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Updated: Nov 12, 2025
Advanced 3D Liver Models for In vitro Genotoxicity Testing Following Long-Term Nanomaterial Exposure
Published on: June 5, 2020
A Critical Perspective on 3D Liver Models for Drug Metabolism and Toxicology Studies
Ana S Serras1, Joana S Rodrigues1, Madalena Cipriano2
1Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
Abstract:
The poor predictability of human liver toxicity is still causing high attrition rates of drug candidates in the pharmaceutical industry at the non-clinical, clinical, and post-marketing authorization stages. This is in part caused by animal models that fail to predict various human adverse drug reactions (ADRs), resulting in undetected hepatotoxicity at the non-clinical phase of drug development. In an effort to increase the prediction of human hepatotoxicity, different approaches to enhance the physiological relevance of hepatic in vitro systems are being pursued. Three-dimensional (3D) or microfluidic technologies allow to better recapitulate hepatocyte organization and cell-matrix contacts, to include additional cell types, to incorporate fluid flow and to create gradients of oxygen and nutrients, which have led to improved differentiated cell phenotype and functionality. This comprehensive review addresses the drug-induced hepatotoxicity mechanisms and the currently available 3D liver in vitro models, their characteristics, as well as their advantages and limitations for human hepatotoxicity assessment. In addition, since toxic responses are greatly dependent on the culture model, a comparative analysis of the toxicity studies performed using two-dimensional (2D) and 3D in vitro strategies with recognized hepatotoxic compounds, such as paracetamol, diclofenac, and troglitazone is performed, further highlighting the need for harmonization of the respective characterization methods. Finally, taking a step forward, we propose a roadmap for the assessment of drugs hepatotoxicity based on fully characterized fit-for-purpose in vitro models, taking advantage of the best of each model, which will ultimately contribute to more informed decision-making in the drug development and risk assessment fields.
Insights
Predicting human liver toxicity from drug candidates remains challenging. Advanced three-dimensional (3D) in vitro liver models offer improved physiological relevance over traditional methods, aiding drug development.
Area of Science:
- Pharmacology and Toxicology
- Biotechnology
- Drug Development
Background:
- Poor predictability of human liver toxicity leads to high drug candidate attrition rates in the pharmaceutical industry.
- Current animal models inadequately predict human adverse drug reactions (ADRs), failing to detect hepatotoxicity early.
- Existing two-dimensional (2D) in vitro systems lack the physiological complexity to accurately assess drug-induced liver injury.
Purpose of the Study:
- To review drug-induced hepatotoxicity mechanisms and current three-dimensional (3D) liver in vitro models.
- To analyze the advantages and limitations of 3D liver models for human hepatotoxicity assessment.
- To propose a roadmap for improved in vitro hepatotoxicity testing in drug development.
Main Methods:
- Comprehensive literature review of drug-induced hepatotoxicity mechanisms.
- Analysis of characteristics, advantages, and limitations of available 3D liver in vitro models.
- Comparative analysis of toxicity studies using 2D and 3D in vitro models with known hepatotoxic compounds (paracetamol, diclofenac, troglitazone).
Main Results:
- Three-dimensional (3D) and microfluidic liver models enhance physiological relevance by recapitulating hepatocyte organization, cell-matrix contacts, fluid flow, and gradients.
- These advanced models show improved hepatocyte phenotype and functionality compared to 2D cultures.
- Comparative studies highlight the superior ability of 3D models to predict toxicity of known hepatotoxic compounds, emphasizing the need for standardized characterization.
Conclusions:
- Advanced 3D liver in vitro models significantly improve the prediction of human hepatotoxicity compared to traditional methods.
- Harmonization of characterization methods for in vitro models is crucial for reliable toxicity assessment.
- A roadmap for fit-for-purpose in vitro models is proposed to enhance drug development decision-making and risk assessment.
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