The 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.
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All of the data supporting the results in this study are available within the Article and its Supplementary Information. The broad range of raw datasets acquired and analysed (or any subsets of it), which for reuse would require contextual metadata, are available from the corresponding author on reasonable request.
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This research was sponsored by funding from: the US Food and Drug Administration (grants HHSF223201310079C and 75F40119C10098), the Defense Advanced Research Projects Agency (under Cooperative Agreement Number W911NF-12-2-0036), AstraZeneca and the Wyss Institute for Biologically Inspired Engineering (to D.E.I.); the US National Institutes of Health (R24 DK099808 and 5U01HL134812 to A.S., R01 DK102165 to C.D.N. and training grant 5T32CA009216-37 to D.B.C.); and the Department of Defense (W81XWH-14-1-0124 to C.D.N.). Additional funding was provided by the Dana-Farber Cancer Center Claudia Adams Barr Award (to C.E.J.) and the EPSRC Centre for Innovative Manufacturing in Regenerative Medicine (to A.R.). The authors thank S. Sweeney for helpful discussions, P. Machado and J. Caramanica for machining expertise, and M. DeLelys, R. Mathews, J. Houston, J. Patel, D. Kingman, A. Shay, J. Graham, S. Chung, T. Spitzer and F. Preffer at the Massachusetts General Hospital, as well as M. Fleming and M. Armant at Boston Children’s Hospital for invaluable help in relation to working with patient data and samples.
D.E.I. is a founder, and holds equity in, Emulate, Inc., and chairs its scientific advisory board. D.B.C., V.F., Y.M., L.S.M.T., O.L., R.N. and D.E.I. are co-inventors on a patent application describing the BM chip. R.D., P.P.-D., D.F., A.M. and L.E. are employed by AstraZeneca, which is developing AZD2811. The remaining authors declare no competing interests.
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Chou, D.B., Frismantas, V., Milton, Y. et al. On-chip recapitulation of clinical bone marrow toxicities and patient-specific pathophysiology. Nat Biomed Eng 4, 394–406 (2020). https://doi.org/10.1038/s41551-019-0495-z
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