TABLE 1.

Overview of the advantages and disadvantages of in vitro models used for respiratory inhalation drug screening.

In vitro model	Applications	Respiratory disease model	Advantages	Disadvantages	References
Air-liquid interface	Drug efficacy, toxicity and transport/delivery studies	COPD, cystic fibrosis, lung cancer	Mimics respiratory tract of the lung when exposed to toxic and therapeutic agents. Dose of inhalation agents highly controllable. Can be implemented in drug transport/delivery studies using impactor technologies.	Restricted to a select range of respiratory cell lines to functionally recapitulate the in vivo airway epithelium. Use of primary cells may possess ethical and cell-culturing limitations.	Grainger et al., 2006, 2012; Ong et al., 2011, 2014; Haghi et al., 2012; Kumar et al., 2020
OrganoidS	Drug efficacy and toxicity studies	Lung cancer, fibrosis, cystic fibrosis, viral and bacterial infections	Capacity to mimic cellular heterogeneity of lung microenvironment. Recapitulates structural architecture and cellular interactions of lung microenvironment. Ability to be implemented in personalized medicine studies through the use of patient-derived organoids	Do not possess breathing mechanics essential in airflow. Do not possess anatomical structures essential for addressing mouth-to-airway transit of inhaled therapies.	Tan et al., 2017; Jung et al., 2019; Miller et al., 2019
Lung-on-chip	Drug toxicity and efficacy studies	Severe asthma, COPD, lung cancer	Able to reproduce key morphological and biological processes of lung airway barriers through emulating cellular stretching of the alveolar microenvironment. Ability to recapitulate mechanical and shear stresses that result from cyclical breathing. Possess cellular heterogeneity and vascular flow rates to simulate the lung in vivo microenvironment.	Inability to evaluate aerosolized bio-pharmacokinetics observed during the mouth-to-airway transit of inhaled particles.	Huh et al., 2010, 2012; Benam et al., 2016; Konar et al., 2016