Physicochemical synergistic retinoic acid modified polycaprolactone scaffolds for dynamic tissue regeneration.

Full-thickness skin defects caused by trauma or surgical resection pose a major clinical challenge in wound repair. Effective healing requires early stable structural support and sustained biochemical regulation. Accordingly, developing dynamically tunable scaffolds that meet stage-specific repair requirements is vital for tissue regeneration. In this work, a retinoic acid (RA)-functionalized PCL scaffold was fabricated using melt electrowriting (MEW). The MEW process produced highly ordered microfibers with a diameter of approximately 15 μm and an interfiber spacing of 200 μm. After surface amination, RA was covalently grafted onto PCL-NH₂ via EDC-mediated activation of its carboxyl group, forming an amide bond. During the early repair phase, the ordered microfibers promoted cell adhesion and migration. Upon immersion in PBS, the functionalized interface gradually evolved, enabling low initial RA release followed by sustained release that provided biochemical regulation at later stages. Transcriptomic analysis revealed differential gene expression and alternative splicing-associated changes involving pathways related to cell adhesion, migration, cytoskeletal remodeling, and inflammatory regulation. In a rat full-thickness skin defect model, the PCL-RA scaffold achieved approximately twofold higher repair efficiency than the blank control group and promoted epithelialization and organized collagen remodeling. This study demonstrates that the PCL-RA scaffold can effectively support early structural guidance and subsequent biochemical regulation, offering a novel scaffold design strategy for full-thickness skin defect repair.