Table 2.

Different hepatocyte-like cell models for hepatotoxicity testing

Models	Descriptions	Advantages	Disadvantages	Applications	References
2D monolayer cell culture	Cells adhere to a solid and flat surface	Easy and low-cost operation	Poor cell–cell and cell–matrix interactions, far different from the environment in vivo, limited enzyme activity	Evaluation of drug metabolism and toxicity, drug–drug interactions, high-throughput drug screening, long-term drug toxicity assessment	[62–64, 67–69]
Complex organoids	Organoids with multiple cell types	Presence of non-parenchymal cells, rich and complex structure	Poor homogeneity and controllability	Specific disease models	[75, 76, 78]
Simplified organoids	Organoids with single-cell type	Good homogeneity and controllability	Relatively simple structure and function	Large-scale drug screening	[82–84]
Scaffold-based organoids	Organoids grown in supportive scaffold	Efficient differentiation, intact vasculature, controllable size, shape, permeability, and porosity	Undefined components, lower stability and repeatability, problems of biocompatibility and cytotoxicity, absorption of test compound by scaffold	Studies of drug metabolism, disease modeling, and implantation in vivo	[86–92, 94, 95]
Scaffold-free organoids	Cells self-aggregate to form organoids	Simple operation, low-cost, high throughput, no compatibility issues, cell–cell and cell–matrix interaction, nutrition, oxygen gradient formation	Hypoxia and necrosis in the center of the organoids	Large-scale drug screening	[97, 99]
Patient-derived organoids	Organoids with patient-specific cells	Donor-specific CYP metabolism and drug responses	Relatively complex operation	Disease modeling, mechanism research, targeted drug screening	[100–105]
Organ-on-a-chip	Organ biomimetic system with organoids grown in a microfluidic chip	Precise and dynamic control of the cellular microenvironment	High-cost, complex operation, need of sophisticated equipment	Prediction of drug absorption, metabolism, and clearance	[108, 118–121]
Chimeric mice with humanized livers	Mouse liver cells are replaced by human hepatocytes	Possessing human drug metabolism and transformation functions, good human relevance	High-cost, time-consuming operation, varying degree of humanization, immune-compromised	Preclinical drug evaluation	[128–130, 136–139]