Construction of a Bioactive ECM Interface Enables Concurrent Suppression of Foreign Body Reaction, Inflammation, and Promotion of Urethral Regeneration

The development of tissue-engineered urethral grafts (TEUGs) remains challenged by significant hurdles, particularly in overcoming intraurethral stricture. A core issue is the foreign body reaction (FBR) induced by the implant, which impairs the integration of TEUGs with the autologous urethra. This study employed a tissue-engineered cellularization strategy to construct a stable, hydrophilic, and elastic bioactive extracellular matrix (ECM) interface on the scaffold surface. This interface effectively resists FBR and enhances TEUG integration with host tissues. We developed an “autologous” cellularized TEUG by combining rabbit-derived smooth muscle cells and endothelial cells with nanofiber scaffolds in vitro. After seeding, the cells attached to the scaffold, synthesized, and deposited ECM, thereby fine-tuning the scaffold’s biophysical and biochemical properties. Specifically, glycosaminoglycans (GAGs) in the ECM enhanced scaffold hydrophilicity, while collagen and elastin regulated its elasticity. In a rabbit model of full-thickness urethral defect, GAGs in TEUGs induced a pro-regenerative immune response, characterized by up-regulated expression of arginase 1, CCAAT/enhancer-binding protein β, and tissue inhibitor of metalloproteinase 1 genes and down-regulated expression of matrix metalloproteinase 9 and interleukin-12 genes. This M2 macrophage-dominated gene expression profile further activated the Th2 signaling pathway, promoting the reconstruction of damaged vascular networks, the ordered proliferation of new tissues, the replacement of original ECM, load transmission in new tissues, and the maturation of functional structures. This study provides a simple yet effective strategy to enhance the patency, urine transport capacity, synchronous contraction, and directional contractile function of TEUGs by engineering a bioactive ECM interface endowed with anti-inflammatory and anti-FBR properties.