Wound healing is a complex process that involves an orderly and sequential series of interactions among multiple cell types and tissue structures. Classically, wound healing has been divided into three phases: inflammation, new tissue formation, and matrix formation and remodeling. Each of these phases is unique, and particular cell types play key roles in the different phases.
Once a disruption of the skin barrier occurs, a cascade of inflammatory mediators are released, and wound healing begins. The disruption of dermal blood vessels allows extravasation of blood into the tissues. The ruptured vessels undergo immediate vasoconstriction. Platelets begin the process of coagulation and initiate the earliest phase of inflammation. The formation of the earliest blood clot provides the foundation for future cell migration into the wound. Many inflammatory mediators are released during this initial phase. Once initial homeostasis is achieved, the platelets discharge the contents of their alpha granules into the extravascular space. Alpha granules contain fibrinogen, fibronectin, von Willebrand’s factor, factor VIII, and many other proteins. The fibrinogen is converted into fibrin, which aids in formation of the fibrin clot. Platelets also play a critical role in releasing growth factors and proteases. The best known of these is platelet derived growth factor (PDGF), which helps mediate the formation of the initial granulation tissue.
During the late portion of the inflammatory phase, leukocytes are seen for the first time. Neutrophils make up the largest component of the initial leukocyte response. Neutrophils are drawn into the area by various cytokines and adhere to the activated vascular endothelium. They enter the extravascular space by a process of diapedesis. These early-arriving neutrophils are responsible for the recruitment of more neutrophils, and they also begin the process of killing bacteria by use of their internal myeloperoxidase system. Through the production of free radicals, neutrophils are efficient at killing large numbers of bacteria. Neutrophil activity continues for a few days, unless the wound is contaminated with bacteria. Once the neutrophil activity has cleared the wound of bacteria and other foreign particles, monocytes are recruited into the wound and activated into macrophages. Macro- phages are critical in clearing the wound of neutrophils and any remaining cellular and bacterial debris. Macrophages are capable of producing nitrous oxide, which can kill bacteria and has also been shown to decrease viral replication. Macrophages also release various cytokines, including PDGF, interleukin-6, and granulocyte colony-stimulating factor (G-CSF), which in turn recruit more monocytes and fibroblasts into the wound.
At this point, new tissue formation, the proliferative phase of wound healing, has begun. This phase typically begins on the third day and ends about 14 days after the initial insult. It is marked by reepithelialization and formation of granulation tissue. Reepithelialization occurs by the movement of epithelial cells (keratinocytes) from the free edge of the wound slowly across the wound defect. The migrating cells have the distinct phenotype of basal keratinocytes. It is believed that a low calcium concentration in the wound causes the keratinocytes to take on the characteristics of basal keratinocytes. PDGF is an important stimulant for keratinocytes and is partially responsible for this migration across the wound. The migrating keratinocytes contain the keratin pairs 5,14 and 6,16. They secrete vascular endothelial growth factor, which promotes the production of dermal blood vessels. At the same time the keratinocytes are migrating, the underlying fibroblasts are synthesizing a backbone matrix, made up predominantly of type III collagen and some proteoglycans. Some of the fibroblasts are converted into myofibroblasts by PDGF and tumor growth factor-β1. These myofibroblasts are important in that they cause he overlying wound to contract, decreasing its surface.
The final phase of wound healing involves scar maturation and tissue remodeling. This phase overlaps in time with the first two phases; it is said to begin with the production of the first granulation tissue. This phase extends for months and is complete when most of the collagen III and fibronectin have been replaced by mature type I collagen. In the final mature scar, the collagen fibers are oriented in large bundles running perpendicular to the basement membrane zone. The resulting scar has only 80% of the tensile strength of the uninjured skin.