Wound Healing Normal and Abnormal Mechanisms and Closure Techniques

Embed Size (px)

DESCRIPTION

w

Citation preview

  • Tinjauan PustakaPembimbing dr. Deddy Saputra, Sp. BP-REThe Physiologic Basis of SurgeryChapter 6Wound Healing: Normal and Abnormal Mechanisms and Closure Techniques

  • Chapter 6Wound Healing: Normal and Abnormal Mechanisms and Closure TechniquesPhases Of Wound HealingCytokines/Chemokines and Growth FactorDisturbances Of Wound HealingChronic Wounds and Abnormal Scar FormationWound Closure

  • Phases Of Wound HealingEarly PhasesIntermediate PhasesLate PhasesTerminal phases

  • Early Wound Healing EventsIn all injuries that penetrate the epidermis, blood vessels are disrupted, resulting in hemorrhage. Hemostasis must be the first event achieved in the healing process. Cellular damage occurs with any injury, and this initiates an inflammatory response. The inflammatory response triggers events that have implications for the entire healing process.

  • Hemostasis is created primarily by aggregated platelets and fibrin.Endothelial lining is disrupted, platelet aggregation exposure to collgen and other intravascular and extravascular proteins.Platelets adhere to collagen and release adenosine diphosphate (ADP) in the presence of calcium, and Thrombin produced by the coagulation cascade and fatty acids released by injured cells further platelet aggregation.

  • Platelet adhesion to other platelets and to subendothelial proteins is mediated primarily by fibrinogen and von Willebrand factor although thrombospondin, fibronectin, vitronectin and laminin may also be involvedPlatelet aggregation release of cytokines platelet-derived growth factor (PDGF), transforming growth factor (TGF-a), TGF-B fibroblast growth factor-2 (FGF-2) and platelet derived epidermal growth factor (EGF).

  • The intrinsic and extrinsic coagulation cascades are triggered by separate events. The alternative extrinsic coagulation pathway tissue factor, which binds factor VII or VIIa production of thrombin, catalyzes the conversion of fibrinogen fibrin. Thrombin contributes to the increased vascular permeability seen after injury, facilitates the extravascular migration of inflammatory cells and may have a role in both epithelialization and angiogenesis.

  • Fibrin, along with fibronectin that becomes bound to it, forms a lattice migration of inflammatory, endothelial, and mesenchymal cells, aids in cellular attachment and modulates the migration of various cell types into the wound. The binding of cell surface integrins with fibronectin allows cells to attach to the lattice pull themselves through the lattice as they migrate to sites. The fibrin-fibronectin lattice also binds cytokines released, serves as a reservoir for these factors as healing progresses, has direct effects on inflammatory cells, stimulus to angiogenesis.

  • Hunter (1794) physical signs of inflammation(erythema, edema, pain, and heat)Vasodilation generates erythema and heat in the area of injury, mediated by histamine, kinins, prostaglandins,leukotrienes and endothelial cell products. The migration of cells and fluid into the injured area generates edema. Alterations in pH resulting from breakdown products of tissue and bacteria, along with swelling and decreased tissue oxygenation from damage to the blood supply pain noted in areas of injury.

  • Neutrophils, macrophages, and lymphocytes are leukocytes involved in the inflammatory response to injury.Neutrophils function as defensive units that engulf foreign material and digest it through the action of hydrolytic enzymes Phagocytosed by macrophages or die, releasing oxygen radicals and destructive enzymes into the wound. Macrophages phagocytose bacteria and dead tissue and also secrete matrix metalloproteinases (MMPs) that break down damaged matrix. Macrophages are a primary source of cytokines that stimulate fibroblast proliferation, collagen production, and other healing processes..Lymphocytes produce factors essential for normal healing (Heparin-binding EGF and a form of basic FGF)

  • Intermediate Wound Healing Eventsinclude mesenchymal cell chemotaxis, mesenchymal cell proliferation, angiogenesis, and epithelialization. These processes predominate 2 to 4 days after wounding and are all mediated by citokines.

  • Fibroblasts are the primary mesenchymal cell involved in wound healing healing, although smooth muscle cells are also involved.Additional fibroblasts migrate to the wounded area under the influence of chemotactic factors (PDGF, Fibronectin, EGF) Fibroblasts have the capacity to secrete matrix MMPs including collagenase or (MMP-l), gelatinase (MMP-2) and stromelysin (MMP-3)

  • The mesenchymal cell population in a wound proliferation of both resident and newly arrived cells. PDGF is a potent mitogenic stimulant for both fibroblasts and smooth muscle cells. (TGF-B, TNF, IL-1, lymphokines, insulin, and insulin-like growth factor (IGF)

  • Angiogenesis reconstructs the vasculature in areas where t has been damaged by wounding and is stimulated by high lactate levels, acidic pH, and decreased oxygen tension in the tissue

  • Small capillary sprouts develop on venules at the periphery of the devascularized area grow with endothelial cell proliferation the cells develop a curvature that results in a lumen they contact other sprouts growing from other directionsinterconnect, forming a vascular loop, and the sprouting process begins anew.Cytokines (FGF-l, Heparin, TGF-a, TGF-b,wound fluids, prostaglandins, adipocyte lipids)

  • the sequence of events that comprise epithelialization include cellular detachment, migration, proliferation, and differentiation

  • In first 24 hours after injury, thickening of the basal cell layer begins. Marginal basal cells elongate, detach from the underlying basement membrane, and migrate into the wound as a monolayer across the denuded area. Migrating orient themselves along collagen fibers and exhibit what is called contact guidance. Basal cells at the edge of the denuded area begin to divide 48 to72 hours after injury. Epithelial cell proliferation contributes new cells to the advancing epithelial monolayer. Cells migrate until they reach cells migrating from a different direction( contact inhibition) differentiate into more basal-like cells with hemidesmosomes. Cellular proliferation continues in the new basal cells as a multilayered epidermis is reestablished. Subsequently, new surface cells begin to keratinize.

  • EGF stimulates the migration and proliferation of epithelial cells. TGF-B stimulates epithelial migration, although it slows epithelial proliferation. Keratinocyte growth factor (KGF), also known as fibroblast growth factor-7 (FGF-7), is another potent stimulant of epithelialization.

  • Regenerated epithelium does not retain all of the functional advantages of normal epithelium. There are fewer basal cells in regenerated epidermis, and the interface between epidermis and dermis is abnormal . The epithelium is thicker at the wound edge than in the midportion of a re-epithelialized area.

  • Late Wound Healing EventsCollagen is synthesized by fibroblasts in a complex process that begins 3 to 5 days after injury, increases rapidly for 2 to 4 weeks in most wounds. It gradually replaces fibrin as the primary structural matrix element in the wound. After 4 weeks, collagen synthesis rates decline, eventually balancing the rate of collagen destruction by collagenase. Age, tension, pressure, and stress affect the rate of collagen synthesis. TGF-B stimulates collagen synthesis, whereas glucocorticoids inhibitit

  • Type I collagen makes up 80% to 90 % of collagen in skin10% to 20 % being type III, are seen embryonically and in early phases of wound healing. Type V predominates in smooth muscle. Types II and XI are seen primarily in cartilage, type IV is seen predominantly in basement membranes.

  • After the collagen molecule is synthesized, it is secreted into the extracellular space it appears in the form of procollagenThis linear extension, or registration peptide, interferes with the subsequent aggregation of collagen molecules into fibrils. Successful cleavage of the registration peptide by specific enzymes yields a collagen molecule, which can aggregate into collagen fibrils. Fibril formation is facilitated by proteoglycans in the extracellular matrix.

  • Another critical component of collagen synthesis is the hydroxylation of lysine and proline moieties within the polypeptide chains.Hydroxlproline is found almost exclusively in collagen and serves as a marker of the quantity of collagen in tissue. This hydroxylation process requires specific enzlrnes for lysine and proline and, in addition, requires as cofactors oxygen, vitamin C, a-ketoglutarate, and ferrous iron

  • fibronectin, are critical components of the mature matrix as well as the provisional matrix that initially forms after wounding. As mentioned, a variety of cell types synthesize it. Elastin is a third component of the connective tissue matrix; however, it is not synthesized in response to injury. Normal skin has elastic properties that scar lacks due to the lack of elastin in scar.

  • Wound contraction, lsuch as collagen synthesis, begins approximately 4 to 5 days after wounding. Wound contraction, centripetal movement of the wound edge toward the center of the wound. Maximal wound contraction continues for 12 to 15 days, although it will continue or longer periods if the wound remains open. A wound where the tissue is loose, will contract much more than a wound where the skin is tighter. Wounds with square edges contract more rapidly than circular wounds.Wound contraction occurs to a greater extent in relatively immobile areas

  • Large numbers of myofibroblasts are found in wounds during wound contractionExperimental work in contracting collagen matrices has suggested that fibroblasts within the wound are primary contributors to wound contraction through interactions with surrounding matrixmyoFibroblasts at the wound perimeter are merely fibroblasts with stress fibers in their cytoplasm.

  • Terminal Wound Healing EventApproximately 21days after injury. Although collagen content is maximal at this point, bursting strength of the wound is only l5% of that of normal skin. The process of scarre modeling dramatically increases wound-bursting strength. The greatest rate of increase occurs between 3 and 6 weeks after wounding. By 6 weeks after wounding, the wound has reached 80 % to 90 %of its eventual strengthThe bursting strength of scar never reaches that of unwounded skin, however, and it reaches a maximum of approximately 80% to 90% of skin breaking strength at 6 months.

  • A continual turnover of collagen molecules occurs as old collagen is broken down by some of the matrix MMPs and new collagen is synthesized in a denser, more organized manner along stress linesDuring this period of scar remodeling, the number of intra- and intermolecular cross-links between collagenfibers increases dramatically.

  • DISTURBANCES OF WOUND HEALING

  • Local FactorInfectionHypoxia and SmokingDelivery of oxygen to healing tissues is critical for prompt wound repair. Oxygen is necessary for cellular respiration and for hydroxylation of proline and lysine residues.Smoking can impair tissue oxygenation as it acutelystimulates vasoconstriction

  • RadiationFibroblasts that migrate into irradiated tissue are often abnormal, Collagen is sinthesized to an abnormal degree in irradiated tissue, causing a characteristic fibrosis.The decreased vascularity and increased fibrosis limits the ability of platelets and inflammatory cells to gain access to wounds in the area. The quantity of cytokines released is therefore limited.

  • Systemic FactorsMalnutritionCollagen synthesis essentially stops in the absence of protein intake resulting in impaired healingWound healing slows when carbohydrate or fat stores are limited. Vitamin C is a necessary cofactor for hydroxylation oflysine and proline during collagen synthesisVitamin A is essential for normal epithelialization, proteoglycan synthesis, and normal immune functionVitamin D is required required for bone healing.Exogenous vitamin E impairs wound healing in rats, most likely by influencing theinflammatory response in a corticosteroid-like mannerZinc deficiency can therefore result in an inhibition of cellular proliferation and deficient granulation tissue formation and healing

  • CancerCancer-induced cachexia, which manifests itself as weight loss, anorexia, and asthenia, significantly limits healing.glucose turnover may be increased,leading to glucose intolerance, protein catabolism may be accelerated, unable to alter their metabolism to conserve energy by relying on fat for most of their energy needs. Vitamin C may be preferentially taken up by some tumorsMacrophages do not migrate or function normally in cancer patients. Inflammatory cell dysfunction may limit the availability of cltokines required for healing and may also predispose toinfection.

  • Advanced AgeThe elderly have been shown to heal less efflciently than younger individuals.DiabetesDiabetes is associated with impaired neutrophil chemotaxis and phagocytic functionSteroids and ImmunosuppressionAdrenocortical steroids inhibit all aspects of the healing process.Chemotherapeutic AgentsChemotherapeutic agents impair healing primarily through inhibitidn of cellular proliferation

  • CHRONIC WOUNDSAny wound that is affected by compromising factors may become a chronic wound. Chronic wounds do not respond to standard care and remain substantially unhealed beyond the 6-week period typically required for normal wound healing. They are also characteized by slow progression of either re-epithelialization or contraction.

  • specific pathologies related to chronic wounds include pressure ulcers, diabetic foot ulcers, venous insufficiency ulcers,hematologic uicers from sickle cell disease and polycythemia, infected wounds, neoplastic wounds, radiation ulcers, neoplastic,wounds including Marjolin ulcers, Kaposi sarcoma, and metastatic lesions, and factitious ulcers. progressive healing can be expected once treatable comorbidities have been treated.

  • ABNORMAL SCAR FORMATIONExcessive healing can result in a raised, thickened scar with both functional and cosmetic complications. If the scar is confined to the margins ofthe original wound, it is called a hypertrophic scar