TY - JOUR
KW - Biological models
KW - Biomimetics
KW - Drug development
KW - Experimental models of disease
KW - Haematological diseases
AU - David B. Chou
AU - Viktoras Frismantas
AU - Yuka Milton
AU - Rhiannon David
AU - Petar Pop-Damkov
AU - Douglas Ferguson
AU - Alexander MacDonald
AU - Özge Vargel Bölükbaşı
AU - Cailin E. Joyce
AU - Liliana S. Moreira Teixeira
AU - Arianna Rech
AU - Amanda Jiang
AU - Elizabeth Calamari
AU - Sasan Jalili-Firoozinezhad
AU - Brooke A. Furlong
AU - Lucy R. O’Sullivan
AU - Carlos F. Ng
AU - Youngjae Choe
AU - Susan Marquez
AU - Kasiani C. Myers
AU - Olga K. Weinberg
AU - Robert P. Hasserjian
AU - Richard Novak
AU - Oren Levy
AU - Rachelle Prantil-Baun
AU - Carl D. Novina
AU - Akiko Shimamura
AU - Lorna Ewart
AU - Donald E. Ingber
AB - 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.
BT - Nature Biomedical Engineering
DA - 2020-04
DO - 10.1038/s41551-019-0495-z
IS - 4
LA - en
N2 - 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.
PY - 2020
SP - 394
EP - 406
T2 - Nature Biomedical Engineering
TI - On-chip recapitulation of clinical bone marrow toxicities and patient-specific pathophysiology
UR - https://www.nature.com/articles/s41551-019-0495-z
VL - 4
Y2 - 2022-06-02
SN - 2157-846X
ER -