Promoting Treg Polarization‐Mediated Anti‐Scar and Appendage Regeneration in Wound Healing

Scar formation and the loss of appendages are major challenges in skin repair following injury. To address these issues, this study introduces a novel bilayer scaffold composed of poly(lactic acid) (PLA) and gelatin methacryloyl (GelMA), which is designed to enhance wound healing and reduce scar formation. Owing to its piezoelectric properties, the upper PLA layer generates an electric field that promotes cell migration, providing dynamic stimulation to the healing tissue. Moreover, the GelMA lower layer functions as an effective drug delivery platform, releasing L-lactic acid (LA) and bone morphogenetic protein 4 (BMP4). LA plays a crucial role in inducing regulatory T-cell (Treg) polarization and modulating the macrophage phenotype, thereby fostering an anti-inflammatory and antifibrotic immune environment. BMP4, on the other hand, inhibits the differentiation of fibroblasts (FBs) into myofibroblasts (MFBs), a key process in excessive collagen deposition, thus preventing fibrosis. In vitro, the bilayer scaffold enhances Treg polarization, promotes the M2 macrophage phenotype, and stimulates FB activity, contributing to a healthier wound healing environment. In vivo, the scaffold accelerated wound closure and promoted tissue regeneration, significantly reducing scar formation. This innovative dual-layered scaffold demonstrates great promise in advancing wound healing by promoting scarless tissue regeneration, offering a potential therapeutic strategy for chronic wound treatment and scar prevention. The integration of piezoelectric stimulation with controlled drug release provides a unique and multifaceted approach, making this strategy a highly innovative and clinically relevant solution for improving wound healing outcomes.