02476nas a2200493   4500000000100000000000100001008004100002260001200043653001000055653001000065653001400075653000900089100002900098700001600127700001700143700002600160700001400186700001800200700001900218700001600237700002100253700001900274700002100293700002200314700002200336700001600358700001900374700002300393700001500416700001900431700001700450700001800467700002500485700002000510700002100530700002400551700002100575700002900596245007400625300001200699490000600711520125100717022001401968       2022                            d  c2022-0410aHeart10aLiver10aMicroRNAs10aSkin1 aKacey Ronaldson-Bouchard1 aDiogo Teles1 aKeith Yeager1 aDaniel Naveed Tavakol1 aYimu Zhao1 aAlan Chramiec1 aSomnath Tagore1 aMax Summers1 aSophia Stylianos1 aManuel Tamargo1 aBusub Marcus Lee1 aSusan P. Halligan1 aErbil Hasan Abaci1 aZongyou Guo1 aJoanna Jacków1 aAlberto Pappalardo1 aJerry Shih1 aRajesh K. Soni1 aShivam Sonar1 aCarrie German1 aAngela M. Christiano1 aAndrea Califano1 aKaren K. Hirschi1 aChristopher S. Chen1 aAndrzej Przekwas1 aGordana Vunjak-Novakovic00aA multi-organ chip with matured tissue niches linked by vascular flow  a351-3710 v63 aEngineered tissues can be used to model human pathophysiology and test the efficacy and safety of drugs. Yet, to model whole-body physiology and systemic diseases, engineered tissues with preserved phenotypes need to physiologically communicate. Here we report the development and applicability of a tissue-chip system in which matured human heart, liver, bone and skin tissue niches are linked by recirculating vascular flow to allow for the recapitulation of interdependent organ functions. Each tissue is cultured in its own optimized environment and is separated from the common vascular flow by a selectively permeable endothelial barrier. The interlinked tissues maintained their molecular, structural and functional phenotypes over 4 weeks of culture, recapitulated the pharmacokinetic and pharmacodynamic profiles of doxorubicin in humans, allowed for the identification of early miRNA biomarkers of cardiotoxicity, and increased the predictive values of clinically observed miRNA responses relative to tissues cultured in isolation and to fluidically interlinked tissues in the absence of endothelial barriers. Vascularly linked and phenotypically stable matured human tissues may facilitate the clinical applicability of tissue chips.  a2157-846X