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Frismantas, Viktoras

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Frismantas

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Viktoras

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Frismantas, Viktoras
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    On-chip recapitulation of clinical bone marrow toxicities and patient-specific pathophysiology
    (Springer Science and Business Media LLC, 2020-01-27) Chou, David; Frismantas, Viktoras; Milton, Yuka; David, Rhiannon; Pop-Damkov, Petar; Ferguson, Douglas; MacDonald, Alexander; Vargel Bolukbasi, Ozge; Joyce, Cailin E.; Moreira Teixeira, Liliana S.; Rech, Arianna; Jiang, Amanda; Calamari, Elizabeth; Jalili-Firoozinezhad, Sasan; Furlong, Brooke; O’Sullivan, Lucy R.; Ng, Carlos F.; Choe, Youngjae; Marquez, Susan; Myers, Kasiani C.; Weinberg, Olga K.; Hasserjian, Robert; Novak, Richard; Levy, Oren; Prantil-Baun, Rachelle; Novina, Carl; Shimamura, Akiko; Ewart, Lorna; Ingber, Donald
    The inaccessibility of living bone marrow hampers the study of its pathophysiology under myelotoxic stress induced by drugs, radiation or genetic mutations. Here, we show that a vascularized human bone-marrow-on-a-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 marrow injury, including myeloerythroid toxicity after clinically relevant exposures to chemotherapeutic drugs and ionizing radiation as well as marrow recovery after drug-induced myelosuppression. The chip comprises a fluidic channel filled with a fibrin gel in which CD34+ cells and bone-marrow-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 bone-marrow 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 bone-marrow-on-a-chip may serve as a human-specific alternative to animal testing for the study of bone-marrow pathophysiology.