Pathophysiology
The complex healing process can be divided into 3 or 5 phases, depending on whether or not haemostasis is included in the inflammatory phase and the re-epithelialisation phase is included in granulation. Furthermore, these different phases overlap with one another, to a certain degree.
The three main phases
of a normal healing
Three essential phases of healing
The inflammatory phase begins immediately and lasts for a few hours to a few days in acute wounds. This process can last for several weeks or even months in chronic wounds and is sustained by the disease that initiated the chronic wound.
The clot formed after the rupture of blood vessels covers the wound and forms a temporary extracellular matrix - composed of fibrin and fibronectin - which seals the wound and minimises blood loss and helps to guide cell migration. Platelets secrete and activate mediators to recruit inflammation cells (polynuclear neutrophils and macrophages), fibroblasts and endothelial cells. Bleeding is controlled at the end of the inflammatory phase, and the wound bed is cleaned through phagocytosis.
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The granulation phase can begin quickly with the proliferation of endothelial cells and fibroblasts to lead to the formation of new blood vessels (angiogenesis) and the synthesis of a new extracellular matrix (ECM). As the new ECM is re-modelled, the existing matrix is degraded by a number of Proteases, enzymes known as Matrix Metalloproteinase's (MMP's), the MMP's help with autolytic debridement (cleansing) of the wound, and cell migration. Their levels increase within the wound after injury & decrease when the inflammation of the wound is resolved.
The fibroblasts then acquire the morphology and biochemical characteristics of smooth muscle cells to become myofibroblasts. This essential differentiation phenomenon takes place under the influence of cytokines and growth factors released during the previous phase.
The myofibroblasts are the main cells responsible for synthesis of the extracellular matrix and contribute to reorganisation of this matrix as the wound contracts. The extracellular matrix plays an important controlling role because some factors may be stored in latent form and activated when they are released. Re-epithelialisation occurs to close the wound with the migration of epithelial cells starting from the edges of the wound and skin appendages. Differentiation of keratinocytes then helps to restore the barrier function of the epidermis.
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The last remodeling phase will last for several months and will result in the final scar. This phase begins early, during the formation of the granulation tissue, with progressive reorganisation of the matrix under the influence of myofibroblasts. These cells contract their microfilament bundles which are bonded to the extracellular matrix, causing compaction of the collagen network and contraction of the wound. New components are then secreted to increase the density of the matrix and to stabilise it. The proportion of the different types of collagen changes: the proportion of type I collagen increases, while the proportion of type III collagen decreases (from 30% to 10%). The cell density of myofibroblasts is reduced by apoptosis to leave room for fibroblasts which will strengthen the extracellular matrix, giving better resistance to mechanical forces.
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