Constructing a biomimetic ECM protective barrier: a strategic interface design for urethral repair to mitigate foreign body reaction

Urethral reconstruction often fails due to the foreign body reaction (FBR) triggered by the graft, leading to chronic inflammation, fibrosis, and lumen obstruction. To address this challenge, we developed an innovative strategy: a 3D-printed polylactic acid (PLA) scaffold was pre-implanted subcutaneously for 14 days to recruit host-derived fibroblasts, monocytes, and adipose-derived stem cells. These cells secreted a biomimetic extracellular matrix (ECM) rich in collagen, elastin, and glycosaminoglycans (GAGs), resulting in a proteoglycan (PG)-enriched, bioactive tissue-engineered urethral graft (TEUG). This PG-rich matrix interface, characterized by a high density of proteoglycans and glycosaminoglycans that mimic the native urethral microenvironment, closely mimicked native urethral tissue in terms of hydrophilicity, surface topography, roughness, and mechanical compliance. More importantly, compared with commercially available small intestinal submucosa (SIS)-based grafts, it significantly enhanced urothelial cell adhesion, spreading, and oriented spatial organization, effectively recapitulating the functional role of the native PG matrix. In a rabbit anterior urethral replacement model, TEUG not only provided essential structural support and elasticity but also maintained the tubular architecture and physiological distensibility of the urethra to accommodate pressure changes during voiding. Furthermore, it acted as a functional bioactive interface that modulated the local immune microenvironment, attenuated inflammatory responses, and resisted FBR. As a result, tissue homeostasis was preserved and regenerative capacity was promoted, leading to early and orderly re-epithelialization with successful formation of a continuous epithelial layer and contractile smooth muscle tissue. In contrast, SIS-mediated regeneration resulted in aberrant epithelial hyperplasia, ultimately causing luminal narrowing or complete occlusion. Throughout the postoperative observation period, TEUG-reconstructed urethras consistently maintained patent lumens and demonstrated superior voiding function. In summary, by engineering an ECM interface with immunomodulatory and anti-FBR properties, our approach offers a simple, efficient, and clinically translatable strategy to achieve functional regeneration in urethral reconstruction.