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However, the pre\u2010vascularization of liver organoids without affecting liver parenchymal specification remains a long\u2010lasting challenge, which is essential for their application in regenerative medicine. Here, the large\u2010scale formation of pre\u2010vascularized human hepatobiliary organoids (vhHBOs) is presented without affecting liver epithelial specification via a novel strategy, namely nonparenchymal cell grafting (NCG). Endothelial and mesenchymal cells are grafted to human hepatobiliary organoids (hHBOs) at the different liver epithelial differentiation stages without supplementing with nonparenchymal culture medium and growth factors. Endothelial grafting at the stage of hepatic maturation offers an optimal integration efficiency compared to the stage of hepatic specification. Additionally, grafting with mesenchymal proves crucial in endothelial invading and sprouting into the liver epithelial cells during the establishment of vhHBOs. Ectopic liver implants into mice further displayed integration of vhHBOs into mice vascular networks. Notably, transplanted vhHBOs self\u2010organized into native liver tissue like hepatic zone and bile ducts, indicating their potential to regenerate damaged hepatic and bile duct tissues. It is believed that nonparenchymal cell grafting will offer a novel technical route to form a high\u2010fidelity complex in vitro model for tissue engineering and regenerative medicine.<\/jats:p>","DOI":"10.1002\/advs.202407945","type":"journal-article","created":{"date-parts":[[2025,1,4]],"date-time":"2025-01-04T23:59:46Z","timestamp":1736035186000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["High\u2010Throughput Formation of Pre\u2010Vascularized hiPSC\u2010Derived Hepatobiliary Organoids on a Chip via Nonparenchymal Cell Grafting"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1617-1539","authenticated-orcid":false,"given":"Han","family":"Fan","sequence":"first","affiliation":[{"name":"Tissue Engineering and Organ Manufacturing (TEOM) Lab Department of Biomedical Engineering Wuhan University TaiKang Medical School (School of Basic Medical Sciences)  Wuhan 430071 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