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Cellular activation states are used to inform process control decisions such as restimulation and can be probed with experimental measurements of cell surface markers. However, these measurements are expensive, time-consuming, and invasive, and an urgent need exists for devising a non-invasive method for activation state monitoring that could be deployed on-line. Raman spectroscopy is a label-free and information-rich optical method that, when coupled to data analytical methods, can ameliorate these experimental issues. In this work, we quantitatively estimated experimental measurements of regulatory T cell activation markers with high accuracy. We simulated a clinical manufacturing setting by building an\n                    <jats:inline-formula>\n                      <jats:tex-math>$${L}_{1}$$<\/jats:tex-math>\n                    <\/jats:inline-formula>\n                    -regularized least-squares model with spectroscopic data from six regulatory T cell donors. Then, we validated the constructed model by accurately estimating different experimental measurements of biomarker values from two external donors, unseen by the model. We have devised a robust program to effectively estimate the activation state of regulatory T cells. We anticipate our method to be used with on-line Raman probes integrated into cell manufacturing devices for label-free monitoring of these processes.\n                  <\/jats:p>","DOI":"10.1038\/s41598-025-16002-8","type":"journal-article","created":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T18:22:06Z","timestamp":1762280526000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Label-free estimation of regulatory T cell activation markers using Raman spectroscopy with machine learning"],"prefix":"10.1038","volume":"15","author":[{"given":"Aria","family":"Azari-Pour","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Chamkalani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shreyas","family":"Rangan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine N.","family":"MacDonald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miles","family":"Huynh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan K.","family":"Levings","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. 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Spectrosc."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-16002-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-16002-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-16002-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T08:50:22Z","timestamp":1766134222000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-16002-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,4]]},"references-count":45,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["16002"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-16002-8","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,4]]},"assertion":[{"value":"12 June 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 August 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 November 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 December 2025","order":5,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Update","order":6,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The original online version of this Article was revised: In the original HTML version of this Article, Figures 1,2,3,4 and 6 were incorrectly rendered and erroneously displayed with a black background. The original HTML Article has been corrected; the\u00a0PDF\u00a0version was correct.","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All methods in this study were carried out in accordance with relevant guidelines and regulations. Experimental cell work was performed with approval from the University of British Columbia Research Ethics Board (H17-01490). Informed consent was obtained from the legal guardians of the thymus donors. Thymus donors were anonymized and referred to by unidentifiable donor numbers throughout this study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}}],"article-number":"38519"}}