An integrated microfluidic pulmonary alveolus system for gradient-controlled investigation of nanoplastic-triggered...

Nanoplastics as emerging pollutants everywhere are suspected of potentially affecting human health. The lab-on-a-chip system facilitates the monitoring of external stimuli-induced biological events in vitro with microscale control. However, the establishment and application of multifunctional biomimetic organ-on-a-chip microsystem with physiological control for the efficient investigation of nanoplastic-induced biological responses in nanotoxicity exploration remains largely out of reach. Here, we propose an integrated microfluidic lung-on-a-chip system combining a nanoparticle gradient generator with multiple alveolar epithelial barrier models. The custom gradient generator allowed the sufficient mixing and linear concentration gradient production of nanoparticles. Subsystem integration and precise microfluidic control enabled multi-parallel and dynamic evaluation of the dose-dependent bioeffects of nanoparticles on in vitro recapitulated human alveolar barriers with organ-level responses at cellular- and molecular-scale resolutions. The clear nanotoxicity of high-dose polystyrene-nanoparticles (PS-NPs, over 50 μg/mL) was summarized based on the results of the inflammatory and injurious responses of the pulmonary alveoli. Low-dose PS-NPs significantly triggered the defense mechanism in the form of structural integrity, high viability, and the moderate up-regulation of antioxidant and proinflammatory activities. This approach offers insights into the potential toxicity risk of nanoplastics in humans. The integrated lung-on-a-chip system provides a proof-of-concept prototype for the efficient and biomimetic exploration of nanomedicine and environmental toxicology.