You are in: eMedicine Specialties > Plastic Surgery > WOUND HEALING Wound Healing, Chronic WoundsArticle Last Updated: May 26, 2006AUTHOR AND EDITOR INFORMATIONSection 1 of 10
  Author: Jorge I de la Torre, MD, FACS, Professor of Surgery and Physical Medicine and Rehabilitation, Residency Program Director, Division of Plastic Surgery, University of Alabama at Birmingham; Director, Center for Advanced Surgical Aesthetics Jorge I de la Torre is a member of the following medical societies: American Association of Plastic Surgeons, American Burn Association, American College of Surgeons, American Medical Association, American Society for Laser Medicine and Surgery, American Society for Reconstructive Microsurgery, American Society of Maxillofacial Surgeons, American Society of Plastic Surgeons, Association for Academic Surgery, and Medical Association of the State of Alabama Coauthor(s): Wayne Stadelmann, MD, Stadelmann Plastic Surgery, PC Editors: Christian Paletta, MD, FACS, Professor, Division Chief and Program Director, Department of Plastic and Reconstructive Surgery, St Louis University School of Medicine; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; R Edward Newsome, MD, Associate Professor, Program Director and Chief, Department of Surgery, Section of Plastic Surgery, Tulane University Health Sciences Center; Nicolas (Nick) G Slenkovich, MD, Practice Director, Colorado Plastic Surgery Center at Swedish Medical Center; Susan E Downey, MD, Clinical Associate Professor, Department of Surgery, Division of Plastic Surgery, University of Southern California Author and Editor Disclosure Synonyms and related keywords: chronic wound, wound healing, ulcer, diabetic ulcer, decubitus ulcer, venous stasis ulcer, pressure sore, chronic sore, bed sore, bedsore, non-healing wounds, nonhealing wounds, fibrin plug, diabetic foot ulcer THE PHYSIOLOGY OF HEALING OF THE CHRONIC WOUNDSection 2 of 10
  Nonhealing chronic wounds are a challenge to the patient, the health care professional, and the health care system. They significantly impair the quality of life for millions of people in the United States. Intensive treatment is required and imparts an enormous burden on society in terms of lost productivity and health care dollars. Therefore, the study of healing chronic wounds is vitally important. Wound healing is a dynamic pathway that optimally leads to restoration of tissue integrity and function. A chronic wound results when the normal reparative process is interrupted. By understanding the biology of wound healing, the physician can optimize the tissue environment in which the wound is present. This article describes these mechanisms, a physiologic basis for wound management based on these processes, and the application of management strategies of common chronic wounds. Healing pathways are set into motion at the moment of wounding. Wound healing is the result of the accumulation of processes, including coagulation, inflammation, ground substance and matrix synthesis, angiogenesis, fibroplasia, epithelialization, wound contraction, and remodeling (see Image 1). These complex, overlapping processes are best organized into 3 phases of healing: the inflammatory phase, the proliferative phase, and the maturation phase. INFLAMMATORY PHASESection 3 of 10
The inflammatory phase of wound healing is clinically characterized by the cardinal signs of redness (rubor), heat (calor), swelling (tumor), pain (dolor), and loss of function (functio laesa). The physiologic processes underlying this inflammation begin immediately upon tissue injury. Simultaneously, the coagulation cascade, the arachidonic acid pathways, and the creation of growth factors and cytokines work together to initiate and maintain the inflammatory phase and the sequence of cells involved in the process. At the moment of wounding with vascular injury, tissue factor and intracellular calcium are released, activating factor VII and initiating the extrinsic coagulation cascade. Concomitant reflex vasoconstriction occurs to aid in hemostasis. Hemostasis is ultimately secured by the end product of the coagulation cascade, the fibrin plug. These fibrin fibers become a provisional wound matrix and are the lattice on which platelets aggregate. Activated platelets are the most abundant cells in the wound in the early postinjury period. They are sources of proinflammatory substances, such as tissue growth factor-beta (TGF-beta) and platelet-derived growth factor (PDGF). Growth factors are peptides that act on inflammatory cells, fibroblasts, and endothelial cells to direct the processes involved in wound healing. They are noted in the earliest period postinjury because PDGF and basic fibroblast growth factor (bFGF) are produced by the injured cell at the time of wounding. Subsequently, activated platelets release TGF-beta and PDGF to mediate chemotaxis of neutrophils, monocytes, and fibroblasts into the wound. Additionally, the injured tissue locally releases eicosanoids, which amplify the early response to injury. Eicosanoids are arachidonic acid metabolites that are derived from cell membrane fatty acids. Activated phospholipase A catalyzes the production of prostaglandins and thromboxane from the arachidonic acid. These substances play central roles in the regulation of vasomotor and platelet activity after injury. Thromboxane A2 helps with hemostasis by its effects of vasoconstriction and platelet aggregation. After the initial insult and resultant vasoconstriction, vascular permeability is then increased. The classic signs of inflammation are generated by these metabolites. For example, the redness caused by vasodilation is primarily a result of prostacyclin (PGI2). Others include prostaglandin A, prostaglandin D, and prostaglandin E (PGE). Swelling is caused by the leakage of plasma proteins through gaps in the vascular endothelium. This edema is potentiated by PGE2 and prostaglandin F2-alpha (PGF2-alpha). PGI2 and PGE2 promote local blood flow, causing the localized warmth in the area of inflammation, but also allow for entry of inflammatory cells into the wound, which is due to increased vascular permeability. These cells then release cytokines responsible for fever production. Pain is elicited by the effects of PGI2, PGE, and PGE2 on peripheral sensory nerve endings. Eicosanoids thus exert mediatory actions on the injured tissue's platelet plug formation, vascular permeability, and cellular chemotaxis to influence wound healing. Another class of mediators involved in this stage of wound healing is the cytokines. After hemostasis has been obtained, polymorphonuclear (PMN) leukocytes enter the area of injury, drawn by chemotactic substances such as those released with the degranulation of platelets. These are then the predominant cells for the first 3 days after wounding, with the number peaking at approximately 48 hours (see Image 2). They are the first to begin bactericidal activities using inflammatory mediators and oxygen free radical metabolites. However, PMN leukocytes have been shown to not be crucial to the wound healing process, with normal healing progression occurring experimentally in their absence. Other leukocytes, specifically helper T cells, are the source of the cytokine interleukin (IL)–2. IL-2 promotes the proliferation of further T cells to aid in the immunogenic response to injury. IL-1 is a cytokine produced by macrophages. Circulating monocytes enter the wound after the PMN leukocytes and reach their maximum numbers 24-36 hours later (see Image 2). They mature into tissue macrophages, which carry the major load of wound debridement. Macrophages secrete substances such as bFGF, a chemotactic and mitogenic factor for fibroblasts and endothelial cells, and IL-1. IL-1 stimulates the proliferation of multiple cells of inflammation and induces the replication of endothelial cells, promoting angiogenesis. The depletion of macrophages causes a severe alteration in wound healing, with poor debridement and inadequate fibroblast proliferation and angiogenesis. As eicosanoids accumulate in the wound during the progression of the inflammatory phase, they begin to interact with the cells present. For example, a rise in the ratio of PGF2-alpha to PGE2 during late inflammation is a stimulus for fibroblasts to begin to synthesize collagen and ground substance. Additionally, the macrophage-derived growth factors are now at optimal levels, strongly influencing the influx of fibroblasts, then keratinocytes and endothelial cells, into the wound. The cellular population of the wound becomes predominantly mononuclear, with a declining number of neutrophils and macrophages, signaling the end of the inflammatory phase and the initiation of the proliferative phase. PROLIFERATIVE PHASESection 4 of 10
The proliferative phase of wound healing begins approximately 2-3 days after wounding and is signaled by the arrival of fibroblasts into the wound. Fibroblasts migrate from the wound margins using the fibrin-based provisional matrix established during the inflammatory phase. Within the first week after wounding, fibroblasts are driven by macrophage-derived bFGF, TGF-beta, and PDGF to proliferate and synthesize glycosaminoglycans and proteoglycans, the building blocks of the new extracellular matrix of granulation tissue, and collagen. Because macrophage numbers have begun to diminish in the acute wound by this time, fibroblasts start to produce bFGF, TGF-beta, and PDGF. They also begin producing keratinocyte growth factor and insulinlike growth factor-1. Fibroblasts become the dominant cell type, reaching their peak numbers at 7-14 days. After secretion of collagen molecules, fibroblasts then assemble them extracellularly into collagen fibers. These fibers are then cross-linked and organized into bundles. Collagen is the major component of acute wound connective tissue, with net production continuing for the next 6 weeks. The increasing content of wound collagen correlates with increasing tensile strength. During fibroblast proliferation, keratinocyte and endothelial cell populations are also stimulated to increase their numbers. In turn, keratinocytes and endothelial cells produce their own growth factors stimulatory for their respective cell proliferation. Simultaneously with cellular proliferation, angiogenesis in the developing granulation tissue occurs through budding from intact vessels at wound margins and requires endothelial cell production from factors described previously. This neovascularization accompanies the advancing line of fibroblasts into the wound to provide them with nutrients and to produce plasminogen activator and collagenase. This begins the degradation of the fibrin clot and provisional matrix once the new granulation tissue (ie, extracellular matrix, collagen, capillaries) is laid down. Granulation tissue production continues until the defect is covered. Finally, as the hyaluronic acid–containing provisional matrix is broken down, the decreasing hyaluronic acid concentration and rising chondroitin sulfate levels signal the slowing of fibroblast migration and proliferation. This shift in the ratio of these glycosaminoglycans acts to inhibit fibroblast activity, inducing them to differentiate, and thus initiating the maturation phase of wound healing. MATURATION PHASESection 5 of 10
New collagen production remains the dominant process in wound healing from the first week after wounding until approximately 6 weeks. Collagen is deposited randomly in acute wound granulation tissue. Remodeling of the collagen into a more organized structure occurs during wound maturation, increasing the wound's tensile strength. During the formation of the scar, the type III collagen of the granulation tissue is replaced by type I collagen until the normal skin ratio of 4:1 for type 1 collagen to type III collagen is present. With the remodeling process, a dynamic turnover of collagen occurs but collagen synthesis equals that of collagenolysis. This results in a tensile strength plateau achieved after approximately 2 years postinjury of approximately 80% of normal strength, beyond which wound strength cannot exceed. The wound is eventually closed by the migration of epithelial cells from the wound edge, filling the defect until they reach other epithelial cells and halt their advance due to contact inhibition. This adds nothing to wound strength, and remodeling continues beneath the epithelial cover. When wound fibroblasts reach a concentration with which their density causes contact inhibition, they differentiate into myofibroblasts containing alpha-smooth muscle actin fibrils. These cells tightly bind to each other and to the wound margins, drawing the wound edges closer together. The extent of importance of the role of myofibroblasts in wound contraction is, at present, equivocal. Some investigators believe the myofibroblast are the principal controller of wound contraction, while others maintain they are only the precursors to cell apoptosis and do not serve in contraction. By whatever means, as wound contraction proceeds, the volume of injured tissue is reduced by replacement with uninjured tissue. DETERRENTS OF WOUND HEALINGSection 6 of 10
The wound healing process can be applied to both acute and chronic wounds. However, in the latter, the sequential process has been disrupted. When a wound proceeds through an orderly and timely reparative process and results in a sustained restoration of anatomic and functional integrity, it is termed an acute wound. Conversely, a chronic wound is one that has failed to proceed through the usual stepwise fashion. As a result, the healing process is prolonged and incomplete, with lack of restoration of integrity. A chronic wound occurs when some factor causes the disruption of the normal, controlled inflammatory phase or the cellular proliferative phase. Thus, each wound should be evaluated to determine what factors are present and how to correct the problem. Many factors can contribute to poor wound healing. The most common include local causes such as wound infection; tissue hypoxia; repeated trauma; the presence of debris and necrotic tissue; and systemic causes such as diabetes mellitus, malnutrition, immunodeficiency, and the use of certain medications. Wound infection is likely the most common reason for poor wound healing. All wounds are contaminated with bacteria. Whether a wound becomes infected is determined by the host's immune competence and the size of the bacterial inoculum. With normal host defenses and adequate debridement, a wound may bear a level of 100,000 (105) microorganisms per gram of tissue and still heal successfully. Beyond this number, a wound may become infected. Soft tissue cellulitis prolongs the inflammatory phase by inducing tissue proteases to degrade new granulation tissue and tissue growth factors and by delaying collagen deposition. Exudative fluid drawn from chronic wounds, in contrast to acute wounds, has elevated protease activity, diminished growth factor activity, and elevated levels of proinflammatory cytokines. Therefore, infection impedes healing by interfering with many steps in the normal progression from inflammation to proliferation to maturation of the wound. Tissue perfusion may be impaired by arterial occlusion or vasoconstriction, hypotension, hypothermia, and peripheral venous congestion. Reduced wound oxygen tension can delay wound healing by slowing the production of collagen. Collagen fibril cross-linking begins to fail as tissue oxygen pressure falls below 40 mm Hg because oxygen is required for the hydroxylation of proline and lysine to synthesize mature collagen. Wound hypoxia also predisposes to bacterial infection because the leukocyte's oxidative phosphorylation bactericidal activities are severely impeded without normal tissue oxygen levels. These factors should be corrected as much as possible. For example, hypoxia due to arterial occlusive disease can be improved by angioplasty or bypass grafting. The patient should be urged to cease using tobacco, which causes arterial vasoconstriction. A hypotensive or hypothermic patient should be properly resuscitated to improve cardiac function and blood volume as needed. Venous stasis is generally treated with compressive garments to improve vascular return. Anemia is not detrimental to healing as long as the hematocrit value is greater than 15% and the patient is euvolemic. Because an adequate tissue oxygen tension directly correlates with the success of wound healing, optimizing oxygen tension is essential in all patients with any type of wound. Devitalized tissue impairs healing because it provides a growth medium for bacteria, increasing the probability of infection. Dead tissue also exudes endotoxins that inhibit the migration of fibroblasts and keratinocytes into the wound. Foreign bodies such as suture material also fall into the category of debris when a wound is chronic in nature. The presence of a silk suture reduces the number of bacteria required to incite infection by a factor of 10,000. Therefore, debridement of all necrotic tissue and debris, whether performed by surgical means or with the use of enzymatic agents or wound dressings, is critical in achieving wound healing. Underlying systemic disease in a patient with a wound can dramatically diminish the probability that the wound will heal in a timely fashion. Diabetes mellitus is a classic example. Wound healing is often delayed because of interruption of the inflammatory and proliferative phases. Neutrophils and macrophages cannot adequately keep the bacterial load of the wound controlled because their glycosylation is inhibitory to phagocytic function. Infection thus prolongs the inflammatory phase. When erythrocytes are affected by glycosylation (as measured by hemoglobin A1c levels), they become less pliable, leading to microvascular sludging and ischemia. Low tissue oxygen tension impairs cellular proliferation and collagen synthesis as previously described. Malnutrition causes a decreased rate of fibroblastic proliferation and neovascularization and impairs both cellular and humoral immunity. A high rate of metabolic activity is present at the wound site, especially within new granulation tissue. If nutrients necessary for those activities are not provided, the health of the tissue is tenuous. Proteins and their amino acid building blocks, such as methionine, proline, glycine, and lysine, are essential for normal cell function and the repair of cutaneous wounds. Linolenic and linoleic acid must be supplied in the diet, which is why they are termed essential fatty acids. Because they are critical constituents of the cell membrane and are the source of prostaglandins that mediate inflammation, deficiency of essential fatty acids causes impaired wound healing. Deficiency of vitamins C or K leads to scurvy and coagulopathy, respectively. Minerals, including calcium, iron, copper, zinc, and manganese, must be delivered to the wound milieu to act as cofactors for vital reactions in the synthesis of proteins needed in the healing process. If the diagnosis is impaired wound healing resulting from malnutrition, ensure that the patient receives adequate protein and energy (caloric) intake. Specific vitamin and mineral supplements may be required for rapid recovery of the necessary nutrients. Finally, some medications prove to be detrimental to wound healing. Corticosteroids suppress inflammation at all levels, thereby blunting this phase of healing. Vitamin A reverses the negative effects of steroids and is indicated for topical and systemic application for all patients with chronic wounds who cannot discontinue corticosteroid therapy. Nonsteroidal anti-inflammatory agents such as aspirin and indomethacin interfere with the arachidonic acid cascade, impeding the elucidation of some of the healing scheme's primary mediators. Additionally, these act to inhibit the actions of platelets and platelet aggregation, thus disrupting the healing process from the first moment of wounding. To provide the best chance for chronic wounds to heal, the surgeon should attempt to identify any factors that may be acting to impede success, and then correct the problem through optimization of the cellular and molecular wound environment. COMMON CHRONIC WOUNDSSection 7 of 10
Common chronic skin and soft tissue wounds include the diabetic foot ulcer, the decubitus ulcer, and the venous stasis ulcer. Diabetic ulcers Diabetic ulcers are the most common cause of foot and leg amputation. In patients with type I and type II diabetes, the incidence rate of developing foot ulcers is approximately 2% per year. The average cost for 2 years of treatment is $27,987 per patient (1999 data). The diabetic foot ulcer is mainly neuropathic in origin, with secondary pathogenesis being a blunted leukocyte response to bacteria and local ischemia due to vascular disease. These wounds usually occur on weight-bearing areas of the foot. The Wound Healing Society's standards of care include off-loading, attentive debridement, and the maintenance of a moist wound environment. Because diabetic ulcers are prone to infection, topical antimicrobials may be used if infection is present; however, systemic antibiotics should be used if cellulitis occurs. Systemic antibiotics should be discontinued once the wound has come into bacterial balance because most agents inhibit fibroblast and keratinocyte proliferation. Because chronic wounds have been demonstrated to have markedly decreased levels of several growth factors, these have been a focus to enhance the repair of the wounds. Topically applied PDGF, TGF-beta, and platelet-derived wound healing factor have been demonstrated to be effective agents to speed the healing of diabetic ulcers. Because clinical trials have proven its efficacy and safety, PDGF (Regranex) is the first recombinant growth factor to be approved by the US Food and Drug Administration for use in the acceleration of wound closure. In patients with diabetic ulcers and in persons with other types of chronic wounds, pursue correction of the cause and institute measures to stimulate healing. Decubitus ulcers The decubitus ulcer is a result of prolonged, unrelieved pressure over a bony prominence that leads to ischemia. The wound tends to occur in patients who are unable to reposition themselves to off-load weight, such as paralyzed, unconscious, or severely debilitated persons. As defined by the US Department of Health and Human Services, the major preventive measures include identification of high-risk patients; frequent assessment; and prophylactic measures such as scheduled repositioning, appropriate pressure-relief bedding, moisture barriers, and adequate nutritional status. Treatment consists of pressure relief, surgical and enzymatic debridement, moist wound care, and control of the bacterial load. Topical applications of antimicrobials and PDGF may be used. The Vacuum-Assisted Closure technique (Kinetic Concepts, Inc) is successful in treating pressure ulcers. These mechanisms of treatment strive to reestablish a normal healing trajectory by correcting the source of the problem. Venous stasis ulcers In the venous stasis ulcer, chronic passive venous congestion of the lower extremities results in local hypoxia. One current hypothesis of the pathogenesis of these wounds includes the impediment of oxygen diffusion into the tissue across thick perivascular fibrin cuffs. Another belief is that macromolecules leaking into the perivascular tissue trap growth factors needed for the maintenance of skin integrity. Additionally, the flow of large white blood cells slows due to venous congestion, occluding capillaries, becoming activated, and damaging the vascular endothelium to predispose to ulcer formation. The standard of care is compression garment therapy, debridement, and a moist wound environment. Partial-thickness meshed skin grafts are effective for venous leg ulcers. Bioengineered skin equivalent (Apligraf) is efficacious in these wounds, acting as a moist dressing and providing a matrix, migration pathways, growth factors, and living dermal and epidermal cells to the wound. CONCLUSIONSection 8 of 10
These indolent wounds are similar in that each is marked by persistent inflammatory stimuli, such as infection, ischemia, and repeated trauma, that disrupt the normal healing process. The goal of wound management is to reestablish the normal healing scheme. Chronic wounds affect millions of patients and impose a great cost to society. Research into using growth factors and new care techniques holds great promise, with the goal of lessening the burden these wounds place on physicians, health care systems, and patients. MULTIMEDIASection 9 of 10
REFERENCESSection 10 of 10
Wound Healing, Chronic Wounds excerpt Article Last Updated: May 26, 2006 | |||||||||||||||||
