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Thus, we have developed and extensively characterized an easily scalable 3D PHH spheroid system in chemically-defined, serum-free conditions. Using whole proteome analyses, we found that PHH spheroids cultured this way were similar to the liver\n                    <jats:italic>in vivo<\/jats:italic>\n                    and even retained their inter-individual variability. Furthermore, PHH spheroids remained phenotypically stable and retained morphology, viability and hepatocyte-specific functions for culture periods of at least 5 weeks. We show that under chronic exposure, the sensitivity of the hepatocytes drastically increased and toxicity of a set of hepatotoxins was detected at clinically relevant concentrations. An interesting example was the chronic toxicity of fialuridine for which hepatotoxicity was mimicked after repeated-dosing in the PHH spheroid model, not possible to detect using previous\n                    <jats:italic>in vitro<\/jats:italic>\n                    systems. Additionally, we provide proof-of-principle that PHH spheroids can reflect liver pathologies such as cholestasis, steatosis and viral hepatitis. Combined, our results demonstrate that the PHH spheroid system presented here constitutes a versatile and promising\n                    <jats:italic>in vitro<\/jats:italic>\n                    system to study liver function, liver diseases, drug targets and long-term DILI.\n                  <\/jats:p>","DOI":"10.1038\/srep25187","type":"journal-article","created":{"date-parts":[[2016,5,4]],"date-time":"2016-05-04T05:10:49Z","timestamp":1462338649000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":712,"title":["Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease"],"prefix":"10.1038","volume":"6","author":[{"given":"Catherine C.","family":"Bell","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delilah F. 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