A novel low-volume two-chamber microfabricated platform for evaluating drug metabolism and toxicity

Bale, Shyam Sundhar; Sridharan, Gautham; Golberg, Inna; Prodanov, Ljupcho; McCarty, William J.; Usta, O. Berk; Jindal, Rohit; Yarmush, Martin L.

doi:10.1142/s2339547815200034

Cited by 13 publications

(25 citation statements)

References 19 publications

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“…However, under static conditions in conventional cell culture dishes, unfavorable high media-to-cell volume ratios exist. Recently, it was shown that decreasing media-to-cell volume ratios resulted in the formation of higher concentrations of drug metabolites [54]. Cell culture of 3 Â 10 5 HepaRG/LX-2 cells in MOTiF biochips requires only 120 ml of culture medium (0.4 nl/hepatocyte) making it a suitable tool for substance screening on a micro-scale basis with minimized wastage of test compounds.…”

Section: Discussionmentioning

confidence: 99%

A microfluidically perfused three dimensional human liver model

et al. 2015

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Section: Discussionmentioning

confidence: 99%

A microfluidically perfused three dimensional human liver model

et al. 2015

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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.

626

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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“…46,47 Multiwell plates are convenient and widely used cell culture platforms that provide an environment resulting in a typical culture media of *1 nL/hepatocyte in the case of monolayer culture of hepatocytes. Cell culture platforms can be broadly divided and evaluated based on the amount of media per hepatocyte (Fig.…”

Section: Progress In Hepatic Cells For Use In Liver Platformsmentioning

confidence: 99%

“…It is important to note that despite achieving relatively lower media volume/hepatocyte ratio in the static microfabricated system, it remains an order of magnitude higher than in vivo, based on simple scaling consideration (blood volume/hepatocyte). 46 Another important consideration for these systems is the relative throughput especially if they intend to be used at the drug screening stage. By far, multiwell plate static configuration offers the highest throughput followed by static microfabricated systems and lastly the modular macroscale bioreactor and microfluidic flow platforms.…”

Section: Progress In Hepatic Cells For Use In Liver Platformsmentioning

confidence: 99%

“…Bale et al 46 demonstrated the importance of media-tocell ratio by utilizing the microscale features of a static coculture system in evaluating drug metabolism and metabolite toxicity/efficacy on the target organ. Using a simple microfabricated two-chamber platform, separated with a tissue culture membrane seeded with hepatocytes and MCF-7 cells, they demonstrated the ability of primary hepatocytes to metabolize the prodrug tegafur, and the subsequent metabolite's (5-fluorouracil) effect on MCF-7 cells.…”

Section: Static Microfabricated Platformsmentioning

confidence: 99%

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EmergingIn VitroLiver Technologies for Drug Metabolism and Inter-Organ Interactions

Bale

Moore

Yarmush

et al. 2016

Tissue Engineering Part B: Reviews

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In vitro liver models provide essential information for evaluating drug metabolism, metabolite formation, and hepatotoxicity. Interfacing liver models with other organ models could provide insights into the desirable as well as unintended systemic side effects of therapeutic agents and their metabolites. Such information is invaluable for drug screening processes particularly in the context of secondary organ toxicity. While interfacing of liver models with other organ models has been achieved, platforms that effectively provide human-relevant precise information are needed. In this concise review, we discuss the current state-of-the-art of liver-based multiorgan cell culture platforms primarily from a drug and metabolite perspective, and highlight the importance of mediato-cell ratio in interfacing liver models with other organ models. In addition, we briefly discuss issues related to development of optimal liver models that include recent advances in hepatic cell lines, stem cells, and challenges associated with primary hepatocyte-based liver models. Liver-based multiorgan models that achieve physiologically relevant coupling of different organ models can have a broad impact in evaluating drug efficacy and toxicity, as well as mechanistic investigation of human-relevant disease conditions.

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A novel low-volume two-chamber microfabricated platform for evaluating drug metabolism and toxicity

Cited by 13 publications

References 19 publications

A microfluidically perfused three dimensional human liver model

A microfluidically perfused three dimensional human liver model

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

EmergingIn VitroLiver Technologies for Drug Metabolism and Inter-Organ Interactions

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