Sequential drug-release microsphere system for scarless wound healing

The dynamic imbalance in skin wound healing is a key factor of hypertrophic scar (HS) formation. Traditional treatments often target only a certain stage of the wound healing process and fail to comprehensively address the dynamic imbalance, thus making it difficult to achieve scarless wound healing. This study developed a chronologically adaptive methacrylylated gelatin (GelMA)-based microsphere delivery system (G/E/T) that achieves comprehensive intervention in wound healing process through precisely orchestrated sequential release of epigallocatechin gallate (EGCG) and triamcinolone acetonide (TA). In vitro studies have confirmed that the G/E/T microsphere system, utilizing this sequential release mechanism, not only alleviates oxidative stress and inflammatory responses in the early stages but also persistently inhibits the excessive proliferation and migration of fibroblasts in the later phases, demonstrating stage-specific therapeutic precision. Moreover, validated through mouse full-thickness wound model and rabbit ear HS model, the system exhibited remarkable scarless healing outcomes. The "sequential release and dual-agent synergy" design paradigm provides an innovative strategy for scarless wound healing while establishing a foundational framework for developing sequential multidrug delivery systems targeting complex pathological processes.