Bioinspired Hyaluronic Acid‐Based Hydrogel Fuels Bi‐Directional Lung Organoid Maturation via PIEZO1 and ITGB1 Mediated Mechanosensation

Abstract Lung diseases are one of the leading causes of global mortality. Advances in induced pluripotent stem cell (iPSC) differentiation have enabled the creation of bronchiolar and alveolar lung organoids, advancing research on lung conditions. Traditional Matrigel encapsulation, reliant on the spontaneous assembly and propagation of cells with limited external intervention, often results in variability and low reproducibility. The absence of hyaluronic acid (HA) in Matrigel, a key lung extracellular matrix component, limits bronchiolar and alveolar cell differentiation, reducing the efficacy and reproducibility of iPSC‐derived organoid generation. To address this, a novel hybrid hydrogel combining HA and 23% Matrigel, inspired by the natural lung environment, is developed. This hydrogel offers improved biochemical support and viscoelastic properties, significantly accelerating organoid development. Within eight days, the hydrogel produces uniformly sized organoids containing both bronchiolar and alveolar epithelial cells. Increased levels of active mechanosensors and transducers, including PIEZO1, Integrin, and Myosin, suggest that the hydrogel's altered viscoelasticity triggers a mechanotransduction cascade. This bioinspired hydrogel provides a robust, fast model for biomedical research, facilitating rapid drug screening, respiratory disease treatment studies, and surfactant trafficking investigations. Furthermore, it enables the exploration of underlying biomechanical mechanisms to enhance the controllability of organoid generation and maturation.