Hydrogel Microsphere-Based Alveolar Models for Toxicity Assessment and Pathogen Infection Studies

The alveolar epithelium plays a critical role in respiratory function, facilitating air exchange and serving as a barrier against inhaled pathogens. Its unique three-dimensional architecture, in which epithelial cells grow on spherical alveolar structures, significantly increases the surface area-to-volume ratio for efficient gas exchange but poses challenges for in vitro reconstruction. Here, we present a biomimetic alveolar model based on gelatin methacryloyl (GelMA) hydrogel microspheres with precisely controlled sizes and composition fabricated via microfluidic technology. These microspheres function as micro-scaffolds for cell adhesion and growth, and an oxygen-permeable honeycomb microwell array facilitates the rapid assembly of cell-laden microspheres into physiologically relevant alveolar-like structures. Using this model, the effects of toxic gas exposure and pathogen infection, and demonstrated its potential use for both basic physiological studies and pathological applications, was investigated. This system recapitulates key features of the alveolar microenvironment and offers a versatile platform for respiratory research and drug screening.