Characterization of drug metabolites and cytotoxicity assay simultaneously using an integrated microfluidic device

Ma, Bo; Zhang, Guohao; Qin, Jianhua; Lin, Bingcheng

doi:10.1039/b809117j

Cited by 97 publications

(82 citation statements)

References 28 publications

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“…Prot et al 31 determined first deteriorations of cell proliferation at 1 mM APAP within their respective microfluidic biochip cultivation system. In another microfluidic biochip used by Ma et al, 19 the viability was reduced to 30% with an APAP concentration of 10 mM which is similar to the results of our study. Xia et al 32 observed that the cells grown in a laminar flow perfusion bioreactor were more sensitive for APAPinduced hepatotoxicity than the cells grown in a static 2D culture, and 60% of cell death was shown after 24 h of treatment with 25 mM of APAP.…”

Section: Discussionsupporting

confidence: 82%

“…4 Furthermore, different microfluidic systems have been developed in the past in which constant growth conditions were achieved by a perfusion flow of cell culture medium providing permanent sustenance with nutrients and oxygen as well as removal of waste metabolites. 18,19 However, to our knowledge, there is still no system described where hepatocytes are cultivated with indirect flow without any physical barrier which would reflect the in vivo situation even better. In order to establish a useful cultivation system for the analysis of hepatocellular functions, we tested the growth, differentiation, and metabolical behavior of HepG2 cells embedded in Matrigel in the OrganoPlate from MIMETAS and Leiden University that combines these unique characteristics.…”

Section: Discussionmentioning

confidence: 99%

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On-chip three-dimensional cell culture in phaseguides improves hepatocyte functions in vitro

et al. 2015

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The in vitro study of liver functions and liver cell specific responses to external stimuli deals with the problem to preserve the in vivo functions of primary hepatocytes. In this study, we used the biochip OrganoPlate TM (MIMETAS) that combines different advantages for the cultivation of hepatocytes in vitro: (1) the perfusion flow is achieved without a pump allowing easy handling and placement in the incubator; (2) the phaseguides allow plating of matrix-embedded cells in lanes adjacent to the perfusion flow without physical barrier; and (3) the matrix-embedding ensures indirect contact of the cells to the flow. In order to evaluate the applicability of this biochip for the study of hepatocyte's functions, Matrigel TM -embedded HepG2 cells were cultured over three weeks in this biochip and compared to a static Matrigel culture (3D) and a monolayer culture (2D). Chip-cultured cells grew in spheroid-like structures and were characterized by the formation of bile canaliculi and a high viability over 14 days. Hepatocyte-specific physiology was achieved as determined by an increase in albumin production. Improved detoxification metabolism was demonstrated by strongly increased cytochrome P450 activity and urea production. Additionally, chip-cultured cells displayed increased sensitivity to acetaminophen. Altogether, the OrganoPlate seems to be a very useful alternative for the cultivation of hepatocytes, as their behavior was strongly improved over 2D and static 3D cultures and the results were largely comparable and partly superior to the previous reports on biochip-cultured hepatocytes. As for the low technical needs, this platform has the appearance of being highly applicable for further studies of hepatocytes' responses to external stimuli. V C 2015 AIP Publishing LLC. [http://dx

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

On-chip three-dimensional cell culture in phaseguides improves hepatocyte functions in vitro

et al. 2015

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“…Despite the fact that conventional macroscopic assays for drug development are still widely used, microfluidic technology has attracted increasing interest in the past years (Nguyen et al 2013;Abkarian et al 2006;Dai et al 2010;Adamo et al 2012;Mao et al 2012;Ma et al 2009). …”

Section: Introductionmentioning

confidence: 99%

A membrane-based microfluidic device for mechano-chemical cell manipulation

Ravetto

Hoefer

Toonder

et al. 2016

Biomed Microdevices

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We introduce a microfluidic device for chemical manipulation and mechanical investigation of circulating cells. The device consists of two crossing microfluidic channels separated by a porous membrane. A chemical compound is flown through the upper Bstimulus channel^, which diffuses through the membrane into the lower Bcell analysis channel^, in which cells are mechanically deformed in two sequential narrow constrictions, one before and one after crossing the stimulus channel. Thus, this system permits to measure cell deformability before and after chemical cues are delivered to the cells within one single chip. The validity of the device was tested with monocytic cells stimulated with an actindisrupting agent (Cytochalasin-D). Furthermore, as proof of principle of the device application, the effect of an antiinflammatory drug (Pentoxifylline) was tested on monocytic cells activated with Lipopolysaccharides and on monocytes from patients affected by atherosclerosis. The results show that the system can detect differences in cell mechanical deformation after chemical cues are delivered to the cells through the porous membrane. Diffusion of Cytochalasin-D resulted in a considerable decrease in entry time in the narrow constriction and an evident increase in the velocity within the constriction. Pentoxifylline showed to decrease the entry time but not to affect the transit time within the constriction for monocytic cells. Monocytes from patients affected by atherosclerosis were difficult to test in the device due to increased adhesion to the walls of the microfluidic channel. Overall, this analysis shows that the device has potential applications as a cellular assay for analyzing cell-drug interaction.

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“…In a similar development, Ma et al [257] developed an integrated multi-layered microfluidic device composed of a quartz substrate with embedded separation microchannels and a perforated three-microwell array containing sol-gel bioreactors of human liver microsome (HLM), and two PDMS layers. The aim of the study was to simultaneously characterise drug metabolites and carry out a cytotoxicity assay.…”

Section: Drug and Toxicological Screeningmentioning

confidence: 99%