Wound Healing =)

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    Mechanism of wound healing /case 9

    Definition

    A wound occurs when the integrity of any tissue is compromised

    (e.g. skin breaks, muscle tears, burns, or a bone fractures). A

    wound may be caused as a result of a fall, or a surgical procedure;

    or by an infectious disease; or by an underlying condition.

    Restorative process

    Regeneration: replacement of exact specializedstructure and function; injured tissue replaced withECM and specialized cells of the same

    type/organization

    Repair : stop gap mechanism by which injured tissue isreplaced with connective tissue resulting in scarformation (imperfect structure/function)

    *often, wound healing is a combination of repair andregeneration process

    Wound heals in 4 phases that partially overlap:

    Hemostasis

    Inflammation Proliferation (fibroplasia) phase

    Remodeling (maturation) phase

    HOMEOSTASIS

    Major Cell Player:

    -Platelets

    Adhesion ,Activation , and aggregation

    Major Events:

    -Tissue trauma results in disruption of vasculature;components of blood come in contact with cells andECM components

    -Vascular spasm; vasoconstriction (slow blood flow)

    -Platelet plug formation

    -Activation of clotting cascade (enzyme series)

    -Formation of fibrin clot

    Stops bleeding

    Provisional scaffold for cell attachment andmigration

    Clot retraction (condensation)

    -Fibrinolysis (clot digestion / removal)1

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    Mechanism of wound healing/ case 9

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    Mechanism of wound healing/ case 9

    INFLAMMATION

    After the initial insult and resultant vasoconstriction,vascular permeability is then increased. The classic signs ofinflammation are generated by these metabolites. For

    example, the redness caused by vasodilation is primarily aresult of prostacyclin (PGI2). Others include prostaglandin A,prostaglandin D, and prostaglandin E (PGE). Swelling iscaused by the leakage of plasma proteins through gaps inthe vascular endothelium. This edema is potentiated byPGE2 and prostaglandin F2-alpha (PGF2-alpha). PGI2 andPGE2 promote local blood flow, causing the localizedwarmth in the area of inflammation, but also allow for entryof inflammatory cells into the wound, which is due toincreased vascular permeability. These cells then release

    cytokines responsible for fever production. Pain is elicited bythe effects of PGI2, PGE, and PGE2 on peripheral sensorynerve endings. Eicosanoids thus exert mediatory actions on

    the injured tissue's platelet plug formation, vascularpermeability, and cellular chemotaxis to influence woundhealing. Another class of mediators involved in this stage ofwound healing is the cytokines. After hemostasis has beenobtained, polymorphonuclear (PMN) leukocytes enter thearea of injury, drawn by chemotactic substances such asthose released with the degranulation of platelets. These

    are then the predominant cells for the first 3 days afterwounding, with the number peaking at approximately 48hours . They are the first to begin bactericidal activitiesusing inflammatory mediators and oxygen free radicalmetabolites. However, PMN leukocytes have been shown tonot be crucial to the wound healing process, with normalhealing progression occurring experimentally in theirabsence. Other leukocytes, specifically helper T cells, arethe source of the cytokine interleukin (IL)2. IL-2 promotesthe proliferation of further T cells to aid in the immunogenic

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    Mechanism of wound healing/ case 9

    response to injury. IL-1 is a cytokine produced bymacrophages. Circulating monocytes enter the wound afterthe PMN leukocytes and reach their maximum numbers 24-36 hours later . They mature into tissue macrophages,which carry the major load of wound debridement.

    Macrophages secrete substances such as bFGF, achemotactic and mitogenic factor for fibroblasts andendothelial cells, and IL-1. IL-1 stimulates the proliferation ofmultiple cells of inflammation and induces the replication ofendothelial cells, promoting angiogenesis. The depletion ofmacrophages causes a severe alteration in wound healing,with poor debridement and inadequate fibroblastproliferation and angiogenesis. As eicosanoids accumulatein the wound during the progression of the inflammatoryphase, they begin to interact with the cells present. Forexample, a rise in the ratio of PGF2-alpha to PGE2 duringlate inflammation is a stimulus for fibroblasts to begin to

    synthesize collagen and ground substance. Additionally, themacrophage-derived growth factors are now at optimallevels, strongly influencing the influx of fibroblasts, thenkeratinocytes and endothelial cells, into the wound. Thecellular population of the wound becomes predominantlymononuclear, with a declining number of neutrophils andmacrophages, signaling the end of the inflammatory phaseand the initiation of the proliferativePhase

    Major Events:

    Vasodilation and increased capillary permeability Chemotaxis of neutrophil and monocyte induced by

    fibrinopeptides and fibrin degradation products

    Phagocytosis of bacteria and other microorganisms

    Debridement (removal of tissue debris)

    Provisional matrix (e.g., fibrin) replaced byproteoglycans, glycosaminoglycans, and collagen

    PROLIFERATION

    The proliferative phase of wound healing begins approximately 2-3days after wounding and is signaled by the arrival of fibroblasts intothe wound. Fibroblasts migrate from the wound margins using the

    fibrin-based provisional matrix established during the inflammatoryphase. Within the first week after wounding, fibroblasts are driven bymacrophage-derived bFGF, TGF-beta, and PDGF to proliferate andsynthesize glycosaminoglycans and proteoglycans, the buildingblocks of the new extracellular matrix of granulation tissue, andcollagen. Because macrophage numbers have begun to diminish inthe acute wound by this time, fibroblasts start to produce bFGF,TGF-beta, and PDGF. They also begin producing keratinocytegrowth factor and insulinlike growth factor-1. Fibroblasts become thedominant cell type, reaching their peak numbers at 7-14 days. Aftersecretion of collagen molecules, fibroblasts then assemble themextracellularly into collagen fibers. These fibers are then cross-linked

    and organized into bundles. Collagen is the major component ofacute wound connective tissue, with net production continuing for thenext 6 weeks. The increasing content of wound collagen correlateswith increasing tensile strength. During fibroblast proliferation,keratinocyte and endothelial cell populations are also stimulated toincrease their numbers. In turn, keratinocytes and endothelial cellsproduce their own growth factors stimulatory for their respective cellproliferation. Simultaneously with cellular proliferation, angiogenesisin the developing granulation tissue occurs through budding fromintact vessels at wound margins and requires endothelial cellproduction from factors described previously. Thisneovascularization accompanies the advancing line of fibroblasts

    into the wound to provide them with nutrients and to produceplasminogen activator and collagenase. This begins the degradationof the fibrin clot and provisional matrix once the new granulationtissue (ie, extracellular matrix, collagen, capillaries) is laid down.Granulation tissue production continues until the defect is covered.Finally, as the hyaluronic acidcontaining provisional matrix isbroken down, the decreasing hyaluronic acid concentration andrising chondroitin sulfate levels signal the slowing of fibroblastmigration and proliferation. This shift in the ratio of theseglycosaminoglycans acts to inhibit fibroblast activity, inducing them

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    Mechanism of wound healing/ case 9

    to differentiate, and thus initiating the maturation phase of woundhealing.

    Major Events:

    Deposition of extracellular matrix componentsincluding collagen, proteoglycans, etc.

    Replacement of provisional matrix

    Increase in tensile strength

    Angiogenesis

    Epithelialization

    Wound contraction (e.g., myofibroblast)

    MATURATION

    New collagen production remains the dominant process inwound healing from the first week after wounding untilapproximately 6 weeks. Collagen is deposited randomly inacute wound granulation tissue. Remodeling of the collageninto a more organized structure occurs during woundmaturation, increasing the wound's tensile strength. Duringthe formation of the scar, the type III collagen of thegranulation tissue is replaced by type I collagen until thenormal skin ratio of 4:1 for type 1 collagen to type IIIcollagen is present. With the remodeling process, a dynamicturnover of collagen occurs but collagen synthesis equals

    that of collagenolysis. This results in a tensile strengthplateau achieved after approximately 2 years postinjury ofapproximately 80% of normal strength, beyond whichwound strength cannot exceed. The wound is eventuallyclosed by the migration of epithelial cells from the woundedge, filling the defect until they reach other epithelial cellsand halt their advance due to contact inhibition. This addsnothing to wound strength, and remodeling continuesbeneath the epithelial cover. When wound fibroblasts reacha concentration with which their density causes contactinhibition, they differentiate into myofibroblasts containing

    alpha-smooth muscle actin fibrils. These cells tightly bind toeach other and to the wound margins, drawing the woundedges closer together. The extent of importance of the roleof myofibroblasts in wound contraction is, at present,equivocal. Some investigators believe the