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Here, we established a bioengineered and 3Rs-complied (animal component-free) hepatocyte-like millifluidic system based on 3D hollow fiber membranes (HFMs), recombinant human laminin 332 coating and adult human stem cell-derived organoids. Organoid fragments formed polarized and tight monolayers on HFMs with improved hepatocyte-like maturation, as compared to standard 3D organoid cultures in Matrigel from matched donors. Gene expression profiling and immunofluorescence revealed that hepatocyte-like monolayers expressed a broad panel of phase I (e.g. CYP3A4, CYP2D6, CYP2C9) and II (e.g. UGTs, SULTs) drug-metabolizing enzymes and drug transporters (e.g. MDR1, MRP3, OATP1B3). Moreover, statically cultured monolayers displayed phase I and II metabolism of a cocktail of six relevant compounds, including midazolam and 7-hydroxycoumarin. We also demonstrated the disposition of midazolam in the basal\/blood-like circulation and apical\/canalicular-like compartment of the millifluidic chip. Finally, we studied the bioavailability of midazolam and coumarin on-a-chip in combination with a small intestine-like system. In conclusion, we generated a proof-of-concept liver organoid-on-a-chip model for examining metabolism and transport of drugs, which can be further developed to predict pharmacokinetics\u2019 (PK)\/absorption, distribution, metabolism and excretion (ADME) profiles in humans.<\/jats:p>","DOI":"10.1088\/1758-5090\/adc3ce","type":"journal-article","created":{"date-parts":[[2025,3,21]],"date-time":"2025-03-21T19:07:38Z","timestamp":1742584058000},"page":"025035","update-policy":"https:\/\/doi.org\/10.1088\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["A hollow fiber membrane-based liver organoid-on-a-chip model for examining drug metabolism and transport"],"prefix":"10.1088","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-6152-5451","authenticated-orcid":true,"given":"Adam","family":"Myszczyszyn","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9560-3985","authenticated-orcid":false,"given":"Anna","family":"Muench","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5555-0486","authenticated-orcid":false,"given":"Vivian","family":"Lehmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theo","family":"Sinnige","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5460-6540","authenticated-orcid":false,"given":"Frank G","family":"van Steenbeek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7141-9939","authenticated-orcid":false,"given":"Manon","family":"Bouwmeester","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roos-Anne","family":"Samsom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8371-5594","authenticated-orcid":false,"given":"Marit","family":"Keuper-Navis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8714-3669","authenticated-orcid":false,"given":"Thomas K","family":"van der Made","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Kogan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Braem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0651-5334","authenticated-orcid":false,"given":"Luc J W","family":"van der Laan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7940-5833","authenticated-orcid":true,"given":"Hossein","family":"Eslami Amirabadi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evita","family":"van de Steeg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1560-1074","authenticated-orcid":true,"given":"Rosalinde","family":"Masereeuw","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8114-0560","authenticated-orcid":true,"given":"Bart","family":"Spee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"266","published-online":{"date-parts":[[2025,4,1]]},"reference":[{"key":"bfadc3cebib1","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1038\/nrd4609","article-title":"An analysis of the attrition of drug candidates from four major pharmaceutical companies","volume":"14","author":"Waring","year":"2015","journal-title":"Nat. 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