WOUND HEALING
WOUND HEALING
Wound healing is classically divided into four phases: haemostatic, inflammatory, proliferative and remodelling. It is worth noting, however, that some authors currently consider the haemostatic phase to be part of the inflammatory phase.
This simplified categorisation incorporates a wide array of immune cells, signalling pathways and chemical mediators, which contribute to the formation of a healed wound. When wounds penetrate the full thickness of the skin, they always produce a scar.
The haemostatic phase is typically an immediate and short-lived phase, lasting only from seconds to minutes. In response to injury, prostaglandins are released from endothelial cells and platelets, leading to vasoconstriction. Collagen exposed in the damaged vessel walls is adhered to by platelets, which then release chemoattractant substances that help to initiate the coagulation cascade. The result is formation of a fibrin–platelet matrix, which functions to control haemorrhage, concentrate growth factors at the site of damage and form the scaffold required for subsequent wound healing processes (Martin, 1997).
The inflammation phase typically lasts between 3 and 5 days. It is important for limiting wound contamination and induction of the proliferative phase of healing. Vasodilatation and increased capillary leakiness occurs, promoting delivery of nutrients and immune cells to the site of injury and thus causing tissue oedema. The stimulus for this is provided by prostaglandins, kinins, histamine, serotonin and bacterial components. Inflammatory cytokines and other mediators (e.g., platelet-derived growth factor, tumour necrosis factor α, interleukin-1) attract granulocytes to the site of injury soon after the injury has occurred. Neutrophils act by phagocytosing debris and microorganisms. These actions are facilitated by the release of proteases to break down damaged tissue and debris and the use of cellular reactive oxygen species to eliminate pathogens. Other immune cells involved in this phase are macrophages, which are terminally differentiated monocytes present in tissues. Monocytes migrate to the wound from local sites to become macrophages within 24–48 hours of injury. Macrophages participate in phagocytosis and are essential in the wound healing process via the release of growth factors. Regulation of the inflammatory phase is important because overstimulation or prolonged stimulation can damage local tissues and, in severe cases, can trigger the systemic inflammatory response syndrome. Conversely, insufficient inflammation and failure to induce proliferation can lead to development of a chronic wound.
The proliferative phase begins soon after an injury and lasts between 4 days and 2 weeks. Re-epithelialisation involves the migration of epithelial cells from the wound margins and other nearby
skin appendages. The purpose of this process is to cover the wound and re-establish an intact epithelial barrier. Angiogenesis is stimulated by the low oxygen tension and high lactate levels typical of underperfused wound tissues. New vessels form under the influence of angiogenic growth factors and matrix metalloproteinases degrade the extracellular matrix to facilitate passage of these vessels. Once vascularisation is improved and the oxygen tension increases, the angiogenic stimulus is switched off and apoptosis occurs. Fibroblasts migrate into the wound to supplement the provisional wound matrix by the secretion of proteoglycans, glycosaminoglycans, collagen and other proteins. A number of fibroblasts will be stimulated to differentiate into myofibroblasts, thus causing wound contraction, an essential process that reduces the size of the wound.
The remodeling phase is the longest phase of wound healing, lasting up to a year after the injury. Collagen is synthesized for about 5 weeks, initially in a disorganised fashion, and predominantly consisting of type III collagen. Continued turnover produces stronger type I collagen, the fibrils of which are laid down in a more organised arrangement affording greater strength. At 1 week, the wound has 3% of normal breaking strength, at 3 weeks 30% and at approximately 3 months after injury, strength peaks at 70–80%.
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