Multi-Organ toxicity demonstration in a functional human in vitro system composed of four organs

Oleaga, Carlota; Bernabini, Catia; Smith, André; Srinivasan, Balaji; Jackson, Max; McLamb, William; Platt, Vivien; Bridges, Richard J.; Cai, Yuanqing; Santhanam, Navaneetha; Berry, Bonnie J.; Najjar, Sarah A.; Akanda, Nesar; Guo, Xiufang; Martin, Candace; Ekman, Gail; Esch, Mandy B.; Langer, Jessica; Ouédraogo, Gladys; Cotovio, José; Breton, Lionel; Shuler, Michael L.; Hickman, James J.

doi:10.1038/srep20030

Cited by 374 publications

(379 citation statements)

References 64 publications

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“…Unfortunately, the two main liver markers (albumin and total proteins) did not exhibit significant variations in either control or treated groups. Similar findings were revealed by Oleaga et al [23] where, doxorubicin which is considered hepatotoxic, did not show any effect on albumin. No significant influence in the liver antioxidants has been recorded, except slight changes (p > 0.05) in the group treated with APAP and SeNPs in MDA and in SeNPs group for TAC.…”

Section: Resultssupporting

confidence: 78%

Selenium Nanoparticles Ameliorative Effect on Acetaminophen Hepatotoxicity in Male Mice

AL-Harbi¹,

Amer²

2017

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Selenium nanoparticles (SeNPs) have been widely used as anti-inflammatory and anti-toxic agent. The present study used Bacillus tequilensis for biosynthesizing SeNPs from sodium selenite (Na 2 SeO 3 ) and investigated its ameliorative effects on acetaminophen (APAP) hepatotoxicity in male mice. The results indicated that Alanine transaminase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) significantly elevated in mice treated with APAP, while other liver markers (total proteins and albumin) did not change. SeNPs either alone or in combination with APAP showed ameliorative effects on liver enzymes to some extents where their activities decreased to be insignificant with those of normal group. A slight variation was shown in total antioxidant capacity (TAC). Histopathologically, the hepatocytes of the mice treated with APAP showed cloudy swelling and vacuolar degeneration, while those treated with SeNPs or both SeNPs and APAP appeared more or less histologically normal. In conclusion, SeNPs can be used to improve or replace today's therapies of APAP hepatotoxicity.

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Section: Resultssupporting

confidence: 78%

Selenium Nanoparticles Ameliorative Effect on Acetaminophen Hepatotoxicity in Male Mice

AL-Harbi¹,

Amer²

2017

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“…To this end, the recently emerged organ-on-a-chip systems that combine advanced microfluidic technologies and tissue engineering approaches to simulate both the biology and physiology of human organs have been developed (8,(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). These miniaturized human organ models have several advantages over conventional models, such as more accurate prediction of human responses and, in particular, multiorgan interactions when different organ modules are assembled in a single fluid circuit (7,31).…”

Section: Significancementioning

confidence: 99%

Multisensor-integrated organs-on-chips platform for automated and continual in situ monitoring of organoid behaviors

Zhang

Aleman

Shin

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

638

571

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Organ-on-a-chip systems are miniaturized microfluidic 3D human tissue and organ models designed to recapitulate the important biological and physiological parameters of their in vivo counterparts. They have recently emerged as a viable platform for personalized medicine and drug screening. These in vitro models, featuring biomimetic compositions, architectures, and functions, are expected to replace the conventional planar, static cell cultures and bridge the gap between the currently used preclinical animal models and the human body. Multiple organoid models may be further connected together through the microfluidics in a similar manner in which they are arranged in vivo, providing the capability to analyze multiorgan interactions. Although a wide variety of human organ-on-a-chip models have been created, there are limited efforts on the integration of multisensor systems. However, in situ continual measuring is critical in precise assessment of the microenvironment parameters and the dynamic responses of the organs to pharmaceutical compounds over extended periods of time. In addition, automated and noninvasive capability is strongly desired for long-term monitoring. Here, we report a fully integrated modular physical, biochemical, and optical sensing platform through a fluidics-routing breadboard, which operates organ-on-a-chip units in a continual, dynamic, and automated manner. We believe that this platform technology has paved a potential avenue to promote the performance of current organ-on-a-chip models in drug screening by integrating a multitude of real-time sensors to achieve automated in situ monitoring of biophysical and biochemical parameters.organ-on-a-chip | microbioreactor | electrochemical biosensor | physical sensor | drug screening D rug discovery is a lengthy process associated with tremendous cost and high failure rate (1). On average, less than 1 in 10 drug candidates are eventually approved by the Food and Drug Administration (2), during which successful transition ratios to next phases are roughly 65, 32, and 60% for phase I, phase II, and phase III, respectively (3). Among the primary causes of failure, nonclinical/ clinical safety (>50%) and efficacy (>10%) stand out in the front, more than all other factors (e.g., strategic, commercial, operational) combined (3, 4). These two major causes not only contribute to the low success rates during the drug development but also lead to the withdrawal of approved drugs from the market. Among all of the drug attritions, it is estimated that safety liabilities related to the cardiovascular system account for 45%, whereas 32% are due to hepatotoxicity (5, 6). These high failure/attrition ratios of drugs SignificanceMonitoring human organ-on-a-chip systems presents a significant challenge, where the capability of in situ continual monitoring of organ behaviors and their responses to pharmaceutical compounds over extended periods of time is critical in understanding the dynamics of drug effects and therefore accurate prediction of human organ reacti...

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“…For example, spheroid-type constructs capture heterotypic cell-cell contacts and can (in some cases) benefit from cell-driven self-assembly, whereas nanoporous membrane-based constructs are generally needed to recapitulate tissue interfaces. Integration of multiple organs in one system is a challenge addressed by a specific line of research (Abaci and Shuler, 2015;Oleaga et al, 2016). It is possible, however, to capitalize on the diversity of approaches and maintain the modularity of the engineered constructs, as long as a common computational platform is developed so that the data from these different constructs, as well as data available from clinical studies, can be integrated across scales.…”

Section: Experimental Approachesmentioning

confidence: 99%

Systems biology for organotypic cell cultures

Grego

Dougherty

Alexander

et al. 2017

ALTEX

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Multi-Organ toxicity demonstration in a functional human in vitro system composed of four organs

Cited by 374 publications

References 64 publications

Selenium Nanoparticles Ameliorative Effect on Acetaminophen Hepatotoxicity in Male Mice

Selenium Nanoparticles Ameliorative Effect on Acetaminophen Hepatotoxicity in Male Mice

Multisensor-integrated organs-on-chips platform for automated and continual in situ monitoring of organoid behaviors

Systems biology for organotypic cell cultures

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