{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T00:19:16Z","timestamp":1775261956595,"version":"3.50.1"},"reference-count":49,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2014,10,31]],"date-time":"2014-10-31T00:00:00Z","timestamp":1414713600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Sensors"],"abstract":"<jats:p>Instrumental limitations such as bulkiness and high cost prevent the fluorescence technique from becoming ubiquitous for point-of-care deoxyribonucleic acid (DNA) detection and other in-field molecular diagnostics applications. The complimentary metal-oxide-semiconductor (CMOS) technology, as benefited from process scaling, provides several advanced capabilities such as high integration density, high-resolution signal processing, and low power consumption, enabling sensitive, integrated, and  low-cost fluorescence analytical platforms. In this paper, CMOS time-resolved, contact, and multispectral imaging are reviewed. Recently reported CMOS fluorescence analysis microsystem prototypes are surveyed to highlight the present state of the art.<\/jats:p>","DOI":"10.3390\/s141120602","type":"journal-article","created":{"date-parts":[[2014,10,31]],"date-time":"2014-10-31T10:32:28Z","timestamp":1414751548000},"page":"20602-20619","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["CMOS Time-Resolved, Contact, and Multispectral Fluorescence Imaging for DNA Molecular Diagnostics"],"prefix":"10.3390","volume":"14","author":[{"given":"Nan","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Physics and Materials Science, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong"}]},{"given":"Ka Wai","family":"Cheung","sequence":"additional","affiliation":[{"name":"Department of Physics and Materials Science, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong"}]},{"given":"Hiu","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Physics and Materials Science, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong"}]},{"given":"Derek","family":"Ho","sequence":"additional","affiliation":[{"name":"Department of Physics and Materials Science, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong"}]}],"member":"1968","published-online":{"date-parts":[[2014,10,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1109\/JPROC.2003.820548","article-title":"Disposable smart lab on a chip for point-of-care clinical diagnostic","volume":"92","author":"Choi","year":"2004","journal-title":"Proc. IEEE"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1109\/TBCAS.2012.2230172","article-title":"CMOS Spectrally-Multiplexed FRET-On-a-Chip for DNA Analysis","volume":"7","author":"Ho","year":"2013","journal-title":"IEEE Trans. Biomed. Circuit. Syst."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1109\/JSSC.2008.925407","article-title":"Active CMOS sensor array for electrochemical biomolecular detection","volume":"43","author":"Levine","year":"2008","journal-title":"IEEE J. Solid-State Circuits"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1109\/JSSC.2006.869785","article-title":"A 0.18-\u03bcm CMOS bioluminescence detection lab-on-chip","volume":"41","author":"Eltoukhy","year":"2006","journal-title":"IEEE J. Solid-State Circuits"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1109\/TBCAS.2013.2243727","article-title":"CMOS Tunable-Wavelength Multi-Color Photogate Sensor","volume":"7","author":"Ho","year":"2013","journal-title":"IEEE Trans. Biomed. Circuits Syst."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1109\/TIE.2008.2011450","article-title":"Biosensor systems in standard CMOS processes: Fact or fiction","volume":"56","author":"Jang","year":"2009","journal-title":"IEEE Trans. Industr. Electron."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1038\/nbt994","article-title":"In vivo cancer targeting and imaging with semiconductor quantum dots","volume":"22","author":"Gao","year":"2004","journal-title":"Nat. Biotechnol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1109\/TBCAS.2009.2033662","article-title":"Fabrication and characterization of a surface-acoustic-wave biosensor in CMOS technology for cancer biomarker detection","volume":"4","author":"Tigli","year":"2010","journal-title":"IEEE Trans. Biomed. Circuits Syst."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1042\/BST0370471","article-title":"Real-time DNA microarrays: Reality check","volume":"37","author":"Chagovetz","year":"2009","journal-title":"Biochem. Soc. Trans."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1109\/TCSI.2010.2043990","article-title":"A CMOS\/Thin-film fluorescence contact imaging microsystem for DNA analysis","volume":"57","author":"Singh","year":"2010","journal-title":"IEEE Trans. Circuits Syst. I"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1126\/science.270.5235.467","article-title":"Quantitative monitoring of gene expression patterns with a complementary DNA microarray","volume":"207","author":"Schena","year":"1995","journal-title":"Science"},{"key":"ref_12","first-page":"133","article-title":"Toward an on-chip multiplexed nucleic acid hybridization assay using immobilized quantum dot-oligonucleotide conjugates and fluorescence resonance energy transfer","volume":"7909","author":"Tavares","year":"2011","journal-title":"Proc. SPIE: Colloidal Quant. Dots\/Nanocrystal. Biomed. Appl."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2438","DOI":"10.1109\/JSSC.2004.837084","article-title":"A fully electronic DNA sensor with 128 positions and in-pixel A\/D conversion","volume":"39","author":"Schienle","year":"2004","journal-title":"IEEE J. Solid-State Circuits"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0925-4005(98)00321-9","article-title":"Surface plasmon resonance sensors: review","volume":"54","author":"Homola","year":"1999","journal-title":"Sens. Actuators B Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1021\/ac403391q","article-title":"Label-Free In-Flow Detection of Single DNA Molecules using Glass Nanopipettes","volume":"86","author":"Gong","year":"2014","journal-title":"Anal. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1038\/nnano.2010.275","article-title":"Label-free single-molecule detection of DNA-hybridization kinetics with a carbon nanotube field-effect transistor","volume":"6","author":"Sorgenfrei","year":"2011","journal-title":"Nat. Nanotechnol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4738","DOI":"10.1039\/c2lc40372b","article-title":"A low-cost, label-free DNA detection method in lab-on-chip format based on electrohydrodynamic instabilities, with application to long-range PCR","volume":"12","author":"Champ","year":"2012","journal-title":"Lab Chip"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.aca.2006.08.026","article-title":"Towards multi-colour strategies for the detection of oligonucleotide hybridization using quantum dots as energy donors in fluorescence resonance energy transfer (FRET)","volume":"581","author":"Algar","year":"2007","journal-title":"Anal. Chim. Acta"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.1126\/science.281.5385.2013","article-title":"Semiconductor nanocrystals as fluorescent biological labels","volume":"281","author":"Bruchez","year":"1998","journal-title":"Science"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1109\/TBCAS.2011.2114660","article-title":"A CMOS in-pixel CTIA high-sensitivity fluorescence imager","volume":"5","author":"Murari","year":"2011","journal-title":"IEEE Trans. Biolog. Circuits Syst."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6041","DOI":"10.1021\/la903751m","article-title":"Developing mixed films of immobilized oligonucleotides and quantum dots for the multiplexed detection of nucleic acid hybridization using a combination of fluorescence resonance energy transfer and direct excitation of fluorescence","volume":"26","author":"Algar","year":"2010","journal-title":"Langmuir"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1038\/nmeth.1207","article-title":"Fluorescent protein FRET pairs for ratiometric imaging of dual biosensors","volume":"5","author":"Ai","year":"2008","journal-title":"Nat. Meth."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1016\/j.talanta.2009.08.027","article-title":"Time-resolved fluorescence based DNA detection using novel europium ternary complex doped silica nanoparticles","volume":"80","author":"Qin","year":"2009","journal-title":"Talanta"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1109\/TBCAS.2008.2006494","article-title":"Handheld fluorometers for lab-on-a-chip applications","volume":"3","author":"Nelson","year":"2009","journal-title":"IEEE Trans. Biomed. Circuits Syst."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1698","DOI":"10.1109\/TCSI.2007.902409","article-title":"Contact imaging: simulation and experiment","volume":"54","author":"Ji","year":"2007","journal-title":"IEEE Trans. Circuits Syst. I"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1039\/b819080a","article-title":"An integrated hybrid interference and absorption filter for fluorescence detection in lab-on-a-chip devices","volume":"9","author":"Richard","year":"2009","journal-title":"Lab Chip"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1016\/j.snb.2011.04.074","article-title":"Contact CMOS imaging of gaseous oxygen sensor array","volume":"157","author":"Daivasagaya","year":"2011","journal-title":"Sens. Actuators B Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2053","DOI":"10.1364\/OE.20.002053","article-title":"CMOS buried quad p-n junction photodetector for multi-wavelength analysis","volume":"20","author":"Richard","year":"2012","journal-title":"Opt. Exp."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.aca.2006.01.107","article-title":"A spatially resolved nucleic acid biochip based on a gradient of density of immobilized probe oligonucleotide","volume":"564","author":"Park","year":"2006","journal-title":"Anal. Chim. Acta"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1109\/TMI.2010.2045005","article-title":"Multiplexed Analysis of Proteins in Tissue Using Multispectral Fluorescence Imaging","volume":"29","author":"Barash","year":"2010","journal-title":"IEEE Trans. Med. Imag."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1049\/iet-nbt:20070033","article-title":"Fluorescent resonance energy transfer based detection of biological contaminants through hybrid quantum dot\u2013quencher interactions","volume":"2","author":"Ramadurai","year":"2008","journal-title":"IET Nanobiotechnol."},{"key":"ref_32","first-page":"6000718:1","article-title":"CMOS SPADs: Design Issues and Research Challenges for Detectors, Circuits, and Arrays","volume":"20","author":"Palubiak","year":"2014","journal-title":"IEEE J. Selected Top. Quant. Electron."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1109\/TNS.2013.2293426","article-title":"Modeling of Single Photon Avalanche Diode Array Detectors for PET Applications","volume":"61","author":"Therrien","year":"2014","journal-title":"IEEE Trans. Nuclear Sci."},{"key":"ref_34","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_35","first-page":"3804810:1","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. Selected Top. Quant. Electron."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1109\/JSSC.2013.2293777","article-title":"A 100 fps, Time-Correlated Single-PhotonCounting-Based Fluorescence-Lifetime Imager in 130 nm CMOS","volume":"49","author":"Field","year":"2014","journal-title":"IEEE J. Solid-State Circuits"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1109\/JSEN.2010.2058846","article-title":"Novel, High-Dynamic-Range, High-Speed, and High-Sensitivity CMOS Imager Using Time-Domain Single-Photon Counting and Avalanche Photodiodes","volume":"11","author":"Palubiak","year":"2011","journal-title":"IEEE Sens. J."},{"key":"ref_38","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 Phot. J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.1109\/JSSC.2009.2016994","article-title":"A 0.18-\u03bcm CMOS array sensor for integrated time-resolved fluorescence detection","volume":"44","author":"Huang","year":"2009","journal-title":"IEEE J. Solid-State Circuits"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Schwartz, D.E., Charbon, E., and Shepard, K.L. (2007, January 14-16). A Single-Photon Avalanche Diode Imager for Fluorescence Lifetime Applications. Kyoto, Japan.","DOI":"10.1109\/VLSIC.2007.4342691"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.bios.2008.04.015","article-title":"Time-resolved F\u00f6rster-resonance-energy-transfer DNA assay on an active CMOS microarray","volume":"24","author":"Schwartz","year":"2008","journal-title":"Biosens. Bioelectron"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2463","DOI":"10.1109\/TNS.2012.2208761","article-title":"A 128-Channel, 8.9-ps LSB, Column-Parallel Two-Stage TDC Based on Time Difference Amplification for Time-Resolved Imaging","volume":"59","author":"Mandai","year":"2012","journal-title":"IEEE Trans. Nuclear Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2725","DOI":"10.1109\/TED.2014.2332068","article-title":"Dead Time Compensation in CMOS Single Photon Avalanche Diodes with Active Quenching and External Reset","volume":"61","author":"Chick","year":"2014","journal-title":"IEEE Trans. Electr. Dev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1109\/LED.2009.2019974","article-title":"A CMOS STI-Bound Single-Photon Avalanche Diode with 27-ps Timing Resolution and a Reduced Diffusion Tail","volume":"30","author":"Hsu","year":"2009","journal-title":"IEEE Electr. Dev. Lett."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3900115:1","DOI":"10.1109\/JPHOT.2014.2304554","article-title":"Novel Lensless Miniature Contact Imaging System for Monitoring Calcium Changes in Live Neurons","volume":"6","author":"Mudraboyina","year":"2014","journal-title":"IEEE Photon. J."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2116","DOI":"10.1109\/TCSI.2013.2239115","article-title":"CMOS tunable-color image sensor with dual-ADC shot-noise-aware dynamic range extension","volume":"60","author":"Ho","year":"2013","journal-title":"IEEE Trans. Circuits Syst. I Regular Pap."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/S0924-4247(01)00544-1","article-title":"Infrared microspectrometer based on a diffraction grating","volume":"92","author":"Kong","year":"2011","journal-title":"Sens. Actuators A Phys."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1109\/JSSC.2002.803049","article-title":"A single-chip CMOS optical microspectrometer with light-to-frequency converter and bus interface","volume":"37","author":"Correia","year":"2002","journal-title":"IEEE J. Solid-State Circuits"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Ho, D., Gulak, G., and Genov, R. (2011, January 19\u201321). CMOS field-modulated color sensor. San Jose, CA, USA.","DOI":"10.1109\/CICC.2011.6055394"}],"container-title":["Sensors"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8220\/14\/11\/20602\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:17:39Z","timestamp":1760217459000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8220\/14\/11\/20602"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,10,31]]},"references-count":49,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2014,11]]}},"alternative-id":["s141120602"],"URL":"https:\/\/doi.org\/10.3390\/s141120602","relation":{},"ISSN":["1424-8220"],"issn-type":[{"value":"1424-8220","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,10,31]]}}}