Wound Healing Part 3...

Maturation Phase

Collagen

Collagen remodeling during the maturation phase depends on continued collagen synthesis in the presence of collagen destruction. Collagenases and matrix metalloproteinases in the wound assist removal of excess collagen while synthesis of new collagen persists. Tissue inhibitors of metalloproteinases limit these collagenolytic enzymes, so that a balance exists between formation of new collagen and removal of old collagen.
During remodeling, collagen becomes increasingly organized. Fibronectin gradually disappears, and hyaluronic acid and glycosaminoglycans are replaced by proteoglycans. Type III collagen is replaced by type I collagen. Water is resorbed from the scar. These events allow collagen fibers to lie closer together, facilitating collagen cross-linking and ultimately decreasing scar thickness. Intramolecular and intermolecular collagen cross-links result in increased wound bursting strength. Remodeling begins approximately 21 days after injury, when the net collagen content of the wound is stable. Remodeling may continue indefinitely.
The tensile strength of a wound is a measurement of its load capacity per unit area. The bursting strength of a wound is the force required to break a wound regardless of its dimension. Bursting strength varies with skin thickness. Peak tensile strength of a wound occurs approximately 60 days after injury. A healed wound only reaches approximately 80% of the tensile strength of unwounded skin.

Cytokines

Cytokines have emerged as important mediators of wound healing events. By definition, a cytokine is a protein mediator, released from various cell sources, which binds to cell surface receptors to stimulate a cell response. Cytokines can reach their target cell by endocrine, paracrine, autocrine, or intracrine routes. Some important cytokines are described as follows:

• Epidermal growth factor was the first cytokine described and is a potent mitogen for epithelial cells, endothelial cells, and fibroblasts. Epidermal growth factor stimulates fibronectin synthesis, angiogenesis, fibroplasia, and collagenase activity.
• Fibroblast growth factor is a mitogen for mesenchymal cells and an important stimulus for angiogenesis. Fibroblast growth factor is a mitogen for endothelial cells, fibroblasts, keratinocytes, and myoblasts. This factor also stimulates wound contraction and epithelialization and production of collagen, fibronectin, and proteoglycans.
• PDGF is released from the alpha granules of platelets and is responsible for the stimulation of neutrophils and macrophages and for the production of transforming growth factor-β. PDGF is a mitogen and chemotactic agent for fibroblasts and smooth muscle cells and stimulates angiogenesis, collagen synthesis, and collagenase. Vascular endothelial growth factor is similar to PDGF but does not bind the same receptors. Vascular endothelial growth factor is mitogenic for endothelial cells and plays an important role in angiogenesis.
• Transforming growth factor-β is released from the alpha granules of platelets and has been shown to regulate its own production in an autocrine manner. This factor is an important stimulant for fibroblast proliferation and the production of proteoglycans, collagen, and fibrin. The factor also promotes accumulation of the extracellular matrix and fibrosis. Transforming growth factor-β has been demonstrated to reduce scarring and to reverse the inhibition of wound healing by glucocorticoids.
• Tumor necrosis factor-α is produced by macrophages and stimulates angiogenesis and the synthesis of collagen and collagenase. Tumor necrosis factor-α is a mitogen for fibroblasts.