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Time-of-flight secondary ion mass spectrometry (ToF\u2013SIMS) offers the unique ability for label-free 3D imaging of organic molecules with sub-micrometer spatial resolution and high sensitivity. Several studies of biofilms have been done with the help of ToF\u2013SIMS, but none of those studies have shown 3D imaging of antibiotics in native-state hydrated biofilms with cell-level resolution. Because ToF\u2013SIMS measurements must be performed in a high-vacuum environment, cryogenic preparation and analysis are necessary to preserve the native biofilm structure and antibiotic spatial distribution during ToF\u2013SIMS measurements. In this study, we have investigated the penetration of the antibiotic ciprofloxacin into <jats:italic>Bacillus subtilis<\/jats:italic> biofilms using sub-micrometer resolution 3D imaging cryo-ToF\u2013SIMS. <jats:italic>B. subtilis<\/jats:italic> biofilms were exposed to physiologically relevant levels of ciprofloxacin. The treated biofilms were then plunge-frozen in liquid propane and analyzed with ToF\u2013SIMS under cryogenic conditions. Multivariate analysis techniques, including multivariate curve resolution (MCR) and inverse maximum signal factor (iMSF) denoising, were used to aid analysis of the data and facilitate high spatial resolution 3D imaging of the biofilm, providing individually resolved cells and spatially resolved ciprofloxacin intensity at \u201creal world\u201d concentrations.<\/jats:p>\n                <jats:p><jats:bold>Graphical Abstract<\/jats:bold><\/jats:p>","DOI":"10.1007\/s00216-022-04496-4","type":"journal-article","created":{"date-parts":[[2023,1,10]],"date-time":"2023-01-10T07:03:08Z","timestamp":1673334188000},"page":"991-999","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Label-free sub-micrometer 3D imaging of ciprofloxacin in native-state biofilms with cryo-time-of-flight secondary ion mass spectrometry"],"prefix":"10.1007","volume":"415","author":[{"given":"Anoosheh","family":"Akbari","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anzhela","family":"Galstyan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard E.","family":"Peterson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heinrich F.","family":"Arlinghaus","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bonnie J.","family":"Tyler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2023,1,10]]},"reference":[{"key":"4496_CR1","first-page":"1","volume":"4","author":"J Muhsin","year":"2015","unstructured":"Muhsin J, Ufaq T, Tahir H, Saadia A. 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