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Surgery_Schwartz. both squamous and basal cell carcinomas.Ischemic Arterial Ulcers. These wounds occur due to a lack of blood supply and are typically extremely painful in patients with pure ischemic ulcers. They usually are associated with other symptoms of peripheral vascular disease, such as history of intermittent claudication, rest pain, and color or trophic changes. These wounds commonly are present at the most distal portions of the extremities such as the interdigital clefts, although more proxi-mal locations are also encountered. On examination, there may be diminished or absent pulses with decreased ankle-brachial index and poor formation of granulation tissue. Other signs of peripheral ischemia, such as dryness of skin, hair loss, scaling, and pallor can be present. The wound itself usually is shallow with smooth mar-gins, and a pale base and surrounding skin may be present. The management of these wounds is two-pronged and includes revas-cularization and wound care.107 Nonhealing of these


Surgery_Schwartz

Surgery_Schwartz. shallow with smooth mar-gins, and a pale base and surrounding skin may be present. The management of these wounds is two-pronged and includes revas-cularization and wound care.107 Nonhealing of these wounds is the norm unless successful revascularization is performed. In patients with ischemia and bed confinement, prevention of ulcer devel-opment is extremely important. Removal of restrictive stockings (in patients with critical ischemia), frequent repositioning, and surveillance are vital to preventing these ulcers.108Venous Stasis Ulcers. Although there is unanimous agree-ment that venous ulcers are due to venous stasis and increased venous pressure, there is less consensus as to what are the exact pathophysiologic pathways that lead to ulceration and impaired healing. On the microvascular level, there is alteration and distention of the dermal capillaries with leakage of fibrinogen into the tissues; polymerization of fibrinogen into fibrin cuffs leads to perivascular cuffing that


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Surgery_Schwartz. level, there is alteration and distention of the dermal capillaries with leakage of fibrinogen into the tissues; polymerization of fibrinogen into fibrin cuffs leads to perivascular cuffing that can impede oxygen exchange, thus contributing to ulceration. These same fibrin cuffs and the leakage of macromolecules such as fibrinogen and α2-macroglobulin trap growth factors and impede wound healing.103 Another hypothesis suggests that neutrophils adhere to the cap-illary endothelium and cause plugging with diminished dermal blood flow. Venous hypertension and capillary damage lead to extravasation of hemoglobin. The products of this breakdown are irritating and cause pruritus and skin damage. The result-ing brownish pigmentation of skin combined with the loss of subcutaneous fat produces characteristic changes called lipoder-matosclerosis. Regardless of the pathophysiologic mechanisms, the clinically characteristic picture is that of an ulcer that fails to reepithelialize despite the


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Surgery_Schwartz. characteristic changes called lipoder-matosclerosis. Regardless of the pathophysiologic mechanisms, the clinically characteristic picture is that of an ulcer that fails to reepithelialize despite the presence of adequate granulation tis-sue in a patient with skin color changes in the area of ulceration and signs of venous hypertension.Venous stasis occurs due to increased venous hyperten-sion caused by either venous insufficiency or venous outflow obstruction. Venous insufficiency can be due to any combina-tion of deep, superficial, and perforator vein valvular reflux. The higher the ambulatory venous hypertension, the higher the chance of ulceration. Chronic venous ulcers are commonly painless. Stasis ulcers tend to occur at the sites of incompetent Figure 9-10. Typical appearance of the malignant transformation of a long-standing chronic wound. (Used with permission by Dr. Robert S. Kirsner, University of Miami.)Brunicardi_Ch09_p0271-p0304.indd 29001/03/19 4:50 PM 291WOUND


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Surgery_Schwartz. the malignant transformation of a long-standing chronic wound. (Used with permission by Dr. Robert S. Kirsner, University of Miami.)Brunicardi_Ch09_p0271-p0304.indd 29001/03/19 4:50 PM 291WOUND HEALINGCHAPTER 9perforators, the most common being above the medial malleo-lus, over Cockett’s perforator. Upon examination, the typical location combined with a history of venous incompetence and other skin changes is diagnostic. The wound usually is shallow with irregular margins and pigmented surrounding skin.The cornerstone of treatment of venous ulcers is compres-sion therapy, although the best method to achieve it remains controversial. Compression can be accomplished via rigid or flexible means. The most commonly used method is the rigid, zinc oxide–impregnated, nonelastic bandage. Others have proposed a four-layered bandage approach as a more optimal method of obtaining graduated compression.109 Wound care in these patients focuses on maintaining a moist wound environ-ment, which


Surgery_Schwartz

Surgery_Schwartz. have proposed a four-layered bandage approach as a more optimal method of obtaining graduated compression.109 Wound care in these patients focuses on maintaining a moist wound environ-ment, which can be achieved with hydrocolloids. Other, more modern approaches include use of vasoactive substances and growth factor application, as well as the use of skin substitutes. Recently, sprayed allogeneic keratinocytes and fibroblasts plus four-layer bandages have been shown to hasten healing when compared to compression alone.110 Addressing the causes of venous hypertension aids in the healing of venous ulcers.109 Unfortunately, recurrences are frequent despite preventative measures, largely because of patients’ lack of compliance.111Diabetic Wounds. Ten percent to 25% of diabetic patients run the risk of developing ulcers. There are approximately 50,000 to 60,000 amputations performed in diabetic patients each year in the United States. The major contributors to the formation of diabetic


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Surgery_Schwartz. the risk of developing ulcers. There are approximately 50,000 to 60,000 amputations performed in diabetic patients each year in the United States. The major contributors to the formation of diabetic ulcers include neuropathy, foot deformity, and isch-emia. It is estimated that 60% to 70% of diabetic ulcers are due to neuropathy, 15% to 20% are due to ischemia, and another 15% to 20% are due to a combination of both. The neuropathy is both sensory and motor and is secondary to persistently elevated glucose levels. The loss of sensory function allows unrecognized injury to occur from ill-fitting shoes, foreign bodies, or other trauma. The motor neuropathy or Charcot’s foot leads to col-lapse or dislocation of the interphalangeal or metatarsophalan-geal joints, causing pressure on areas with little protection. There is also severe microand macrovascular circulatory impairment.Once ulceration occurs, the chances of healing are poor and the chances of recurrent ulceration are high. The


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Surgery_Schwartz. little protection. There is also severe microand macrovascular circulatory impairment.Once ulceration occurs, the chances of healing are poor and the chances of recurrent ulceration are high. The treatment of diabetic wounds involves local and systemic measures.112 Achievement of adequate blood sugar levels is very impor-tant. Most diabetic wounds are infected, and eradication of the infectious source is paramount to the success of healing. Treatment should address the possible presence of osteomyeli-tis and should employ antibiotics that achieve adequate levels both in soft tissue and bone. Wide debridement of all necrotic or infected tissue is another cornerstone of treatment. Offloading of the ulcerated area by using specialized orthotic shoes or casts allows for ambulation while protecting the fragile wound environment. Topical application of PDGF and granulocyte-macrophage colony-stimulating factor has met with limited but significant success in achieving closure.113 The


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Surgery_Schwartz. protecting the fragile wound environment. Topical application of PDGF and granulocyte-macrophage colony-stimulating factor has met with limited but significant success in achieving closure.113 The application of engineered skin allograft substitutes, although expensive, also has shown some significant success.114 Preven-tion and specifically foot care play an important role in the man-agement of diabetics.115Decubitus or Pressure Ulcers. The incidence of pressure ulcers ranges from 2.7% to 9% in the acute care setting, in com-parison to 2.4% to 23% in long-term care facilities. A pressure ulcer is a localized area of tissue necrosis that develops when soft tissue is compressed between a bony prominence and an external surface. Excessive pressure causes capillary collapse and impedes the delivery of nutrients to body tissues. Pressure ulcer formation is accelerated in the presence of friction, shear forces, and moisture. Other contributory factors in the patho-genesis of pressure


Surgery_Schwartz

Surgery_Schwartz. the delivery of nutrients to body tissues. Pressure ulcer formation is accelerated in the presence of friction, shear forces, and moisture. Other contributory factors in the patho-genesis of pressure ulcers include immobility, altered activity levels, altered mental status, chronic conditions, and altered nutritional status. The four stages of pressure ulcer formation are as follows: stage I, no blanching erythema of intact skin; stage II, partial-thickness skin loss involving epidermis or der-mis or both; stage III, full-thickness skin loss, but not through the fascia; and stage IV, full-thickness skin loss with extensive involvement of muscle and bone.The treatment of established pressure ulcers is most suc-cessful when carried out in a multidisciplinary manner by involving wound care teams consisting of physicians, nurses, dietitians, physical therapists, and nutritionists. Care of the ulcer itself comprises debridement of all necrotic tissue, maintenance of a favorable moist wound


Surgery_Schwartz

Surgery_Schwartz. consisting of physicians, nurses, dietitians, physical therapists, and nutritionists. Care of the ulcer itself comprises debridement of all necrotic tissue, maintenance of a favorable moist wound environment that will facilitate healing, relief of pressure, and addressing host issues such as nutritional, metabolic, and circulatory status. Debridement is most efficiently carried out surgically, but enzymatic proteo-lytic preparations and hydrotherapy also are used. The wound bed should be kept moist by employing dressings that absorb secretions but do not desiccate the wound.116 Operative repair, usually involving flap rotation, has been found to be useful in obtaining closure. Unfortunately, recurrence rates are extremely high, owing to the population at risk and the inability to fully address the causative mechanisms.117EXCESS HEALING Clinically, excess healing can be as significant as delayed or nonhealing. It is likely that more operative interventions are required for correction


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Surgery_Schwartz. the causative mechanisms.117EXCESS HEALING Clinically, excess healing can be as significant as delayed or nonhealing. It is likely that more operative interventions are required for correction of the morbidity associated with excessive healing than are required for wound failure. The clinical manifestations of exuberant healing are protean and dif-fer in the skin (mutilating or debilitating scars, burn contrac-tions), tendons (frozen repairs), the GI tract (strictures or stenoses), solid organs (cirrhosis, pulmonary fibrosis), or the peritoneal cavity (adhesive disease).Hypertrophic scars (HTSs) and keloids represent an over-abundance of fibroplasia in the dermal healing process. HTSs rise above the skin level but stay within the confines of the origi-nal wound and often regress over time. Keloids rise above the skin level as well, but they extend beyond the border of the original wound and rarely regress spontaneously (Fig. 9-11). Both HTSs and keloids occur after trauma to the skin


Surgery_Schwartz

Surgery_Schwartz. Keloids rise above the skin level as well, but they extend beyond the border of the original wound and rarely regress spontaneously (Fig. 9-11). Both HTSs and keloids occur after trauma to the skin and may be tender, pruritic, and cause a burning sensation. Keloids are 15 times more common in darker-pigmented ethnicities, with individuals of African, Spanish, and Asian ethnicities being especially susceptible. Men and women are equally affected. Genetically, the predilection to keloid formation appears to be autosomal dominant with incomplete penetration and variable expression.117,118HTSs usually develop within 4 weeks after trauma. The risk of HTS increases if epithelialization takes longer than 21 days, independent of site, age, and race. Rarely elevated more than 4 mm above the skin level, HTSs stay within the boundaries of the wound. They usually occur across areas of tension and flexor surfaces, which tend to be at right angles to joints or skin creases. The lesions are


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Surgery_Schwartz. skin level, HTSs stay within the boundaries of the wound. They usually occur across areas of tension and flexor surfaces, which tend to be at right angles to joints or skin creases. The lesions are initially erythematous and raised and over time may evolve into pale, flatter scars.4Brunicardi_Ch09_p0271-p0304.indd 29101/03/19 4:50 PM 292BASIC CONSIDERATIONSPART IKeloids can result from surgery, burns, skin inflamma-tion, acne, chickenpox, zoster, folliculitis, lacerations, abrasions, tattoos, vaccinations, injections, insect bites, or ear piercing, or may arise spontaneously. Keloids tend to occur 3 months to years after the initial insult, and even minor injuries can result in large lesions. They vary in size from a few millimeters to large, pedun-culated lesions with a soft to rubbery or hard consistency. While they project above surrounding skin, they rarely extend into underlying subcutaneous tissues. Certain body sites have a higher incidence of keloid formation, including


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Surgery_Schwartz. or hard consistency. While they project above surrounding skin, they rarely extend into underlying subcutaneous tissues. 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. They rarely occur on eyelids, genitalia, palms, soles, or across joints. Keloids rarely involute spontaneously, and surgical intervention can lead to recurrence, often with a worse result (Table 9-8).Histologically, both HTSs and keloids demonstrate increased thickness of the epidermis with an absence of rete ridges. There is an abundance of collagen and glycoprotein deposition. Normal skin has distinct collagen bundles, mostly parallel to the epithelial surface, with random connections between bundles by fine fibrillar strands of collagen. In HTS, the collagen bundles are flatter and more random, and the fibers are in a wavy pattern. In keloids, the collagen bundles are virtu-ally nonexistent, and the fibers


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Surgery_Schwartz. strands of collagen. In HTS, the collagen bundles are flatter and more random, and the fibers are in a wavy pattern. In keloids, the collagen bundles are virtu-ally nonexistent, and the fibers are connected haphazardly in loose sheets with a random orientation to the epithelium. The collagen fibers are larger and thicker, and myofibroblasts are generally absent.119Keloidal fibroblasts have normal proliferation param-eters but synthesize collagen at a rate 20 times greater than that observed in normal dermal fibroblasts, and 3 times higher than fibroblasts derived from HTS. Abnormal amounts of extracel-lular matrix such as fibronectin, elastin, and proteoglycans also are produced. The synthesis of fibronectin, which promotes clot generation, granulation tissue formation, and reepithelializa-tion, decreases during the normal healing process; however, production continues at high levels for months to years in HTSs and keloids. This perturbed synthetic activity is mediated by altered


Surgery_Schwartz

Surgery_Schwartz. decreases during the normal healing process; however, production continues at high levels for months to years in HTSs and keloids. This perturbed synthetic activity is mediated by altered growth factor expression. TGF-β expression is higher in HTS, and both HTSand keloid-derived fibroblasts respond to lower concentrations of TGF-β than do normal dermal fibro-blasts. HTSs also express increased levels of insulin-like growth factor-1, which reduces collagenase mRNA activity and increases mRNA for types I and II procollagen.120 Keloid fibroblasts have enhanced expression of TGF-β1 and TGF-β2, VEGF, and plasminogen activator inhibitor-1 and an increased number of PDGF receptors; they also have upregulated anti-apoptotic gene expression, which can be differentially expressed within different areas of the same scar.The 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, although the exact


Surgery_Schwartz

Surgery_Schwartz. areas of the same scar.The 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, although the exact relationship is unknown. Much is inferred from the presence of various immune cells in HTSs and keloids. For example, in both HTSs and keloids, keratinocytes express human leuko-cyte antigen (HLA)-2 and ICAM-1 receptors, which are absent Figure 9-11. Recurrent keloid on the neck of a 17-year-old patient that had been revised several times. (Reproduced with permission from Cohen IK, Diegelmann RF, Lindblad WJ: Wound Healing: Biochemical and Clinical Aspects. Philadelphia, PA: WB Saunders/ Elsevier; 1992.)Table 9-8Characteristics of keloids and hypertrophic scars KELOIDHYPERTROPHIC SCARIncidenceRareFrequentEthnic groupsAfrican American, Asian, HispanicNo predilectionPrior injuryYesYesSite predilectionNeck, chest, ear lobes, shoulders, upper backAnywhereGeneticsAutosomal dominant with incomplete


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Surgery_Schwartz. groupsAfrican American, Asian, HispanicNo predilectionPrior injuryYesYesSite predilectionNeck, chest, ear lobes, shoulders, upper backAnywhereGeneticsAutosomal dominant with incomplete penetrationNoTimingSymptom-free interval; may appear years after injury4–6 weeks post injurySymptomsPain, pruritus, hyperesthesia, growth beyond wound marginsRaised, some pruritus, respects wound confinesRegressionNoFrequent spontaneousContractureRareFrequentHistologyHypocellular, thick, wavy collagen fibers in random orientationParallel orientation of collagen fibersBrunicardi_Ch09_p0271-p0304.indd 29201/03/19 4:50 PM 293WOUND HEALINGCHAPTER 9in normal scar keratinocytes. Keloids also have increased deposition of immunoglobulins IgG, IgA, and IgM, and their formation correlates with serum levels of IgE. 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. There is also a


Surgery_Schwartz

Surgery_Schwartz. 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. There is also a larger number of mast cells present in both HTSs and keloids compared to normal scars. Another recently described cell pop-ulation is the fibrocyte, a leukocyte subpopulation derived from peripheral mononuclear cells. Present in large numbers at the site of excess scarring, fibrocytes can stimulate fibroblast num-bers and collagen synthesis. They also generate large numbers of cytokines, growth factors, and extracellular matrix proteins, which are characteristically upregulated in keloid tissue. Other mechanisms that may cause abnormal scarring include mechani-cal tension (although keloids often occur in areas of minimal tension) and prolonged irritation and/or inflammation that may lead to the generation of abnormal concentrations of profibrotic cytokines.Treatment goals for keloid and HTS


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Surgery_Schwartz. occur in areas of minimal tension) and prolonged irritation and/or inflammation that may lead to the generation of abnormal concentrations of profibrotic cytokines.Treatment goals for keloid and HTS include restoration of function to the area, relief of symptoms, and prevention of recurrence. Many patients seek intervention due to cosmetic concerns. Because the underlying mechanisms causing keloids and HTSs remain unknown, many different modalities of treat-ment have been used without consistent success.121Excision alone of keloids is subject to a high recurrence rate, ranging from 45% to 100%. Inclusion of the dermal advancing edge that characterizes keloids, use of incisions in skin tension lines, and tension-free closure all have been pro-posed to decrease recurrence rates. There are fewer recurrences when surgical excision is combined with other modalities such as intralesional corticosteroid injection, topical application of silicone sheets, or the use of radiation or pressure.


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Surgery_Schwartz. fewer recurrences when surgical excision is combined with other modalities such as intralesional corticosteroid injection, topical application of silicone sheets, or the use of radiation or pressure. Surgery is recommended for debulking large lesions or as second-line therapy when other modalities have failed. Silicone application is relatively painless and should be maintained for 24 hours a day for about 3 months to prevent rebound hypertrophy. It may be secured with tape or worn beneath a pressure garment. The mechanism of action is not understood, but increased hydration of the skin, which decreases capillary activity, inflammation, hyperemia, and collagen deposition, may be involved. Silicone is more effective than other occlusive dressings and is an espe-cially good treatment for children and others who cannot toler-ate the pain involved in other modalities.102Intralesional corticosteroid injections decrease fibroblast proliferation, collagen and glycosaminoglycan synthesis, the


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Surgery_Schwartz. and others who cannot toler-ate the pain involved in other modalities.102Intralesional corticosteroid injections decrease fibroblast proliferation, collagen and glycosaminoglycan synthesis, the inflammatory process, and TGF-β levels. When used alone, however, there is a variable rate of response and recurrence; therefore, steroids are recommended as first-line treatment for keloids and second-line treatment for HTSs if topical thera-pies have failed. Intralesional injections are more effective on younger scars. They may soften, flatten, and give symptomatic relief to keloids, but they cannot make the lesions disappear, and they cannot narrow wide HTSs. Success is enhanced when used in combination with surgical excision. Serial injections every 2 to 3 weeks are required. Complications include skin atrophy, hypopigmentation, telangiectasias, necrosis, and ulceration.Although radiation destroys fibroblasts, it has variable, unreliable results and produces poor results, with 10% to 100%


Surgery_Schwartz

Surgery_Schwartz. skin atrophy, hypopigmentation, telangiectasias, necrosis, and ulceration.Although radiation destroys fibroblasts, it has variable, unreliable results and produces poor results, with 10% to 100% recurrence when used alone. It is more effective when combined with surgical excision. The timing, duration, and dosage for radiation therapy are still controversial, but doses ranging from 1500 to 2000 rads appear effective. Given the risks of hyperpig-mentation, pruritus, erythema, paresthesias, pain, and possible secondary malignancies, radiation should be reserved for adults with scars resistant to other modalities.Pressure aids collagen maturation, flattens scars, and improves thinning and pliability. It reduces the number of cells in a given area, possibly by creating ischemia, which decreases tissue metabolism and increases collagenase activity. External compression is used to treat HTSs, especially after burns. Ther-apy must begin early, and a pressure between 24 and 30 mmHg must be


Surgery_Schwartz

Surgery_Schwartz. tissue metabolism and increases collagenase activity. External compression is used to treat HTSs, especially after burns. Ther-apy must begin early, and a pressure between 24 and 30 mmHg must be achieved in order to exceed capillary pressure, yet pre-serve peripheral blood circulation. Garments should be worn for 23 to 24 hours a day for up to 1 or more years to avoid rebound hypertrophy. Scars older than 6 to 12 months respond poorly.Topical retinoids also have been used as treatment for both HTSs and keloids, with reported responses of 50% to 100%. Intralesional injections of IFN-γ, a cytokine released by T lymphocytes, reduce collagen types I, II, and III by decreasing mRNA and possibly by reducing levels of TGF-β. As mono-therapy, IFN-γ has failed because of high recurrence rates due to resistance to repeated injections. More recently, imiquimod, an immunomodulator that induces IFN-γ and other cytokines at the site of application, has been recommended following exci-sion.


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Surgery_Schwartz. due to resistance to repeated injections. More recently, imiquimod, an immunomodulator that induces IFN-γ and other cytokines at the site of application, has been recommended following exci-sion. Intralesional injections of chemotherapeutic agents such as 5-fluorouracil have been used both alone and in combina-tion with steroids. The use of bleomycin or mitomycin C has been reported to achieve some success in older scars resistant to steroids.Peritoneal Scarring. Peritoneal adhesions are fibrous bands of tissues formed between organs that are normally separated and/or between organs and the internal body wall. Most intra-abdominal adhesions are a result of peritoneal injury, either by a prior surgical procedure or due to intra-abdominal infection. Postmortem examinations demonstrate adhesions in 67% of patients with prior surgical procedures and in 28% with a history of intra-abdominal infection. Intra-abdominal adhesions are the most common cause (65%–75%) of small bowel obstruction,


Surgery_Schwartz

Surgery_Schwartz. in 67% of patients with prior surgical procedures and in 28% with a history of intra-abdominal infection. Intra-abdominal adhesions are the most common cause (65%–75%) of small bowel obstruction, especially in the ileum. Operations in the lower abdomen have a higher chance of producing small bowel obstruction. Follow-ing rectal surgery, left colectomy, or total colectomy, there is an 11% chance of developing small bowel obstruction within 1 year, and this rate increases to 30% by 10 years. Adhesions also are a leading cause of secondary infertility in women and can cause substantial abdominal and pelvic pain. Adhesions account for 2% of all surgical admissions and 3% of all lapa-rotomies in general surgery.122Adhesions form when the peritoneal surface is damaged due to surgery, thermal or ischemic injury, inflammation, or foreign body reaction. The injury disrupts the protective meso-thelial cell layer lining the peritoneal cavity and the underlying connective tissue. The injury


Surgery_Schwartz

Surgery_Schwartz. or ischemic injury, inflammation, or foreign body reaction. The injury disrupts the protective meso-thelial cell layer lining the peritoneal cavity and the underlying connective tissue. The injury elicits an inflammatory response consisting of hyperemia, fluid exudation, release, and activation of white blood cells and platelets in the peritoneal cavity, activa-tion of inflammatory cytokines, and the onset of the coagulation and complement cascades. Fibrin deposition occurs between the damaged but opposed serosal surfaces. These filmy adhesions often are transient and degraded by proteases of the fibrinolytic system, with restoration of the normal peritoneal surface. If insufficient fibrinolytic activity is present, permanent fibrous adhesions will form by collagen deposition within 1 week of the injury (Fig. 9-12).Brunicardi_Ch09_p0271-p0304.indd 29301/03/19 4:50 PM 294BASIC CONSIDERATIONSPART IExtensive research has been done on the effect of surgery and peritonitis on the


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Surgery_Schwartz. 1 week of the injury (Fig. 9-12).Brunicardi_Ch09_p0271-p0304.indd 29301/03/19 4:50 PM 294BASIC CONSIDERATIONSPART IExtensive research has been done on the effect of surgery and peritonitis on the fibrinolytic and inflammatory cascades within the peritoneal cavity. During normal repair, fibrin is prin-cipally degraded by the fibrinolytic protease plasmin, which is derived from inactive plasminogen through the action of two plasminogen activators (PA): tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). Fibrino-lytic activity in peritoneal fluid is reduced after abdominal sur-gery due to initial decreases in tPA levels and later to increases in plasminogen activator inhibitor-1 (PAI-1), which are induced by various cytokines, including TNF-α, IL-1, and interleukin-6 (IL-6).123There are two major strategies for adhesion prevention or reduction. Surgical trauma is minimized within the peritoneum by careful tissue handling, avoiding desiccation and


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Surgery_Schwartz. interleukin-6 (IL-6).123There are two major strategies for adhesion prevention or reduction. Surgical trauma is minimized within the peritoneum by careful tissue handling, avoiding desiccation and ischemia, and spare use of cautery, laser, and retractors. Fewer adhesions form with laparoscopic surgical techniques due to reduced tis-sue trauma. The second major advance in adhesion prevention has been the introduction of barrier membranes and gels, which separate and create barriers between damaged mesothelial sur-faces, allowing for adhesion-free healing. Currently, only three products are Food and Drug Administration (FDA) approved for reducing adhesion formation: Interceed (oxidized regen-erated cellulose, indicated only in pelvic surgery), Seprafilm (a film composed of hyaluronic acid and carboxymethylcel-lulose) that is usually applied below the incision, and Adept (4% icodextrin, a corn starch derivative in electrolyte solution, also for use mainly in pelvic surgery). However,


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Surgery_Schwartz. and carboxymethylcel-lulose) that is usually applied below the incision, and Adept (4% icodextrin, a corn starch derivative in electrolyte solution, also for use mainly in pelvic surgery). However, use of these substances directly over bowel anastomoses is contraindicated due to an elevated risk of leak.124 There have been innumerable studies investigating different molecules in hopes of preventing adhesion formation, but most of the success is limited to animal models, and clinically significant results in humans have yet to be achieved.TREATMENT OF WOUNDSLocal Care (Fig. 9-13)Management of acute wounds begins with obtaining a careful history of the events surrounding the injury. The history is fol-lowed by a meticulous examination of the wound. Examination should assess the depth and configuration of the wound, the extent of nonviable tissue, and the presence of foreign bodies and other contaminants. The wound/ulcer should be described based on location, dimensions, presence of


Surgery_Schwartz

Surgery_Schwartz. configuration of the wound, the extent of nonviable tissue, and the presence of foreign bodies and other contaminants. The wound/ulcer should be described based on location, dimensions, presence of infection, drainage and type of drainage, base characteristics, presence or absence of necrosis, presence of pain, and description of edges. Possible etiology should be mentioned, and the presence of sys-temic factors and circulation should be evaluated.After completion of the history, examination, and admin-istration of tetanus prophylaxis, the wound should be meticu-lously anesthetized. Lidocaine (0.5%–1%) or bupivacaine (0.25%–0.5%) combined with a 1:100,000 to 1:200,000 dilution of epinephrine provides satisfactory anesthesia and hemostasis. 5ThrombinCoagulationFibrinogenPeritoneal fluidInflammationFibrin++PAI-1, PAI-2tPA, uPAFibrin residuesFibrinolysisFibrinolysisdegradationRestitutionFibroblasts and capillariesFibrous adhesionPeritoneal


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Surgery_Schwartz. fluidInflammationFibrin++PAI-1, PAI-2tPA, uPAFibrin residuesFibrinolysisFibrinolysisdegradationRestitutionFibroblasts and capillariesFibrous adhesionPeritoneal injuryBleedingMacrophagesmesotheliumPlateletsTFFigure 9-12. Fibrin formation and degradation in peritoneal tis-sue repair and adhesion formation. PAI-1, PAI-2 = types 1 and 2 plasminogen activator inhibitor; TF = tissue factor; tPA = tissue plasminogen activator; uPA = urokinase plasminogen activator.Figure 9-13. Algorithm for management of acute wounds.Management of Acute Wounds1. Examinationa) Depth? Underlying structures injuredb) Configuration?c) Nonviable tissue?4. Follow-upa) Cellulitis/drainage?b) Suture removal -4–5 days for face -7–10 days other skin3. Approximationa) Deep layers -Fascial layers only -Absorbable sutureb) Superficial layers -Meticulous alignment -Nonabsorbable sutures in skin -Staples -Monofilament -Dermal glues2. Preparationa) Anesthetic -Lidocaine w or w/o epinephrineb) Exploration -Underlying


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Surgery_Schwartz. Superficial layers -Meticulous alignment -Nonabsorbable sutures in skin -Staples -Monofilament -Dermal glues2. Preparationa) Anesthetic -Lidocaine w or w/o epinephrineb) Exploration -Underlying structures injuredc) Cleansing -Pulsed irrigation, saline onlyd) Hemostasise) Debride nonviable tissuef) Betadine on surrounding sking) Antibiotics (rare)h) TetanusBrunicardi_Ch09_p0271-p0304.indd 29401/03/19 4:50 PM 295WOUND HEALINGCHAPTER 9Epinephrine should not be used in wounds of the fingers, toes, ears, nose, or penis, due to the risk of tissue necrosis secondary to terminal arteriole vasospasm in these structures.Irrigation to visualize all areas of the wound and remove foreign material is best accomplished with normal saline (with-out additives). High-pressure wound irrigation is more effective in achieving complete debridement of foreign material and non-viable tissues. Iodine, povidone-iodine, hydrogen peroxide, and organically based antibacterial preparations have all been shown


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Surgery_Schwartz. in achieving complete debridement of foreign material and non-viable tissues. Iodine, povidone-iodine, hydrogen peroxide, and organically based antibacterial preparations have all been shown to impair wound healing due to injury to wound neutrophils and macrophages, and thus should not be used. All hematomas present within wounds should be carefully evacuated and any remaining bleeding sources controlled with ligature or cautery. If the injury has resulted in the formation of a marginally viable flap of skin or tissue, this should be resected or revascularized prior to further wound repair and closure.After the wound has been anesthetized, explored, irri-gated, and debrided, the area surrounding the wound should be cleaned, inspected, and the surrounding hair clipped. The area surrounding the wound should be prepared with povi-done iodine, chlorhexidine, or similar bacteriostatic solutions and draped with sterile towels. Having ensured hemostasis and adequate debridement of nonviable


Surgery_Schwartz

Surgery_Schwartz. the wound should be prepared with povi-done iodine, chlorhexidine, or similar bacteriostatic solutions and draped with sterile towels. Having ensured hemostasis and adequate debridement of nonviable tissues and removal of any remaining foreign bodies, irregular, macerated, or beveled wound edges should be debrided in order to provide a fresh edge for reapproximation. Although plastic surgical techniques such as Wor Z-plasty are seldom recommended for acute wounds, great care must be taken to realign wound edges properly. This is particularly important for wounds that cross the vermilion border, eyebrow, or hairline. Initial sutures that realign the edges of these different tissue types will speed and greatly enhance the aesthetic outcome of the wound repair.In general, the smallest suture required to hold the vari-ous layers of the wound in approximation should be selected in order to minimize suture-related inflammation. Nonabsorbable or slowly absorbing monofilament sutures are most


Surgery_Schwartz

Surgery_Schwartz. required to hold the vari-ous 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 abdomi-nal wall. Subcutaneous tissues should be closed with braided absorbable sutures, with care to avoid placement of sutures in fat. Multiple layer closure of the abdominal wall is preferable. However, additional layers with sutures might increase the risk of wound infection.In areas of significant tissue loss, rotation of adjacent mus-culocutaneous flaps or free flaps may be required to provide sufficient tissue mass for closure. In cases of significant superfi-cial tissue loss, split-thickness skin grafting (placed in a delayed manner to assure an adequate tissue bed) may be required and will speed formation of an intact epithelial barrier to fluid loss and infection. In acute, contaminated wounds with skin loss, use


Surgery_Schwartz

Surgery_Schwartz. manner to assure an adequate tissue bed) may be required and will speed formation of an intact epithelial barrier to fluid loss and infection. In acute, contaminated wounds with skin loss, use of porcine skin xenografts or skin cadaveric allografts might be needed to avoid infection.After closing deep tissues and replacing significant tissue deficits, skin edges should be reapproximated for cosmesis and to aid in rapid wound healing. Skin edges may be quickly reap-proximated with stainless steel staples or nonabsorbable mono-filament sutures. Care must be taken to remove these from the wound prior to epithelialization of the skin tracts where sutures or staples penetrate the dermal layer. Failure to remove the sutures or staples prior to 7 to 10 days after repair will result in a cosmetically inferior wound. Where wound cosmesis is impor-tant, the aforementioned problems may be avoided by place-ment of buried dermal sutures using absorbable braided sutures. This method of wound


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Surgery_Schwartz. inferior wound. Where wound cosmesis is impor-tant, the aforementioned problems may be avoided by place-ment of buried dermal sutures using absorbable braided sutures. This method of wound closure allows for a precise reapproxi-mation of wound edges and may be enhanced by application of wound closure tapes to the surface of the wound. Intradermal absorbable sutures do not require removal.The development of octyl-cyanoacrylate tissue glues has shown good results for the management of simple, linear wounds with viable skin edges. These new glues are less prone to brittleness and have superior burst-strength characteristics. Studies have shown them to be suitable for use in contaminated situations without significant risk of infection. When used in the previously mentioned types of wounds, these glues appear to provide superb cosmetic results and result in significantly less trauma than sutured repair, particularly when used in pediatric patients.AntibioticsAntibiotics should be used


Surgery_Schwartz

Surgery_Schwartz. these glues appear to provide superb cosmetic results and result in significantly less trauma than sutured repair, particularly when used in pediatric patients.AntibioticsAntibiotics should be used only when there is an obvious wound infection. Most wounds are contaminated or colonized with bacteria. The presence of a host response constitutes an infection and justifies the use of antibiotics. Signs of infec-tion to look for include erythema, cellulitis, swelling, and puru-lent 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. When a single specific organism is suspected, treatment may be commenced using a single antibiotic. Conversely, when multiple organisms are suspected, as with enteric contamination or when a patient’s immune function is impaired by diabetes,


Surgery_Schwartz

Surgery_Schwartz. treatment may be commenced using a single antibiotic. Conversely, when multiple organisms are suspected, as with enteric contamination or when a patient’s immune function is impaired by diabetes, chronic disease, or medication, treatment should commence with a broad-spectrum antibiotic or several agents in combination. Antibiotics also can be delivered topically as part of irrigations or dressings, although their efficacy is questionable.DressingsThe main purpose of wound dressings is to provide the ideal envi-ronment for wound healing. The dressing should facilitate the major changes taking place during healing to produce an opti-mally healed wound. Although the ideal dressing still is not a clinical reality, technological advances are promising (Table 9-9).Dressings should take into account the type of wound and the comorbid conditions and associated factors such as edema and circulation. In patients with edema, dressing should compress the edematous area to aid in healing. In


Surgery_Schwartz

Surgery_Schwartz. account the type of wound and the comorbid conditions and associated factors such as edema and circulation. In patients with edema, dressing should compress the edematous area to aid in healing. In patients with significant circulation compromise, a compressing dress-ing should be avoided. The dressing should maintain 67Table 9-9Desired characteristics of wound dressingsPromote wound healing (maintain moist environment)ConformabilityPain controlOdor controlNonallergenic and nonirritatingPermeability to gasSafetyNontraumatic removalCost-effectivenessConvenienceBrunicardi_Ch09_p0271-p0304.indd 29501/03/19 4:50 PM 296BASIC CONSIDERATIONSPART Ian adequate moist environment but should help absorption excessive drainage. Occlusion of a wound with dressing mate-rial helps healing by controlling the level of hydration and oxy-gen 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


Surgery_Schwartz

Surgery_Schwartz. the level of hydration and oxy-gen 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. Occlusion also helps in dermal collagen synthesis and epithelial cell migration and lim-its tissue desiccation. Since it may enhance bacterial growth, occlusion is contraindicated in infected and/or highly exudative wounds.Dressings can be classified as primary or secondary. A pri-mary dressing is placed directly on the wound and may provide absorption of fluids and prevent desiccation, infection, and adhe-sion of a secondary dressing. A secondary dressing is one that is placed on the primary dressing for further protection, absorption, compression, and occlusion. Although the ideal dressing does not exist, many types of dressings help achieve certain goals, so knowledge of the


Surgery_Schwartz

Surgery_Schwartz. primary dressing for further protection, absorption, compression, and occlusion. Although the ideal dressing does not exist, many types of dressings help achieve certain goals, so knowledge of the wound and the dressing function is essential to make it possible to choose the appropriate dressing.Absorbent Dressings. This type of dressing helps con-trol exudate without soaking through the dressing, which can increase infection potential.Nonadherent Dressings. Nonadherent dressings are impreg-nated 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 water-proof and impervious to microbes but permeable to water vapor and oxygen.Hydrophilic and Hydrophobic Dressings. These dressings are


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Surgery_Schwartz. clean, minimally exudative wounds. These film dressings are water-proof and impervious to microbes but permeable to water vapor and oxygen.Hydrophilic and Hydrophobic Dressings. These dressings are components of a composite dressing. Hydrophilic dressing aids in absorption, whereas a hydrophobic dressing is water-proof and prevents absorption.Hydrocolloid and Hydrogel Dressings. Hydrocolloid and hydrogel dressings attempt to combine the benefits of occlusion and absorbency. Hydrocolloids and hydrogels 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 wound treatment.Alginates. Alginates


Surgery_Schwartz

Surgery_Schwartz. 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 wound treatment.Alginates. Alginates are derived from brown algae and con-tain long chains of polysaccharides containing mannuronic and glucuronic acid. The ratios of these sugars vary with the species of algae used, as well as the season of harvest. Processed as the calcium forms, 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. Alginates are being used when there is skin loss, in open surgical wounds with medium exudation, and on full-thickness chronic wounds. Alginate widely used as primary dressing and can be reinforced with other forms of dressing such as compression dressing.Absorbable Materials. Absorbable materials are mainly used within wounds as hemostats and include collagen, gelatin, oxi-dized cellulose,


Surgery_Schwartz

Surgery_Schwartz. with other forms of dressing such as compression dressing.Absorbable Materials. Absorbable materials are mainly used within wounds as hemostats and include collagen, gelatin, oxi-dized cellulose, and oxidized regenerated cellulose.Medicated Dressings. Medicated dressings have long been used as a drug-delivery system. Agents delivered in the dress-ings include benzoyl peroxide, zinc oxide, neomycin, and bacitracin-zinc. These agents have been shown to increase epi-thelialization by 28%.The type of dressing to be used depends on the amount of wound drainage. A nondraining wound can be covered with semiocclusive dressing. Drainage of less than 1 to 2 mL/d may require a semiocclusive or absorbent nonadherent dressing. Moderately draining wounds (3–5 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 as mod-erately draining wounds, but with


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Surgery_Schwartz. layer plus an absorbent secondary layer plus an occlusive dressing to protect normal tissue. Heavily draining wounds (>5 mL/d) require a similar dressing as mod-erately draining wounds, but with the addition of a highly absor-bent secondary layer.Mechanical Devices. Mechanical therapy augments and improves on certain functions of dressings, in particular the absorption of exudates and control of odor. The negative pres-sure dressing systems 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 posi-tioned in the wound cavity or over a flap or graft. The continu-ous negative pressure is very effective in removing exudates from the wound. This form of therapy has been found to be effective for chronic open wounds (diabetic ulcers and stages III and IV pressure ulcers), acute and traumatic wounds,125 flaps and grafts, and subacute


Surgery_Schwartz

Surgery_Schwartz. This form of therapy has been found to be effective for chronic open wounds (diabetic ulcers and stages III and IV pressure ulcers), acute and traumatic wounds,125 flaps and grafts, and subacute wounds (i.e., dehisced incisions), although more randomized trials need to be carried out to con-firm efficacy. Different types of sponges are available to use on wounds with negative pressure systems.Skin ReplacementsAll wounds require coverage in order to prevent evaporative losses and infection and to provide an environment that pro-motes healing. Both acute and chronic wounds may demand use of skin replacement, and several options are available.Conventional Skin Grafts. Skin grafts have long been used to treat both acute and chronic wounds. Split(partial-) thickness grafts consist of the epidermis plus part of the dermis, whereas full-thickness grafts retain the entire epidermis and dermis. Autologous grafts (autografts) are transplants from one site on the body to another; allogeneic


Surgery_Schwartz

Surgery_Schwartz. plus part of the dermis, whereas full-thickness grafts retain the entire epidermis and dermis. Autologous grafts (autografts) are transplants from one site on the body to another; allogeneic grafts (allografts, homografts) are transplants from a living nonidentical donor or cadaver to the host; and xenogeneic grafts (heterografts) are taken from another species (e.g., porcine). 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. Allo-geneic and xenogeneic grafts require the availability of tissue, are subject to rejection, and may contain pathogens.The use of skin grafts or bioengineered skin substitutes and other innovative treatments (e.g., topically applied growth factors, systemic agents, and gene therapy) cannot be effec-tive unless the wound bed is adequately prepared. This may include debridement to remove necrotic


Surgery_Schwartz

Surgery_Schwartz. (e.g., topically applied growth factors, systemic agents, and gene therapy) cannot be effec-tive unless the wound bed is adequately prepared. This may include debridement to remove necrotic or fibrinous tissue, control of edema, revascularization of the wound bed, reduc-tion in the bacterial burden, with minimal exudate. Temporary Brunicardi_Ch09_p0271-p0304.indd 29601/03/19 4:50 PM 297WOUND HEALINGCHAPTER 9placement of allografts or xenografts may be used to prepare the wound bed.Cellular and Tissue-Based Products in Chronic Wound and Ulcer ManagementWound management and ulcer healing are among the most chal-lenging problems in medical practices. The lack of large clini-cal trials, the heterogeneity of wound causes, and mechanisms of chronicity add to the complexity of wound management. In most cases, management is based on the experi-ence of the providers and the availability of the treatment modalities within the health facilities. In spite of advances in wound care, the basic


Surgery_Schwartz

Surgery_Schwartz. In most cases, management is based on the experi-ence of the providers and the availability of the treatment modalities within the health facilities. In spite of advances in wound care, the basic principles of wound management remain to be essential to healing. Additional measures and products might accelerate the rate of healing but will not replace basic wound care. The basic principles include achieving optimal blood flow, control of infection, removal of debris, proper dress-ing, offloading the injured area, and compression therapy in certain cases. Once these basic principles have been achieved, advanced treatment modalities such as cellular and tissue-based products (CTP) can be considered for enhanced healing. CTPs presumably act by altering the biology of wounds and ulcers or by preparing the wound/ulcer bed for healing and other potential procedures. CTPs are divided into two categories: dermoindu-cive and democonductive.126 As the name indicates, dermoindu-cive products help


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Surgery_Schwartz. the wound/ulcer bed for healing and other potential procedures. CTPs are divided into two categories: dermoindu-cive and democonductive.126 As the name indicates, dermoindu-cive products help provide cells and factors that will activate healing within the wound by inducing tissue growth or inducing granulation within the wound. Such products include Apligraph (Organogenesis, Canton, MA), Theraskin (Soluble systems, LLC, Newport News, VA), and Dermagraft (Organogenesis Canton, MA). None of these products have achieved healing in all wounds, but generally they have improved the percentage of healing, or achieved healing over a shorter period of time. In a pivotal Apligraf study, for example, it was found that patients who received Apligraf achieved 56% healing over 65 days com-pared to 38% healing over 90 days in those who received saline dressing.127 On the other hand, the dermoconductive products provide scaffolding to a wound ending in a neodermis by allow-ing migration of


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Surgery_Schwartz. to 38% healing over 90 days in those who received saline dressing.127 On the other hand, the dermoconductive products provide scaffolding to a wound ending in a neodermis by allow-ing migration of surrounding tissues across the wound, and this helps healing. An example of such products is Integra, which is composed of type 1 bovine collagen, shark chrondroitin 6-sulfate, and a silicone layer and helps to prepare the wound bed for subsequent skin grafting.128 In our experience, we use Integra for wound bed preparation in superficial wounds but also, in some cases, in deeper wounds. In addition, we also use it to cover exposed bone, especially smaller areas and tendons; how-ever, it might require more than one application in some cases to achieve optimal wound bed preparation. In a systematic review of the literature, the authors reviewed 15 randomized trials, one prospective comparative study, and five systematic reviews. The authors concluded that living cell-based skin sub-stitutes


Surgery_Schwartz

Surgery_Schwartz. review of the literature, the authors reviewed 15 randomized trials, one prospective comparative study, and five systematic reviews. The authors concluded that living cell-based skin sub-stitutes have a convincing supportive body of evidence in wound healing with some promise for acellular skin substitutes.129 In their review, the authors indicated that the evidence they based their review on was of low quality. Stem cell–based therapy is gaining more traction in the management of difficult wounds. Although it was initially used as an attempt to achieve scarless healing, stem cell therapy has gained more popularity in recent years as a means for enhanced healing and skin regeneration, in addition to reduction of scar formation. Similar to other fields, stem cells in wound healing produce growth factors and che-mokines that can differentiate into different cells and tissues. Stem cells in wound healing are mostly derived from human amniotic membrane of placental tissue. Examples of


Surgery_Schwartz

Surgery_Schwartz. growth factors and che-mokines that can differentiate into different cells and tissues. Stem cells in wound healing are mostly derived from human amniotic membrane of placental tissue. Examples of such prod-ucts include Epiphex (MiMedx Group Inc, Marietta CA) and Grafix (Osirix Therapeutics Inc, Columbia, MD), among others. It is believed that the growth factors in the amniotic membranes are preserved through different processes, thus assisting with wound healing. Multiple growth factors derived from the amni-otic membrane are thought to contribute to wound healing, including vascular endothelia growth factor, platelet-derived growth factor, epidermal growth factor, transforming growth factor, and others.130,131 A significant drawback of such products is that they are extremely expensive. Furthermore, it is recom-mended that these products should be used weekly to achieve optimal healing, which adds to the cost of using such products.Originally, these products were devised to provide


Surgery_Schwartz

Surgery_Schwartz. Furthermore, it is recom-mended that these products should be used weekly to achieve optimal healing, which adds to the cost of using such products.Originally, these products were devised to provide cover-age of extensive wounds because of the limited availability of autografts, which remains the ideal tissue coverage. However, CTPs have now gained acceptance as natural dressings. Manu-factured by tissue engineering, they combine novel materials with living cells to provide functional skin substitutes, providing a bridge between dressings and skin grafts.Skin substitutes have the theoretical advantages of being readily available and not requiring painful harvests like in skin grafts, and they may be applied freely or with surgical sutur-ing. In addition, they promote healing, either by stimulating host cytokine generation or by providing cells that may also produce growth factors locally. Their disadvantages include limited sur-vival, high cost, and the need for multiple applications


Surgery_Schwartz

Surgery_Schwartz. host cytokine generation or by providing cells that may also produce growth factors locally. Their disadvantages include limited sur-vival, high cost, and the need for multiple applications (Table 9-10). Allografting, albeit with a very thin graft, may at times be required to accomplish complete coverage.A variety of skin substitutes are available, each with its own set of advantages and disadvantages; however, the ideal skin substitute has yet to be developed (Table 9-11). The devel-opment of the newer composite substitutes, which provide both the dermal and epidermal components essential for permanent skin replacement, may represent an advance toward that goal.Cultured epithelial autografts (CEAs) represent expanded autologous or homologous keratinocytes. CEAs are expanded from a biopsy of the patient’s own skin, will not be rejected, and can stimulate reepithelialization as well as the growth of underlying connective tissue. Keratinocytes harvested from a biopsy roughly the size of


Surgery_Schwartz

Surgery_Schwartz. of the patient’s own skin, will not be rejected, and can stimulate reepithelialization as well as the growth of underlying connective tissue. Keratinocytes harvested from a biopsy roughly the size of a postage stamp are cultured with fibroblasts and growth factors and grown into sheets that can cover large areas and give the appearance of normal skin. Until the epithelial sheets are sufficiently expanded, the wound must be covered with an occlusive dressing or a temporary allograft or xenograft. The dermis regenerates very slowly, if at all, for full-thickness wounds because the sheets are very fragile, are difficult to work with, are susceptible to infection, and do not resist contracture well, leading to poor cosmetic results.8Table 9-10Desired features of tissue-engineered skinRapid reestablishment of functional skin (epidermis/dermis)Receptive to body’s own cells (e.g., rapid “take” and integration)Graftable by a single, simple procedureGraftable on chronic or acute


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Surgery_Schwartz. skinRapid reestablishment of functional skin (epidermis/dermis)Receptive to body’s own cells (e.g., rapid “take” and integration)Graftable by a single, simple procedureGraftable on chronic or acute woundsEngraftment without use of extraordinary clinical intervention (i.e., immunosuppression)Brunicardi_Ch09_p0271-p0304.indd 29701/03/19 4:50 PM 298BASIC CONSIDERATIONSPART ICEAs are available from cadavers, unrelated adult donors, or neonatal foreskins. Fresh or cryopreserved cultured alloge-neic keratinocytes can be left in place long enough to be super-seded by multiplying endogenous skin cells because, unlike allografts containing epidermal Langerhans cells, they do not express major histocompatibility antigens. Cryopreserved CEAs are readily available “off the shelf,” and provide growth factors that may aid healing. However, like autologous keratinocyte sheets, the grafts lack the strength provided by a dermal compo-nent and pose a risk of disease transmission.Viable fibroblasts


Surgery_Schwartz

Surgery_Schwartz. factors that may aid healing. However, like autologous keratinocyte sheets, the grafts lack the strength provided by a dermal compo-nent and pose a risk of disease transmission.Viable fibroblasts can be grown on bioabsorbable or non-bioabsorbable meshes to yield living dermal tissue that can act as a scaffold for epidermal growth. Fibroblasts stimulated by growth factors can produce type I collagen and glycosamino-glycans (e.g., chondroitin sulfates), which adhere to the wound surface to permit epithelial cell migration, as well as adhesive ligands (e.g., the matrix protein fibronectin), which promote cell adhesion. This approach has the virtue of being less timeconsuming and expensive than culturing keratinocyte sheets. There are a number of commercially available, bioengineered dermal replacements approved for use in burn wound treatment as well as other indications.Bioengineered skin substitutes have evolved from kera-tinocyte monolayers to dermal equivalents to split-thickness


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Surgery_Schwartz. replacements approved for use in burn wound treatment as well as other indications.Bioengineered skin substitutes have evolved from kera-tinocyte monolayers to dermal equivalents to split-thickness products with a pseudo-epidermis, and most recently, to prod-ucts containing both epidermal and dermal components that resemble the three-dimensional structure and function of nor-mal skin (see Table 9-11). Indicated for use with standard com-pression therapy in the treatment of venous insufficiency ulcers and for the treatment of neuropathic diabetic foot ulcers, these bilayered skin equivalents also are being used in a variety of wound care settings.Growth Factor Therapy. As discussed previously, it is believed that nonhealing wounds result from insufficient or inadequate growth factors in the wound environment. A simplistic solu-tion would be to flood the wound with single or multiple growth factors in order to “jump-start” healing and reepithelialization. Although there is a large body


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Surgery_Schwartz. wound environment. A simplistic solu-tion would be to flood the wound with single or multiple growth factors in order to “jump-start” healing and reepithelialization. Although there is a large body of work demonstrating the effects of growth factors in animals, translation of these data into clinical practice has met with limited success. Growth factors for clinical use may be either recombinant or homologous/autologous. Autol-ogous growth factors are harvested from the patient’s own plate-lets, yielding an unpredictable combination and concentration of factors, which are then applied to the wound. This approach allows treatment with patient-specific factors at an apparently physiologic ratio of growth factor concentrations. Disappoint-ingly, a recent meta-analysis failed to demonstrate any value for autologous platelet-rich plasma in the treatment of chronic wounds.132 Recombinant molecular biologic means permit the purification of high concentrations of individual growth factors.


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Surgery_Schwartz. any value for autologous platelet-rich plasma in the treatment of chronic wounds.132 Recombinant molecular biologic means permit the purification of high concentrations of individual growth factors. Current FDA-approved formulations, as well as those used exper-imentally, deliver concentrations approximately 103 times higher than those observed physiologically.At present, only platelet-derived growth factor BB (PDGF-BB) is currently approved by the FDA for treatment of diabetic foot ulcers. Application of recombinant human PDGF-BB in a gel suspension to these wounds increases the incidence of total healing and decreases healing time. Several other growth factors have been tested clinically and show some promise, but currently none are approved for use. 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.Gene or Cell Therapy. Given the disappointing


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Surgery_Schwartz. about the concentration, temporal release, and receptor cell population before growth factor therapy is to make a consistent impact on wound healing.Gene or Cell Therapy. Given the disappointing results from the application of purified growth factors onto wounds, the pos-sible therapeutic potential of gene therapy has been recognized and studied. Direct access to the open wound bed, which char-acterizes almost all chronic wounds, has facilitated this therapy. Gene delivery to wounds includes traditional approaches such as viral vectors and plasmid delivery or, more recently, electro-poration and microseeding.Although a variety of genes expressing interleukin-8, PDGF, IGF-1, keratinocyte growth factor, and laminin-5 have been successfully delivered to wounds in both animal and human models, the effects have been modest and specific to unique wound situations. Delivering extra genes into the wound bed presents the challenge of expression of the necessary signals to turn the genes on and


Surgery_Schwartz

Surgery_Schwartz. the effects have been modest and specific to unique wound situations. Delivering extra genes into the wound bed presents the challenge of expression of the necessary signals to turn the genes on and off at appropriate times so that dys-regulated, hypertrophic, and abnormal healing does not occur. Elaborate systems have been created for topical use as on/off switches for genes. The more important question is which genes to express, in what temporal sequence, and in what regions of the wound bed, as it is unlikely that a single gene coding for one protein can significantly affect overall healing. There is growing consensus that delivery of genes is not going to represent the universal solution. Although gene therapy replaces missing or Table 9-11Advantages and disadvantages of various bioengineered skin substitutesSKIN SUBSTITUTEADVANTAGESDISADVANTAGESCultured allogeneic keratinocyte graftNo biopsy needed“Off the shelf” availabilityProvides wound coveragePromotes healingUnstableDoes not


Surgery_Schwartz

Surgery_Schwartz. skin substitutesSKIN SUBSTITUTEADVANTAGESDISADVANTAGESCultured allogeneic keratinocyte graftNo biopsy needed“Off the shelf” availabilityProvides wound coveragePromotes healingUnstableDoes not prevent wound contractureInadequate cosmesisPossibility of disease transmissionFragileBioengineered dermal replacementPrevents contractureGood prep for graft applicationLimited ability to drive reepithelializationLargely serves as temporary dressingCultured bilayer skin equivalentMore closely mimics normal anatomyDoes not need secondary procedureEasily handledCan be sutured, meshed, etc.CostShort shelf lifeTrue engraftment questionableBrunicardi_Ch09_p0271-p0304.indd 29801/03/19 4:50 PM 299WOUND HEALINGCHAPTER 9defective genes, most acute wounds already have and express the necessary genes for successful healing and the wound envi-ronment produces signals adequate to the activation of these genes. What, if any, are the deficiencies in gene expression or activity in failed wounds is


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Surgery_Schwartz. for successful healing and the wound envi-ronment produces signals adequate to the activation of these genes. What, if any, are the deficiencies in gene expression or activity in failed wounds is unknown.Another approach is to deliver multiple genes coding for proteins that can act synergistically and even in a timed sequence, as would occur during normal healing. This would involve the use of activated cells that participate in the heal-ing sequence that could be delivered in an activated state to the wound environment. Use of mesenchymal stem cells as a delivery vector for many genes simultaneously is the latest such approach. The feasibility of applying bone marrow-derived, umbilical cord-derived, adipose-derived, and epidermal stem cells that can differentiate into various cells that participate in the wound healing response also has been documented. These cells, as part of their differentiation and activation in the wound, have been shown to produce a variety of growth factors


Surgery_Schwartz

Surgery_Schwartz. participate in the wound healing response also has been documented. These cells, as part of their differentiation and activation in the wound, have been shown to produce a variety of growth factors includ-ing VEGF, PDGF, bFGF, and MMP-9. The challenges remain how to maintain the viability and activity of the transplanted cells, how to document that the observed effects are due to the delivered cells, and what are the mechanisms necessary for reg-ulating or ending their activity.Oxygen Therapy in Wound HealingOxygen is required for almost all steps of wound healing and is also an important factor in the body’s defense against bacterial infection.133 In addition to its role in healing, oxygen plays an essential role in the production of reactive oxygen species such as superoxide that are angiogenesis stimulators and are bacterio-static. Chronic wounds have a decreased oxygen supply, and for a long time lack of oxygen was recognized as a potential cause of delayed healing. To counteract


Surgery_Schwartz

Surgery_Schwartz. stimulators and are bacterio-static. Chronic wounds have a decreased oxygen supply, and for a long time lack of oxygen was recognized as a potential cause of delayed healing. To counteract this delay, supple-mental oxygen therapy was used to improve healing, and both local oxygen therapy and systemic therapy were used for that purpose. Local therapy included oxygen dressings and topical oxygen therapy, while systemic therapy included supplemental inspired oxygen therapy and pressurized oxygen treatment.134 Of the different methods of oxygen therapy, pressurized oxy-gen, also termed hyperbaric oxygen therapy (HBOT) is the most used modality and the most investigated. In HBOT, oxygen is delivered under pressure, more than atmospheric pressure, lead-ing to a higher concentration of oxygen in tissues. The Undersea and Hyperbaric Medical Society (UHMS) defined HBOT as an intervention that involves breathing near 100% oxygen intermit-tently under high pressure achieved by a pressurized


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Surgery_Schwartz. in tissues. The Undersea and Hyperbaric Medical Society (UHMS) defined HBOT as an intervention that involves breathing near 100% oxygen intermit-tently under high pressure achieved by a pressurized chamber to more than sea level pressure (sea level pressure = 1 atmosphere absolute [ATA]). The therapeutic pressure should be at least 1.4 ATA. Chambers can be single occupancy or multiple occu-pancy.135 Although there are numerous indications and potential indications for HBOT, there are 14 accepted indications by Undersea and Hyperbaric Medical Society, and the FDA. Indi-cations related to wounds and ulcers include clostridial myone-crosis, crush injury, radiation-induced soft tissue and bone necrosis, necrotizing soft tissue infections, diabetic ulcers Wag-ner III or higher, refractory osteomyelitis, and thermal burns.135 Two systemic reviews were published on the effect of HBOT on wound healing. The first one was published in 2003 on all stud-ies done up to 2001.136 Generally, the


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Surgery_Schwartz. osteomyelitis, and thermal burns.135 Two systemic reviews were published on the effect of HBOT on wound healing. The first one was published in 2003 on all stud-ies done up to 2001.136 Generally, the review showed beneficial effects of HBOT on different disease processes. HBOT was found to improve graft survival, complete healing of grafts, and lessen infection in patients with a graft. Patients with osteoradionecrosis showed improved bone changes. The effect on tissue radionecrosis was described as positive, but not all studies showed statistical significance. HBOT was found to have improved amputation rates in patients with gas gangrene with better healing. In addition, HBOT was found to reduce mortality rates from necrotizing fasciitis, and significantly decreased wound size in nonhealing diabetic wounds. In the sec-ond systemic review, a total of 29 studies published between 2001 and 2016 were included. A total of 14 studies were related to chronic wounds: 12 studies in acute


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Surgery_Schwartz. diabetic wounds. In the sec-ond systemic review, a total of 29 studies published between 2001 and 2016 were included. A total of 14 studies were related to chronic wounds: 12 studies in acute wounds, 1 study on both acute and chronic wounds, and 2 experimental studies. Out of those 29 studies, 18 (62%) showed at least one positive out-come.134 One of the drawbacks of such studies in general is the lack of heterogeneity and the lack of accurate randomization. Perhaps, HBOT in diabetic foot ulcers attracted more attention than other forms of skin ulcers. In patients with diabetic foot ulcers, studies showed that HBOT led to significantly more healing wounds at 1 year,137 greater reduction in the wound bed,138 greater healing with less proximal amputation,139 and more complete wound healing at 1 month after HBOT.140Biofilm and Chronic Wound HealingTraditionally, nonhealing of chronic wounds has been associ-ated with numerous risk factors, including longer duration of ulcers, advanced


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Surgery_Schwartz. at 1 month after HBOT.140Biofilm and Chronic Wound HealingTraditionally, nonhealing of chronic wounds has been associ-ated with numerous risk factors, including longer duration of ulcers, advanced age, increased body mass index, venous reflux, arterial and venous disease, nutritional deficiencies, diabetes mellitus, and smoking. Chronic bacterial infection is another factor that has been associated with nonhealing wounds.Chronic wounds, in general, behave differently in relation to bacterial growth when compared to acute wounds. Chronic wounds develop bacterial growth that is resistant to invasion by antibiotics and is protected from the host immune defenses. Biofilm is the term used for the bacterial growth on a chronic wound that is encapsulated by a protective layer made up of the host and bacterial proteins. Bjarnsholt et al have suggested a simplified definition of the biofilm as “an aggregate of bacteria tolerant to treatment and the host defense.” It has been found that more


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Surgery_Schwartz. and bacterial proteins. Bjarnsholt et al have suggested a simplified definition of the biofilm as “an aggregate of bacteria tolerant to treatment and the host defense.” It has been found that more than 60% of chronic wounds have a biofilm.141 Biofilms lead to a chronic inflammatory process that will interfere with healing.142 Biofilms are formed in three stages. The first stage—the reversible bacterial adhesion stage—is formed by adhesion of bacteria to the surface of the wound. The second stage is the permanent adhesion or maturation stage in which the organisms permanently attach, proliferate, and maturate in the wound surface. This stage depends on a micro-bial-to-microbial cell communication system, called quorum sensing, in which small signaling molecules are released and gradually increase in concentration. The signaling molecules regulate gene expression and help form the biofilm. Lastly, in the third stage, organisms secrete a surrounding protective matrix called the


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Surgery_Schwartz. increase in concentration. The signaling molecules regulate gene expression and help form the biofilm. Lastly, in the third stage, organisms secrete a surrounding protective matrix called the extracellular polymeric substance (EPS). Once a biofilm colony forms, it will continuously shed bacteria to uncolonized areas, causing more biofilm colonies to form.143,144The presence of biofilms protects bacteria from the host defenses. Bacteria will then begin to exhibit phenotypic and genotypic plurality: the former allows bacteria to adapt to dif-ferent growth conditions such as nutrient availability, pH, and oxidizing potential within the biofilm, while the latter allows for virulence and bacterial resistance to drugs. The genetic plurality is passed horizontally among bacteria in the wound, adding to the resistance to treatment and allowing the bacteria to avoid the defense mechanisms of the host such as bacterial phagocytosis, 910Brunicardi_Ch09_p0271-p0304.indd 29901/03/19 4:50 PM


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Surgery_Schwartz. adding to the resistance to treatment and allowing the bacteria to avoid the defense mechanisms of the host such as bacterial phagocytosis, 910Brunicardi_Ch09_p0271-p0304.indd 29901/03/19 4:50 PM 300BASIC CONSIDERATIONSPART Ineutrophil degranulation, and formation of reactive oxygen spe-cies.145-147 In some cases, the biofilm allows bacteria to become quiescent and thus become less sensitive to antimicrobials that typically affect dividing bacterial cells.144,148Biofilms can form and recover from debridement rap-idly. Fully mature biofilm colonies can form within 2 to 4 days depending on the species and growth conditions. Common bacterial species such as Staphylococcus, Streptococcus, and Pseudomonas can attach to the surface of the wound in min-utes, forming adherent microcolonies in 2 to 4 hours. Bacterial species develops the extracellular polymeric substances (EPS) and resistance to disinfectants, antiseptics, and antibiotics in 6 to 12 hours. The biofilm then develops into


Surgery_Schwartz

Surgery_Schwartz. in 2 to 4 hours. Bacterial species develops the extracellular polymeric substances (EPS) and resistance to disinfectants, antiseptics, and antibiotics in 6 to 12 hours. The biofilm then develops into mature colonies in 2 to 4 days. Furthermore, it rapidly recovers form mechanical disruption, such as debridement, within 24 hours.144The presence of biofilms leads to delayed wound healing by stimulating chronic inflammation in the wound. The host responds to the biofilms by mobilizing macrophages and neutro-phils to the biofilm area, resulting in secretions of high levels of reactive oxygen species and proteases that can cause damage to the normal and healing tissue. The resulting increase in exudate production provides a source of nutrients to the biofilms, lead-ing to more resistance to healing.149The best method of treating wounds with biofilms is not well defined. It is believed that frequent debridement to mechanically remove the biofilm remains to be the best method of treatment.


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Surgery_Schwartz. best method of treating wounds with biofilms is not well defined. It is believed that frequent debridement to mechanically remove the biofilm remains to be the best method of treatment. The frequency of debridement is not well defined, although a weekly debridement has been suggested to improve healing. More than one method of debridement might be needed in wounds resistant to healing. A few products have been sug-gested to control and remove biofilms, such as surfactant and some wound cleansing formulas. In addition, topical broad-spectrum antimicrobials such as silver, iodine, honey, and others have been suggested to aid in the treatment of biofilms. Using a various combination of debridement methods, cleansing agents, and antimicrobials may be needed in resistant chronic wounds. An effective therapy to combat biofilm should include effective removal of the biofilm, antimicrobial eradication of bacteria/organisms, and prevention of biofilm recurrence, and these treat-ment options


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Surgery_Schwartz. therapy to combat biofilm should include effective removal of the biofilm, antimicrobial eradication of bacteria/organisms, and prevention of biofilm recurrence, and these treat-ment options may need to be repeated multiple times to achieve effective therapy. Many agents and devices thought to be effec-tive in eradicating and treating biofilms are under evaluation or development; however, their long-term effect is yet to be proven.REFERENCESEntries highlighted in bright blue are key references. 1. Winter GD. Formation of the scab and the rate of epithelialisa-tion of superficial wounds in the skin of the young domestic pig. Nature. 1962;193:293-294. 2. Gulliver G, ed. The Works of John Hunter. London: Longman; 1837. 3. Feiken E, Romer J, Eriksen J, et al. Neutrophils express tumor necrosis factor-alpha during mouse skin wound healing. J Invest Dermatol. 1995;105(1):120-123. 4. Dovi JV, He L-K, DiPietro LA. Accelerated wound closure in neutrophil-depleted mice. J Leukoc Biol.


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Surgery_Schwartz. necrosis factor-alpha during mouse skin wound healing. J Invest Dermatol. 1995;105(1):120-123. 4. Dovi JV, He L-K, DiPietro LA. Accelerated wound closure in neutrophil-depleted mice. J Leukoc Biol. 2003;73(4):448-455. 5. Leibovich SJ, Ross R. The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum. Am J Pathol. 1975;78(1):71-100. 6. DiPietro LA. Wound healing: the role of the macrophage and other immune cells. Shock. 1995;4(4):233-240. 7. Zabel DD, Feng JJ, Scheuenstuhl H, et al. Lactate stimula-tion of macrophage-derived angiogenic activity is associated with inhibition of poly(ADP-ribose) synthesis. Lab Invest. 1996;74(4):644-649. 8. Schäffer MR, Barbul A. Lymphocyte function in wound heal-ing and following injury. Br J Surg. 1998;85(4):444-460. 9. Efron JE, Frankel HL, Lazarou SA, Wasserkrug HL, Barbul A. Wound healing and T-lymphocytes. J Surg Res. 1990;48(5):460-463. 10. Barbul A, Breslin RJ, Woodyard JP, Wasserkrug HL, Efron G. The


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Surgery_Schwartz. Brody AR. Differential proliferation of rat lung fibroblasts induced by the platelet-derived growth factor-AA, -AB, and -BB isoforms secreted by rat alveolar macrophages. Am J Respir Cell Mol Biol. 1991;5(6):539-547. 14. Pricolo VE, Caldwell MD, Mastrofrancesco B, Mills CD. Modulatory activities of wound fluid on fibroblast prolifera-tion and collagen synthesis. J Surg Res. 1990;48(6):534-538. 15. Regan MC, Kirk SJ, Wasserkrug HL, Barbul A. The wound environment as a regulator of fibroblast phenotype. J Surg Res. 1991;50(5):442-448. 16. Gimbel ML, Hunt TK, Hussain MZ. Lactate controls collagen gene promoter activity through poly-ADP-ribosylation. Surg Forum. 2000;51:26-27. 17. Ghani QP, Hussain MZ, Hunt TK. Control of procollagen gene transcription and prolyl hydroxylase activity by poly(ADP-ribose). In: Poirier G, Moreaer A, eds. ADP-Ribosylation Reactions. New York: Springer-Verlag; 1992:111-117. 18. Xiong M, Elson G, Legarda D, Leibovich SJ. Production of vascular endothelial


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Surgery_Schwartz. Depalma L. Re-epithelialization. In: Clark RAF, Hensen PM, eds. The Molecular and Cellular Biology of Wound Repair. New York: Plenum; 1988:321-325. 23. Johnson FR, McMinn RMH. The cytology of wound healing of the body surface in mammals. Biol Rev Camb Philos Soc. 1960;35:364-412. 24. Woodley DT, Bachman PM, O’Keefe EJ. The role of matrix components in human keratinocyte re-epithelialization. In: Barbul A, Caldwell MD, Eaglstein WH, et al, eds. Clinical and Experimental Approaches to Dermal and Epidermal Repair. Normal and Chronic Wounds. New York: Wiley-Liss; 1991:129. 25. Lynch SE. Interaction of growth factors in tissue repair. In: Barbul A, Caldwell MD, Eaglstein WH, et al, eds. Clinical and Experimental Approaches to Dermal and Epidermal Repair. Normal and Chronic Wounds. New York: Wiley-Liss; 1991:341.Brunicardi_Ch09_p0271-p0304.indd 30001/03/19 4:50 PM 301WOUND HEALINGCHAPTER 9 26. Jans DA, Hassan G. Nuclear targeting by growth factors, cytokines, and their receptors: a role


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Surgery_Schwartz. 1991:341.Brunicardi_Ch09_p0271-p0304.indd 30001/03/19 4:50 PM 301WOUND HEALINGCHAPTER 9 26. Jans DA, Hassan G. Nuclear targeting by growth factors, cytokines, and their receptors: a role in signaling? BioEssays. 1998;20:400-411. 27. Schmitt-Graff A, Desmouliere A, Gabbiani G. Heterogeneity of myofibroblast phenotypic features: an example of fibroblas-tic cell plasticity. Virchows Arch. 1994;425(1):3-24. 28. Darby I, Skalli O, Gabbiani G. Alpha-smooth muscle actin is transiently expressed by myofibroblasts during experimental wound healing. Lab Invest. 1990;63(1):21-29. 29. Desmouliere A, Redard M, Darby I, Gabbiani G. Apop-tosis mediates the decrease in cellularity during the tran-sition between granulation tissue and scar. Am J Pathol. 1995;146(1):56-66. 30. Ehrlich HP. Wound closure: evidence of cooperation between fibroblasts and collagen matrix. Eye (Lond). 1988; 2(pt 2):149-157. 31. Phillips C, Wenstrup RJ. Biosynthetic and genetic disorders of collagen. In: Cohen IK,


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Surgery_Schwartz. A, Brandling-Bennett H, Morel K, Chung WK. Novel SLC39A4 mutation in acrodermatitis enteropathica. Pediatr Dermatol. 2011;28(6):697-700. 42. Kruse-Jarres JD. Pathogenesis and symptoms of zinc defi-ciency. Am Clin Lab. 2001;20(3):17-22. 43. Okada A, Takagi Y, Nezu R, et al. Zinc in clinical surgery—a research review. Jpn J Surg. 1990;20(6):635-644. 44. Olivas A, Shogan B, Valuckaite V, et al. Intestinal tissues induce an SNP mutation in Pseudomonas aeruginosa that enhances its virulence: possible role in anastomotic leak. PLOS One. 2012;7(8):e44326. 45. Thornton FJ, Barbul A. Healing in the gastrointestinal tract. Surg Clin North Am. 1997;77(3):549-573. 46. Choy PYG, Bissett IP, Docherty JG, Parry BR, Merrie AEH. Stapled versus handsewn methods for ileocolic anastomoses. Cochrane Database Syst Rev. 2007;3:CD004320. 47. Marjanovic G, Vilain C, Juettner E, et al. Impact of differ-ent crystalloid volume regimens on anastomotic stability. Ann Surg. 2009;249:181-185. 48. Schnuriger B, Inaba


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Surgery_Schwartz. Rev. 2007;3:CD004320. 47. Marjanovic G, Vilain C, Juettner E, et al. Impact of differ-ent crystalloid volume regimens on anastomotic stability. Ann Surg. 2009;249:181-185. 48. Schnuriger B, Inaba K, Wu T, et al. Crystalloids after primary colon resection and anastomosis at initial trauma laparotomy: excessive volumes are associated with anastomotic leakage. J Trauma. 2011;70:603-610. 49. Lorenz PH, Whitby DJ, Longaker MT, Adzick NS. Fetal wound healing. The ontogeny of scar formation in the non-human primate. Ann Surg. 1993;217(4):391-396. 50. Longaker MT, Whitby DJ, Ferguson MWJ, Lorenz HP, Harrison MR, Adzick NS. Adult skin wounds in the fetal envi-ronment heal with scar formation. Ann Surg. 1994;219(1): 65-72. 51. Lorenz HP, Longaker MT, Perkocha LA, Jennings RW, Harrison MR, Adzick NS. Scarless wound repair: a human fetal skin model. Development. 1992;114(1):253-259. 52. Adzick NS, Harrison MR, Glick PL, et al. Comparison of fetal, newborn and adult rabbit wound healing by


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Surgery_Schwartz. injury. Clin Plast Surg. 1990;17(3):509-517. 68. Cruse PJE, Foord RA. A prospective study of 23,649 surgical wounds. Arch Surg. 1973;107(2):206-210. 69. Yue DK, McLennan S, Marsh M, et al. Effects of experimental diabetes, uremia, and malnutrition on wound healing. Diabetes. 1987;36(3):295-299. 70. Goodson WH III, Hunt TK. Studies of wound healing in exper-imental diabetes mellitus. J Surg Res. 1977;22(3):221-227. 71. Black E, Vibe-Petersen J, Jorgensen LN, et al. Decrease in collagen deposition in wound repair in type I diabetes independent of glycemic control. Arch Surg. 2003;138(1): 34-40.Brunicardi_Ch09_p0271-p0304.indd 30101/03/19 4:50 PM 302BASIC CONSIDERATIONSPART I 72. Spiliotis J, Tsiveriotis K, Datsis AD, et al. Wound dehiscence is still a problem in the 21st century: a retrospective study. World J Emerg Surg. 2009;4:12. 73. Coon D, Gusenoff JA, Kannan N, et al. Body mass and surgi-cal complications in the postbariatric reconstructive patient: analysis of 511 cases. Ann


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Surgery_Schwartz. study. World J Emerg Surg. 2009;4:12. 73. Coon D, Gusenoff JA, Kannan N, et al. Body mass and surgi-cal complications in the postbariatric reconstructive patient: analysis of 511 cases. Ann Surg. 2009;249:397-401. 74. Arthurs ZM, Cuadrado D, Sohn V, et al. Post-bariatric pan-niculectomy: pre-panniculectomy body mass index impacts the complication profile. Am J Surg. 2007;193:567-570. 75. Tsukada K, Miyazaki T, Kato H, et al. Body fat accumulation and postoperative complications after abdominal surgery. Am Surg. 2004;70:347-351. 76. Williams JZ, Barbul A. Nutrition and wound healing. Surg Clin North Am. 2003;83(3):571-596. 77. Goodson WH, Jensen JA, Gramja-Mena L, West J, Granja-Mena L, Chavez-Estrella J. The influence of a brief pre-operative illness on postoperative healing. Ann Surg. 1987;205(3):250-255. 78. Winsor JA, Knight GS, Hill GL. Wound healing in surgical patients: recent food intake is more important than nutritional status. Br J Surg. 1988;75(2):135-137. 79. Haydock DA,


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Surgery_Schwartz. JA, Knight GS, Hill GL. Wound healing in surgical patients: recent food intake is more important than nutritional status. Br J Surg. 1988;75(2):135-137. 79. Haydock DA, Hill GL. Improved wound healing response in surgical patients receiving intravenous nutrition. Br J Surg. 1987;74(4):320-323. 80. Seifter E, Rettura G, Barbul A, Levenson SM. Argi-nine: an essential amino acid for injured rats. Surgery. 1978;84(2):224-230. 81. Barbul A, Lazarou S, Efron DT, Wasserkrug HL, Efron G. Arginine enhances wound healing in humans. Surgery. 1990;108(2):331-336. 82. Kirk SJ, Regan MC, Holt D, Holt DR, Wasserkrug HL, Barbul A. Arginine stimulates wound healing and immune function in aged humans. Surgery. 1993;114(2):155-159. 83. Williams JZ, Abumrad NN, Barbul A. Effect of a specialized amino acid mixture on human collagen deposition. Ann Surg. 2002;236(3):369-374. 84. Levenson SM, Seifter E, VanWinkle W. Nutrition. In: Hunt TK, Dunphy JE, eds. Fundamentals of Wound Management in Surgery. New