Fetal Wound Healing and Translational Applications for Scarless Skin Repair

Fetal wound healing represents a unique model of scarless tissue repair and provides an important biological framework for developing regenerative therapies for adult skin wounds. Unlike adult wound healing, which often results in fibrosis and permanent scar formation, early-gestation fetal wounds can restore normal skin architecture with minimal inflammation, rapid re-epithelialization, organized extracellular matrix deposition, and reduced myofibroblast activation. This review summarizes the cellular, molecular, immunological, and biomechanical mechanisms underlying fetal scarless wound healing and discusses their translational relevance for tissue engineering and regenerative medicine. Key features of fetal repair include a hyaluronic acid-rich extracellular matrix, a higher collagen III/I ratio, increased transforming growth factor-β3 activity relative to TGF-β1 and TGF-β2, attenuated inflammatory cytokine signaling, fetal-specific fibroblast phenotypes, and a mechanically compliant wound environment. Particular attention is given to mechanotransduction pathways, including integrin-mediated signaling, focal adhesion kinase, Rho/ROCK, and YAP/TAZ, which link matrix stiffness and tissue tension to fibroblast activation and scar formation. The review further examines fetal-inspired therapeutic strategies, including hyaluronic acid-based hydrogels, immunomodulatory biomaterials, stem cell-derived secretomes, controlled growth factor delivery, anti-fibrotic agents, RNA-based therapies, and bioengineered skin substitutes. Although these approaches have shown promising preclinical and early clinical potential, true scarless regeneration in adult human skin remains challenging due to the complexity of the fetal wound microenvironment, differences in immune maturity, delivery timing, safety concerns, and regulatory barriers. Understanding fetal wound healing as an integrated and dynamically regulated process may guide the design of multi-cue regenerative therapies aimed not only at reducing scar formation but also at restoring functional skin architecture.