Targeting Inflammatory Cytokines and Extracellular Matrix Composition to Promote Wound Regeneration

Significance: Delayed wound healing is one of the most challenging complications of several diseases, including diabetes. There is a vast interest in finding efficient treatments that promote scarless wound healing. The ability of the fetus to regenerate skin wounds after injury has generated much interest in the fetus as a model of regeneration. In this review, we evaluate the role and differential regulation of inflammation, extracellular matrix (ECM) composition, and mechanical stress in determining wound phenotype after injury. Recent Advances: Comparisons between postnatal and fetal wounds have revealed many differences in the healing process. Fetal skin wound healing is characterized by a reduced inflammatory response, an ECM rich in type III collagen and high-molecular-weight hyaluronic acid (HMW-HA), and minimal mechanical stress. In contrast, adult wounds have a sustained inflammatory response, an ECM with increased type I collagen, and low-molecular-weight (LMW-HA) and are subject to significant mechanical load. Critical Issues: The differential regulation of these processes in the fetus compared with the adult plays a critical role in promoting regeneration in the fetus while resulting in scar formation in the adult. Future Directions: Understanding the significance of inflammation and biomechanical forces in wound healing may help in designing therapeutic strategies for the management of chronic nonhealing wounds.