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Efficient bile transport requires coordinated organization between hepatocytes and cholangiocytes at the hepatobiliary junction, a structure that remains poorly captured in existing in vitro models of liver disease. Here, we present a 3D multicellular spheroid\u2010based model of the human hepatobiliary junction. Building on advances in organoid and spheroid engineering, we co\u2010aggregate human hepatocytes and intrahepatic cholangiocytes, supported by murine fibroblasts, into adult hepatobiliary organoids (aHBOs). aHBOs directionally transport bile from hepatocyte canaliculi to cholangiocyte\u2010lined ductule\u2010like structures, visualized through a high\u2010throughput imaging assay. Hepatobiliary junction formation and bile flow dynamics are quantified over time using a fluorescent bile acid analog and AI\u2010assisted image analysis. When subjected to hypoxia\u2010reoxygenation, aHBOs exhibit disrupted bile transport and distinct cell\u2010type\u2010specific responses, enabling interrogation of hepatocyte and cholangiocyte vulnerability to transplant\u2010associated biliary hypoxia. Our findings suggest a reversible reduction in hepatocyte canalicular function under hypoxia, followed by selective cholangiocyte death upon reoxygenation, potentially contributing to biliary dysfunction after ischemic injury. This human\u2010derived, scalable platform provides a phenotypically relevant model for dissecting mechanisms of biliary dysfunction and discovering therapeutics for hypoxic liver injury and cholestatic diseases.<\/jats:p>","DOI":"10.1002\/advs.202514855","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T10:58:40Z","timestamp":1776682720000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A 3D In Vitro Model of the Human Hepatobiliary Junction"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9665-3548","authenticated-orcid":false,"given":"Ashley D.","family":"Westerfield","sequence":"first","affiliation":[{"name":"Institute of Medical Engineering and Science Massachusetts Institute of Technology  Cambridge Massachusetts USA"},{"name":"David H. 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Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie","family":"Katsuyama","sequence":"additional","affiliation":[{"name":"Department of Biological Engineering Massachusetts Institute of Technology  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1280-2161","authenticated-orcid":false,"given":"Vardhman","family":"Kumar","sequence":"additional","affiliation":[{"name":"David H. Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bess M.","family":"Miller","sequence":"additional","affiliation":[{"name":"David H. Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joa","family":"Yun","sequence":"additional","affiliation":[{"name":"David H. Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesse","family":"Kirkpatrick","sequence":"additional","affiliation":[{"name":"Institute of Medical Engineering and Science Massachusetts Institute of Technology  Cambridge Massachusetts USA"},{"name":"David H. Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology  Cambridge Massachusetts USA"},{"name":"Department of Medicine Brigham and Women's Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Mankus","sequence":"additional","affiliation":[{"name":"David H. Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret E.","family":"Bisher","sequence":"additional","affiliation":[{"name":"David H. Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail K.R.","family":"Lytton\u2010Jean","sequence":"additional","affiliation":[{"name":"David H. Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Z. 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