Experimental liver models: From cell culture techniques to microfluidic organs‐on‐chip

Abstract

The liver is one of the most studied organs of the human body owing to its central role in xenobiotic and drug metabolism. In recent decades, extensive research has aimed at developing in vitro liver models able to mimic liver functions to study pathophysiological clues in high‐throughput and reproducible environments. Two‐dimensional (2D) models have been widely used in screening potential toxic compounds but have failed to accurately reproduce the three‐dimensionality (3D) of the liver milieu. To overcome these limitations, improved 3D culture techniques have been developed to recapitulate the hepatic native microenvironment. These models focus on reproducing the liver architecture, representing both parenchymal and nonparenchymal cells, as well as cell interactions. More recently, Liver‐on‐Chip (LoC) models have been developed with the aim of providing physiological fluid flow and thus achieving essential hepatic functions. Given their unprecedented ability to recapitulate critical features of the liver cellular environments, LoC have been extensively adopted in pathophysiological modelling and currently represent a promising tool for tissue engineering and drug screening applications. In this review, we discuss the evolution of experimental liver models, from the ancient 2D hepatocyte models, widely used for liver toxicity screening, to 3D and LoC culture strategies adopted for mirroring a more physiological microenvironment for the study of liver diseases.

A Comprehensive Evaluation of Sdox, a Promising H2S-Releasing Doxorubicin for the Treatment of Chemoresistant Tumors

“…To further confirm the data obtained in HepG2 cells, we analyzed more in depth a second non-transformed liver model, i.e., primary isolated rat hepatocytes, which, although characterized by short life-span, exhibit higher levels of expression and activity of drug-metabolizing enzymes than HepG2 cells ( Soldatow et al, 2013 ; Polidoro et al, 2021 ).…”

Advancements in the Alcohol-Associated Liver Disease Model

“…Nevertheless, current 2D cell models are limited to the short-term analysis of hepatotoxicity. This is because even when cultured in an improved 2D sandwich, the 3D environment of the ALD liver cannot be accurately reproduced due to the short lifespan and dedifferentiation process of the cells [ 190 ].…”

“…The 3D cell culture system is simple to operate, provides a microenvironment that is more similar to the living conditions in vivo for cells, and displays cell activities such as differentiation and intercellular reactions. Therefore, it can realize the real cell biology and function, accurately establish the target tissue model, and effectively predict the course of disease and drug response [ 190 ].…”

Multi-Organs-on-Chips for Testing Small-Molecule Drugs: Challenges and Perspectives

“…Two-dimensional culture has been widely used for high-throughput screening, but it fails to replicate the 3-D model of the liver; thus, the 3-D culture technique was developed. A liver-on-chip platform was designed to recapitulate the native hepatic microenvironment, provide physiological fluid flow and recapitulate hepatic function (Figure 4A) [113]. The organ-on-chip has been applied to mimic rat, dog, and human liver platforms, where the cells were subjected to physiological flow.…”