Table 2.

The comparisons of different model systems for studying SARS‐CoV‐2 infection

Models	Advantages	Limitations
2D cell cultures (e.g., cell lines, primary cells, and tissue explants)	Often be highly susceptible to viruses Convenient for the isolation and replication of viral particles including SARS‐CoV‐2 Studying mechanism of viral invasion Large‐scale screening anti‐viral drugs	Lacking cell–cell/matrix interactions and complex 3D tissue organization Different from native tissues in terms of gene profiles, epigenetics, and functions Limited sources and short viability of primary cells/tissues Difficult to study virus tropism
Organoids	Recapitulating key features of organ development Modeling viral life cycle Amenable to extended cultivation and manipulation Long‐term preservation of cell phenotype and genotype in vitro Available for studying virus tropism with multiple cell types High‐throughput drug screening	Uncontrolled biochemical and biophysical environmental cues High variability Lack of relevant mechanical signals, such as blood perfusion and air flow Often use of ill‐defined animal‐derived matrices (e.g., Matrigel) Lack of tissue–tissue interfaces Lack of immune cells or vascular structure Difficult access of virus to apical epithelium surface
Organs‐on‐chips	Mimicking in vivo‐like tissue microenvironment Recapitulating the human‐relevant tissues or organs physiology and pathology Precise control of mechanical cues (e.g., fluid flow) Mimicking tissue–tissue interfaces Studying cell–cell interactions by cell co‐cultures Enable apical surface accessibility of virus Studying host‐immune responses to viral infection and viral evolution In situ and real‐time imaging	Limited cell types The PDMS material of chip device may influence drug testing Low throughput for drug screening in the viral‐infected organ chips
Animal models	Widely used in evaluating preclinical therapeutic drugs or vaccines Studying organism responses to viral infection and pathogenesis Available for viral infection by gene editing (e.g., hACE2 transgenic mice) Nonhuman primates possess similar physiology and immunology to humans	Many animals are not the natural host for SARS‐CoV‐2 (e.g., rodents) Exhibiting varying susceptibility and different symptoms from human Limited throughput Difficult to real‐time imaging High financial costs and complex husbandry requirements in animal biosafety level 3 (BLS‐3) lab Ethical issues