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Artificial intelligence (AI) offers the potential to simplify these assays by predicting cell viability directly from brightfield microscopy images, but current models lack generalizability across diverse cell types and treatments. Here, we introduce a strategy called \u201cregularized imaging\u201d, where single cells are isolated in nanowells to generate standardized image patches that simplify segmentation and improve training data quality. We trained our model using example images of live and dead cells from a single cell line exposed to four cytotoxic conditions (ethanol, andrographolide, daunorubicin, and serum starvation). Despite this narrow training dataset, the resulting model accurately identified live and dead cells after treatments by previously unseen compounds, successfully replicating dose\u2010response curves comparable to fluorescence live\/dead assays. Importantly, this model effectively generalized across diverse cell types, including both adherent and suspension cells. Additionally, microscopy\u2010based cell viability analysis is non\u2010destructive, enabling repeated measurements to perform kinetic studies to distinguish between fast\u2010 and slow\u2010acting compounds. Our findings highlight how regularized single\u2010cell imaging enables the training of broadly generalizable AI models to recognize biologically relevant cell features for label\u2010free cell screening workflows.<\/jats:p>","DOI":"10.1002\/smtd.202501369","type":"journal-article","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T08:51:38Z","timestamp":1769158298000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Regularized Single\u2010Cell Imaging Enables Generalizable AI Models for Stain\u2010Free Cell Viability Screening"],"prefix":"10.1002","volume":"10","author":[{"given":"Pan","family":"Deng","sequence":"first","affiliation":[{"name":"Department of Mechanical Engineering University of British Columbia  Vancouver Canada"},{"name":"Centre for Blood Research University of British Columbia  Vancouver Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deasung","family":"Jang","sequence":"additional","affiliation":[{"name":"Department of Mechanical Engineering University of British Columbia  Vancouver Canada"},{"name":"Centre for Blood Research University of British Columbia  Vancouver Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel G.","family":"Berryman","sequence":"additional","affiliation":[{"name":"Department of Mechanical Engineering University of British Columbia  Vancouver Canada"},{"name":"Centre for Blood Research University of British Columbia  Vancouver Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon P.","family":"Duffy","sequence":"additional","affiliation":[{"name":"Centre for Blood Research University of British Columbia  Vancouver Canada"},{"name":"British Columbia Institute of Technology  Vancouver Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5459-6493","authenticated-orcid":false,"given":"Hongshen","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Mechanical Engineering University of British Columbia  Vancouver Canada"},{"name":"Centre for Blood Research University of British Columbia  Vancouver Canada"},{"name":"School of Biomedical Engineering University of British Columbia  Vancouver Canada"},{"name":"Vancouver Prostate Centre Vancouver General Hospital  Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,1,23]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/fft2.44"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2006.179"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/cyto.a.22213"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/jmi.12133"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/bies.201700003"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbf.4007"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1364\/BOE.452471"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/cyto.a.24475"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010021\u201089895\u2010w"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41420\u2010021\u201000616\u20108"},{"key":"e_1_2_9_12_1","doi-asserted-by":"crossref","unstructured":"O.Melouk A.Klingner R. 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A.\u2010M.Salem Auto\u2010encoders for Detection and Counting of Live\/Dead Cells IEEE International Conference on Intelligent Computing and Information Systems (ICICIS)(2023):45\u201351 https:\/\/doi.org\/10.1109\/ICICIS58388.2023.10391191.","DOI":"10.1109\/ICICIS58388.2023.10391191"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010022\u201028214\u2010x"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.microc.2025.113159"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.analchem.2c00878"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010022\u201012914\u2010x"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.03.040"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abe0431"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.21873\/anticanres.16888"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.688333"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592\u2010021\u201001249\u20106"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1101\/2025.04.28.651001"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1039\/D0LC00965B"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1039\/D4LC00413B"},{"key":"e_1_2_9_25_1","first-page":"795","article-title":"Comparing Apoptosis and Necrosis Effects of Arctium Lappa Root Extract and Doxorubicin on MCF7 and MDA\u2010MB\u2010231 Cell Lines","volume":"18","author":"Ghafari F.","year":"2017","journal-title":"Asian Pacific Journal of Cancer Prevention: APJCP"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules27113544"},{"key":"e_1_2_9_27_1","first-page":"55","article-title":"Andrographolide\u2010induced Autophagy: Pro\u2010survival or Pro\u2010death Signal","volume":"16","author":"Alzaharma M. 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