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Sontheimer-Phelps, Alexandra

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Sontheimer-Phelps

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Alexandra

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Sontheimer-Phelps, Alexandra
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    Development of a primary human Small Intestine-on-a-Chip using biopsy-derived organoids
    (Nature Publishing Group UK, 2018) Kasendra, Magdalena; Tovaglieri, Alessio; Sontheimer-Phelps, Alexandra; Jalili-Firoozinezhad, Sasan; Bein, Amir; Chalkiadaki, Angeliki; Scholl, William; Zhang, Cheng; Rickner, Hannah; Richmond, Camilla; Li, Hu; Breault, David; Ingber, Donald
    Here we describe a method for fabricating a primary human Small Intestine-on-a-Chip (Intestine Chip) containing epithelial cells isolated from healthy regions of intestinal biopsies. The primary epithelial cells are expanded as 3D organoids, dissociated, and cultured on a porous membrane within a microfluidic device with human intestinal microvascular endothelium cultured in a parallel microchannel under flow and cyclic deformation. In the Intestine Chip, the epithelium forms villi-like projections lined by polarized epithelial cells that undergo multi-lineage differentiation similar to that of intestinal organoids, however, these cells expose their apical surfaces to an open lumen and interface with endothelium. Transcriptomic analysis also indicates that the Intestine Chip more closely mimics whole human duodenum in vivo when compared to the duodenal organoids used to create the chips. Because fluids flowing through the lumen of the Intestine Chip can be collected continuously, sequential analysis of fluid samples can be used to quantify nutrient digestion, mucus secretion and establishment of intestinal barrier function over a period of multiple days in vitro. The Intestine Chip therefore may be useful as a research tool for applications where normal intestinal function is crucial, including studies of metabolism, nutrition, infection, and drug pharmacokinetics, as well as personalized medicine.
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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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    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.
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    Publication
    Microfluidic Organ-on-a-Chip Models of Human Intestine
    (Elsevier, 2018) Bein, Amir; Shin, Woojung; Jalili-Firoozinezhad, Sasan; Park, Min Hee; Sontheimer-Phelps, Alexandra; Tovaglieri, Alessio; Chalkiadaki, Angeliki; Kim, Hyun Jung; Ingber, Donald
    Microfluidic organ-on-a-chip models of human intestine have been developed and used to study intestinal physiology and pathophysiology. In this article, we review this field and describe how microfluidic Intestine Chips offer new capabilities not possible with conventional culture systems or organoid cultures, including the ability to analyze contributions of individual cellular, chemical, and physical control parameters one-at-a-time; to coculture human intestinal cells with commensal microbiome for extended times; and to create human-relevant disease models. We also discuss potential future applications of human Intestine Chips, including how they might be used for drug development and personalized medicine.