April 2011 | Volume 10 | Issue 4 | Original Article | 427 | Copyright © April 2011

News, Views and Reviews provides focused updates, topic reviews and editorials concerning the latest developments in dermatologic therapy.

Wound Healing: From Basic Science to Clinical Practice and Beyond

Cutaneous wounds disrupt the protective barrier of the skin, exposing tissues to bacterial invasion and loss of vital fluids.1 In healthy individuals, wound healing occurs by systematic cellular and molecular processes leading to timely wound closure and minimal morbidity. Dysregulation of these processes, as occurs in diabetes mellitus, venous stasis and pressure ulcers, results in chronic wounds, disability and possibly death.2,3 In the U.S. alone, it is estimated that 6.5 million people suffer from chronic skin ulcers and 1.25 million from burns each year,3 consuming over $25 billion dollars of health care spending.4 As a result, several treatment modalities have been devised to correct impaired or dysfunctional wound healing, with the goal of achieving rapid wound closure and a functional, aesthetically-pleasing scar.3,4 This review discusses the basic science of wound healing as well as current and future therapies (Table 1). 4,5

Basic Science of Wound Healing

Wound healing is a complex symphony of biological activity orchestrated by numerous cytokines, proteases, growth factors, cellular elements and extracellular matrix components. The process is divided into three distinct phases: inflammation, proliferation and remodeling, although there is considerable overlap.

Inflammatory Phase: Hemostasis, Inflammation, Chemotaxis

The inflammatory phase begins immediately after wounding and lasts approximately 4–6 days. Hemostasis is the first step, and comprises of vasoconstriction of damaged dermal vasculature and activation of the intrinsic coagulation pathway. A provisional clot is formed from collagen, platelets, thrombin and fibronectin, allowing for key cells to invade the wound site.6 The components also release cytokines and growth factors that initiate the inflammatory response.
Neutrophils are first to enter the scene, attracted to the wound site by interleukin (IL)-1, tumor necrosis factor (TNF)-α, fibrin split products and leukotrienes. They clear invading bacteria and cellular debris by releasing caustic proteolytic enzymes and by generating free radicals via myeloperoxidase. Shortly after their arrival, the neutrophils succumb to an unidentified apoptotic stimulus and are replaced by macrophages 48–96 hours after wounding.6 Specifically, monocytes are drawn into the wound site by chemoattractants such as transforming growth factor (TGF)-β and transform into activated macrophages. 3 Although macrophages do not possess myeloperoxidase, they participate in ongoing pathogen killing by generating nitric oxide (NO), which produces toxic peroxynitrite and hydroxyl radicals through interactions with peroxide ion oxygen radicals.6 Macrophages also begin the proliferative phase by mediating angiogenesis via release of vascular endothelial growth factor (VEGF) and TNFα and fibroplasia through the production of platelet derived growth factor (PDGF), epidermal growth factor (EGF) and TGF-β.6

Proliferative Phase: Epithelization, Provisional Matrix Formation and Angiogenesis

Fibroblasts and endothelial cells are the predominant cells proliferating during this phase, which occurs from days four through 14 after wounding. Epithelialization is initiated when macrophages stimulate fibroblasts with IL-1 and TNF-α, upregulating keratinocyte growth factor (KGF) gene expression in fibroblasts. Through IL-6 and KGF-2, fibroblasts stimulate keratinocytes to proliferate and migrate from the wound edges.6 This process self-perpetuates when the activated keratinocytes express IL-6, which results in further production of NO.
Concurrently, macrophages initiate provisional matrix formation via PDGF and TNF-α. PDGF stimulates fibroblast synthesis of fibronectin, glycosaminoglycans and type III collagen, while TNF-α upregulates integrins that anchor cells to the temporary matrix.3,6 Macrophages also activate TGF-β, which stimulates fibroblast synthesis of type I collagen and increases the secretion of tissue proteinase inhibitors that protect the newly formed matrix.6
Angiogenesis is necessary to sustain this newly formed matrix, thus macrophages and fibroblasts stimulate keratinocytes to express VEGF. NO from endothelial cells also increases the expression of VEGF. VEGF, in turn, results in the formation of new endothelial cells and capillaries at the wound edges.3

Remodeling: Contracture and Maturation

The final phase of wound healing is arguably the most important, as it is during this period that collagen is arranged in an ordered network that provides scar strength. Fibroblasts with-