www.PRSJournal.com 907 A dult mammalian wound healing involves a complex series of molecular and cellular events that typically culminate in a fibrotic “patch-like” repair. Wound healing can be con- sidered in three overlapping stages. The first stage, inflammation, begins with the formation of a fibrin clot in conjunction with platelets at the site of injury. This provides a temporary extracel- lular matrix, and a stimulus that recruits inflam- matory cells to the wound environment. The first immune cells to arrive are neutrophils, whose pri- mary function is prevention of bacterial infection. They are found in highest concentrations 1 to 2 days after injury. 1,2 Days 2 and 3 after wounding see the arrival of circulating monocytes and macrophages, 3 which play a role in the transition between the inflam- matory stage and subsequent proliferative stage of wound healing. Early wound macrophages serve to phagocytose apoptotic neutrophils and clear debris. In days 5 to 7 after injury, wound macrophages adopt a more antiinflammatory role in preparation for tissue rebuilding. More- over, secretion of growth factors, such as platelet- derived growth factor and transforming growth factor (TGF)-β, allows macrophages to stimulate fibroblast migration and activation. 1,4 The proliferative phase of wound healing is estimated to begin within 48 hours to 10 days after wounding and is characterized by replace- ment of the temporary, fibrin-based extracellular matrix with granulation tissue, 3 which consists of a vascularized extracellular matrix formed by fibroblasts and endothelial cells. The forma- tion of granulation tissue facilitates reepitheli- alization, which occurs through the migration and proliferation of keratinocytes, beginning hours after wounding. 5 The migrating fibroblasts secrete newly formed extracellular matrix, com- posed of glycosaminoglycans, proteoglycans, and collagen, although the proportion of type III to type I collagen is higher in early scar tissue than Disclosure: The authors wish to voluntarily declare a potential conflict of interest involving Neodyne Bio- sciences. Dr. Gurtner and Dr. Longaker are founders and serve on the board of directors. The other authors have no financial information to disclose. Copyright © 2015 by the American Society of Plastic Surgeons DOI: 10.1097/PRS.0000000000000972 Graham G. Walmsley, B.A. Zeshaan N. Maan, M.B.B.S., M.S. Victor W. Wong, M.D. Dominik Duscher, M.D. Michael S. Hu, M.D. Elizabeth R. Zielins, M.D. Taylor Wearda, B.A. Ethan Muhonen, B.A. Adrian McArdle, M.B., B.Ch., B.A.O. Ruth Tevlin, M.B., B.Ch., B.A.O. David A. Atashroo, M.D. Kshemendra Senarath-Yapa, M.A., M.B.B.Chir. H. Peter Lorenz, M.D. Geoffrey C. Gurtner, M.D. Michael T. Longaker, M.D., M.B.A. Stanford, Calif.; and Baltimore, Md. Summary: Over 100 million patients acquire scars in the industri- alized world each year, primarily as a result of elective operations. Although undefined, the global incidence of scarring is even larger, extending to significant numbers of burn and other trauma-related wounds. Scars have the potential to exert a profound psychological and physical impact on the individual. Beyond aesthetic consider- ations and potential disfigurement, scarring can result in restriction of movement and reduced quality of life. The formation of a scar following skin injury is a consequence of wound healing occurring through reparative rather than regenerative mechanisms. In this arti- cle, the authors review the basic stages of wound healing; differences between adult and fetal wound healing; various mechanical, genetic, and pharmacologic strategies to reduce scarring; and the biology of skin stem/progenitor cells that may hold the key to scarless regenera- tion. (Plast. Reconstr. Surg. 135: 907, 2015.) From the Hagey Laboratory for Pediatric Regenerative Medi- cine, Department of Surgery, Plastic and Reconstructive Surgery, and the Institute for Stem Cell Biology and Regen- erative Medicine, Stanford University School of Medicine; and the Department of Surgery, Division of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine. Received for publication May 15, 2014; accepted August 14, 2014. Scarless Wound Healing: Chasing the Holy Grail REGENERATIVE MEDICINE