Abstract

Electrospun nanofiber membranes hold promise for abdominal wall repair due to their biomimetic architecture and tunable properties. However, their porous structure often induces an elevated foreign body response (FBR) that impedes tissue integration and remodeling. While previous strategies have employed ibuprofen (IBU) to mitigate inflammation, its non-selective cyclooxygenase (COX) inhibition and rapid systemic clearance limit local therapeutic efficacy. Herein, we functionalized electrospun polylactic acid (PLA)/gelatin (Gel) nanofiber-bundle membranes with chitosan (CS) and loxoprofen (LOX), a prodrug-type nonsteroidal anti-inflammatory drug with enhanced tissue penetration and cyclooxygenase-2 (COX-2) selectivity to achieve sustained local immunomodulation while preserving membrane porosity. The PLA/Gel-CS-LOX membrane exhibited favorable physicochemical properties, sustained LOX release over 28 days, and potent antibacterial activity. It showed good cytocompatibility and downregulated pro-inflammatory genes and upregulated anti-inflammatory genes of LPS-stimulated macrophages, and significantly reduced oxygen species (ROS) production. In a rat full-thickness abdominal wall defect model, the PLA/Gel-CS-LOX membrane facilitated robust cell infiltration, angiogenesis, and tissue integration. At 90 days post-implantation, regenerated tissues exhibited mechanical properties comparable to native abdominal wall, with optimized collagen remodeling evidenced by balanced matrix metalloproteinase 9 (MMP9)/tissue inhibitor of metalloproteinase 1 (TIMP1) expression. These results demonstrate that CS-LOX functionalization represents a promising strategy to modulate inflammatory responses to the electrospun mesh and promote functional tissue remodeling for clinical abdominal wall repair.