Three-Dimensional Cell Co-Culture Liver Models and Their Applications in Pharmaceutical Research

Ma, Yinping; Hu, Lei; Tang, Jianhua; Guo, Weiwei; Feng, Yujie; Liu, Yanmiao; Tang, Fushan

doi:10.3390/ijms24076248

Cited by 11 publications

(4 citation statements)

References 109 publications

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“…One of the major drawbacks for the use of iHep in drug development studies is their functional immaturity when cultured alone in a standard 2D condition . Instead, it is widely accepted that a 3D microenvironment and the co-culturing with non-parenchymal cells can lead to the stabilization of the hepatocyte phenotype and functions …”

Section: Discussionmentioning

confidence: 99%

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

Fanizza

Boeri

Donnaloja

et al. 2023

ACS Biomater. Sci. Eng.

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Liver-related drug metabolism is a key aspect of pharmacokinetics and possible toxicity. From this perspective, the availability of advanced in vitro models for drug testing is still an open need, also to the end of reducing the burden of in vivo experiments. In this scenario, organ-on-a-chip is gaining attention as it couples a state-of-the art in vitro approach to the recapitulation of key in vivo physiological features such as fluidodynamics and a tri-dimensional cytoarchitecture. We implemented a novel liver-on-a-chip (LoC) device based on an innovative dynamic device (MINERVA 2.0) where functional hepatocytes (iHep) have been encapsulated into a 3D hydrogel matrix interfaced through a porous membrane with endothelial cells (iEndo)]. Both lines were derived from human-induced pluripotent stem cells (iPSCs), and the LoC was functionally assessed with donepezil, a drug approved for Alzheimer’s disease therapy. The presence of iEndo and a 3D microenvironment enhanced the 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 dynamic study conducted to assess the amount of donepezil diffused into the LoC indicated that the molecule should be able to pass through the iEndo and reach the target iHep construct. Then, we performed experiments of donepezil kinetics that confirmed the numerical simulations. Overall, our iPSC-based LoC reproduced the in vivo physiological microenvironment of the liver and was suitable for potential hepatotoxic screening studies.

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Section: Discussionmentioning

confidence: 99%

“… 28 Instead, it is widely accepted that a 3D microenvironment and the co-culturing with non-parenchymal cells can lead to the stabilization of the hepatocyte phenotype and functions. 29 …”

Section: Discussionmentioning

confidence: 99%

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

Fanizza

Boeri

Donnaloja

et al. 2023

ACS Biomater. Sci. Eng.

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“…Dynamic models based on liver-on-chip are a suitable platform for replicating metabolic zonation. [179] The mechanical stimuli induced by medium flow are also essential for differentiation not only of hepatocytes but of other hepatic cell types such as LSECs.…”

Section: Conclusion: What Is Beyond State-of-the-art In Vitro Models ...mentioning

confidence: 99%

The Material World of 3D‐Bioprinted and Microfluidic‐Chip Models of Human Liver Fibrosis

Carvalho,

Bansal,

Barrias

et al. 2023

Advanced Materials

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Biomaterials are extensively used to mimic the cell‐matrix interactions, which are essential for cell growth, function and differentiation. This is particularly relevant when developing in vitro disease models of organs rich in extracellular matrix, like the liver. Liver disease involves a chronic wound‐healing response with formation of scar tissue known as liver fibrosis. At early stages, liver disease can be reverted, but as disease progresses, reversion is no longer possible, and there is no cure. Research for new therapies is hampered by the lack of adequate models that replicate the mechanical properties and biochemical stimuli present in the fibrotic liver. Fibrosis is associated with changes in the composition of the extracellular matrix that directly influence cell behavior. Biomaterials could play an essential role in better emulating the disease microenvironment. In this paper, the recent and cutting‐edge biomaterials used for creating in vitro models of human liver fibrosis are revised, in combination with cells, bioprinting and/or microfluidics. These technologies have been instrumental to replicate the intricate structure of the unhealthy tissue and promote medium perfusion that improves cell growth and function, respectively. A comprehensive analysis of the impact of material hints and cell‐material interactions in a 3D context is provided.This article is protected by copyright. All rights reserved

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“…During drug development, in vitro hepatocyte models are commonly used to test the cytotoxicity of prodrugs [4]. The origin of the cells selected for these models is crucial to the relevance and predictive value of these models.…”

Section: Introductionmentioning

confidence: 99%

High-Voltage Electrostatic Field Hydrogel Microsphere 3D Culture System Improves Viability and Liver-like Properties of HepG2 Cells

Liu,

Ge,

et al. 2024

IJMS

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Three-dimensional (3D) hepatocyte models have become a research hotspot for evaluating drug metabolism and hepatotoxicity. Compared to two-dimensional (2D) cultures, 3D cultures are better at mimicking the morphology and microenvironment of hepatocytes in vivo. However, commonly used 3D culture techniques are not suitable for high-throughput drug screening (HTS) due to their high cost, complex handling, and inability to simulate cell–extracellular matrix (ECM) interactions. This article describes a method for rapid and reproducible 3D cell cultures with ECM–cell interactions based on 3D culture instrumentation to provide more efficient HTS. We developed a microsphere preparation based on a high-voltage electrostatic (HVE) field and used sodium alginate- and collagen-based hydrogels as scaffolds for 3D cultures of HepG2 cells. The microsphere-generating device enables the rapid and reproducible preparation of bioactive hydrogel microspheres. This 3D culture system exhibited better cell viability, heterogeneity, and drug-metabolizing activity than 2D and other 3D culture models, and the long-term culture characteristics of this system make it suitable for predicting long-term liver toxicity. This system improves the overall applicability of HepG2 spheroids in safety assessment studies, and this simple and controllable high-throughput-compatible method shows potential for use in drug toxicity screening assays and mechanistic studies.

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Three-Dimensional Cell Co-Culture Liver Models and Their Applications in Pharmaceutical Research

Cited by 11 publications

References 109 publications

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

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

The Material World of 3D‐Bioprinted and Microfluidic‐Chip Models of Human Liver Fibrosis

High-Voltage Electrostatic Field Hydrogel Microsphere 3D Culture System Improves Viability and Liver-like Properties of HepG2 Cells

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