorescence-Lifetime Imager in 130 Nm CMOS","volume":"49","author":"Field","year":"2014","journal-title":"IEEE J. Solid-State Circuits"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1109\/JPHOT.2012.2198459","article-title":"SPAD Smart Pixel for Time-of-Flight and Time-Correlated Single-Photon Counting Measurements","volume":"4","author":"Villa","year":"2012","journal-title":"IEEE Photonics J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1109\/LSSC.2020.3005760","article-title":"A Fast 50 \u00d7 40-Pixels Single-Point DTOF SPAD Sensor With Photon Counting and Programmable ROI TDCs, With \u03c3 < 4 Mm at 3 m up to 18 Klux of Background Light","volume":"3","author":"Perenzoni","year":"2020","journal-title":"IEEE Solid-State Circuits Lett."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Henderson, R.K., Johnston, N., Chen, H., Li, D.D.-U., Hungerford, G., Hirsch, R., McLoskey, D., Yip, P., and Birch, D.J.S. (2018, January 3\u20136). A 192 \u00d7 128 Time Correlated Single Photon Counting Imager in 40 nm CMOS Technology. Proceedings of the ESSCIRC 2018\u2014IEEE 44th European Solid State Circuits Conference (ESSCIRC), Dresden, Germany.","DOI":"10.1109\/ESSCIRC.2018.8494330"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1109\/JSSC.2019.2894355","article-title":"A CMOS SPAD Line Sensor With Per-Pixel Histogramming TDC for Time-Resolved Multispectral Imaging","volume":"54","author":"Erdogan","year":"2019","journal-title":"IEEE J. Solid-State Circuits"},{"key":"ref_27","first-page":"214","article-title":"Compact CMOS Analog Counter for SPAD Pixel Arrays","volume":"61","author":"Panina","year":"2014","journal-title":"IEEE Trans. Circuits Syst. II Express Briefs"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1109\/TBCAS.2019.2892825","article-title":"A Compact Analog Histogramming SPAD-Based CMOS Chip for Time-Resolved Fluorescence","volume":"13","author":"Dieguez","year":"2019","journal-title":"IEEE Trans. Biomed. Circuits Syst."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3442","DOI":"10.1109\/TED.2013.2276752","article-title":"SPAD Image Sensor With Analog Counting Pixel for Time-Resolved Fluorescence Detection","volume":"60","author":"Pancheri","year":"2013","journal-title":"IEEE Trans. Electron Devices"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2715","DOI":"10.1007\/s12633-020-00619-7","article-title":"Design and Analysis of Low Power and High Frequency Current Starved Sleep Voltage Controlled Oscillator for Phase Locked Loop Application","volume":"13","author":"Rajalingam","year":"2021","journal-title":"Silicon"},{"key":"ref_31","unstructured":"(2024, July 23). AD7274. Available online: https:\/\/www.mouser.es\/ProductDetail\/Analog-Devices\/AD7274?qs=%252BEew9%252B0nqrDFn8D0j2eBuw%3D%3D."},{"key":"ref_32","unstructured":"(2024, July 23). DE0-Nano Development and Education Board. Available online: https:\/\/www.terasic.com.tw\/cgi-bin\/page\/archive.pl?Language=English&No=593."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3647","DOI":"10.1109\/TIM.2018.2880940","article-title":"A 2.3-Ps RMS Resolution Time-to-Digital Converter Implemented in a Low-Cost Cyclone V FPGA","volume":"68","author":"Sui","year":"2019","journal-title":"IEEE Trans. Instrum. Meas."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"18256","DOI":"10.1109\/ACCESS.2019.2896640","article-title":"Low Detection Limit Time-Correlated Single Photon Counting Lifetime Analytical System for Point-of-Care Applications","volume":"7","author":"Tian","year":"2019","journal-title":"IEEE Access"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1002\/lsm.23651","article-title":"Point-of-care Devices Based on Fluorescence Imaging and Spectroscopy for Tumor Margin Detection during Breast Cancer Surgery: Towards Breast Conservation Treatment","volume":"55","author":"Thapa","year":"2023","journal-title":"Lasers Surg. Med."},{"key":"ref_36","unstructured":"Franch Masdeu, N. (2022). Development of a Nano-Illumination Microscope. [Ph.D. Thesis, Universitat de Barcelona]."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Canals, J., Franch, N., Alonso, O., Vil\u00e0, A., and Di\u00e9guez, A. (2019). A Point-of-Care Device for Molecular Diagnosis Based on CMOS SPAD Detectors with Integrated Microfluidics. Sensors, 19.","DOI":"10.3390\/s19030445"},{"key":"ref_38","unstructured":"(2024, May 10). Laser Diodes Green Laser Diode 520 nm, 30 mW. Available online: https:\/\/eu.mouser.com\/ProductDetail\/ams-OSRAM\/PL-520_B1_2?qs=P%252BGkiCIryJuOxJrFamAdJQ%3D%3D."},{"key":"ref_39","unstructured":"(2024, May 10). \u039c-Slide I Luer Glass Bottom. Available online: https:\/\/ibidi.com\/channel-slides\/244-4645--slide-i-luer-glass-bottom.html#\/29-surface_modification-15h_170_%C2%B5m_5_%C2%B5m_d_263_m_schott_glass_sterilized\/33-pcs_box-15_individually_packed\/318-channel_version_channel_height-02_channel_height_250_%C2%B5m."},{"key":"ref_40","unstructured":"(2024, May 10). Streptavidin, Alexa FluorTM 546 Conjugate. Available online: https:\/\/www.thermofisher.com\/order\/catalog\/product\/S11225?SID=srch-srp-S11225."},{"key":"ref_41","unstructured":"(2024, August 31). Streptavidin, Alexa FluorTM 568 Conjugate. Available online: https:\/\/www.thermofisher.com\/order\/catalog\/product\/es\/en\/S11226."},{"key":"ref_42","unstructured":"(2024, March 19). QdotTM 705 ITKTM Amino (PEG) Quantum Dots. Available online: https:\/\/www.thermofisher.com\/order\/catalog\/product\/Q21561MP?SID=srch-srp-Q21561MP."},{"key":"ref_43","unstructured":"(2024, May 16). Fluorescence Quantum Yields (QY) and Lifetimes (\u03c4) for Alexa Fluor Dyes. Available online: https:\/\/www.thermofisher.com\/es\/en\/home\/references\/molecular-probes-the-handbook\/tables\/fluorescence-quantum-yields-and-lifetimes-for-alexa-fluor-dyes.html."},{"key":"ref_44","unstructured":"Periasamy, A., and So, P.T.C. (2009, January 24\u201329). Fluorescence Lifetime Based Contrast Imaging Using Variable Period Excitation Pulse Trains. Proceedings of the Multiphoton Microscopy in the Biomedical Sciences IX, San Jose, CA, USA."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1038\/nmeth.1248","article-title":"Quantum Dots versus Organic Dyes as Fluorescent Labels","volume":"5","author":"Grabolle","year":"2008","journal-title":"Nat. Methods"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Veerappan, C., Richardson, J., Walker, R., Li, D.-U., W Fishburn, M., Maruyama, Y., Stoppa, D., Borghetti, F., Gersbach, M., and K Henderson, R. (2011, January 20\u201324). A 160\u00d7128 Single-Photon Image Sensor with on-Pixel 55ps 10b Time-to-Digital Converter. Proceedings of the IEEE International Solid-State Circuits Conference, San Francisco, CA, USA.","DOI":"10.1109\/ISSCC.2011.5746333"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1109\/JSSC.2012.2188466","article-title":"A Time-Resolved, Low-Noise Single-Photon Image Sensor Fabricated in Deep-Submicron CMOS Technology","volume":"47","author":"Gersbach","year":"2012","journal-title":"IEEE J. Solid-State Circuits"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1049\/el.2018.7914","article-title":"Histogram-based Mixed-signal Time-to-digital-converter Array for Direct Time-of-flight Depth Sensors","volume":"55","author":"Seo","year":"2019","journal-title":"Electron. Lett."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2819","DOI":"10.1109\/JSSC.2020.3005756","article-title":"A 32 \u00d7 32-Pixel CMOS Imager for Quantum Optics with Per-SPAD TDC, 19.48% Fill-Factor in a 44.64-\u039cm Pitch Reaching 1-MHz Observation Rate","volume":"55","author":"Zarghami","year":"2020","journal-title":"IEEE J. Solid-State Circuits"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Gao, L., Ma, Y., Huang, L., Sen, C., Burri, S., Polytechnique, E., De Lausanne, F., Bruschini, C., Yang, X., and Cameron, R. (2023). Light-Eld Tomographic Uorescence Lifetime Imaging Microscopy. Res. Sq.","DOI":"10.21203\/rs.3.rs-2883279\/v1"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1109\/JSEN.2015.2483565","article-title":"SPAD Figures of Merit for Photon-Counting, Photon-Timing, and Imaging Applications: A Review","volume":"16","author":"Bronzi","year":"2016","journal-title":"IEEE Sens. J."}],"container-title":["Sensors"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8220\/24\/17\/5763\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:48:46Z","timestamp":1760111326000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8220\/24\/17\/5763"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,4]]},"references-count":51,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["s24175763"],"URL":"https:\/\/doi.org\/10.3390\/s24175763","relation":{},"ISSN":["1424-8220"],"issn-type":[{"value":"1424-8220","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,4]]}}}