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While 3D organoid systems effectively recapitulate tissue development, systematic investigation of microenvironmental parameters remains challenging. Here, complementary approaches are developed utilizing 2D cellular microarrays and 3D polyethylene glycol(PEG)\u2010based microwells to examine human stem cell\u2010derived hepatoblast differentiation. High\u2010throughput microarray platform enables systematic evaluation of 60 distinct microenvironmental conditions, combining 15 ECM compositions with 4 growth factor treatments. Position\u2010dependent expression of hepatocytic and cholangiocytic markers is observed including HNF4a, SOX9, and CK19, with differentiation patterns varying substantially across ECM and growth factor conditions. Based on these findings, specific ECM combinations are selected \u2013 Collagen 1, Fibronectin, and their combination \u2013 for integration into a modular 3D PEG hydrogel system. This 3D platform provides independent control over microtissue geometry and matrix composition, enabling investigation of spatial organization in hepatic differentiation. Through this integrated approach combining high\u2010throughput screening and defined 3D culture, a framework is established for dissecting the microenvironmental regulation of human liver development.<\/jats:p>","DOI":"10.1002\/adhm.202501370","type":"journal-article","created":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T11:11:58Z","timestamp":1759144318000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Effect of 2D and 3D ECM and Biomechanical Cues on Human iPSC\u2010Derived Liver Progenitor Cell Differentiation"],"prefix":"10.1002","volume":"15","author":[{"given":"Ishita","family":"Jain","sequence":"first","affiliation":[{"name":"Department of Bioengineering University of Illinois at Urbana\u2010Champaign  Urbana IL 61820 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brock","family":"Grenci","sequence":"additional","affiliation":[{"name":"Department of Bioengineering University of Illinois at Urbana\u2010Champaign  Urbana IL 61820 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyeon","family":"Ryoo","sequence":"additional","affiliation":[{"name":"Department of Bioengineering University of Illinois at Urbana\u2010Champaign  Urbana IL 61820 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering University of Illinois Chicago  Chicago IL 60612 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salman R.","family":"Khetani","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering University of Illinois Chicago  Chicago IL 60612 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1002-5335","authenticated-orcid":false,"given":"Gregory H.","family":"Underhill","sequence":"additional","affiliation":[{"name":"Department of Bioengineering University of Illinois at Urbana\u2010Champaign  Urbana IL 61820 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,9,29]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2006.03.015"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.340305"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.4161\/cc.5.2.2341"},{"key":"e_1_2_8_4_1","first-page":"1727","volume":"136","author":"Zong Y.","year":"2009","journal-title":"Dev. 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