Hydrogel-Based Airway-on-Tube With Perfusable Endothelial Lumen and Outward Epithelialization

Chronic lung diseases are a leading cause of mortality worldwide, yet therapeutic options remain limited. A major barrier to pulmonary drug development is the lack of preclinical models that recapitulate lung complexity. While recent airway-on-chip models have advanced by integrating vascular and extracellular matrix (ECM) components, these are largely limited to planar configurations. Only a few tubular designs exist, yet they generally lack a perfusable vascular compartment that supports dynamic endothelial-epithelial interactions. To address this gap, we introduce an airway-on-tube that integrates an engineered ECM (EnECM) hydrogel, tuned to match lung tissue stiffness, with a tubular melt electrowritten (MEW) scaffold. The MEW reinforces the EnECM hydrogel for dynamic culture without affecting cell behavior. The tubular EnECM/MEW construct incorporates patient-derived primary human lung microvascular endothelial cells embedded within the EnECM hydrogel, forming a perfusable endothelial lumen, while primary human bronchial epithelial cells are cultured on the outer (abluminal) surface, establishing an outward-facing epithelium at the air-liquid interface (ALI). Pulsatile perfusion through the endothelial lumen delivers nutrients and mechanical cues (shear stress and cyclic stretch) while maintaining ALI culture. Together, this study establishes a versatile hydrogel-based platform for next-generation airway-on-chip models, opening new opportunities for preclinical lung research and precision therapeutic development.