D101-01 A Next-Generation Personalized Small-Airway-On-A-Chip for Modelling Genetic Diseases

Rationale People with Down Syndrome (DS), the most common chromosomal abnormality in humans, are known to have high susceptibility to infection due to immunity defects. Among the infection sites, infection in the lungs and airways is most frequent and accounts for 54% of hospital admission. Yet, tailored therapeutic development for this condition is extremely challenging due to difficulty in collecting samples and the lack of effective, pathophysiological relevance preclinical models. Methods We report the development of a next-generation, personalized iPSC-derived Small Airway-on-a-Chip (iAirway-Chip) designed to address these challenges. Following rigorous design, development, and characterization, this living artificial lung model was employed to study infection in individuals with Down syndrome by introducing influenza virus into the airway lumen and analyzing protein secretion from both the airway fluid and vascular effluent. Results We successfully fabricated iAirway-Chips with complex, physiologically relevant geometry to recreate the structural and functional features of the human small airway microenvironment. The device incorporates circular airway and microvascular channels that mirror in vivo dimensions, connected through a natural hydrogel matrix engineered to match native tissue stiffness. To reconstruct the multicellular architecture of the small airway, we integrated four principal human cell types - well differentiated mucociliated epithelial, vascular endothelial, stromal, and tissue-resident mononuclear phagocytes, all from iPSCs derived from either healthy (disomic 21 [21]) or DS (trisomic 21 [T21]) individuals. This approach enabled the creation of the first personalized DS Airway-on-a-Chip microfluidic platform. Functional assessment confirmed physiological ciliary beating and vascular barrier integrity, demonstrating organ-level functionality. Upon influenza virus infection, the iAirway-Chip exhibited disease-relevant pathological responses and revealed exaggerated inflammatory signaling in DS-derived tissues compared with healthy controls. Conclusions We successfully designed, fabricated, and validated the iAirway-Chip, a personalized, immune-competent model that recreates the structural, functional, and pathological complexity of human small airways. Using this platform, we demonstrated an exaggerated inflammatory response in DS-derived tissues following influenza infection. Together, these findings establish the iAirway-Chip as a powerful tool for modeling disease mechanisms and advancing therapeutic development for rare and genetic disorders.