02770nas a2200553   4500000000100000000000100001008004100002260001200043653002200055653001600077653002100093653003500114653002800149100001800177700002400195700001600219700001900235700002100254700002100275700002400296700003100320700002000351700003200371700001700403700001700420700002300437700003100460700002200491700002500513700001700538700001800555700001800573700002100591700002100612700002500633700001800658700001400676700002600690700001900716700002000735700001600755700002100771245009900792856005400891300001200945490000600957520123900963022001402202       2020                            d  c2020-0410aBiological models10aBiomimetics10aDrug development10aExperimental models of disease10aHaematological diseases1 aDavid B. Chou1 aViktoras Frismantas1 aYuka Milton1 aRhiannon David1 aPetar Pop-Damkov1 aDouglas Ferguson1 aAlexander MacDonald1 aÖzge Vargel Bölükbaşı1 aCailin E. Joyce1 aLiliana S. Moreira Teixeira1 aArianna Rech1 aAmanda Jiang1 aElizabeth Calamari1 aSasan Jalili-Firoozinezhad1 aBrooke A. Furlong1 aLucy R. O’Sullivan1 aCarlos F. Ng1 aYoungjae Choe1 aSusan Marquez1 aKasiani C. Myers1 aOlga K. Weinberg1 aRobert P. Hasserjian1 aRichard Novak1 aOren Levy1 aRachelle Prantil-Baun1 aCarl D. Novina1 aAkiko Shimamura1 aLorna Ewart1 aDonald E. Ingber00aOn-chip recapitulation of clinical bone marrow toxicities and patient-specific pathophysiology  uhttps://www.nature.com/articles/s41551-019-0495-z  a394-4060 v43 aThe inaccessibility of living bone marrow (BM) hampers the study of its pathophysiology under myelotoxic stress induced by drugs, radiation or genetic mutations. Here, we show that a vascularized human BM-on-a-chip (BM chip) supports the differentiation and maturation of multiple blood cell lineages over 4 weeks while improving CD34+ cell maintenance, and that it recapitulates aspects of BM injury, including myeloerythroid toxicity after clinically relevant exposures to chemotherapeutic drugs and ionizing radiation, as well as BM recovery after drug-induced myelosuppression. The chip comprises a fluidic channel filled with a fibrin gel in which CD34+ cells and BM-derived stromal cells are co-cultured, a parallel channel lined by human vascular endothelium and perfused with culture medium, and a porous membrane separating the two channels. We also show that BM chips containing cells from patients with the rare genetic disorder Shwachman–Diamond syndrome reproduced key haematopoietic defects and led to the discovery of a neutrophil maturation abnormality. As an in vitro model of haematopoietic dysfunction, the BM chip may serve as a human-specific alternative to animal testing for the study of BM pathophysiology.  a2157-846X