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

David B. Chou, Viktoras Frismantas, Yuka Milton, Rhiannon David, Petar Pop-Damkov, Douglas Ferguson, Alexander MacDonald, Özge Vargel Bölükbaşı, Cailin E. Joyce, Liliana S. Moreira Teixeira, Arianna Rech, Amanda Jiang, Elizabeth Calamari, Sasan Jalili-Firoozinezhad, Brooke A. Furlong, Lucy R. O’Sullivan, Carlos F. Ng, Youngjae Choe, Susan Marquez, Kasiani C. MyersOlga K. Weinberg, Robert P. Hasserjian, Richard Novak, Oren Levy, Rachelle Prantil-Baun, Carl D. Novina, Akiko Shimamura, Lorna Ewart, Donald E. Ingber*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

64 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)394-406
Number of pages13
JournalNature Biomedical Engineering
Volume4
Issue number4
Early online date27 Jan 2020
DOIs
Publication statusPublished - 1 Apr 2020
Externally publishedYes

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