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ABSTRACT 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. Access through your institution Buy or subscribe This is a preview

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ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS A MICROFLUIDIC BONE MARROW CHIP FOR THE

SAFETY PROFILING OF BIOLOGICS IN PRE-CLINICAL DRUG DEVELOPMENT Article Open access 15 May 2025 GENERATING HUMAN BONE MARROW ORGANOIDS FOR DISEASE MODELING AND DRUG DISCOVERY Article 26 March

2024 BIOENGINEERED NICHES THAT RECREATE PHYSIOLOGICAL EXTRACELLULAR MATRIX ORGANISATION TO SUPPORT LONG-TERM HAEMATOPOIETIC STEM CELLS Article Open access 10 July 2024 DATA AVAILABILITY 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. CHANGE HISTORY * _ 12 FEBRUARY 2020 A Correction to this paper has

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_Invest. New Drugs_ 30, 1519–1530 (2012). Article  CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS 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. AUTHOR INFORMATION Author notes * These authors contributed equally:

David B. Chou, Viktoras Frismantas. AUTHORS AND AFFILIATIONS * Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA David B. Chou, Viktoras Frismantas, 

Yuka Milton, Liliana S. Moreira Teixeira, Arianna Rech, Elizabeth Calamari, Sasan Jalili-Firoozinezhad, Brooke A. Furlong, Lucy R. O’Sullivan, Carlos F. Ng, Youngjae Choe, Susan Marquez, 

Richard Novak, Oren Levy, Rachelle Prantil-Baun & Donald E. Ingber * Department of Pathology, Massachusetts General Hospital, Boston, MA, USA David B. Chou & Robert P. Hasserjian *

Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK Rhiannon David & Lorna Ewart * DMPK, Oncology R&D, AstraZeneca, Boston, MA, USA

Petar Pop-Damkov & Douglas Ferguson * Clinical and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, Pharmaceutical Sciences, R&D, AstraZeneca, Cambridge, UK

Alexander MacDonald * Dana Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, MA, USA Özge Vargel Bölükbaşı & Akiko Shimamura * Department of Cancer Immunology and

Virology, Dana-Farber Cancer Institute, Boston, MA, USA Cailin E. Joyce & Carl D. Novina * Department of Medicine, Harvard Medical School, Boston, MA, USA Cailin E. Joyce & Carl D.

Novina * Department of Chemical Engineering, Loughborough University, Loughborough, UK Arianna Rech * Vascular Biology Program and Department of Surgery, Boston Children’s Hospital and

Harvard Medical School, Boston, MA, USA Amanda Jiang & Donald E. Ingber * Department of Bioengineering and Institute for Bioengineering and Biosciences (iBB), Instituto Superior Técnico,

Universidade de Lisboa, Lisbon, Portugal Sasan Jalili-Firoozinezhad * Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA Kasiani C. Myers * Division

of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital, Cincinnati, OH, USA Kasiani C. Myers * Department of Pathology, Boston Children’s Hospital, Boston, MA,

USA Olga K. Weinberg * Broad Institute of Harvard and MIT, Cambridge, MA, USA Carl D. Novina * Harvard John A. Paulson School of Engineering and Applied Sciences, Cambridge, MA, USA Donald

E. Ingber Authors * David B. Chou View author publications You can also search for this author inPubMed Google Scholar * Viktoras Frismantas View author publications You can also search for

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search for this author inPubMed Google Scholar * Petar Pop-Damkov View author publications You can also search for this author inPubMed Google Scholar * Douglas Ferguson View author

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Google Scholar CONTRIBUTIONS D.B.C. and V.F. participated in the design and performance of all experiments and analysed the data, alongside D.E.I., who also supervised all of the work. Y.M.

helped design and perform the experiments. R.D., P.P.-D., D.F., A.M. and L.E. helped to design experiments relating to drug testing, performed the mass spectrometry and pharmacokinetics

modelling, analysed the data and helped to write the manuscript. O.V.B. and C.E.J. helped to design, perform and interpret SDS-related studies, with input from and supervision of A.S. and

C.D.N. K.C.M. and O.K.W. provided access to patient data and material for SDS-related studies. L.S.M.T. and A.R. helped to conceive the BM chip design and performed the experiments. A.J.

helped to perform the radiation-related studies. B.A.F. and L.R.O. helped to analyse the data and revise the manuscript. E.C., C.F.N., Y.C. and S.C. fabricated and participated in the design

of the BM chip with input from and supervision of R.N. and D.E.I. E.C., S.J.-F. and S.C. helped to perform the oxygen studies. R.P.H. provided scientific supervision, as well as access to

patient material. O.L. and R.P.-B. helped to design the experiments and interpret the data, and supervised all of the work. D.B.C., V.F. and D.E.I. prepared the manuscript, with input from

all authors. CORRESPONDING AUTHOR Correspondence to Donald E. Ingber. ETHICS DECLARATIONS COMPETING INTERESTS 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. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with

regard to jurisdictional claims in published maps and institutional affiliations. SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION Supplementary Figs. 1–7, Table 1 and references.

REPORTING SUMMARY RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 23 October 2018 *

Accepted: 22 November 2019 * Published: 27 January 2020 * Issue Date: 01 April 2020 * DOI: https://doi.org/10.1038/s41551-019-0495-z SHARE THIS ARTICLE Anyone you share the following link

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