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      Human kidney proximal tubule-on-a-chip for drug transport and nephrotoxicity assessment

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          Abstract

          Kidney toxicity is one of the most frequent adverse events reported during drug development. The lack of accurate predictive cell culture models and the unreliability of animal studies have created a need for better approaches to recapitulate kidney function in vitro. Here, we describe a microfluidic device lined by living human kidney epithelial cells exposed to fluidic flow that mimics key functions of the human kidney proximal tubule. Primary kidney epithelial cells isolated from human proximal tubule are cultured on the upper surface of an extracellular matrix-coated, porous, polyester membrane that splits the main channel of the device into two adjacent channels, thereby creating an apical 'luminal' channel and a basal 'interstitial' space. Exposure of the epithelial monolayer to an apical fluid shear stress (0.2 dyne cm(-2)) that mimics that found in living kidney tubules results in enhanced epithelial cell polarization and primary cilia formation compared to traditional Transwell culture systems. The cells also exhibited significantly greater albumin transport, glucose reabsorption, and brush border alkaline phosphatase activity. Importantly, cisplatin toxicity and Pgp efflux transporter activity measured on-chip more closely mimic the in vivo responses than results obtained with cells maintained under conventional culture conditions. While past studies have analyzed kidney tubular cells cultured under flow conditions in vitro, this is the first report of a toxicity study using primary human kidney proximal tubular epithelial cells in a microfluidic 'organ-on-a-chip' microdevice. The in vivo-like pathophysiology observed in this system suggests that it might serve as a useful tool for evaluating human-relevant renal toxicity in preclinical safety studies.

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          Most cited references66

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          NIH Image to ImageJ: 25 years of image analysis

          For the past twenty five years the NIH family of imaging software, NIH Image and ImageJ have been pioneers as open tools for scientific image analysis. We discuss the origins, challenges and solutions of these two programs, and how their history can serve to advise and inform other software projects.
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            Reconstituting organ-level lung functions on a chip.

            Here, we describe a biomimetic microsystem that reconstitutes the critical functional alveolar-capillary interface of the human lung. This bioinspired microdevice reproduces complex integrated organ-level responses to bacteria and inflammatory cytokines introduced into the alveolar space. In nanotoxicology studies, this lung mimic revealed that cyclic mechanical strain accentuates toxic and inflammatory responses of the lung to silica nanoparticles. Mechanical strain also enhances epithelial and endothelial uptake of nanoparticulates and stimulates their transport into the underlying microvascular channel. Similar effects of physiological breathing on nanoparticle absorption are observed in whole mouse lung. Mechanically active "organ-on-a-chip" microdevices that reconstitute tissue-tissue interfaces critical to organ function may therefore expand the capabilities of cell culture models and provide low-cost alternatives to animal and clinical studies for drug screening and toxicology applications.
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              Is Open Access

              Mechanisms of Cisplatin Nephrotoxicity

              Cisplatin is a widely used and highly effective cancer chemotherapeutic agent. One of the limiting side effects of cisplatin use is nephrotoxicity. Research over the past 10 years has uncovered many of the cellular mechanisms which underlie cisplatin-induced renal cell death. It has also become apparent that inflammation provoked by injury to renal epithelial cells serves to amplify kidney injury and dysfunction in vivo. This review summarizes recent advances in our understanding of cisplatin nephrotoxicity and discusses how these advances might lead to more effective prevention.
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                Author and article information

                Journal
                Integrative Biology
                Royal Society of Chemistry (RSC)
                1757-9708
                September 2013
                September 19 2013
                May 03 2013
                September 2013
                September 19 2013
                May 03 2013
                : 5
                : 9
                : 1119-1129
                Affiliations
                [1 ]Wyss Institute for Biologically Inspired Engineering at Harvard University, CLSB Bldg. 5th floor, 3 Blackfan Circle, Boston, MA 02115 USA. Fax: +1 617-432-7048; Tel: +1 617-432-7044
                [2 ]Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA
                [3 ]Massachusetts College of Pharmacy and Health Sciences, Boston, MA 02115, USA
                [4 ]School of Mechanical and Aerospace Engineering, Seoul National University, Seoul 151-742 South Korea
                [5 ]Vascular Biology Program, Departments of Pathology and Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA
                [6 ]School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA
                Article
                10.1039/c3ib40049b
                23644926
                6f47ec54-e78a-45e3-aeec-20cbb2df5593
                © 2013
                History

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