2016
DOI: 10.1021/acs.chemrestox.6b00150
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Novel 3D Culture Systems for Studies of Human Liver Function and Assessments of the Hepatotoxicity of Drugs and Drug Candidates

Abstract: The liver is an organ with critical importance for drug treatment as the disposition and response to a given drug is often determined by its hepatic metabolism. Patient-specific factors can entail increased susceptibility to drug-induced liver injury, which constitutes a major risk for drug development programs causing attrition of promising drug candidates or costly withdrawals in postmarketing stages. Hitherto, mainly animal studies and 2D hepatocyte systems have been used for the examination of human drug m… Show more

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Cited by 207 publications
(174 citation statements)
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References 162 publications
(264 reference statements)
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“…Yet, the confidence in conventional human in vitro models, such as hepatoma cell lines or primary hepatocytes in 2D culture, is also limited, as these simple systems do not accurately mimic human liver biology and function. To overcome these hurdles, a plethora of advanced 3D hepatic in vitro models have been developed that permit the maintenance of hepatic phenotypes for extended periods (18). However, to obtain regulatory approval substantial evidence for increased translational confidence has to be presented, which requires comprehensive characterization of these novel culture paradigms, as well as an extensive data and experience base (45).…”
Section: Discussionmentioning
confidence: 99%
See 1 more Smart Citation
“…Yet, the confidence in conventional human in vitro models, such as hepatoma cell lines or primary hepatocytes in 2D culture, is also limited, as these simple systems do not accurately mimic human liver biology and function. To overcome these hurdles, a plethora of advanced 3D hepatic in vitro models have been developed that permit the maintenance of hepatic phenotypes for extended periods (18). However, to obtain regulatory approval substantial evidence for increased translational confidence has to be presented, which requires comprehensive characterization of these novel culture paradigms, as well as an extensive data and experience base (45).…”
Section: Discussionmentioning
confidence: 99%
“…To overcome these obstacles, various hepatic 3-dimensional (3D) systems have been developed in which cultured hepatocytes remain viable and functional for prolonged times (17, 18). PHHs cultured in 3D cellular aggregates termed spheroids present a functionally and phenotypically stable, versatile system in which bile canaliculi are formed and hepatocytes retain their periportal and perivenous phenotypes (19, 20).…”
mentioning
confidence: 99%
“…However, their rapid dedifferentiation in conventional two-dimensional (2D) monolayer cultures, paralleled by a loss of hepatic functionality, renders them unsuitable for long-term studies and significantly impairs their predictive power for DILI risk (Gerets et al, 2012; Lauschke et al, 2016c; Sison-Young et al, 2016; Heslop et al, 2017). To prevent dedifferentiation, an array of three-dimensional (3D) culture techniques has been developed in which hepatic phenotypes are maintained for extended periods of time (Lauschke et al, 2016a). One promising strategy is the culture of PHHs as 3D spheroidal aggregates in which hepatocyte-specific functions can be retained for several weeks (Bell et al, 2016), thus enabling repeated-exposure experiments.…”
Section: Introductionmentioning
confidence: 99%
“…Organ-on-a-chip platforms can imitate the hemodynamics of the in vivo liver by perfusion, and generate efficient nutrient exchange and shear stress at the in vitro setting (Domansky et al, 2010). On the other hand, such 3D-culture methods are difficult to operate, leading to their being unsuitable for large-scale screening of new chemical compounds (Lauschke et al, 2016). Manipulating hepatocytes in the Cell-able ® is rather simple and fulfills the terms of high throughput screening for exclusion of hepatotoxins.…”
Section: Discussionmentioning
confidence: 99%