Modeling the Interaction of Aerosol Particles With Lung Epithelial Cells Using the Lung-On-A-Chip Platform

BACKGROUND: The assessment of inhalation toxicity of natural and artificial aerosols and the efficacy of aerosolized drugs is an important practical task. However, in numerous in vitro studies, the test substance is dissolved in a liquid that completely covers the lung tissue cells. For inhalation therapy, this method substantially differs from the physiological scenario of aerosol interaction with the pulmonary epithelium. AIM: The aim is to develop a platform to study the interaction of inhaled aerosol particles with the pulmonary epithelium on the internal surface of the lung alveoli at the liquid–air interface capable of simulating scenarios of periodic variation of liquid levels during breathing. METHODS: The A549 human adenocarcinoma cell line was used as a model culture of pulmonary epithelial cells. Cell viability was analyzed using fluorescent microscopy under various exposure conditions at the liquid–air interface and during the deposition of different aerosol particles. RESULTS: A device has been designed, built, and tested to simulate the internal surface of pulmonary alveoli. It consists of a cell layer located at the air–liquid interface. The cells are cultured on a porous polymer membrane on the surface of a reservoir with culture medium. The hydration level of the cells is controlled by altering the liquid pressure beneath the membrane and recorded by an optical sensor that measures the scattering of laser beam reflected from the surface of the cell layer. The membrane with the cell layer is placed in a chamber allowing to create a directed electric field normal to the aerosol flow passing over the cell layer, which is connected to one electrode. The electric field significantly accelerates the delivery of aerosol particles with an electric charge onto the cell surface. We determined the parameters of static exposure of the model cell monolayer at the air–liquid interface, allowing to maintain high cell viability. The study showed that cyclic variation of cell hydration simulating the respiratory cycle is effective to maintain cell viability for an extended period (60 min). The study showed that doxorubicin nanoaerosol is effective when deposited on the surface of human adenocarcinoma tumor cells located at the liquid–air phase boundary. A model aerosol of a non-toxic substance (glucose) does not have toxic effects under similar conditions. CONCLUSION: The proposed lung-on-a-chip model is a comprehensive platform to study the inhalation toxicity of natural and artificial aerosols and test the safety and efficacy of aerosolized drugs in situ.