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Levy, Oren

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Levy

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Oren

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Levy, Oren
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    Quantitative prediction of human pharmacokinetic responses to drugs via fluidically coupled vascularized organ chips
    (Springer Science and Business Media LLC, 2020-01-27) Herland, Anna; Maoz, Ben M.; Das, Debarun; Somayaji, Mahadevabharath R.; Prantil-Baun, Rachelle; Novak, Richard; Cronce, Michael; Huffstater, Tessa; Jeanty, Sauveur S.F.; Ingram, Miles; Chalkiadaki, Angeliki; Chou, David; Clauson, Susan; Delahanty, Aaron; Jalili-Firoozinezhad, Sasan; Milton, Yuka; Sontheimer-Phelps, Alexandra; Swenor, Ben; Levy, Oren; Parker, Kevin K.; Przekwas, Andrzej; Ingber, Donald
    Analyses of drug pharmacokinetics (PKs) and pharmacodynamics (PDs) performed in animals are often not predictive of drug PKs and PDs in humans, and in vitro PK and PD modelling does not provide quantitative PK parameters. Here, we show that physiological PK modelling of first-pass drug absorption, metabolism and excretion in humans-using computationally scaled data from multiple fluidically linked two-channel organ chips-predicts PK parameters for orally administered nicotine (using gut, liver and kidney chips) and for intravenously injected cisplatin (using coupled bone marrow, liver and kidney chips). The chips are linked through sequential robotic liquid transfers of a common blood substitute by their endothelium-lined channels (as reported by Novak et al. in an associated Article) and share an arteriovenous fluid-mixing reservoir. We also show that predictions of cisplatin PDs match previously reported patient data. The quantitative in-vitro-to-in-vivo translation of PK and PD parameters and the prediction of drug absorption, distribution, metabolism, excretion and toxicity through fluidically coupled organ chips may improve the design of drug-administration regimens for phase-I clinical trials.
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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.
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    Publication
    Robotic fluidic coupling and interrogation of multiple vascularized organ chips
    (Springer Science and Business Media LLC, 2020-01-27) Novak, Richard; Ingram, Miles; Marquez, Susan; Das, Debarun; Delahanty, Aaron; Herland, Anna; Maoz, Ben; Jeanty, Sauveur; Somayaji, Mahadevabharath R.; Burt, Morgan; Calamari, Elizabeth; Chalkiadaki, Angeliki; Cho, Alexander; Choe, Youngjae; Chou, David; Cronce, Michael; Dauth, Stephanie; Divic, Toni; Fernandez-Alcon, Jose; Ferrante, Thomas; Ferrier, John; FitzGerald, Edward; Fleming, Rachel; Jalili Firoozinezhad, Sasan; Grevesse, Thomas; Goss, Josue; Hamkins-Indik, Tiama; Henry, Olivier; Hinojosa, Chris; Huffstater, Tessa; Jang, Kyung-Jin; Kujala, Ville; Leng, Lian; Mannix, Robert; Milton, Yuka; Nawroth, Janna; Nestor, Bret; Ng Pitti, Carlos; O'Connor, Blakely; Park, Tae-Eun; Sanchez, Henry; Sliz, Josiah; Sontheimer-Phelps, Alexandra; Swenor, Ben; Thompson, Guy; Touloumes, George J.; Tranchemontagne, Zachary; Wen, Norman; Yedid, Moran; Bahinski, Anthony; Hamilton, Geraldine; Levner, Daniel; Levy, Oren; Przekwas, Andrzej; Prantil-Baun, Rachelle; Parker, Kevin; Ingber, Donald
    Organ chips can recapitulate organ-level (patho)physiology, yet pharmacokinetic and pharmacodynamic analyses require multi-organ systems linked by vascular perfusion. Here, we describe an ‘Interrogator’ employing liquid-handling robotics, custom software and an integrated mobile microscope for the automated culture, perfusion, medium addition, fluidic linking, sample collection and in situ microscopic imaging of up to 10 Organ Chips inside a standard tissue-culture incubator. The robotic interrogator maintained the viability and organ-specific functions of eight vascularized, two-channel organ chips (intestine, liver, kidney, heart, lung, skin, blood–brain barrier and brain) for 3 weeks in culture when intermittently fluidically coupled via a common blood substitute through their medium reservoirs and endothelium-lined vascular channels. We used the robotic interrogator and a physiological multi-compartmental reduced-order model of the experimental system to quantitatively predict the distribution of an inulin tracer perfused through the multi-organ Human-Body-on-Chips. The automated culture system allows for the imaging of cells in the organ chips, and for repeated sampling of both the vascular and interstitial compartments without compromising fluidic coupling.