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On-chip recapitulation of clinical bone marrow toxicities and patient-specific pathophysiology

Nature Biomedical Engineering volume 4, pages 394–406 (2020)Cite this article

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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.

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Fig. 1: Design of the primary human BM chip.
Fig. 2: Sustained myeloerythroid proliferation and differentiation in the BM chip.
Fig. 3: The BM chip predicts clinically observed haematotoxicities at patient-relevant drug exposures.
Fig. 4: Confirmation of maturation-dependent cytotoxicity and modelling of BM recovery with the BM chip.
Fig. 5: The human BM chip recapitulates haematopoietic abnormalities observed in patients with SDS.

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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.

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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.

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  1. These authors contributed equally: David B. Chou, Viktoras Frismantas.

Authors and Affiliations

  1. 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

  2. Department of Pathology, Massachusetts General Hospital, Boston, MA, USA

    David B. Chou & Robert P. Hasserjian

  3. Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK

    Rhiannon David & Lorna Ewart

  4. DMPK, Oncology R&D, AstraZeneca, Boston, MA, USA

    Petar Pop-Damkov & Douglas Ferguson

  5. Clinical and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, Pharmaceutical Sciences, R&D, AstraZeneca, Cambridge, UK

    Alexander MacDonald

  6. Dana Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, MA, USA

    Özge Vargel Bölükbaşı & Akiko Shimamura

  7. Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA

    Cailin E. Joyce & Carl D. Novina

  8. Department of Medicine, Harvard Medical School, Boston, MA, USA

    Cailin E. Joyce & Carl D. Novina

  9. Department of Chemical Engineering, Loughborough University, Loughborough, UK

    Arianna Rech

  10. Vascular Biology Program and Department of Surgery, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA

    Amanda Jiang & Donald E. Ingber

  11. Department of Bioengineering and Institute for Bioengineering and Biosciences (iBB), Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal

    Sasan Jalili-Firoozinezhad

  12. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Kasiani C. Myers

  13. Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital, Cincinnati, OH, USA

    Kasiani C. Myers

  14. Department of Pathology, Boston Children’s Hospital, Boston, MA, USA

    Olga K. Weinberg

  15. Broad Institute of Harvard and MIT, Cambridge, MA, USA

    Carl D. Novina

  16. Harvard John A. Paulson School of Engineering and Applied Sciences, Cambridge, MA, USA

    Donald E. Ingber

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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.

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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.

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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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