Liver-related drug metabolism is a key aspect of pharmacokineticsand possible toxicity. From this perspective, the availability ofadvanced in vitro models for drug testing is still an open need, alsoto the end of reducing the burden of in vivo experiments. In thisscenario, organ-on-a-chip is gaining attention as it couples a state-of-theart in vitro approach to the recapitulation of key in vivo physiologicalfeatures such as fluidodynamics and a tri-dimensional cytoarchitecture.We implemented a novel liver-on-a-chip (LoC) device based on an innovativedynamic device (MINERVA 2.0) where functional hepatocytes (iHep) havebeen encapsulated into a 3D hydrogel matrix interfaced through a porousmembrane with endothelial cells (iEndo)]. Both lines were derivedfrom human-induced pluripotent stem cells (iPSCs), and the LoC wasfunctionally assessed with donepezil, a drug approved for Alzheimer'sdisease therapy. The presence of iEndo and a 3D microenvironment enhancedthe expression of liver-specific physiologic functions as in iHep,after 7 day perfusion, we noticed an increase of albumin, urea production,and cytochrome CYP3A4 expression compared to the iHep static culture.In particular, for donepezil kinetics, a computational fluid dynamicstudy conducted to assess the amount of donepezil diffused into theLoC indicated that the molecule should be able to pass through theiEndo and reach the target iHep construct. Then, we performed experimentsof donepezil kinetics that confirmed the numerical simulations. Overall,our iPSC-based LoC reproduced the in vivo physiological microenvironmentof the liver and was suitable for potential hepatotoxic screeningstudies.

Development of an Induced Pluripotent Stem Cell-Based Liver-on-a-Chip Assessed with an Alzheimer’s Disease Drug

Fanizza F;Boeri L;Donnaloja F;Perottoni S;Giordano C;
2023-01-01

Abstract

Liver-related drug metabolism is a key aspect of pharmacokineticsand possible toxicity. From this perspective, the availability ofadvanced in vitro models for drug testing is still an open need, alsoto the end of reducing the burden of in vivo experiments. In thisscenario, organ-on-a-chip is gaining attention as it couples a state-of-theart in vitro approach to the recapitulation of key in vivo physiologicalfeatures such as fluidodynamics and a tri-dimensional cytoarchitecture.We implemented a novel liver-on-a-chip (LoC) device based on an innovativedynamic device (MINERVA 2.0) where functional hepatocytes (iHep) havebeen encapsulated into a 3D hydrogel matrix interfaced through a porousmembrane with endothelial cells (iEndo)]. Both lines were derivedfrom human-induced pluripotent stem cells (iPSCs), and the LoC wasfunctionally assessed with donepezil, a drug approved for Alzheimer'sdisease therapy. The presence of iEndo and a 3D microenvironment enhancedthe expression of liver-specific physiologic functions as in iHep,after 7 day perfusion, we noticed an increase of albumin, urea production,and cytochrome CYP3A4 expression compared to the iHep static culture.In particular, for donepezil kinetics, a computational fluid dynamicstudy conducted to assess the amount of donepezil diffused into theLoC indicated that the molecule should be able to pass through theiEndo and reach the target iHep construct. Then, we performed experimentsof donepezil kinetics that confirmed the numerical simulations. Overall,our iPSC-based LoC reproduced the in vivo physiological microenvironmentof the liver and was suitable for potential hepatotoxic screeningstudies.
2023
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11311/1256908
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