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| Scar Tissue |
| An Overview Skin healing and scar tissue formation is a complex process entails a number of overlapping phases, including inflammation, epithelialization, angiogenesis and collagen deposition. Ultimately these processes are resolved leading to a mature wound and macroscopic scar formation. Although inflammation and repair mostly occur concurrently, the sensitivity of the process is underscored by the consequences of disruption of the balance of regulatory cytokines. Consequently, cytokines, which are central to this constellation of events, have become targets for therapeutic intervention to modulate the wound healing process. Depending on the cytokine and its role, it may be appropriate to either enhance (recombinant cytokine, gene transfer) or inhibit (cytokine or receptor antibodies, soluble receptors, signal transduction inhibitors, antisense) the cytokine to achieve the desired outcome. Acute inflammation, the first response to injured skin Response to injury in the skin initiated by coagulation and an acute local inflammation. This follows by mesenchymal cell migration, proliferation and matrix synthesis. Failure to resolve the inflammation can lead to chronic nonhealing wounds, whereas uncontrolled matrix accumulation, often involving aberrant cytokine pathways, leads to excess scarring and fibrotic sequelae. Manipulation of cytokines provides therapeutic opportunities to control abnormal wound healing and scar formation. Connective Tissue Repair: where repair cannot be accomplished with resolution, scar tissue forms. Fibroblasts migrate to the site of injury and proliferate following stimulation by TGF-beta and many other cytokines and growth factors. New endothelial cells proliferate upon induction by VEGF. This forms granulation tissue within 3-5 days of injury. Granulation tissue is pink in appearance and characterized by the formation of new vessels, production of ECM, fibrosis, and initial repair that lays down the structure on which the final scar will be formed. Angiogenesis proceeds by formation of new leaky vessels from existing vessels. Basic fibroblast growth factor and VEGF induce angiogenesis. Fibrosis develops with deposition of ECM by fibroblasts. Collagen synthesis and decreased degradation of collagen gives strength to the healing wound. IL-1, TNF, TGF-beta, b-FGF all work to increase the production of collagen locally. Specialized enzymes degrade collagen (metalloproteinases, gelatinases, and collagenases) to remodel the wound and form the final scar. The following cascade explain sequence of events occur in tissue injury: Skin injury, blood vessel damage, coagulation response, platelet aggregation, release of cytokines from aggregated, degranulating platelets, TGF-beta (transforming growth factor), PDGF (platelet derived growth factor), VEGF (vascular endothelial growth factor), leakage of plasma proteins influenced by VEGF, involvement of TGF-beta in all steps of wound healing from the initial clot generation to matrix formation and remodeling. Release of adhesion molecules, (VCAM, ICAM, ELAM) induced by cytokines, facilitated extravasation of leukocytes by adhesion molecules, release of proteases from leukocytes mediated by TGF-beta, IL-1, TNF. This causes phagocytosis of debris, microbes and degraded matrix components. Neutrophil recruitment typically peaks around 24-48 hours post wounding, followed by an increasing representation of monocytes which are essential for optimal wound healing. Formation of a new epithelium and granulation tissue Resolution of a wound of infections agents and debris triggers relief of inflammation and followed by migration and proliferation of epithelial cells. This ensures closure of exposed area of the wound. Migration of epithelial cells is dependent to the growth factors and loss of contact between adjacent cells. Once contact is established between opposing keratinocytes, migration stops. This is majority mediated by TGF-beta. Underlying this newly-formed epithelium, granulation tissue forms. Granulation tissue consists of fibroblasts and new vessels. Neovascularization is under the control of different cytokines. TNF, IL-1 and TGF-beat are among the important ones. This process is under a tight control and there are cytokines responsible to stop the process at certain point. Matrix formation and collagen synthesis By deposition of granulation tissue, fibroblast initiates collagen deposition. TGF-beta contributes to the fibrotic process by stimulating fibroblasts to synthesize collagen I, III and V, proteoglycans and fibronectin. TGF-beta also inhibits proteases, favoring matrix accumulation. In contrast, PDGF, released by activated macrophages, fibroblasts and endothelial cells, upregulates proteases. PDGF, also has a role in matrix deposition. IL-1 and TNF also influence wound healing either directly by affecting fibroblasts or endothelial cells or indirectly by inducing other cytokines and growth factors. Collagen Remodeling This phase is also cytokine mediated. Serine proteases, elastase and matrix metaloproteases function to deposit, remove and organize collagen and other matrix proteins. Tensile strength of the scar tissue would not be as strong as the original tissue, however, it is comparable in many respects. The more prolonged the inflammation, the more likely formation of scar tissue. Even though proteases work to eliminate excess collagen, as long as the inflammation persists, matrix deposition by TGF-beta is active. Inhibition of this growth factor is induced by various immunoglobulins and decorin which act to reduce scarring. IL-10 and inhibitors of TNF also demonstrate some activity in collagen removal and activation of proteases.
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| Healing by First Intention involves healing of clean edges such as a surgical cut. A fibrin clot closes the wound quickly. Neutrophils are evident within 24 hours, followed by epithelial cell migration along the cut surfaces to meet within 48 hours. Macrophages and granulation tissue predominate by day 3 with collagen fibers being secreted. Granulation tissue and angiogenesis are evident by 3-5 days. Collagen becomes organized to bridge the wound by the end of the first week. Functional epidermis is formed, although dermal structures are permanently disrupted. After one week, would strength is only 10% of normal, but increases to 70-80% by 3 months. Healing by Second Intention occurs with more serious wounds that are larger, less linear, with edges not opposed. Inflammation and scarring leads to wound contraction at the margins. Granulation tissue will cover a larger area, persist for longer, and develop into thicker scar tissue. Secondary infection and a heightened inflammatory response is more likely. Infection, corticosteroids, and poor perfusion decrease the rate of healing. Location of the injury and the type of tissue also matters. |
