Biodegradable Double-Layer Hydrogels with Sequential Drug Release for Multi-Phase Collaborative Regulation in Scar-Free Wound Healing

Scarring is a prevalent and often undesirable outcome of the wound healing process, impacting millions worldwide. The complex and dynamic nature of wound healing, including hemostasis, inflammation, proliferation, and remodeling, necessitates precise, making it hard for stage-specific interventions to prevent pathological scarring. This study introduces a double-layer hydrogel system designed for sequential drug release, aligning with the stage-specific need for wound healing. The lower layer, containing curcumin-loaded chitosan nanoparticles, shows early anti-inflammatory and antioxidant effects, while the upper layer, with pirfenidone-encapsulated gelatin microspheres, presents late-stage anti-fibrotic activity. The hydrogel's unique design, with varying degradation rates and mechanical properties in each layer, facilitates cascade drug release in synchrony with wound healing stages. Rapid release of curcumin from the lower layer promotes proliferation by mitigating inflammation and oxidative stress, while the sustained release of pirfenidone from the upper layer inhibits excessive fibrillation during late proliferation and remodeling. In a rat model of full-thickness skin defect, treatment with a double-layer hydrogel drug delivery system accelerated the wound closure, improved scar quality, and promoted the formation of hair follicles. Therefore, this innovative approach lays a promising foundation for future clinical applications in anti-scar therapies, offering a significant advancement in wound care and regenerative medicine.