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

Abstract

ABSTRACT 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.