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Bone marrow–on–a–chip replicates hematopoietic niche physiology in vitro

Abstract

Current in vitro hematopoiesis models fail to demonstrate the cellular diversity and complex functions of living bone marrow; hence, most translational studies relevant to the hematologic system are conducted in live animals. Here we describe a method for fabricating 'bone marrow–on–a–chip' that permits culture of living marrow with a functional hematopoietic niche in vitro by first engineering new bone in vivo, removing it whole and perfusing it with culture medium in a microfluidic device. The engineered bone marrow (eBM) retains hematopoietic stem and progenitor cells in normal in vivo–like proportions for at least 1 week in culture. eBM models organ-level marrow toxicity responses and protective effects of radiation countermeasure drugs, whereas conventional bone marrow culture methods do not. This biomimetic microdevice offers a new approach for analysis of drug responses and toxicities in bone marrow as well as for study of hematopoiesis and hematologic diseases in vitro.

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Figure 1: In vivo bone marrow engineering.
Figure 2: Localization of cytokines and hematopoietic cell composition of the eBM.
Figure 3: In vitro microfluidic culture of eBM within the bone marrow–on–a–chip.
Figure 4: Radiation toxicity of the bone marrow–on–a–chip.

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Acknowledgements

We thank G.Q. Daley for guidance and helpful discussions and P.L. Wenzel, N. Arora, E. Jiang, A. Jiang, B. Mosadegh, D. Huh, A. Bahinski and G.A. Hamilton for their technical assistance and advice. This work was supported by the Wyss Institute for Biologically Inspired Engineering at Harvard University, the Defense Advanced Research Projects Agency under Cooperative Agreement Number W911NF-12-2-0036, and the US Food and Drug Administration (FDA) HHSF223201310079C.

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Y.-s.T., C.S.S. and D.E.I. conceived of the experiments; Y.-s.T. and C.S.S. performed the experiments, designed research and analyzed data with assistance from T.M., A.M., J.C.W., T.T., J.J.C. and D.E.I. Y.-s.T., C.S.S. and D.E.I. wrote the manuscript.

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Correspondence to Donald E Ingber.

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The authors declare no competing financial interests.

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Torisawa, Ys., Spina, C., Mammoto, T. et al. Bone marrow–on–a–chip replicates hematopoietic niche physiology in vitro. Nat Methods 11, 663–669 (2014). https://doi.org/10.1038/nmeth.2938

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