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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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References

  1. Doulatov, S., Notta, F., Laurenti, E. & Dick, J. E. Hematopoiesis: a human perspective. Cell Stem Cell 10, 120–136 (2012).

    Article  CAS  PubMed  Google Scholar 

  2. Eaves, C. J. Hematopoietic stem cells: concepts, definitions, and the new reality. Blood 125, 2605–2613 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Wognum, B., Yuan, N., Lai, B. & Miller, C. L. Colony forming cell assays for human hematopoietic progenitor cells. Methods Mol. Biol. 946, 267–283 (2013).

    Article  CAS  PubMed  Google Scholar 

  4. Dexter, T. M., Allen, T. D. & Lajtha, L. G. Conditions controlling the proliferation of haemopoietic stem cells in vitro. J. Cell Physiol. 91, 335–344 (1977).

    Article  CAS  PubMed  Google Scholar 

  5. Sieber, S. et al. Bone marrow-on-a-chip: long-term culture of human haematopoietic stem cells in a three-dimensional microfluidic environment. J. Tissue Eng. Regen. Med. 12, 479–489 (2018).

    Article  CAS  PubMed  Google Scholar 

  6. Thon, J. N. et al. Platelet bioreactor-on-a-chip. Blood 124, 1857–1867 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Di Maggio, N. et al. Toward modeling the bone marrow niche using scaffold-based 3D culture systems. Biomaterials 32, 321–329 (2011).

    Article  CAS  PubMed  Google Scholar 

  8. Rodling, L. et al. 3D models of the hematopoietic stem cell niche under steady-state and active conditions. Sci. Rep. 7, 4625 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Bourgine, P. E. et al. In vitro biomimetic engineering of a human hematopoietic niche with functional properties. Proc. Natl Acad. Sci. USA 115, E5688–E5695 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Morrison, S. J. & Scadden, D. T. The bone marrow niche for haematopoietic stem cells. Nature 505, 327–334 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Boitano, A. E. et al. Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells. Science 329, 1345–1348 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Fares, I. et al. Cord blood expansion. Pyrimidoindole derivatives are agonists of human hematopoietic stem cell self-renewal. Science 345, 1509–1512 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ferreira, M. S. et al. Cord blood-hematopoietic stem cell expansion in 3D fibrin scaffolds with stromal support. Biomaterials 33, 6987–6997 (2012).

    Article  PubMed  CAS  Google Scholar 

  14. Lee, H. Y. et al. PPAR-α and glucocorticoid receptor synergize to promote erythroid progenitor self-renewal. Nature 522, 474–477 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Pineault, N. & Abu-Khader, A. Advances in umbilical cord blood stem cell expansion and clinical translation. Exp. Hematol. 43, 498–513 (2015).

    Article  PubMed  Google Scholar 

  16. Pessina, A. et al. Application of the CFU-GM assay to predict acute drug-induced neutropenia: an international blind trial to validate a prediction model for the maximum tolerated dose (MTD) of myelosuppressive xenobiotics. Toxicol. Sci. 75, 355–367 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Boulais, P. E. & Frenette, P. S. Making sense of hematopoietic stem cell niches. Blood 125, 2621–2629 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Méndez-Ferrer, S. et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466, 829–834 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Sacchetti, B. et al. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 131, 324–336 (2007).

    Article  CAS  PubMed  Google Scholar 

  20. Rafii, S., Butler, J. M. & Ding, B. S. Angiocrine functions of organ-specific endothelial cells. Nature 529, 316–325 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hassell, B. A. et al. Human organ chip models recapitulate orthotopic lung cancer growth, therapeutic responses, and tumor dormancy in vitro. Cell Rep. 21, 508–516 (2017).

    Article  CAS  PubMed  Google Scholar 

  22. Huh, D. et al. Reconstituting organ-level lung functions on a chip. Science 328, 1662–1668 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Dorrell, C., Gan, O. I., Pereira, D. S., Hawley, R. G. & Dick, J. E. Expansion of human cord blood CD34+CD38− cells in ex vivo culture during retroviral transduction without a corresponding increase in SCID repopulating cell (SRC) frequency: dissociation of SRC phenotype and function. Blood 95, 102–110 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Von Laer, D. et al. Loss of CD38 antigen on CD34+CD38+ cells during short-term culture. Leukemia 14, 947–948 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Danet, G. H., Lee, H. W., Luongo, J. L., Simon, M. C. & Bonnet, D. A. Dissociation between stem cell phenotype and NOD/SCID repopulating activity in human peripheral blood CD34+ cells after ex vivo expansion. Exp. Hematol. 29, 1465–1473 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. Csaszar, E. et al. Rapid expansion of human hematopoietic stem cells by automated control of inhibitory feedback signaling. Cell Stem Cell 10, 218–229 (2012).

    Article  CAS  PubMed  Google Scholar 

  27. Jalili-Firoozinezhad, S. et al. A complex human gut microbiome cultured in an anaerobic intestine-on-a-chip. Nat. Biomed. Eng. 3, 520–531 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Longley, D. B., Harkin, D. P. & Johnston, P. G. 5-fluorouracil: mechanisms of action and clinical strategies. Nat. Rev. Cancer 3, 330–338 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Lee, J. J., Beumer, J. H. & Chu, E. Therapeutic drug monitoring of 5-fluorouracil. Cancer Chemother. Pharm. 78, 447–464 (2016).

    Article  CAS  Google Scholar 

  30. Saif, M. W., Choma, A., Salamone, S. J. & Chu, E. Pharmacokinetically guided dose adjustment of 5-fluorouracil: a rational approach to improving therapeutic outcomes. J. Natl Cancer Inst. 101, 1543–1552 (2009).

    Article  CAS  PubMed  Google Scholar 

  31. Santini, J. et al. 5-FU therapeutic monitoring with dose adjustment leads to an improved therapeutic index in head and neck cancer. Br. J. Cancer 59, 287–290 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Trump, D. L. et al. Pharmacokinetic and pharmacodynamic analysis of fluorouracil during 72-hour continuous infusion with and without dipyridamole. J. Clin. Oncol. 9, 2027–2035 (1991).

    Article  CAS  PubMed  Google Scholar 

  33. Malerba, I., Casati, S., Diodovich, C., Parent-Massin, D. & Gribaldo, L. Inhibition of CFU-E/BFU-E and CFU-GM colony growth by cyclophosphamide, 5-fluorouracil and taxol: development of a high-throughput in vitro method. Toxicol. Vitr. 18, 293–300 (2004).

    Article  CAS  Google Scholar 

  34. Carmena, M., Wheelock, M., Funabiki, H. & Earnshaw, W. C. The chromosomal passenger complex (CPC): from easy rider to the godfather of mitosis. Nat. Rev. Mol. Cell Biol. 13, 789–803 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Boss, D. S. et al. Clinical evaluation of AZD1152, an i.v. inhibitor of Aurora B kinase, in patients with solid malignant tumors. Ann. Oncol. 22, 431–437 (2011).

    Article  CAS  PubMed  Google Scholar 

  36. Kantarjian, H. M. et al. Stage I of a phase 2 study assessing the efficacy, safety, and tolerability of barasertib (AZD1152) versus low-dose cytosine arabinoside in elderly patients with acute myeloid leukemia. Cancer 119, 2611–2619 (2013).

    Article  CAS  PubMed  Google Scholar 

  37. Schwartz, G. K. et al. Phase I study of barasertib (AZD1152), a selective inhibitor of Aurora B kinase, in patients with advanced solid tumors. Invest. New Drugs 31, 370–380 (2013).

    Article  CAS  PubMed  Google Scholar 

  38. Yang, J. et al. AZD1152, a novel and selective Aurora B kinase inhibitor, induces growth arrest, apoptosis, and sensitization for tubulin depolymerizing agent or topoisomerase II inhibitor in human acute leukemia cells in vitro and in vivo. Blood 110, 2034–2040 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Waselenko, J. K. et al. Medical management of the acute radiation syndrome: recommendations of the strategic national stockpile radiation working group. Ann. Intern. Med. 140, 1037–1051 (2004).

    Article  PubMed  Google Scholar 

  40. Singh, V. K. & Seed, T. M. A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: part I. Radiation sub-syndromes, animal models and FDA-approved countermeasures. Int. J. Radiat. Biol. 93, 851–869 (2017).

    Article  CAS  PubMed  Google Scholar 

  41. Dror, Y. et al. Draft consensus guidelines for diagnosis and treatment of Shwachman–Diamond syndrome. Ann. NY Acad. Sci. 1242, 40–55 (2011).

    Article  PubMed  Google Scholar 

  42. Myers, K. C., Davies, S. M. & Shimamura, A. Clinical and molecular pathophysiology of Shwachman–Diamond syndrome: an update. Hematol. Oncol. Clin. North Am. 27, 117–128 (2013).

    Article  PubMed  Google Scholar 

  43. Bezzerri, V. & Cipolli, M. Shwachman–Diamond syndrome: molecular mechanisms and current perspectives. Mol. Diagnosis Ther. 23, 281–290 (2019).

    Article  CAS  Google Scholar 

  44. Myers, K. C. et al. Variable clinical presentation of Shwachman–Diamond syndrome: update from the North American Shwachman–Diamond syndrome registry. J. Pediatr. 164, 866–870 (2014).

    Article  PubMed  Google Scholar 

  45. Finch, A. J. et al. Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes Shwachman–Diamond syndrome. Genes Dev. 25, 917–929 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Raaijmakers, M. H. et al. Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature 464, 852–857 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Rawls, A. S., Gregory, A. D., Woloszynek, J. R., Liu, F. & Link, D. C. Lentiviral-mediated RNAi inhibition of Sbds in murine hematopoietic progenitors impairs their hematopoietic potential. Blood 110, 2414–2422 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zambetti, N. A. et al. Deficiency of the ribosome biogenesis gene Sbds in hematopoietic stem and progenitor cells causes neutropenia in mice by attenuating lineage progression in myelocytes. Haematologica 100, 1285–1293 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Zhang, S., Shi, M., Hui, C. C. & Rommens, J. M. Loss of the mouse ortholog of the Shwachman–Diamond syndrome gene (Sbds) results in early embryonic lethality. Mol. Cell Biol. 26, 6656–6663 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Dror, Y. & Freedman, M. H. Shwachman–Diamond syndrome: an inherited preleukemic bone marrow failure disorder with aberrant hematopoietic progenitors and faulty marrow microenvironment. Blood 94, 3048–3054 (1999).

    Article  CAS  PubMed  Google Scholar 

  51. Kuijpers, T. W. et al. Hematologic abnormalities in Shwachman Diamond syndrome: lack of genotype–phenotype relationship. Blood 106, 356–361 (2005).

    Article  CAS  PubMed  Google Scholar 

  52. Walasek, M. A., van Os, R. & de Haan, G. Hematopoietic stem cell expansion: challenges and opportunities. Ann. NY Acad. Sci. 1266, 138–150 (2012).

    Article  CAS  PubMed  Google Scholar 

  53. Lis, R. et al. Conversion of adult endothelium to immunocompetent haematopoietic stem cells. Nature 545, 439–445 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Sugimura, R. et al. Haematopoietic stem and progenitor cells from human pluripotent stem cells. Nature 545, 432–438 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kohn, L. A. et al. Lymphoid priming in human bone marrow begins before expression of CD10 with upregulation of l-selectin. Nat. Immunol. 13, 963–971 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Rawlings, D. J., Quan, S. G., Kato, R. M. & Witte, O. N. Long-term culture system for selective growth of human B-cell progenitors. Proc. Natl Acad. Sci. USA 92, 1570–1574 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Harrison, J. S., Rameshwar, P., Chang, V. & Bandari, P. Oxygen saturation in the bone marrow of healthy volunteers. Blood 99, 394 (2002).

    Article  CAS  PubMed  Google Scholar 

  58. Nombela-Arrieta, C. et al. Quantitative imaging of haematopoietic stem and progenitor cell localization and hypoxic status in the bone marrow microenvironment. Nat. Cell Biol. 15, 533–543 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Spencer, J. A. et al. Direct measurement of local oxygen concentration in the bone marrow of live animals. Nature 508, 269–273 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Broxmeyer, H. E., O’Leary, H. A., Huang, X. & Mantel, C. The importance of hypoxia and extra physiologic oxygen shock/stress for collection and processing of stem and progenitor cells to understand true physiology/pathology of these cells ex vivo. Curr. Opin. Hematol. 22, 273–278 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Andre, V. et al. Mesenchymal stem cells from Shwachman–Diamond syndrome patients display normal functions and do not contribute to hematological defects. Blood Cancer J. 2, e94 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Dror, Y. et al. Immune function in patients with Shwachman–Diamond syndrome. Br. J. Haematol. 114, 712–717 (2001).

    Article  CAS  PubMed  Google Scholar 

  63. Orelio, C. & Kuijpers, T. W. Shwachman–Diamond syndrome neutrophils have altered chemoattractant-induced F-actin polymerization and polarization characteristics. Haematologica 94, 409–413 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Novak, R. et al. Scalable fabrication of stretchable, dual channel, microfluidic organ chips. J. Vis. Exp. 140, e58151 (2018).

    Google Scholar 

  65. Keizer, R. J., Zandvliet, A. S., Beijnen, J. H., Schellens, J. H. & Huitema, A. D. Two-stage model-based design of cancer phase I dose escalation trials: evaluation using the phase I program of barasertib (AZD1152). Invest. New Drugs 30, 1519–1530 (2012).

    Article  CAS  PubMed  Google Scholar 

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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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Author notes

  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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