WOUND HEALING koushik

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it covers most of the aspects of wound healing and local wound care along with some recent advances

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WOUND HEALING AND LOCAL WOUND CARE:

WOUND HEALING AND LOCAL WOUND CARE By : Dr. P. Koushik Guide: Dr.(Brig) B. B. Dogra 1 28/02/2012

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Dr. P. Koushik Chief Resident Dr. D. Y. Patil medical college Pimpri , Pune. 2

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CONTENTS :

CONTENTS INTRODUCTION DEFINITIONS PHASES OF WOUND HEALING HEALING BY PRIMARY INTENTION HEALING BY SECONDARY INTENTION HEALING BY TERTIARY INTENTION HEALING IN SPECIFIC TISSUE GIT BONE FETAL WOUND HEALING FACTORS AFFECTING WOUND HEALING CLASSIFICATION OF SURGICAL WOUNDS HYPERTROPHIC SCARS AND KELOIDS LOCAL WOUND CARE RECENT ADVANCES 4

Introduction :

Introduction A surgeon’s role in wound management is to create an environment in which the healing process can proceed in an optimal fashion . As noted by John Hunter, “. . . the injury alone has in all cases a tendency to produce the disposition and the means of a cure.” 5

Definitions :

Definitions Wound – Disruption of normal tissue structure and function. Wound healing – Is an intricate process in which the skin (or another organ-tissue) repairs itself after injury Regeneration –Perfect restoration of the pre existing tissue architecture in the absence of scar formation . Acute wounds –Healing occurs through an orderly and timely process leading to restoration and functional integrity Chronic wounds –Wounds fail to follow this course and are often associated with underlying pathology. 6

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PHASES OF WOUND HEALING Wound healing has three main phases : Inflammation, Proliferation, and Remodelling 8

Events after injury:

Events after injury After injury there is initial local vasoconstriction of arterioles and capillaries Vasodilation Increased vascular permeability 9

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Increased permeability is due to - formation of endothelial gaps in venules , - direct endothelial injury, - delayed prolonged leakage, - leucocyte mediated endothelial injury, -increased transcytosis and leakage from new vessels The combination of intense vasodilation and increased vascular permeability leads to clinical findings of inflammation, rubor (redness), tumor (swelling), calor (heat), and dolor (pain). 10

I. INFLAMMATORY PHASE:

I. INFLAMMATORY PHASE Hemostasis is also aided by plugging of capillaries with erythrocytes . 11 factor IV & V Von Willebrand factor(factor VIII) HEMOSTASIS

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Trap RBC’s to form clot and seal the wound. The lattice framework that results will be scaffold for the endothelial cells, inflammatory cells, fibroblasts. Degradation of the cell membrane leads to formation of Thromboxane A 2 and Prostaglandin F 2 ɑ which assist in platelet aggregation and vasoconstriction. 12

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13 Platelet α granules secrete Platelet derived growth factor Transforming growth factor Insulin like growth factor Fibronectin Fibrinogen Thrombospondin von Willebrand factor The dense bodies contain vasoactive amines like serotonin leading to increased vascular permeability and vasodilatation

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Polymorphonuclear cells (PMNs):

Polymorphonuclear cells (PMNs) First infiltrating cells to enter the wound site, peaking at 24 to 48 hours Neutrophil migration is stimulated by - Increased vascular permeability, - local prostaglandin release PMNs are also a major source of cytokines early during inflammation, especially TNF-α, also release proteases such as collagenases. Following functional activation neutrophils scavenge necrotic debris, foreign material, and bacteria. 15

Factors resulting in neutrophil adherence and migration:

Factors resulting in neutrophil adherence and migration 16 C5a Leukoterine B4 Platelet aggrevating factor Thrombin Leukoterine C4 &D4 neutrophil adherence Monocytes and endothelial cells IL-1, TNF α Neutrophil migration Lysosomes, Elastase , Proteases in ECM

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Stimulated neutrophils generate free oxygen radicals with electrons donated by the reduced form of nicotinamide adenine dinucleotide phosphate, (NADPH ). The electrons are transported across the membrane into lysosomes where superoxide anion ( O 2- ) and hydroxyl (OH - ) are formed. This very potent free (OH - ) radical is bactericidal , but it is also toxic to neutrophils and surrounding viable tissues. Migration of PMNs stops when wound contamination has been controlled , usually within the first few days after injury. 18

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PMNs do not survive longer than 24 hours If wound contamination persists or secondary infection occurs, continuous activation of the complement system and other pathways provides a steady supply of chemotactic factors, resulting in a sustained influx of PMNs into the wound. PMNs are not essential to wound healing because their role in phagocytosis and antimicrobial defense may be taken over by macrophages. Sterile incisions will heal normally without the presence of PMNs 19

Macrophages:

Macrophages Second population of inflammatory cells that invades the wound . Macrophage is the one cell that is truly central to wound healing, serving to orchestrate the release of cytokines and stimulate many of the subsequent processes of wound healing. 20

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Chemotaxis of migrating blood monocytes occur in 24- 48 hours. Chemotactic factors specific for monocytes include Bacterial products, Fibronectin, Complement degradation products (C5a), Collagen, Thrombin, TGF-β 21

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Activated integrin expression promotes adhesion-mediated gene induction in monocytes that transforms them into wound macrophages. Increased phagocytic activity and selective expression of cytokines. 22

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Bacterial debris such as lipopolysaccharide – Activate monocytes to release free radicals and cytokines that mediate angiogenesis and fibroplasia . IL-2 increases the release of free radicals and thus enhances bactericidal activity. Activity of the free radicals is potentiated by IL-2. 23

Functions of Macrophages:

Functions of Macrophages Apoptosis of PMN Permit surface recognition of opsonized pathogens and facilitate phagocytosis . Activated wound macrophages also produce nitric oxide which has antimicrobial properties . Phospholipase is induced, causing enzymatic degradation of the cell membrane phospholipids, releasing thromboxane A2 and prostaglandin F2α. Releases leukotriene B4 & C4 – potent neutrophil chemoattractant . Release proteinases, including matrix metalloproteinases (MMP-1, MMP-2, MMP-3, and MMP-9) which degrade the ECM and are crucial for removing foreign material, promoting cell movement through tissue spaces, and regulating ECM turn over . Release growth factors that stimulate fibroblast, endothelial cell, and keratinocyte proliferation 24

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Cytokine Activity in Wound Healing:

Proinflammatory Cytokines CYTOKINE CELL SOURCE BIOLOGIC ACTIVITY TNF- α Macrophages PMN margination and cytotoxicity , with or without collagen synthesis; provides metabolic substrate IL-1 Macrophages Fibroblast and keratinocyte chemotaxis , collagen synthesis Keratinocytes IL-2 T lymphocytes Increases fibroblast infiltration and metabolism IL-6 Macrophages Fibroblast proliferation , hepatic acute phase protein synthesis PMNs Fibroblasts IL-8 Macrophages Macrophage and PMN chemotaxis , keratinocyte maturation Fibroblasts IFN- γ T lymphocytes Activates macrophages and PMNs, retards collagen synthesis and cross-linking, stimulates collagenase activity Macrophages Cytokine Activity in Wound Healing 26 Anti-inflammatory Cytokines CYTOKINE CELL SOURCE BIOLOGIC ACTIVITY IL-4 T lymphocytes Inhibition of TNF, IL-1, IL-6 production; fibroblast proliferation, collagen synthesis Basophils Mast cells IL-10 T lymphocytes Inhibition of TNF, IL-1, IL-6 production; inhibition of macrophage and PMN activation Macrophages Keratinocytes

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CYTOKINE SOURCE FUNCTIONS Platelet-derived growth factor (PDGF) Platelets, macrophages, endothelial cells, keratinocytes Chemotactic for PMNs, macrophages, fibroblasts, activates PMNs, macrophages, and fibroblasts; mitogenic for fibroblasts, endothelial cells; stimulates production of MMP s, fibronectin, and HA; stimulates angiogenesis and wound contraction; remodeling Transforming growth factor-β (including isoforms β1, β2, and β3 ) (TGF- β ) Platelets, T lymphocytes, macrophages, endothelial cells, keratinocytes, fibroblasts Chemotactic for PMNs, macrophages, lymphocytes, and fibroblasts; stimulates TIMP synthesis , keratinocyte migration, angiogenesis, and fibroplasia ; inhibits production of MMPs and keratinocyte proliferation ; induces TGF- β production Epidermal growth factor (EGF) Platelets, macrophages Mitogenic for keratinocytes and fibroblasts; stimulates keratinocyte migration Transforming growth factor- α (TGF- α ) Macrophages, T lymphocytes, keratinocytes Similar to EGF Fibroblast growth factor-1 and -2 family (FGF) Macrophages, mast cells, T lymphocytes, endothelial cells, fibroblasts Chemotactic for fibroblasts; mitogenic for fibroblasts and keratinocytes; stimulates keratinocyte migration, angiogenesis, wound contraction, and matrix deposition Keratinocyte growth factor (also called FGF-7 ) (KGF) Fibroblasts Stimulates keratinocyte migration, proliferation, and differentiation Insulin-like growth factor (IGF-I) Macrophages, fibroblasts Stimulates synthesis of sulfated proteoglycans, collagen, keratinocyte migration, and fibroblast proliferation; endocrine effects similar to those of growth hormone Vascular endothelial cell growth factor ( VEGF) Keratinocytes Increases vasopermeability ; mitogenic for endothelial cells 27

T lymphocytes:

T lymphocytes Another population of inflammatory/immune cells that routinely invades the wound . Less numerous than macrophages, numbers peak at about 1 week post injury Bridge the transition from the inflammatory to the proliferative phase of healing Depletion of most wound T lymphocytes decreases wound strength and collagen content . Effects on fibroblasts by producing Stimulatory cytokines – IL-2, fibroblast activating factor. Inhibitory cytokines – TGF- β , TNF- α , IFN-ɣ. 28

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Role of IFN-ɣ secreted by T lymphocytes Stimulate macrophages to release cascade of cytokines Decrease synthesis of prostaglandins Suppresses collagen sy nthesis Inhibits macrophages from leaving the site of injury. It appears to be an important mediator of chronic non healing wounds. 30

II. Proliferation Phase:

II. Proliferation Phase Acute responses of hemostasis & inflammation begin to resolve The scaffolding is laid for repair of the wound through Angiogenesis Fibroplasia Epithelialization 31

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This phase is characterized by formation of granulation tissue which consists of Capillary bed Fibroblasts Macrophages Loose arrangement of collagen, fibronectin, hyaluronic acid Many studies have used various growth factors to modify the granulation tissue, particularly fibroplasia. Adenoviral transfer Topical application and subcutaneous application of PDGF TGF- β KGF VEGF EGF 32

ANGIOGENESIS :

ANGIOGENESIS Process of new blood vessel formation Its necessary to support healing wound environment 33

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34 Injury FGF, PDGF, TGF- β Attachment of fibrin, fibronectin, fibrinogen Express adhesion molecules ( eg : integrin) Injuried endothelial cells Migration of endothelial cells into wound Degrade basement endothelium Matrix degrading enzymes ( plasmin & MMP) released & activated Up regulation of VCAM-1 Endothelium Adhering blood cells Numerous soluble factors

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Capillary tube formation is a complex process Involves cell – cell, cell – matrix interactions Modulated by PECAM-1 β 1 integrin aids in stabilizin g these contacts New capillaries differentiate Arterioles Venules Others undergo involution & apoptosis with subsequent ingestion by macrophages. 35

FIBROPLASIA :

FIBROPLASIA Fibroblasts are specialized cells that differentiate from resting mesenchymal cells in connective tissue. 36 (PDGF, TGF- β), C5 fragments, thrombin, TNF- α, eicosanoids, elastin fragments, leukotriene B 4 , and fragments of collagen and fibronectin

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Fibroblasts can also stimulate replicati on in an autocrine manner by releasing FGF-2. Primary function of the fibroblasts is synthesis of collagen , which begins in the infl ammation phase of healing. The rate of collagen synthesis declines after 4 weeks and eventually balances the rate of collagen destruction by collagenase (MMP-1 ). At this point the wound enters a phase of collagen maturation. 37

EPITHELIALIZATION:

EPITHELIALIZATION Re-epithelialization of wounds begins within hours after injury The wound is rapidly sealed by clot formation and then by epithelial (epidermal) cell migration across the defect. Keratinocytes located at the basal layer of the residual epidermis or in the depths of epithelium-lined dermal appendages migrate to resurface the wound. Epithelialization involves a sequence of changes in wound keratinocytes 38

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Epidermal cells express integrin receptors that allow them to interact with ECM proteins such as fibronectin . The migrating cells dissect the wound by separating the desiccated eschar from viable tissue. This path of dissection is determined by the integrins that the epidermal cells express on their cell membranes. Degradation of the ECM, required if epidermal cells are to migrate between the collagenous dermis and fibrin eschar , is driven by epidermal cell production of collagenase (MMP-1) and plasminogen activator, which activates collagenase and plasmin. 39

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The migrating cells are also phagocytic and remove debris in their path . Cells behind the leading edge of migrating cells begin to proliferate. The epithelial cells move in a leapfrog and tumbling fashion until the edges establish contact. If the basement membrane zone is not intact, it will be repaired first. Absence of neighbouring cells at the wound margin may be a signal for the migration and proliferation of epidermal cells . 40

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Local release of EGF, TGF-α, and KGF and increased expression of their receptors may also stimulate these processes. Basement membrane proteins, such as laminin , reappear in a highly ordered sequence from the margin of the wound inward. After the wound is completely re-epithelialized, the cells become columnar and stratified again while firmly attaching to the re-established basement membrane and underlying dermis. 41

Extracellular Matrix (ECM):

Extracellular Matrix (ECM) Functions : Mechanical support for cell anchorage and cell migration, and maintenance of cell polarity Control of cell growth – Regulates cell proliferation by signalling through cellular receptors of the integrin family . Maintenance of cell differentiation. Scaffolding for tissue renewal – The integrity of the basement membrane or the stroma of the parenchymal cells is critical for the organized regeneration of tissues. Although labile and stable cells are capable of regeneration, injury to these tissues results in restitution of the normal structure only if the ECM is not damaged. Disruption of these structures leads to collagen deposition and scar formation. Storage and presentation of regulatory molecules. 42

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Components of the Extracellular Matrix 1) fibrous structural proteins such as collagens and elastins , which confer tensile strength and recoil; 2 ) water-hydrated gels such as proteoglycans and hyaluronan , which permit resilience and lubrication; and 3 ) adhesive glycoproteins that connect the matrix elements to one another and to cells. 43

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Collagen: Composed of 3 separate polypeptide chains braided into a rope like triple helix About 50 types are identified Some collagen types( eg : I, II, III, V) form fibrils by the virtue of lateral crosslinking of triple helix These fibillar collagens form a major proportion of connective tissue in healing wounds & particularly scars The crosslinking is a result of covalent bond catalysed by enzyme lysyl - oxidase . This process is dependent on vitamin C. Some types of collagen : I – skin & bone IV – basement membrane VIII – dermal-epidermal junction IX – intervertebral disc. 44

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Synthesis of collagen: 45

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Elastin: Its mainly present in large vessels, uterus, skin, ligaments. Morphologically – consists of a central core of elastin surrounded by a mesh like network of fibrillin glycoprotein. 46

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Proteoglycans : They form highly hydrated & compressible gels confering resilience & lubrication ( eg : in cartilage & joints). Consists: Glycosaminoglycans – long ploysaccaride ( eg : heparin sulfate, dermatan sulfate) Hyaluronan – because of its ability to bind to water it forms a viscous gelatin like matrix. Functions: Provides compressibility to tissue Serves as reservoir for growth factors secreted into ECM Can be integral cell membrane protein & have roles in proliferation, migration & adhesion. 47

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Adhesive glycoproteins & adhesion receptors : They are involved in cell to cell adhesion Linkage between cells & ECM Binding between ECM components Adhesive glycoproteins: Fibrinonectin Laminin Adhesion receptors: Immunoglobin Selectin Cadherins Integrins 48

Maturational phase:

Maturational phase Wound contractions occurs in the centripetal movement of the whole thickness of the surrounding skin . Reduce the amount of disorganized scar. It’s a result of complex interactions of ECM & fibroblasts which mechanism is not completely understood 49

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Mechanisms involved Aborted cell locomotion – bunching & contraction of the collagen fibres . Fibroblasts in the contracting wound under go changes to stimulated cells referred to as myofibroblasts Cytokines like TGF- β 1 affect wound contraction by increasing the expression of β 1 integrin MMPs - appear to be important for wound contraction.(MMP-3/ stromyelysin ) Stromyelysin with participation of integrin β 1 allows modification of attachments sites between fibroblasts & collagen fibres 50

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III. REMODELING :

III. REMODELING ↓se fibroblasts Dense capillary network regress Wound strength ↑ ses When compared to normal skin – scarred skin tensile strength is only 30% Epidermo -dermal interface lacks rete pegs → ↑ sed fragility & predisposes to avulsion after minor trauma. 52

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The incision causes only focal disruption of epithelial basement membrane continuity and death of a relatively few epithelial and connective tissue cells. Epithelial regeneration predominates over fibrosis. A small scar is formed, but there is minimal wound contraction. The narrow incisional space first fills with fibrin-clotted blood, which is rapidly invaded by granulation tissue and covered by new epithelium. 53 HEALING BY PRIMARY INTENTION

HEALING BY SECONDARY INTENTION :

HEALING BY SECONDARY INTENTION When tissue loss is more extensive, (large wounds, abscess formation, and ulceration) the repair process is more complex . In healing by secondary intension the inflammatory reaction is more intense, there is abundant development of granulation tissue, and the wound contracts by the action of myofibroblasts . This is followed by accumulation of ECM and formation of a large scar. 54

WOUND HEALING BY TERTIARY INTENTION:

WOUND HEALING BY TERTIARY INTENTION Wound healing by tertiary intention is also referred to as delayed primary closure . A contaminated wound is initially treated by repeated debridement , systemic or topical antibiotics, or negative pressure wound therapy for several days to control infection. Once the wound is assessed as being ready for closure, surgical intervention, such as suturing, skin graft placement, or flap design, is performed. 55

Healing in Specific tissues:

Healing in Specific tissues GASTROINTESTINAL TRACT Healing of full-thickness injury to the GI tract remains an unresolved clinical issue . Healing of full-thickness GI wounds begins with a surgical or mechanical re-apposition of the bowel ends , which is most often the initial step in the repair process Repair of the GI tract is vital to restoring the integrity of the luminal structure, and to the resumption of motor, absorptive, and barrier functions. The submucosa is the layer that imparts the greatest tensile strength and greatest suture-holding capacity . Additionally, serosal healing is essential for quickly achieving a watertight seal from the luminal side of the bowel. 56

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Injuries to all parts of the GI tract undergo the same sequence of healing as cutaneous wounds. Mesothelial ( serosal ) and mucosal healing can occur without scarring . Collagenase activity occurs early in the healing process, and during the first 3 to 5 days collagen breakdown far exceeds collagen synthesis. Collagenase is expressed postinjury in all segments of the GI tract, but it is much more marked in the colon compared to the small bowel . Collagen synthesis in the GI tract is carried out by both fibroblasts and smooth muscle cells. Ultimate anastomotic strength is not always related to the absolute amount of collagen, and the structure and arrangement of the collagen matrix may be more important . 57

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Bone Initial stage of hematoma formation The next stage accomplishes the liquefaction and degradation of nonviable products at the fracture site. The normal bone adjacent to the injury site can then undergo revascularization, with new blood vessels growing into the fracture site . Three to 4 days after injury, soft tissue forms a bridge between the fractured bone segments in the next stage (soft callus stage). 58

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The next phase (hard callus stage) consists of mineralization of the soft callus and conversion to bone. This may take up to 2 to 3 months and leads to complete bony union. This stage is followed by the remodeling phase, in which the excessive callus is reabsorbed and the marrow cavity is recanalized . By stimulating the differentiation of mesenchymal cells into chondroblasts and osteoblasts , bone morphogenic proteins directly affect bone and cartilage repair. 59

Fetal Wound Healing:

Fetal Wound Healing The main characteristic that distinguishes the healing of fetal wounds from that of adult wounds is the apparent lack of scar formation . Early fetal healing is characterized by the absence of scarring and resembles tissue regeneration . There is a phase of transition during gestational life when a more adult-like healing pattern emerges which occurs at the beginning of the third trimester and during this period there is scarless healing; however, there is a loss of the ability to regenerate skin appendages . Number of characteristics that may influence the differences between fetal and adult wounds. 60

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Wound Environment Inflammation Growth Factors Wound Matrix The fetus is bathed in a sterile, temperature-stable fluid environment , though this alone does not explain the observed differences. Reduced fetal inflammation due to the immaturity of the fetal immune system may partially explain the lack of scarring observed. Fetal wounds are notable for the absence of TGF , which may have a significant role in scarring. The fetal wound is characterized by excessive and extended hyaluronic acid production , a glycosaminoglycan that is produced primarily by fibroblasts. Experiments have demonstrated that scarless healing may occur outside of the amniotic fluid environment, and, conversely, scars can form in utero. Not only is the fetus neutropenic , but fetal wounds also contain lower numbers of PMNs and macrophages. Conversely, blocking TGF1 or TGF2 using neutralizing antibodies considerably reduces scar formation in adult wounds. Components of amniotic fluid, most specifically fetal urine, have a unique ability to stimulate hyaluronic acid production. Exogenous application of TGF3 downregulates TGF1 and TGF2 levels at the wound site with a resultant reduction in scarring. Fetal fibroblasts produce more collagen than adult fibroblasts, and the increased level of hyaluronic acid may aid in the orderly organization of collagen. 61

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Factors Affecting Wound Healing Systemic Local Age Mechanical injury Nutrition Infection Trauma Edema Metabolic diseases Ischemia/necrotic tissue Immunosuppression Topical agents Connective tissue disorders Ionizing radiation Smoking Low oxygen tension Foreign bodies 62

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AGE Aging produces intrinsic physiologic changes that result in delayed or impaired wound healing . Dermal collagen content decreases with aging and aging collagen fibers show distorted architecture and organization . The increased incidence of cardiovascular disease, metabolic diseases (diabetes mellitus, malnutrition, and vitamin deficiencies), cancer all contribute to the higher incidence of wound problems in the elderly Non collagenous protein accumulation at wounded sites is decreased with aging , which may impair the mechanical properties of scarring in elderly patients 63

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HYPOXIA, ANEMIA, AND HYPOPERFUSION Low oxygen tension has a profoundly deleterious effect on all aspects of wound healing. Fibroplasia , although stimulated initially by the hypoxic wound environment, is significantly impaired by local hypoxia . Optimal collagen synthesis requires oxygen as a cofactor , for the hydroxylation steps. Increasing subcutaneous oxygen tension levels for brief periods during and immediately after surgery results in enhanced collagen deposition and in decreased rates of wound infection after elective surgery. 64

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STEROIDS Large doses or chronic usage of glucocorticoids reduce collagen synthesis and wound strength. Inhibit the inflammatory phase of wound healing (angiogenesis, neutrophil and macrophage migration, and fibroblast proliferation) and the release of lysosomal enzymes . Steroids used after the first 3 to 4 days postinjury do not affect wound healing as severely as when they are used in the immediate postoperative period. Steroid-delayed healing of cutaneous wounds can be stimulated to epithelialize by topical application of vitamin A 65

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CHEMOTHERAPEUTIC DRUGS All chemotherapeutic antimetabolite drugs adversely affect wound healing by inhibiting early cell proliferation and wound DNA and protein synthesis , all of which are critical to successful repair. Delay in the use of such drugs for about 2 weeks post injury appears to lessen the wound healing impairment. 66

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METABOLIC DISORDERS Uncontrolled diabetes results in reduced inflammation, angiogenesis, and collagen synthesis . Defects in granulocyte function, capillary ingrowth, and fibroblast proliferation all have been described in diabetes Obesity, insulin resistance, hyperglycemia, and diabetic renal failure contribute significantly and independently to the impaired wound healing observed in diabetics. Diabetic wound appears to be lacking in sufficient growth factor levels , which signal normal healing . Uremia also has been associated with disordered wound healing. 67

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NUTRITION Not fully understood Efforts are being made to develop wound-specific nutritional interventions and the pharmacologic use of individual nutrients as modulators of wound outcomes . Malnourished patients have diminished hydroxyproline accumulation (an index of collagen deposition ) It reflects impaired healing response as well as reduced cell-mediated immunity, phagocytosis, and intracellular killing of bacteria by macrophages and neutrophils. 68

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The main effect of Arginine on wound healing is to enhance wound collagen deposition . Arginine deficiency results in decreased wound-breaking strength and wound collagen accumulation. Vitamins most closely involved with wound healing are vitamin C and vitamin A . vitamin C deficiency , leads to a defect in wound healing, particularly via a failure in collagen synthesis and cross-linking . Biochemically , vitamin C is required for the conversion of proline and lysine to hydroxyproline and hydroxylysine , respectively. Vitamin C deficiency has also been associated with an increased incidence of wound infection 69

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Vitamin A deficiency impairs wound healing, whereas supplemental vitamin A benefits wound healing. Vitamin A increases the inflammatory response in wound healing, probably by increasing the lability of lysosomal membranes. Vitamin A directly increases collagen production and epidermal growth factor receptors when it is added in vitro to cultured fibroblasts . Supplemental vitamin A can reverse the inhibitory effects of corticosteroids on wound healing. Vitamin A also can restore wound healing that has been impaired by diabetes, tumor formation, cyclophosphamide, and radiation. Doses ranging from 25,000 to 100,000 IU per day 70

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ZINC In deficiency states there is decreased fibroblast proliferation, decreased collagen synthesis, impaired overall wound strength, and delayed epithelialization . 71

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INFECTION If the wound is contaminated with >10 5 microorganisms, the risk of wound infection is markedly increased , but this threshold may be much lower in the presence of foreign materials . The most common organisms responsible for wound infections, in order of frequency, are Staphylococcus species, coagulase-negative Streptococcus , enterococci, and Escherichia coli . Bacteria prolong the inflammatory phase and interfere with epithelialization, contraction, and collagen deposition . Bacteria may accelerate expression or increase concentrations of MMPs, growth factors, and cytokines in chronic-type wounds 72

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IONIZING RADIATION Causes endothelial cell injury with endarteritis resulting in atrophy, fibrosis, and delayed tissue repair Angiogenesis is not initiated Rapidly dividing cell populations like keratinocytes and fibroblasts are most sensitive to radiation . 73

Classification of Surgical Wounds:

Classification of Surgical Wounds 74

Hypertrophic scar & Keloid:

Hypertrophic scar & Keloid Hypertrophic scars (HTSs) and keloids represent an overabundance of fibroplasia in the dermal healing process. 75

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Hypertrophic scar Keloid HTSs rise above the skin level but stay within the confines of the original wound and often regress over time Keloids rise above the skin level as well, but extend beyond the border of the original wound and rarely regress spontaneously HTSs occur after trauma to the skin, and may be tender, pruritic, and cause a burning sensation. keloids occur after trauma to the skin, and may be tender, pruritic, and cause a burning sensation HTSs usually develop within 4 weeks after trauma. Keloids tend to occur 3 months to years after the initial insult, and even minor injuries can result in large lesions. Keloids can result from surgery, burns, skin inflammation, acne, chickenpox, zoster, folliculitis, lacerations, abrasions, tattoos, vaccinations, injections, insect bites, ear piercing, or may arise spontaneously They usually occur across areas of tension and flexor surfaces, which tend to be at right angles to joints or skin creases. Certain body sites have a higher incidence of keloid formation, including the skin of the earlobe as well as the deltoid, presternal , and upper back regions . Initially erythematous and raised, and over time may evolve into pale, flatter scars. They vary in size from a few millimetres to large, pedunculated lesions with a soft to rubbery or hard consistency The collagen bundles are flatter , more random, and the fibres are in a wavy pattern Collagen bundles are virtually non-existent , and the fibres are connected haphazardly in loose sheets with a random orientation to the epithelium 76

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Underlying mechanisms that cause HTSs and keloids are not known. The immune system appears to be involved in the formation of both HTSs and keloids. In both HTSs and keloids, keratinocytes express human leukocyte antigen-2 and intercellular adhesion molecule-1 receptors, which are absent in normal scar keratinocytes . Keloids also have increased deposition of immunoglobulin G ( IgG ), IgA, and IgM . Antinuclear antibodies against fibroblasts, epithelial cells, and endothelial cells are found in keloids , but not HTSs. HTSs have higher T-lymphocyte and Langerhans cell contents. Larger number of mast cells –HTSs and keloids. Other mechanisms Mechanical tension Prolonged irritation and/or inflammation that may lead to the generation of abnormal concentrations of profibrotic cytokines. 77

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78 Local wound care

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Biosurgery The use of sterile maggots , also known as biosurgery . It has a selective technique of slough and necrotic tissue digestion from wounds without damaging the surrounding healthy tissue. Along with its antimicrobial effect , biosurgery is best suited for wounds with slough and infection. It is cost-effective and tolerance is excellent. Contraindications presence of fistulas proximity of the wound to major blood vessels or vital organs Limitations lack of aesthetic appeal , short self-life of maggots and increased pain at the wound site which is found in some patients . 79 Wai-Ping Linda Fan, Mamun Rashid, Stuart Enoch. Current advances in modern wound healing. Wounds. 2010, Vol 6, No 3; 22-36 .

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DRESSING The main purpose of wound dressings is to provide the ideal environment for wound healing . Ideal dressing – not a clinical reality. 80 DESIRED CHARACTERISTICS OF WOUND DRESSINGS Promote wound healing (maintain moist environment) Conformability Pain control Odor control Nonallergenic and nonirritating Permeability to gas Safety Nontraumatic removal Cost-effectiveness Convenience

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Occlusion also helps in dermal collagen synthesis and epithelial cell migration and limits tissue desiccation. As it may enhance bacterial growth, occlusion is contraindicated in infected and highly exudative wounds. Dressings can be classified as primary or secondary . A primary dressing is placed directly on the wound and may provide absorption of fluids and prevent desiccation, infection, and adhesion of a secondary dressing. A secondary dressing is one that is placed on the primary dressing for further protection, absorption, compression, and occlusion. 81

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Absorbent Dressings Absorb without getting soaked through , as this would permit bacteria from the outside to enter the wound. Cotton, wool, and sponge. Non adherent Dressings Dressings impregnated with paraffin, petroleum jelly, or water-soluble jelly for use as non adherent coverage. A secondary dressing must be placed on top to seal the edges and prevent desiccation and infection. 82

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Occlusive and Semiocclusive Dressings Good environment for clean & minimally exudative wounds . Waterproof and impervious to microbes, Permeable to water vapour and oxygen. 83

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Hydrophilic and hydrophobic dressings Components of a composite dressing. Hydrophilic dressing aids in absorption, Hydrophobic dressing is waterproof and prevents absorption. Hydrocolloid and Hydrogel Dressings Form complex structures with water, and fluid absorption occurs with particle swelling, which aids in atraumatic removal of the dressing . Hydrogel is a cross-linked polymer that has high water content . Hydrogels allow a high rate of evaporation without compromising wound hydration, which makes them useful in burn treatment . 84

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Alginates Brown algae and contain long chains of polysaccharides containing mannuronic and glucuronic acid. Processed as the calcium form, alginates turn into soluble sodium alginate through ion exchange in the presence of wound exudates. The polymers gel, swell, and absorb a great deal of fluid . Used when there is skin loss, in open surgical wounds with medium exudation, and on full-thickness chronic wounds. 85

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Absorbable Materials used within wounds as hemostats collagen gelatin , oxidized cellulose, oxidized regenerated cellulose. Medicated Dressings used as a drug-delivery system. chlorhexidine benzoyl peroxide, zinc oxide, neomycin, and bacitracin-zinc. 86

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Type of dressing to be used depends on the amount of wound drainage Nondraining Wound - with a semiocclusive dressing . Mild Drainage (1 to 2 mL/d) - semiocclusive or absorbent nonadherent dressing . Moderately draining wounds (3 to 5 mL/d) - dressed with a nonadherent primary layer plus an absorbent secondary layer plus an occlusive dressing to protect normal tissue. Heavily draining wounds (>5 mL/d) require a similar dressing to moderately draining wounds, but with the addition of a highly absorbent secondary layer. 87

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Vacuum-assisted closure system assists in wound closure by applying localized negative pressure to the surface and margins of the wound . Found to be effective for chronic open wounds (diabetic ulcers and stages 3 and 4 pressure ulcers), acute and traumatic wounds, flaps and grafts, dehisced incisions. Mechanism of action Problems – Pain, fluid loss, especially in large wounds, and risk of bleeding. It is contraindicated in patients with frail, thin or easily bruised skin, and in those with neoplasms forming part of the wound floor. 88

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Skin Replacements All wounds require coverage in order to prevent evaporative losses and infection and to provide an environment that promotes healing . Conventional Skin Grafts Split thickness grafts Full-thickness grafts Autologous grafts Allogeneic grafts Xenogeneic grafts ( e.g., porcine). 89

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Skin Substitutes Originally devised to provide coverage of extensive wounds with limited availability of autografts , skin substitutes also have gained acceptance as natural dressings. Theoretical advantages Readily available , Doesn’t require painful harvest, and Can be applied freely or with surgical suturing. Promote healing , either by stimulating host cytokine generation or by providing cells that may also produce growth factors locally. Their disadvantages include limited survival, high cost, and the need for multiple applications. 90

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The acellular (e.g., native collagen or synthetic material) component Acts as a scaffold Promotes cell migration and growth Activates tissue regeneration and remodeling . The cellular elements Re-establish lost tissue and associated function Synthesize extracellular matrix components Produce essential mediators such as cytokines and growth factors Promote proliferation and migration. 91

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Desired Features of Tissue-Engineered Skin Rapid re-establishment of functional skin (epidermis/dermis) Receptive to body's own cells (e.g., rapid "take" and integration) Graftable by a single, simple procedure Graftable on chronic or acute wounds Engraftment without use of extraordinary clinical intervention (i.e., immunosuppression) 92

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Growth Factor Therapy Nonhealing wounds result from insufficient or inadequate growth factors in the wound environment . A simplistic solution would be to flood the wound with single or multiple growth factors in order to "jump-start" healing and re-epithelialization. At present, only platelet-derived growth factor BB (PDGF-BB) is currently approved by the Food and Drug Administration for treatment of diabetic foot ulcers. 94

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Hyperbaric oxygen As adjunct in the management of nonhealing wounds. Most non-healing tissues are hypoxic Mechanism of action of hyperbaric oxygen Hyperoxygenation causes Immune stimulation by restoring WBC function and enhancing their phagocytic capabilities and Neo-vascularization in hypoxic areas by augmenting fibroblastic activity and capillary growth. Vasoconstriction reduces edema and tissue swelling while ensuring adequate Oxygen delivery. Bactericidal for anaerobic organisms & inhibits growth of aerobic bacteria. It Inhibits production of alpha-toxin by C Welchii and is synergistic with Aminoglycosides and Quinolones. Thus it is life saving in gas gangrene and severe necrotising infections. Tarun Sahni , S. Hukku , Madhur Jain, Arun Prasad, Rajendra Prasad, Kuldeep Singh. Recent Advances in Hyperbaric Oxygen Therapy The Association of Physicians of India . Medicine Update, Volume 14, 2004 . 95

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Stemcells and tissue-engineered skin. Charruyer A, Ghadially R Skin Pharmacol Physiol 2009; 22(2): 55–62:

Stemcells and tissue-engineered skin. Charruyer A, Ghadially R Skin Pharmacol Physiol 2009; 22(2 ): 55–62 Genes may be employed to augment an effect (e.g. promote healing ). These include genes for growth factors and their receptors . Alternatively, they may be used to inhibit an effect (e.g . suppress excessive scarring). These include genes for antibodies against specific growth factors. Gene therapy as applied to wound healing is currently in its primitive stages 97

Mast Cells Contribute to Scar Formation during Fetal Wound Healing Brian C Wulff, Allison E Parent, Melissa A Meleski, Luisa A DiPietro, Megan E Schrementi and Traci A Wilgus Journal of Investigative Dermatology 132, 458-465 (February 2012) :

Mast Cells Contribute to Scar Formation during Fetal Wound Healing Brian C Wulff , Allison E Parent, Melissa A Meleski , Luisa A DiPietro , Megan E Schrementi and Traci A Wilgus Journal of Investigative Dermatology 132, 458-465 (February 2012) Abstract Scar formation is a potentially detrimental process of tissue restoration in adults, affecting organ form and function. During fetal development, cutaneous wounds heal without inflammation or scarring at early stages of development; however, they begin to heal with significant inflammation and scarring as the skin becomes more mature. One possible cell type that could regulate the change from scarless to fibrotic healing is the mast cell. We show here that dermal mast cells in scarless wounds generated at embryonic day 15 (E15) are fewer in number, less mature, and do not degranulate in response to wounding as effectively as mast cells of fibrotic wounds made at embryonic day 18 (E18). Differences were also observed between cultured mast cells from E15 and E18 skin, with regard to degranulation and preformed cytokine levels. Injection of mast cell lysates into E15 wounds disrupted scarless healing, suggesting that mast cells interfere with scarless repair. Finally, wounds produced at E18, which normally heal with a scar, healed with significantly smaller scars in mast cell-deficient mice. Together, these data suggest that mast cells enhance scar formation, and that these cells may mediate the transition from scarless to fibrotic healing during fetal development. 98

Autologous Bone Marrow-Derived Stem Cells for Chronic Wounds of the Lower Extremity: A Retrospective Study Gerit D. Mulder, Daniel K. Lee, Nilofar Faghihnia, WOUNDS 2010;22(9):219–225.:

Autologous Bone Marrow-Derived Stem Cells for Chronic Wounds of the Lower Extremity: A Retrospective Study Gerit D. Mulder, Daniel K. Lee , Nilofar Faghihnia , WOUNDS 2010;22(9):219–225 . Abstract : Recent evidence suggests that stem cells derived from bone marrow have the potential to treat many disorders given their plasticity and ability to differentiate into various types of tissues, including skin cells. Stem cells are known to participate in cell migration and proliferation, contributing to the repair and regeneration of injured tissue, as observed in chronic wounds. This retrospective review of patients treated with autologous bone marrow aspirate (BMA) was performed to determine whether the treatment will help heal lower extremity ulcers by expediting wound closure and reducing the risk of lower limb amputation. The applied technique also exemplifies a simple, safe, and effective method of collecting the aspirate and applying it to the wound directly. Eight patients, 32- to 96-years-old, underwent this procedure between January 2010–March 2010. The subjects had previously undergone at least 1 year of conventional wound care treatment without any signs of healing. Wounds were evaluated and measured at each visit. Three subjects showed a decrease in wound size, and three subjects utilized alternative therapies, including biologic dressings or grafts at week 6, 11, and 16 following surgery since no significant improvement was noted. Although topically applied bone marrow derived stem cells may lead to dermal rebuilding and aid in healing, more research is needed to support their use in chronic wounds. 99

The effect of autologous bone marrow-derived cells on healing chronic lower extremity wounds: results of a randomized controlled study. Jain P, Perakath B, Jesudason MR, Nayak S Ostomy Wound Manage.2011 Jul;57(7):38-44.:

The effect of autologous bone marrow-derived cells on healing chronic lower extremity wounds: results of a randomized controlled study. Jain P, Perakath B, Jesudason MR, Nayak S Ostomy Wound Manage.2011 Jul;57(7):38-44. Abstract Case studies suggest that bone marrow-derived stem cells may improve chronic wound healing. A prospective, randomized, clinical study was conducted to compare the rate of healing chronic lower limb wounds in patients with diabetes mellitus whose wounds were treated with topically applied and locally injected bone marrow-derived cells or whole blood (control). Of the 48 patients participating in the study, 25 were randomized to study treatment and 23 to control treatment. At baseline, no significant differences were observed between the two groups for patient age, comorbidity, ulcer history, or baseline area. All wounds were surgically debrided. Wounds of study participants randomized to the treatment group were injected and oversprayed with a total of 5 cc of autologous bone marrow-derived cells. Using a similar procedure, the wounds of patients randomized to the control group were injected with 5 cc of autologous peripheral blood. All wounds were covered with saline-moistened gauze and cotton pads. Patients were followed for a maximum of 3 months. The average decrease in wound area at 2 weeks was 17.4 % in the treatment group compared to 4.84% in the control group. After 12 weeks, the average decrease in wound area was 36.4% in the treatment group compared to 27.32% in the control group. No adverse events were observed. No wound infections occurred, and all patients reported resumption of normal daily activity the day after the procedure. The results of this study show that a single application of autologous bone marrow-derived cells increases the rate of healing chronic lower extremity wounds in the early weeks of treatment. Additional studies to elucidate the treatment mode of action and optimal application frequency as well as comparisons between this and other treatment modalities are warranted . 100

Scar-free healing: from embryonic mechanisms to adult therapeutic intervention Mark W. J. Ferguson, Sharon O’Kane Phil. Trans. R. Soc. Lond. B 2004; 359, 839–850. :

Scar-free healing: from embryonic mechanisms to adult therapeutic intervention Mark W. J. Ferguson, Sharon O’Kane Phil. Trans . R. Soc. Lond . B 2004; 359, 839–850. Abstract : Skin wounds on early mammalian embryos heal perfectly with no scars whereas wounds to adult mammals scar. Embryonic wounds that heal without a scar have low levels of TGF1 andTGF2, low levels of platelet-derived growth factor and high levels of TGF3 . We have experimentally manipulated healing adult wounds in mice, rats and pigs to mimic the scar-free embryonic profile, e.g. neutralizing PDGF, neutralizing TGF1 and TGF2 or adding exogenous TGF3. These experiments result in scar-free wound healing in the adult. Such experiments have allowed the identification of therapeutic targets to which we have developed novel pharmaceutical molecules , which markedly improve or completely prevent scarring during adult wound healing in experimental animals . Some of these new drugs have successfully completed safety and other studies, such that they have entered human clinical trials with approval from the appropriate regulatory authorities. Initial trials involve application of the drug or placebo in a double-blind randomized design, to experimental incision or punch biopsy wounds under the arms of human volunteers. Based on encouraging results from such human volunteer studies, the lead drugs have now entered human patient-based trials e.g. in skin graft donor sites. By subtly altering the ratio of growth factors present during adult wound healing, we can induce adult wounds to heal perfectly with no scars , with accelerated healing and with no adverse effects, e.g. on wound strength or wound infection rates. This means that scarring may no longer be an inevitable consequence of modern injury or surgery and that a completely new pharmaceutical approach to the prevention of human scarring is now possible. 101

A review of the biologic effects, clinical efficacy, and safety of silicone elastomer sheeting for hypertrophic and keloid scar treatment and management. Berman B, Perez OA, Konda S, Kohut BE, Viera MH, Delgado S, Zell D, Li Q. Dermatol Surg. 2007 Nov;33(11):1291-302.:

A review of the biologic effects, clinical efficacy, and safety of silicone elastomer sheeting for hypertrophic and keloid scar treatment and management. Berman B, Perez OA, Konda S, Kohut BE, Viera MH, Delgado S, Zell D, Li Q. Dermatol Surg. 2007 Nov;33(11): 1291-302. Abstract Silicone elastomer sheeting is a medical device used to prevent the development of and improve the appearance and feel of hypertrophic and keloid scars. The precise mechanism of action of silicone elastomer sheeting has not been defined, but clinical trials report that this device is safe and effective for the treatment and prevention of hypertrophic and keloid scars if worn over the scar for 12 to 24 hours per day for at least 2 to 3 months. Some of the silicone elastomer sheeting products currently on the market are durable and adhere well to the skin. These products are an attractive treatment option because of their ease of use and low risk of adverse effects compared to other treatments, such as surgical excision, intralesional corticosteroid injections, pressure therapy, radiation, laser treatment, and cryotherapy . Additional controlled clinical trials with large patient populations may provide further evidence for the efficacy of silicone elastomer sheeting in the treatment and prevention of hypertrophic and keloid scars. The purpose of this article is to review the literature on silicone elastomer sheeting products and to discuss their clinical application in the treatment and prevention of hypertrophic and keloid scars . 102

Evolution of silicone therapy and mechanism of action in scar management. Mustoe TA. Aesthetic Plast Surg. 2008 Jan;32(1):82-92. :

Evolution of silicone therapy and mechanism of action in scar management. Mustoe TA . Aesthetic Plast Surg. 2008 Jan;32(1):82-92. Abstract Silicone-based products are widely used in the management of hypertrophic scarring and keloids. Silicone gel sheeting has been used successfully for more than 20 years in scar management. A new formulation of silicone gel applied from a tube forms a thin flexible sheet over the newly epithelialized wound or more mature scar . Results from clinical trials and clinical experience suggest that silicone gel is equivalent in efficacy to traditional silicone gel sheeting but easier to use. The mechanism of action of silicone therapy has not been completely determined but is likely to involve occlusion and hydration of the stratum corneum with subsequent cytokine-mediated signaling from keratinocytes to dermal fibroblasts. 103

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