Strategies for prevention of scars: what can we learn from fetal skin?

Fetal wound healing occurs rapidly and without scar formation early in gestation. Studying the mechanisms of scarless repair can lead to novel scar-preventive approaches. In fetal wounds, collagen is deposited early and is fine and reticular with less cross-linking. Several important differences of fetal vs. postgestational wound-healing response have been determined, such as the presence of less inflammation, higher hyaluronic acid concentration and a greater ratio of collagen type III to type I. Compared with typical wounds, there are also altered ratios of signaling molecules, such as higher ratios of transforming growth factor (TGF)-β3 to TGF-β1 and -β2, and matrix metalloproteinases to tissue inhibitors of metalloproteinases. Furthermore, fetal fibroblasts do not exhibit TGF-β1-induced collagen production compared with their mature counterparts. Patterning genes (homeobox genes) involved in organogenesis are more active in the fetal period and are believed to be the "first domino" in the fetal cutaneous wound repair regulatory cascade. The recommended scar-preventive agents, such as Scarguard MD®, silicone gel and sheet, Seprafilm® Bioresorbable Membrane, topical hyaluronan, onion extract, oral tamoxifen and 585-nm pulsed dye laser are reviewed in this study. Despite the lack of supporting evidence, there is a widespread false presumption that the acceleration of healing with the widely assumed scar-preventive commercial agents is associated with decreased scar formation. Humans are erroneously inclined to make a negative correlation between the healing rate and the degree of scar formation, while such a correlation does not exist in reality. Despite the importance of scar prevention, no FDA-approved therapy for this purpose is available in the 21st century, which reflects the important challenges, such as the presence of redundant pathways, that these approaches are facing.