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Premium member Presentation Transcript Physiology of Wound Healing : Physiology of Wound Healing CHAIRPERSON: Dr. B Jagadish Professor of Surgery Surgical G Unit Head PRESENTED BY: Dr. Rommel Post Graduate 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.” Introduction: Introduction contd.. : The repair of tissue damage broadly separated into two processes, regeneration and healing . Regeneration refers to growth of cells and tissues to replace lost structures. Wound healing is the effort of tissues to restore normal function and structure after injury -To reform barriers to fluid loss and infection, -limit further entry of foreign organisms and material, -re-establish normal blood and lymphatic flow patterns, -restore the mechanical integrity of the injured system. Introduction contd.. History : The earliest accounts of wound healing date back to about 2000 B.C Galen of Pergamum emphasized the importance of maintaining a moist environment to ensure adequate healing. Ambriose Paré found that simply dressed gunshot wounds heal faster and are less painful than when treated with boiling oil, the previously accepted method. Ignaz Philipp Semmelweis advocated need for washing hands Joseph Lister began soaking his instruments in phenol and spraying the operating rooms, reducing the mortality rates from 50 to 15%. History Primary mediators of wound healing : Primary mediators of wound healing Wound healing process is orchestrated by the carefully regulated release of cytokines Growth factors bind to specific receptors on cells which deliver signals which have two general effects 1.stimulation of transcription 2.regulation of cell entry into the cell cycle Growth Factors: : Polypeptides produced in normal and wounded tissue that stimulate cellular migration, proliferation, and function. Often named for the cells from which they were first derived. Names are often misleading, because growth factors have been demonstrated to have multiple functions. Most growth factors are extremely potent and produce significant effects in nanomolar concentrations. Growth Factors: Slide 9: Cytokines : Small proteins or glycoproteins secreted for the purpose of altering the function of target cells in an endocrine (uncommon), paracrine, or autocrine fashion. Pleiotropic Cytokines Slide 12: Anti inflammatory cytokines Phases of wound healing : Normal wound healing follows a predictable pattern that can be divided into overlapping phases defined by characteristic cellular populations and biochemical activities (a) Hemostasis and Inflammation (b) Proliferation (c) Maturation and Remodeling Phases of wound healing Slide 14: Phases of wound healing I. Inflammatory Phase : Represents the tissue’s attempt to limit damage Closely related with healing process Healing impossible without inflammation The events can be divided into: Vascular events Cellular events I. Inflammatory Phase 1.Vascular events : Earliest manifestation is vasodilatation, it follows a transient constriction of arterioles lasting a few seconds. Wounding disrupts tissue integrity and direct exposure of extracellular matrix to platelets Initial contact between platelets and collagen requires the von Willebrand factor (vWF) Binding results in changes in platelet conformation, triggering intracellular signal transduction pathways that result in platelet activation and the release of biologically active proteins. 1.Vascular events Vascular events contd… : Platelet α granules are storage organelles that contain -Platelet-derived growth factor (PDGF), -Transforming growth factor(TGF)-β, -Insulin-like growth factor (IGF)-1, -Fibronectin, -Fibrinogen, -Thrombospondin, -vWF. The dense bodies contain the vasoactive amines, such as serotonin, which cause vasodilation and increased vascular permeability. The clotting cascade is initiated through both the intrinsic and the extrinsic pathways. Vascular events contd… Slide 19: Vasodilation is followed by increased permeability of the microvasculature, followed by stasis, which leads to accumulation of leucocytes along the vascular endothelium which then migrate through the vascular wall into the interstitial tissue. 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). 2.Cellular events : 2.Cellular events Cellular infiltration after injury follows a characteristic, predetermined sequence . Polymorphonuclear cells : 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, and - the presence of chemotactic substances, such as complement factors, interleukin-1 (IL-1), tumor necrosis factor alpha (TNF-α), TGF β, platelet factor 4, or bacterial products. 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. Polymorphonuclear cells Polymorphonuclear cells contd.. : 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 (O2-) is formed. This very potent free 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. Polymorphonuclear cells contd.. Polymorphonuclear cells contd.. : 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 Polymorphonuclear cells contd.. 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 Derived from circulating monocytes, achieve significant numbers in the wound by 48 to 96 hours post injury and remain present until wound healing is complete. Chemotactic factors specific for monocytes include -bacterial products, -fibronectin, -complement degradation products (C5a), -collagen, -thrombin, -TGF-β Macrophages: Functions of Macrophages : 1.Macrophages induce PMN apoptosis 2. Macrophages have specific receptors for IgG (Fc-receptor), C3b (CR1 and CR3), and fibronectin (integrin receptors), which permit surface recognition of opsonized pathogens and facilitate phagocytosis. 3. Activated wound macrophages also produce nitric oxide which has antimicrobial properties. 4. Phospholipase is induced, causing enzymatic degradation of the cell membrane phospholipids, releasing thromboxane A2 and prostaglandin F2α Functions of Macrophages Functions of Macrophages contd.. : 5. Releases leukotriene B4 ,a potent neutrophil chemoattractant, and C4 and 15- and 5-hydroxyeicosatetraenoic acid. 6. 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 turnover. 7. Release growth factors that stimulate fibroblast, endothelial cell, and keratinocyte proliferation Functions of Macrophages contd.. 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 Also exert a down regulating effect on fibroblast collagen synthesis by cell-associated interferon-γ, TNF-α, and IL-1. T lymphocytes II. Proliferation Phase : Second phase of wound healing and roughly spans days 4 through 12 It is during this phase that tissue continuity is re-established Fibroblasts and endothelial cells are the last cell populations to infiltrate the healing wound, and the strongest chemotactic factor for fibroblasts is PDGF. Recruited fibroblasts first need to proliferate, and then become activated, to carry out their primary function of matrix synthesis remodeling. II. Proliferation Phase Slide 30: Proliferation Phase contd.. The four major events are Fibroplasia Angiogenesis Epithelialization Contraction 1.Fibroplasia : The proliferative phase begins with degradation of the initial fibrin-platelet provisional matrix. During fibroplasia, fibroblasts synthesize and deposit the replacement ECM at the wound site As fibroblasts proliferate, they become predominant cell types by 3 to 5 days in clean, non infected wounds. The initial fibrin matrix is replaced by a provisional matrix of fibronectin and hyaluron, which facilitates fibroblast migration. 1.Fibroplasia Fibroblasts : Specialized cells that differentiate from resting mesenchymal cells in connective tissue They do not arrive in the wound cleft by diapedesis from circulating cells. After injury, the normally quiescent and sparse fibroblasts are chemoattracted to the inflammatory site, where they divide and produce the components of the ECM. Fibroblasts Fibroblasts contd.. : Normally arrested in the G0 phase Undergoes replication and proliferation after stimulation by macrophage and platelet-derived cytokines and growth factors Time required for undifferentiated mesenchymal cells to differentiate into highly specialized fibroblasts accounts for the delay between injury and the appearance of collagen in a healing wound. Fibroblasts contd.. Extracellular matrix: : Cells grow, move, and differentiate in intimate contact with macromolecules outside the cells that constitute the ECM. Secreted locally and assembles into a network in the spaces surrounding cells Forms a significant proportion of the volume of any tissue. Extracellular matrix: Functions of ECM : Matrix protein sequester water that provide turgor to soft tissue and minerals that give rigidity to skeletal tissues Reservoir for growth factors controlling cell proliferation Provide cell to cell interaction and substratum for cells to adhere, migrate, and proliferate Functions of ECM Components of ECM : 1.Fibrous structural proteins such as collagen and elastins 2. Adhesive glycoproteins or cell adhesion molecules 3. Proteoglycans and hyaluronic acid 4. Basal Lamina Components of ECM 1.Fibrous structural proteins such as collagen and elastins : Collagen : Most common protein in the animal world providing the extracellular framework for all multicellular organisms Its deposition, maturation, and subsequent remodeling are essential to the functional integrity of the wound. At least 27 types of collagen encoded by 41 genes dispersed on atleast 14 chromosomes, 1.Fibrous structural proteins such as collagen and elastins Collagen : Type I collagen is the major component of extracellular matrix in skin. Type III, normally present in skin, becomes more prominent and important during the repair process Type IV is non fibrillar, main component of basement membrane together with laminin. Each chain of collagen is composed of a glycine residue in every third position. The second position in the triplet is made up of proline or lysine Collagen : Collagen : Collagen synthesis, as well as post translational modifications, is highly dependent on systemic factors such as an adequate oxygen supply the presence of sufficient nutrients (amino acids and carbohydrates) cofactors (vitamins and trace metals) the local wound environment (vascular supply and lack of infection). Collagen Elastins, fibrillin and elastic fibre : Provide the resilience to allow for recoil after transient stretch. Elastin is composed of hydrophobic and alanine- and lysine-rich α-helical segments that alternate along the polypeptide chain Elastic fibers consist of an elastin core covered with a sheath of microfibrils, which are composed of several distinct glycoproteins, such as fibrillin. Microfibrils appear before elastin in developing tissues and seem to form a scaffold on which the secreted elastin molecules are deposited. Elastins, fibrillin and elastic fibre 2. Adhesive glycoproteins or cell adhesion molecules : Located in the cell membrane where they function as receptors or they are stored in the cytoplasm. Provide interaction between the same cells(homotypic) or different cells(heterotypic). Integrin Family of cell surface receptors that are closely coupled with the cell’s cytoskeleton Serve two major functions: (1) to interact with components of the ECM, such as fibronectin, and to provide adhesion and (2) to provide signal transduction to the cell interior. 2. Adhesive glycoproteins or cell adhesion molecules Adhesive glycoproteins or cell adhesion molecules : Crucial for cell motility and are required in inflammation and normal wound healing Following extravasation, PMNs, attracted by chemotaxins, migrate through the ECM by means of transient interactions between integrin receptors and their ligands. Four phases of integrin-mediated cell motility have been described Adhesion Spreading Contractility or traction Retraction Adhesive glycoproteins or cell adhesion molecules Slide 44: Spreading is characterized by the development of lamellipodia and filopodia. Traction at the leading edge of the cell develops through binding of the integrin, followed by translocation of the cell over the adherent segment of the plasma membrane. The integrin is shifted to the rear of the cell and releases its substrate, permitting cell advancement. Binding sites for integrins have been identified on collagen, laminin, and fibronectin 3.Proteoglycans and hyaluronic acid : Glycosaminoglycans comprise a large portion of the "ground substance" that makes up granulation tissue The polysaccharide chain is made up of repeating disaccharide units composed of glucuronic or iduronic acid and a hexosamine, which is usually sulfated. Four types of GAGS exist: (1) hyaluronan (2) chondroitin sulfate and dermatan sulfate (3) heparan sulfate (4) keratan sulphate Major glycosaminoglycans present in wounds are dermatan and chondroitin sulfate Fibroblasts synthesize these compounds, increasing their concentration greatly during the first 3 weeks of healing 3.Proteoglycans and hyaluronic acid Slide 46: Functions 1. Role in chemical signaling, by binding various secreted signal molecules, such as growth factors, and modulating their signaling activity. 2. Also bind other secreted proteins, such as proteases and protease inhibitors 3. Act as coreceptors that work with other cell surface receptor proteins, binding cells to the ECM and initiating the response of cells to extracellular signaling proteins. Slide 47: Proteoglycans Contd…. As scar collagen is deposited, the proteoglycans are incorporated into the collagen scaffolding. With scar maturation and collagen remodeling, the content of proteoglycans gradually diminishes The ECM has other noncollagen proteins, such as the fibronectins, that have multiple domains and can bind to other matrix macromolecules and cell surface receptors. Fibronectin exists as soluble and fibrillar isoforms Soluble plasma fibronectin circulates in various body fluids, enhancing blood clotting, wound healing, and phagocytosis The highly insoluble fibrillar forms assemble on cell surfaces and are deposited in the ECM. 4.Basal Lamina : Flexible, thin (40- to 120-nm thick) mats of specialized ECM that separate cells and epithelia from the underlying or surrounding connective tissue In the skin, the basal lamina is tethered to the underlying connective tissue by specialized anchoring fibrils This composite of basal lamina and collagen is the basement membrane Most mature basal laminae contain type IV collagen and the glycoproteins laminin . 4.Basal Lamina 4.Basal Lamina contd… : The basal lamina serves numerous functions 1. As a molecular filter, preventing passage of macromolecules (i.e., in kidney glomerulus) 2. As a selective barrier to certain cells (i.e., the lamina beneath the epithelium prevents fibroblasts from contacting epithelial cells, but does not stop macrophages or lymphocytes) 3. As a scaffold for regenerating cells to migrate 4. Is important in tissue regeneration where the basal lamina survives. 4.Basal Lamina contd… Slide 50: Laminins Consist of three long polypeptide chains (α, β, and γ). Many of the cell surface receptors for type IV collagen and laminin are members of the integrin family. Slide 52: Fibronectin and the GAG hyaluronic acid compose the initial wound matrix Hyaluronic acid provides a matrix that enhances cell migration because of its large water of hydration Adhesion glycoproteins including fibronectin, laminin, and tenascin, are present throughout the early matrix and facilitate cell attachment and migration. Integrin receptors on cell surfaces bind to the matrix GAGs and glycoproteins As fibroblasts enter and populate the wound, they secrete hyaluronidase to digest the provisional hyaluronic acid rich matrix, and larger, sulfated GAGs are subsequently deposited Concomitantly, new collagen is deposited by fibroblasts onto the fibronectin and the GAG scaffold in a disorganized manner, resulting in scar formation. Granulation : Dense population of blood vessels, macrophages and fibroblast embedded within a loose provisional matrix of fibronectin, hyaluronic acid and collagen. Clinically characterized by its beefy red appearance, proud flesh and is present in open wounds. Consequence of the rich bed of new capillary networks that form by endothelial cell division. The directed growth of vascular endothelium is stimulated by platelet and activated macrophage and fibroblast products. Granulation tissue is a clinical indicator that an open wound is amenable to skin graft treatment. Granulation Angiogenesis : Process of new blood vessel formation Macrophage orchestrates angiogenesis during the inflammatory phase. Angiogenesis is by 1.Degradation of the basement membrane of postcapillary venules 2.Migration of cells through this gap promoted by FGF, PDGF, and TGF-β. PECAM-1, also found on endothelial cells, modulates their interaction with each other as they migrate into the wound 3.Tubule or lumen formation involving cell-cell and cell-matrix interactions. New capillaries differentiate into arterioles and venules, whereas others undergo involution and apoptosis, with ingestion by macrophages. 4.Deposition of the basement membrane resulting in capillary maturation. Angiogenesis Contraction : Process in which the surrounding skin is pulled circumferentially toward an open wound. Does not occur with closed surgical incisions. Decrease in the size of the wound dramatically without new tissue formation. Speeds wound closure compared to epithelisation and scar formation alone The amount of contraction is related to both the size of the wound and the mobility of the skin. In humans contractions is greatest in the trunk and perineum, least on the extremities, and intermediate on the head and neck. Contraction Slide 57: Cellular mechanisms are not well understood. 1.Contractile forces are likely to be generated by myofibroblasts, which are fibroblast like cells that contain smooth muscle actin and microfilaments in their cytoplasm. 2.Membranemetalloproteinases Appear to be important for wound contraction. Stromelysin-1 (MMP-3) strongly affects wound contraction. May be necessary to allow cleavage of the attachment between the fibroblast and the collagen so that the lattice can be made to contract. Wound contraction must be distinguished from contracture. Clinically, contracture is defined as tissue shortening or distortion that causes decreased joint mobility and function. Scar contracture commonly refers to decreased function in the area, whereas scar contraction refers to shortening of the scar length compared with the original. Epithelisation: : New epithelial cells for wound closure are provided by fixed basal cells in a zone near the edge of the wound The epidermal cell layer thickens and the marginal basal cells migrate over the wound defect. Once these keratinocytes begin migrating they do not divide until epidermal continuity is restored. Daughter cells flatten and migrate over the wound as a sheet, moving in a leapfrog and tumbling fashion (epiboly). Epithelisation: Epithelisation contd… : Migration of keratinocytes over the wound is guided by cell adhesion glycoproteins, such as tenascin and fibronectin, which are their “railroad tracks”. After re-establishment of the epithelial layer, keratinocytes and fibroblast secrete laminin and type IV collagen to form basement membrane Keratinocytes become columnar and divide to restore the layering of the epidermis and reform a barrier. Epithelisation contd… Epithelisation contd… : The migrating cells dissect the wound, separating the desiccated eschar from the viable tissue If the basement membrane zone is intact, epithelialization proceeds more rapidly. If not intact, it will be repaired first 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 Epithelisation contd… Remodeling : The ECM is dynamic and is constantly undergoing remodeling Collagen cross linking decreases its degradation and improves wound tensile strength. Lysyl oxidase is the major intermolecular cross linking enzyme. Degradation is by collagenases, gelatinases and matrix metalloproteinases Scar formation is the ultimate outcome of wound repair in children and adults The ultimate pattern of collagen in scar is one of densely packed fibres and not the reticular pattern found in unwounded dermis Remodeling Remodeling contd… : Scar has no epidermal appendages (hair follicles and sebaceous glands) and it has a collagen pattern that is distinctly different from the unwounded skin Remodeling occurs during months to years to form a mature scar. The early scar appearance is red due to its dense capillary network induced at the injury site Scars are usually hypo pigmented after full maturation. However can become hyper pigmented in darker pigmented patients and in those lighter pigmented patients who receive sun exposure. Remodeling contd… Slide 63: During remodeling, wounds gradually become stronger with time. Wound tensile strength increases rapidly from 1 to 8 weeks after wounding and correlates with collagen cross linkage. It increases at a slower pace till 1 year. Tensile strength of the wound best reaches only 80% that of unwounded skin. Factors Affecting Wound Healing : Age Infections Nutrition Hypoxia Anaemia Hypoperfusion Metabolic disorders Steroids and chemotherapeutic drugs Ionising radiation Factors Affecting Wound Healing Factors Affecting Wound Healing contd… : AGE Aging produces intrinsic physiologic changes that result in delayed or impaired wound healing. With aging, collagen undergoes qualitative and quantitative changes. 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 Factors Affecting Wound Healing contd… Factors Affecting Wound Healing contd… : Infections Probably the most common cause of healing delays If the bacterial count in the wound exceeds 105organisms per gram of tissue, or if any β-hemolytic streptococci are present, the wound will not heal by any means. Bacteria prolong the inflammatory phase and interfere with epithelialization, contraction, and collagen deposition. Endotoxins stimulate phagocytosis and release of collagenase Bacteria may accelerate expression or increase concentrations of MMPs, growth factors, and cytokines in chronic-type wounds. Factors Affecting Wound Healing contd… Factors Affecting Wound Healing contd… : Infections Inactive precursors of MMPs are activated by bacterial proteinases of the thermolysin family (Pseudomonas, Vibrio, and Serratia) Bacterial phospholipase C can disrupt normal reepithelialization by decreasing cell-cell contact and increasing cell migration, possibly by altering integrin expression and by upregulating MMP-9. Factors Affecting Wound Healing contd… Factors Affecting Wound Healing contd… : Nutrition Precise calorie requirements for optimal healing has not been determined. Malnourished patients have diminished hydroxyproline accumulation (an index of collagen deposition) into subcutaneously implanted polytetrafluoroethylene tubes when compared to normally nourished patients. Malnutrition correlates clinically with enhanced rates of wound complications and increased wound failure after diverse surgical procedures. Factors Affecting Wound Healing contd… Factors Affecting Wound Healing contd… : Nutrition - Arginine Arginine deficiency results in decreased wound-breaking strength and wound collagen The main effect of arginine on wound healing is to enhance wound collagen deposition. As increases in breaking strength during the first weeks of healing are directly related to new collagen synthesis Arginine supplementation may result in an improvement in wound strength as a consequence of enhanced collagen deposition Factors Affecting Wound Healing contd… Slide 70: Nutrition - Vitamin A Deficiency impairs wound healing, whereas supplemental vitamin A benefits wound healing in non deficient humans and animals. Vitamin A increases the inflammatory response in wound healing, probably by increasing the lability of lysosomal membranes. There is an increased influx of macrophages, with an increase in their activation and increased collagen synthesis. 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. Factors Affecting Wound Healing contd… : Nutrition - Scurvy, or vitamin C deficiency Leads to a defect in wound healing, particularly via a failure in collagen synthesis and cross-linking. 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 Zinc In deficiency states there is decreased fibroblast proliferation, decreased collagen synthesis, impaired overall wound strength, and delayed epithelialization. Factors Affecting Wound Healing contd… Factors Affecting Wound Healing contd… : Hypoxia, Anemia, and Hypoperfusion Low oxygen tension has a profoundly deleterious effect on all aspects of wound healing. Fibroplasia is significantly impaired by local hypoxia. Optimal collagen synthesis requires oxygen as a cofactor Factors affecting local oxygen delivery -systemic reasons (low volume or cardiac failure) -local causes (arterial insufficiency, local vasoconstriction, or excessive tension on tissues). The level of vasoconstriction of the subcutaneous capillary bed is exquisitely responsive to fluid status, temperature, and hyperactive sympathetic tone as is often induced by postoperative pain. Factors Affecting Wound Healing contd… Factors Affecting Wound Healing contd… : Steroids and Chemotherapeutic Drugs Large doses or chronic usage of glucocorticoids reduce collagen synthesis and wound strength. Major effect is to inhibit the inflammatory phase of wound healing and the release of lysosomal enzymes Steroids also inhibit epithelialization and contraction and contribute to increased rates of wound infection, regardless of the time of administration All chemotherapeutic antimetabolite drugs adversely affect wound healing by inhibiting early cell proliferation and wound DNA and protein synthesis Factors Affecting Wound Healing contd… Factors Affecting Wound Healing contd… : Metabolic Disorders 1. Diabetes Mellitus Uncontrolled Diabetes results in reduced inflammation, angiogenesis, and collagen synthesis. The accompanying large and small vessel disease contributes to local hypoxemia. Defects in granulocyte function, capillary ingrowth, and fibroblast proliferation all have been described in Diabetes. Factors Affecting Wound Healing contd… Factors Affecting Wound Healing contd… : Metabolic Disorders - Diabetes Mellitus contd.. Obesity, insulin resistance, hyperglycemia, and diabetic renal failure contribute significantly and independently to the impaired wound healing observed in diabetics. Reduced expression of growth factors like VEGF, IGF 1 FGF 1 KGF and PDGF Diabetic fibroblasts and keratinocytes have reduced proliferation rates and collagen production. Factors Affecting Wound Healing contd… Factors Affecting Wound Healing contd… : Metabolic Disorders 2. Uremia Associated with disordered wound healing. Experimentally, uremic animals demonstrate decreased wound collagen synthesis and breaking strength Factors Affecting Wound Healing contd… Factors Affecting Wound Healing contd… : 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. Factors Affecting Wound Healing contd… Classification of Surgical Wounds : Classification of Surgical Wounds Slide 79: Healing in surgical wounds Treatment of Wounds : Treatment of Wounds Treatment of Wounds : The smallest suture required to hold the various layers of the wound in approximation should be selected in order to minimize suture-related inflammation. Nonabsorbable or slowly absorbing monofilament sutures are most suitable for approximating deep fascial layers, particularly in the abdominal wall. Subcutaneous tissues should be closed with braided absorbable sutures, with care to avoid placement of sutures in fat. Drains may be placed in areas at risk of forming fluid collections. In areas of significant tissue loss, rotation of adjacent musculocutaneous flaps may be required to provide sufficient tissue mass for closure. In areas with significant superficial tissue loss, split-thickness skin grafting (placed in a delayed manner to assure an adequate tissue bed) may be required Treatment of Wounds Treatment of Wounds : Antibiotics Should be used only when there is an obvious wound infection. Signs of infection to look for include erythema, cellulitis, swelling, and purulent discharge. Indiscriminate use of antibiotics should be avoided to prevent emergence of multidrug resistant bacteria. Antibiotic treatment of acute wounds must be based on organisms suspected to be found within the infected wound and the patient's overall immune status. Antibiotics can also be delivered topically as part of irrigations or dressings, although their efficacy is questionable. Treatment of Wounds Treatment of Wounds : Dressings The main purpose of wound dressings is to provide the ideal environment for wound healing. The dressing should facilitate the major changes taking place during healing to produce an optimally healed wound. Desired Characteristics of Wound Dressings to -Promote wound healing (maintain moist environment) -Conformability -Pain control -Odor control -Nonallergenic and nonirritating -Permeability to gas Safety -Nontraumatic removal -Cost-effectiveness -Convenience Treatment of Wounds Treatment of Wounds : Dressings Covering a wound with a dressing mimics the barrier role of epithelium and prevents further damage. Application of compression provides hemostasis and limits edema. Occlusion of a wound with dressing material helps healing by controlling the level of hydration and oxygen tension within the wound. It also allows transfer of gases and water vapor from the wound surface to the atmosphere. Occlusion affects both the dermis and epidermis, and it has been shown that exposed wounds are more inflamed and develop more necrosis than covered wounds. Treatment of Wounds Treatment of Wounds : 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 Treatment of Wounds Slide 87: For incisional wounds, dressings optimally include several layers with different functions. 1. The layer immediately adjacent to the wound must be sterile and non adhering and should not be occlusive. A fine meshed gauze impregnated with a hydrophilic substance meets these demands. 2. The layer over the contact layer should be absorptive and should wick exudates or transudate away from the wound surface. Wide meshed gauze facilitates this capillary action and drainage. Such absorptive layers must not become saturated which will then collect on the wound surface and cause maceration. 3. The outermost layer of the dressing is the binding layer that fixes the dressing in place. Tape is commonly used, though wraps are used in extremities. Treatment of Wounds : Dressings The type of dressing to be used depends on the amount of wound drainage. A nondraining wound can be covered with a semiocclusive dressing. -Drainage of less than 1 to 2 mL/d may require a semiocclusive or absorbent nonadherent dressing. -Moderately draining wounds (3 to 5 mL/d) can be 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 Treatment of Wounds Treatment of Wounds : Absorbent Dressings Accumulation of wound fluid can lead to maceration and bacterial overgrowth. The Dressing should absorb without getting soaked through, as this would permit bacteria from the outside to enter the wound. The dressing must be designed to match the exudative properties of the wound and may include cotton, wool, and sponge. Treatment of Wounds Treatment of Wounds : Nonadherent Dressings Nonadherent dressings are impregnated with paraffin, petroleum jelly, or water-soluble jelly for use as nonadherent coverage. A secondary dressing must be placed on top to seal the edges and prevent desiccation and infection. Occlusive and Semiocclusive Dressings Occlusive and semiocclusive dressings provide a good environment for clean, minimally exudative wounds. These film dressings are waterproof and impervious to microbes, but permeable to water vapor and oxygen. Treatment of Wounds Treatment of Wounds : Hydrophilic and Hydrophobic Dressings Hydrophilic and hydrophobic dressings are components of a composite dressing. Hydrophilic dressing aids in absorption, whereas a hydrophobic dressing is waterproof and prevents absorption. Hydrocolloid and Hydrogel Dressings Attempt to combine the benefits of occlusion and absorbency. Form complex structures with water, and fluid absorption occurs with particle swelling, which aids in atraumatic removal of the dressing. Absorption of exudates by the hydrocolloid dressing leaves a yellowish-brown gelatinous mass after dressing removal that can be washed off. 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. Treatment of Wounds Treatment of Wounds : Absorbable Materials Are mainly used within wounds as hemostats and include collagen, gelatin, oxidized cellulose, and oxidized regenerated cellulose Medicated Dressings Used as a drug-delivery system. Agents include benzoyl peroxide, zinc oxide, neomycin, and bacitracin-zinc. These agents have been shown to increase epithelialization by 28%. Treatment of Wounds Treatment of Wounds : Mechanical Devices Augments and improves on certain functions of dressings, in particular the absorption of exudates and control of odor. The vacuum-assisted closure system assists in wound closure by applying localized negative pressure to the surface and margins of the wound. The negative pressure therapy is applied to a special foam dressing cut to the dimensions of the wound and positioned in the wound cavity or over a flap or graft. This form of therapy has been found to be effective for chronic open wounds (diabetic ulcers and stages 3 and 4 pressure ulcers), acute and traumatic wounds, flaps and grafts. Treatment of Wounds Treatment of Wounds : Skin Replacements Conventional Skin Grafts: Skin grafts have long been used to treat both acute and chronic wounds. Split- or partial-thickness grafts consist of the epidermis plus part of the dermis, whereas full-thickness grafts retain the entire epidermis and dermis. Split-thickness grafts require less blood supply to restore skin function. The dermal component of full-thickness grafts lends mechanical strength and resists wound contraction better, resulting in improved cosmesis Treatment of Wounds Treatment of Wounds : Skin Replacements Skin Substitutes Manufactured by tissue engineering, they combine novel materials with living cells to provide functional skin substitutes, providing a bridge between dressings and skin grafts. Have advantages of being readily available, not requiring painful harvest, and they may be applied freely or with surgical suturing. They promote healing, either by stimulating host cytokine generation or by providing cells that may also produce growth factors locally. Disadvantages include limited survival, high cost, and the need for multiple applications . Allografting, albeit with a very thin graft, may at times be required to accomplish complete coverage. Treatment of Wounds Treatment of Wounds : Skin Replacements Skin Substitutes The acellular (e.g., native collagen or synthetic material) component acts as a scaffold, promotes cell migration and growth, and 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, and promote proliferation and migration. Bioengineered skin substitutes have evolved from keratinocyte monolayers to dermal equivalents to split-thickness products with a pseudoepidermis and, most recently, to products containing both epidermal and dermal components that resemble the three-dimensional structure and function of normal skin . Treatment of Wounds Treatment of Wounds : Growth Factor Therapy Growth factors for clinical use may be either recombinant or homologous/autologous. Autologous growth factors are harvested from the patient's own platelets, yielding an unpredictable combination and concentration of factors, which are then applied to the wound. Recombinant molecular biologic means permit the purification of high concentrations of individual growth factors. 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. A great deal more needs to be discovered about the concentration, temporal release, and receptor cell population before growth factor therapy is to make a consistent impact on wound healing. Treatment of Wounds Slide 104: Remember Treat the WHOLE patient and not just the HOLE in the patient You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.