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This study demonstrates that when a body-on-a-chip microdevice is coupled with miniaturized physiological support systems, it can create a multi-organ microphysiological system capable of more accurately mimicking the physiological complexity of a body, thereby offering potential for preclinical drug testing. To exemplify this concept, we have developed a model system comprising 18 types of microtissues interconnected by a vascular network that replicates the in vivo blood distribution among the organs. Furthermore, this system includes an excretory system with a micro-stirrer that ensures elimination efficiency akin to in vivo conditions. Our findings indicate that this system can: (1) survive and function for almost two months; (2) achieve two-compartment pharmacokinetics of a drug; (3) investigate the dynamic relationship between the tissue distribution and toxicity of a drug; (4) establish the multimorbidity model and evaluate the effectiveness of polypharmacy, challenging tasks with traditional animal models; (5) reduce animal usage in drug evaluations. Notably, features from points (2) to (4) are capabilities not achievable by other in vitro models. The strategy proposed in this study can also be applied to the development of multi-organ microphysiological systems that mimic the physiological complexity of human organs or the entire body.<\/jats:p>","DOI":"10.1038\/s41378-025-00933-3","type":"journal-article","created":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T23:26:16Z","timestamp":1747178776000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["An eighteen-organ microphysiological system coupling a vascular network and excretion system for drug discovery"],"prefix":"10.1038","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2877-6516","authenticated-orcid":false,"given":"Jing","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huixue","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueyang","family":"Qu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuhui","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenni","family":"Ji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxiu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7854-6466","authenticated-orcid":false,"given":"Xiuli","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,14]]},"reference":[{"key":"933_CR1","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1038\/nrd1382","volume":"3","author":"M Dickson","year":"2004","unstructured":"Dickson, M. & Gagnon, J. 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