Merging bioreactor technology with 3D hepatocyte-fibroblast culturing approaches: Improved in vitro models for toxicological applications

Leite, Sofia B.; Teixeira, Augusto; Miranda, Joana P.; Tostoes, Rui; Clemente, João J.; Sousa, Marcos F. Q.; Carrondo, Manuel J.T.; Alves, Paula M.

doi:10.1016/j.tiv.2011.02.002

Cited by 46 publications

(30 citation statements)

References 51 publications

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“…They observed that albumin secretion and drug metabolizing activity was superior in co-cultured spheroids; and also demonstrated that stellate cells played an important role in the formation of stable and uniformly sized spheroidal aggregates. In a similar study, spheroids of hepatocytes and fibroblasts were formed and then cultured in either a bioreactor or a spinner flask 242 . This study demonstrated significantly improved longevity, albumin production and phase I/II drug metabolizing activity.…”

Section: In-vitro Platforms For Mimicking the Liver Physiology Andmentioning

confidence: 99%

Microengineered cell and tissue systems for drug screening and toxicology applications: Evolution of in-vitro liver technologies

et al. 2015

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The liver performs many key functions, the most prominent of which is serving as the metabolic hub of the body. For this reason, the liver is the focal point of many investigations aimed at understanding an organism’s toxicological response to endogenous and exogenous challenges. Because so many drug failures have involved direct liver toxicity or other organ toxicity from liver generated metabolites, the pharmaceutical industry has constantly sought superior, predictive in-vitro models that can more quickly and efficiently identify problematic drug candidates before they incur major development costs, and certainly before they are released to the public. In this broad review, we present a survey and critical comparison of in-vitro liver technologies along a broad spectrum, but focus on the current renewed push to develop “organs-on-a-chip”. One prominent set of conclusions from this review is that while a large body of recent work has steered the field towards an ever more comprehensive understanding of what is needed, the field remains in great need of several key advances, including establishment of standard characterization methods, enhanced technologies that mimic the in-vivo cellular environment, and better computational approaches to bridge the gap between the in-vitro and in-vivo results.

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Section: In-vitro Platforms For Mimicking the Liver Physiology Andmentioning

confidence: 99%

Microengineered cell and tissue systems for drug screening and toxicology applications: Evolution of in-vitro liver technologies

et al. 2015

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“…One way to measure UGT activity is the fluorescent substrate 4-methylumbelliferone (4-MU), which is a coumarin derivative that undergoes glucuronidation [136, 137]. UGT's role in clearance of steroids makes steroidal compounds good substrates to assay for UGT specific activity as well [82].…”

Section: Assays Detecting Susceptibility For Idiosyncratic Reactionsmentioning

confidence: 99%

Idiosyncratic Drug-Induced Liver Injury (IDILI): Potential Mechanisms and Predictive Assays

Roth

Lee

2017

BioMed Research International

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Idiosyncratic drug-induced liver injury (IDILI) is a significant source of drug recall and acute liver failure (ALF) in the United States. While current drug development processes emphasize general toxicity and drug metabolizing enzyme- (DME-) mediated toxicity, it has been challenging to develop comprehensive models for assessing complete idiosyncratic potential. In this review, we describe the enzymes and proteins that contain polymorphisms believed to contribute to IDILI, including ones that affect phase I and phase II metabolism, antioxidant enzymes, drug transporters, inflammation, and human leukocyte antigen (HLA). We then describe the various assays that have been developed to detect individual reactions focusing on each of the mechanisms described in the background. Finally, we examine current trends in developing comprehensive models for examining these mechanisms. There is an urgent need to develop a panel of multiparametric assays for diagnosing individual toxicity potential.

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“…It has been reported accordingly that various functions of hepatocytes were better maintained within cocultures, particularly albumin secretion [12][13][14] and both ECOD (Ethoxycoumarin O-Deethylase, phase I) and UGT (UDP-Glucuronosyltransferase, phase II) enzymatic activities [7]. It has been reported accordingly that various functions of hepatocytes were better maintained within cocultures, particularly albumin secretion [12][13][14] and both ECOD (Ethoxycoumarin O-Deethylase, phase I) and UGT (UDP-Glucuronosyltransferase, phase II) enzymatic activities [7].…”

Section: Cell Cultivation In Microbioreactorsmentioning

confidence: 99%

“…Several recent approaches used porous cell supporting substrates which had been microstructured [2][3][4][5] and integrated into perfusable bioreactor systems [4,6,7] and into miniaturized microbioreactors [8,9]. This includes the integration of various sensing device as well, which can monitor the physiological and electrophysiological changes over time.…”

Section: Introductionmentioning

confidence: 99%

Mimicking the biological world: Methods for the 3D structuring of artificial cellular environments

Schober

Fernekorn

Singh

et al. 2013

Engineering in Life Sciences

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Combining modern methods in microsystem technology with the latest advancements in the life sciences, namely those in tissue engineering and advanced cell culturing, is promoting the development of a promising toolbox for modeling biological systems. The core problem to solve using this toolbox is the design of 3D artificial cellular environments, both in fluidic systems and on solid substrates. The construction of 3D biological fluidic environments involves the use of microfluidic devices where fluid direction and behavior can be tightly regulated in a geometrically constrained environment for advanced cell cultivation. This is used in modern cultivation devices, such as bioreactors and multicompartment systems, including systems with integrated multielectrode arrays in both 2D and 3D. The construction of 3D cell cultures on substrates involves various fabrication techniques that use different polymers and biopolymers processed by micromachining, chemical pattern guided cell cultivation, photopolymerization, and organ printing methods. These methods together have the potential to create an artificial system with the complete hierarchical, geometrical, and functional organization found in an actual biological system. In this review, we describe representative developments in this research area and the fusion of formerly unrelated disciplines that are generating new beneficial applications in life sciences.

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Merging bioreactor technology with 3D hepatocyte-fibroblast culturing approaches: Improved in vitro models for toxicological applications

Cited by 46 publications

References 51 publications

Microengineered cell and tissue systems for drug screening and toxicology applications: Evolution of in-vitro liver technologies

Microengineered cell and tissue systems for drug screening and toxicology applications: Evolution of in-vitro liver technologies

Idiosyncratic Drug-Induced Liver Injury (IDILI): Potential Mechanisms and Predictive Assays

Mimicking the biological world: Methods for the 3D structuring of artificial cellular environments

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