Учебники / Otolaryngology - Basic Science and Clinical Review

wound healing difficulty by several mechanisms. Scars crossing the RSTLs are more likely to be under more tension, creating a tendency to hypertrophy, and more visible, because they lose the natural camouflage of the RSTLs. Contraction of such scars may also result in deformity of adjacent structures, such as the eyelids or the mouth. Proper planning of incisions to avoid crossing the RSTLs will minimize wound-healing difficulties and result in less visible scar formation. Scar revision techniques such as Z-plasty can reorient scars closer to the RSTLs. There are many techniques for maximizing the quality of wound healing while decreasing the chance of wound dehiscence and scar formation: (1) proper planning of the incision;

(2) closure of multiple tissue layers to keep tension subepidermal; (3) debridement of irregular and contaminated edges; (4) advancement flap, and rotation flap reconstruction of soft tissue defects, if possible using adjacent matched tissue types, rather than skin grafts; (5) use of nonreactive suture material; and (6) long-term follow-up of the healing process to allow timely intervention if signs of hypertrophic scar, keloid, or contracture appear.

UNSATISFACTORY SCARS

Unsatisfactory scars may be hypertrophic, keloid, or widened. These are scars in which the healing process has been adversely affected. A partial list of such forces includes: (1) nature of the injury (crush, foreign body, severe burn, poor wound management, infection, significant tissue loss); (2) location of the injury (running perpendicular to the lines of least skin tension or Langer’s lines); and (3) natural biology of the patient’s healing process (previous history of keloid, family history of keloids,or history of other connective tissue abnormalities, malnutrition, previous radiation, chronic hypoxia, current smoking, etc.).

Widened Scars

Widened scars occur during the final phase of wound healing, remodeling, when tension or excess mobility of the wound results in a flat and frequently depressed scar. These scars frequently appear on the shoulder, knee, and back. They are also noted as stretch marks, widening subepidermal disruptions of the dermis that follow changes in subcutaneous skin volume (i.e., pregnancy, weight loss, and accompanying chronic steroid use) or Cushing’s disease.

Keloids and Hypertrophic Scars

Keloids and hypertrophic scars are unique human dermal fibroproliferative disorders that develop following trauma, surgery, and burns, or in wounds with

significant inflammation. Hypertrophic scarring and keloid formation represent aberrations in cell migration and proliferation, inflammation, increased synthesis, secretion of cytokines and ECM proteins, and remodeling of the newly synthesized matrix resulting in a disordered collagen pattern. Such scars will benefit from either early revision or manipulation of the ongoing healing process by any of several measures: reexcision and rerepair (as might be necessary if the vermilion border is misaligned), local steroid injection, and pressure therapy, among others.

Hypertrophic scars are often mistaken for keloids. They are characterized by thickening, widening, erythema, pruritis, and fibrosis. Such scars are confined to the area of the original wound and are often associated with contractures. Contracture (shortening of the scar) may be associated with deformity, causing loss of function, cosmetic distortion, or impairment in range of motion. In contrast, contraction is a functional part of wound healing that occurs in an open wound, reducing the wound surface as the contraction proceeds. All contracture is caused by contraction, but not all contraction results in contracture.

Hypertrophic scars may be differentiated from keloids by their natural history, in that they tend to improve spontaneously in 2 years.Aggressive management of hypertrophic scars will force their improvement in a shorter time period. See Figs. 2-3 to 2-5 for illustration. Fig. 2-3 demonstrates an auricular keloid that commonly occurs at piercing sites.

Figure 2-3 A keloid scar of the pinna after ear piercing.

Figure 2-4 A hypertrophic scar in a postauricular incision for a tympanomastoidectomy.

Fig. 2-4 shows a hypertrophic postauricular from a tympanomastoidectomy.The scar is over 1 year old and has not been treated yet with any modality. Fig. 2-5 is a surgical neck scar. Notice how one portion of the scar is hypertrophic, while the scar extending from the lower lip to the chin is much finer, thinner, and less noticeable. It is not uncommon for young adults and teenagers to develop hypertrophic scars in areas that would otherwise heal well for adults or young children.

Alibert in 1806 coined the term keloid in a paper differentiating keloids from malignant growths.A keloid

Figure 2-5 Hypertrophic and normal scars on the neck of an adolescent.

is an overgrowth of scar tissue that looks much like a hypertrophic scar, thick, red, and unsightly, usually developing after healing of a skin injury but occasionally occurring spontaneously. This scar tissue extends beyond the borders of the original wound and does not regress spontaneously. Keloids have a strong familial disposition, affect both sexes equally, and may be age dependent, occurring more frequently in adolescence and young adulthood.The genetics of keloids are reported as either autosomal dominant or recessive and are associated with human leukocyte antigen (HLA) factors B14, B21, BW16, BW 35 DR5, DQW3, and blood group A.

Keloids are often reported to occur more frequently in dark-pigmented skin. Images with keloids appear in western Nigeria Yoruba sculptures of the 13th century. These scars are principally limited to the dermis but can occur in the cornea as well. The occurrence of keloids may be quite variable. Individuals with multiple injuries may develop the scar in some but not all of the wounds. High-risk areas include the chest, in a triangle extending from the clavicle to the lower sternum, ears, arms, and upper back.

The biochemical composition of keloids has been extensively studied and shows significant aberrations. In comparison with normal skin, keloids have increases in water, calcium, histamine, acid phosphatase, alanine transaminase, lactic dehydrogenase, the globulins, fibronectins, elastin, glycosaminoglycans, chondroitin sulfate, typeVI collagen,TGF- , and abnormal collagen cross-linkage. They contain decreases in procollagen polypeptides due to increased degradation. Collagen types I and III may be increased, decreased, or similar to normal skin. Serum immunglobulins (Ig)M and IgG may be increased or the same as normal. Autoimmune antifibroblast antibodies (AFAs) are found in lymphocyte isolates of patients with keloids. Antinuclear antibodies (ANAs) directed against fibroblasts are found in patients with keloids but not in those with hypertrophic scars. Cytokine production is also abnormal, with increased production of TNF- , interferon- , and interleukin-6, and decreased production of interferon- , interferon- , and TNF- .

Treatment of keloids begins with identification of risk factors, such as family history, examination of old scars, and an understanding that keloids may be region specific (i.e., more likely to occur on the ear, the mandibular margin, and the triangle between the shoulders and the xyphoid on the anterior chest wall). Careful incisional placement, following Langer’s lines, meticulous tissue handling, closure with attention to alignment of skin margins, and use of low reactivity

suture material, will minimize the inflammatory process and initiate the best possible circumstances for healing. But a keloid may appear despite preventive management.

Keloid formation responds to intervention only a certain percentage of the time, so the initial conversation with the patient must include a detailed education. Large disfiguring keloids may require initial surgical management in combination with other modalities. Smaller lesions may respond to triamcinolone acetonide injections, pressure (such as the use of broad-backed clips on earrings for lobe keloids), or 20% hydrocortisone topical applications. Recurrence rates are reported from 5 to 50% following an initial successful response. With excision and immediate local steroid treatment, topical silicone, and pressure dressing, 50% successful response rates can be anticipated. Excision and topical treatment accompanied by immediate radiation therapy (short course, 3–50 Gy) results in a 20 to 45% recurrence rate. Brachytherapy is now available, and initial reports of 20% recurrence in 1 year have been reported. Brachytherapy in conjunction with hyaluronidase injection in one study has been reported to have a zero recurrence rate at 1 year. Various regimens employing laser therapy, including the carbon dioxide laser at 10,600 nm wavelength, neodymium:yttrium-aluminum- garnet (Nd:YAG) laser at 1064 nm, and the argon laser at 488 nm, all report recurrence rates ranging from 25 to 90%. Repeated treatment with cryotherapy yields up to a 75% improvement response rate, and in combination with intralesional corticosteroid injection, prevents recurrence more significantly than with either alone.

Advances in understanding the biochemistry of wound healing have created new options for keloid prevention and treatment. Interferonsand - , and - reduce fibroblast synthesis of collagen types III,VI, and I and increase collagenase activity. Interferonsand - also reduce glycosaminoglycan synthesis. These actions have not translated into clinical efficacy as yet, and repeated injections into active keloids reduced keloids by 50% only. Injection into surgical excision sites has had limited success. The effective actions of anti-TGF- , procollagen peptides, cis-hydroxyproline, and pentoxifylline are still under investigation.

The list of previously investigated failed therapies is even longer than the list of those currently accepted as at least partially effective: injections of formalin, mustine combined with triamcinolone, pepsin, hydrochloric acid, creosote, nitrogen mustard, thiotrexate, topical ultrasound, surgery combined with tocophol, thiotepa, penicillamine, oral betaaminopropionitrile (BAPN),

colchicine, topical zinc tape, retinoic acid, and tetrahydroquinone. Many of these agents, although known to play a significant role in collagen synthesis and degradation, have failed to prevent keloids, despite excellent rationalization of their possible efficacy.

FAILURES OF WOUND HEALING

When a wound does not heal, consideration of the intrinsic or extrinsic factors contributing to the problem should nearly always yield an appropriate solution. Extrinsic factors such as the cachexia of advanced malignancy and malnutrition; systemic diseases such as diabetes, hypertension, arteriosclerosis, and sickle cell disease; autoimmune conditions; neurological conditions such as multiple sclerosis and spinal cord injury; pulmonary insufficiency; alcoholism; smoking; and steroid use must be addressed in advance of surgery for a successful outcome to be ensured. Optimizing those circumstances that are not completely reversible may require several weeks of advanced preparation. In the presurgical and postoperative phases, attention to these factors by close monitoring of the patient through clinical observation and laboratory analysis is mandatory. Protein malnutrition, morbid obesity, trace mineral deficiency, hypoxia, hyperglycemia, smoking or chewing tobacco, steroids, irradiation, hypothyroidism, and use of cytotoxic drugs such as methotrexate negatively affect wound healing by their actions, inhibiting the inflammation and proliferation required to initiate the appropriate cellular and biochemical responses of wound healing. Failure to note and address these adverse conditions will harm both the patient and the reputation of the physician/surgeon.

Intrinsic conditions that can affect wound healing include previous radiation in the wound site, infection, hematoma and seroma, ischemia, vasculitis, retained foreign body, excessive motion across or tension on the suture line, and persistence of tumor following resection. Social circumstances of the patient and living conditions such as sanitation, domestic violence, and alcohol or drug abuse should also be considered. Intractable persistent wounds should only be considered factitious when all other possibilities are ruled out. Wound infection remains one of the most common and expensive complications of modern surgery. Prediction of risk of surgical wound infection includes such factors as surgical time in excess of 2 hours, hypothermia, hypoxia, contamination, and the presence of multisystem diseases. Risk reduction strategies for the perioperative period include (1) maintenance of oxygen above 90%

for at least 2 hours following surgery, (2) maintenance of body temperature in the normal range during and after surgery, (3) use of preoperative antibiotics if contamination of the wound is predicted, (4) a normal wound oxygen tension, (5) an adequate intravascular volume, (6) albumin level above 3%, (7) adequate pain control, and (8) appropriate dressing techniques.

SPECIFIC NUTRITIONAL FACTORS AND THEIR EFFECT ON

WOUND HEALING

Optimum healing occurs only in the presence of optimum circumstances. It is well known that grossly malnourished patients experience delayed wound healing and increased rates of wound infection. These factors can be reversed. The marked increase in energy demands and the caloric requirements that can lead to cannibalization of lean body mass contribute significantly to morbidity. Several clinical studies have demonstrated that malnourished patients whose caloric needs are met during the week before surgery can exhibit normal wound healing capacity. In addition to overt malnutrition, metabolic deficiencies or disorders of specific nutrients can result in delays in wound closure. These range from macronutrients such as amino acids to micronutrients including vitamins and trace minerals. Attention to the nutritional status of the patients is an important component of presurgical planning. The head and neck cancer patient has a strong disposition toward malnutrition, and subsequently poor wound healing. There are several reasons why this is so. Because of odnophagia or dysphagia, these patients have poor oral intake of foods. The high prevalence of alcoholism and an unbalanced diet in the head and neck cancer patient population contribute to poor baseline nutrition. Also, hypermetabolism of the tumor may cannibalize the host patient.

Optimum nutritional support for the compromised patient has several key components. First, an assessment of the caloric requirements needed to meet energy demands and a provision of sufficient protein for routine protein synthesis including calculated requirements for wound healing should be part of the patient’s evaluation. Second, dietary supplements with sufficient micronutrients should be initiated and maintained through either the oral or the intravenous route.Third, consideration to the use of anabolic hormones should be given in those cases where preexisting malnutrition and a prolonged recovery can be anticipated.

AMINO ACIDS

Gross deficiency of dietary amino acids and protein results in delayed wound closure through impairment of protein (mainly collagen) synthesis. Protein breakdown occurs during stress-induced catabolism, and unless adequate protein replacement is provided during this process, a rapid loss of lean body tissue including muscle and visceral proteins will continue even if carbohydrate-based calories are being provided. A cessation of caloric protein intake can actually result in the complete halting of collagen synthesis. Decreased protein intake also impairs the immune response and inflammation. Supplements beyond normal requirements are not beneficial, except arginine, which has strong evidence that enteral or parenteral supplementation beyond regular dietary requirements results in accelerated wound healing and enhancement of early collagen deposition. In protein malnutrition, methionine (one of the essential amino acids) is converted to cysteine and is crucial to the inflammatory process and the production of fibroblasts. Loss of lean body mass contributes substantially to such postoperative complications as profound weakness, a significant decrease of immune function contributing to wound infection and ammonia and other sources of sepsis, the already described impairments of wound healing, and increased risk of pressure sores. An inadequate intake of protein and calories to meet demand results in a condition known as protein energy malnutrition (PEM).

VITAMIN A

Vitamin A is an essential fat-soluble vitamin. Its primary physiological roles include maintaining epithelial integrity and cell membrane integrity, serving as a protective factor against infection, and operating as a cofactor in collagen synthesis. It serves an important role in the wound healing process at multiple levels. Deficiencies in vitamin A result in decreased collagen synthesis and decreased rates of epithelialization. Serious injury and systemic stress (e.g., sepsis) increase vitamin A requirements and thus predispose to deficiency and impaired wound healing. Multiple studies have demonstrated that supplemental vitamin A can reverse the inhibitory effects of systemic corticosteroids, can potentially reverse the negative wound-healing effects of diabetes, cyclophosphamide, and radiation, and has multiple beneficial effects on wound healing, including an increased inflammatory response, increased collagen synthesis, increased macrophage infiltration of the wound site, and increased lability of the lysosomal membranes of inflammatory cells. Supplemental vitamin A also

appears to decrease the incidence and severity of stress ulcers in both experimental animal models and in human patients.

Vitamin A is stored in the liver. Uncomplicated elective surgical procedures will not result in vitamin deficiencies. Prolonged decreased food intake, malabsorption, and chronic malnutrition will result in vitamin A deficiencies. All patients experiencing severe stress, such as a major burn injury, multisystem trauma, or postoperative complications, should receive 25,000 international units (IU) per day. This is 5 times the minimum daily requirements but should not result in significant toxicity. Vitamin A should also be given to those patients who are taking chronic steroids. Vitamin A given orally at 25,000 IU per day or topically as an ointment as 200,000 IU every 8 hours, will reverse the inhibiting effect steroids have on wound healing. Larger doses should be avoided, because vitamin A is toxic to the liver and cornea.

VITAMIN C (ASCORBATE)

Sixteenth-century explorers and physicians clearly described the condition now known as scurvy. Long-term deficiency of vitamin C (at least 6 months of ascorbatefree diet) has long been known to delay wound healing and can actually cause previously healed wounds to reopen. In the 18th century Lind demonstrated that limejuice could prevent scurvy.This made it possible for the British to deliver healthy soldiers and sailors after long sea voyages and gave Britain the manpower to create the empire upon which the sun never set; hence the nickname “Limey” was given to British sailors. In 1926 Wolbach published a classic study. He created an experimental scurvy in guinea pigs, which demonstrated the failure of collagen synthesis.This effect was immediately reversed once ascorbic acid was given. Vitamin C is a well-established cofactor in the hydroxylation of the amino acid proline to hydroxyproline, an amino acid required in collagen synthesis.Vitamin C deficiency manifests itself as a failure of cross-linking of collagen fibers, and subsequently a loss of wound strength. Other cofactors in the hydroxylation process include oxygen,-ketoglutarate, and ferrous iron.

Cellular effects of vitamin C deficiency in the healing wound include the proliferation of fibroblasts that are immature and do not mature, and the formation of defective capillaries that can cause local hemorrhage. Biochemical effects include the failure of formation of mature extracellular collagen, the production of chemically detectable levels of alkaline phosphatase, and proteolysis of intracellular unhydroxylated protein.

Vitamin C deficiency is also associated with an increased rate of wound infection. Impaired collagen synthesis reduces the ability of the body to wall off an abscess because of reduced collagen synthesis. There is also a reduction in neutrophil function, resulting in decreased bacterial killing.Ascorbic acid is also involved in the reduction of oxygen to superoxide. Complementdependent immune reactions are seen to be depressed. Popular belief that vitamin C protects against the common cold or shortens its normal course has not been confirmed.

Excess doses of vitamin C do not enhance normal wound healing, and megadoses may cause renal oxalate stones. Replacement during extended illness or periods of extreme physiological stress maintains normal healing, so ascorbic acid should be administered in 1 or 2 g doses on a daily basis until recovery is complete. This daily dose is the equivalent of the total amount of vitamin C stored in the adult body, a lack of reserve that explains the importance of replacement and maintenance.

VITAMIN B COMPLEX

The B-complex vitamins serve as cofactors in a wide variety of enzyme systems. Deficiency in these vitamins, especially pyridoxine, pantothenic acid, and folic acid, results in major effects on resistance to infection. Antibody formation and neutrophil function are impaired in deficiency states. Supplemental intake of 5 to 10 times the minimum daily requirements of these vitamins is recommended in the treatment of severe injury and acute illness. Estrogens are known to increase requirements for pyridoxine and for folic acid.Addition of folic acid to prenatal vitamins significantly reduces neural tube defects like meningomyelocele.

VITAMIN D

Vitamin D is essential to the normal absorption, transportation, and metabolism of calcium, and indirectly for phosphorus metabolism. It is important in normal bone growth and in bone healing. Severe vitamin D deficiency results in rickets that can be avoided through moderate sun exposure. Recent work on hospitalized elderly patients in the northeastern United States recognized that over 50% of hospitalized elderly are vitamin D deficient. With increased avoidance of sun exposure and reduced dairy intake, this problem is increasingly widespread.Vitamin D deficiency results in loss of bone strength, increases the risk of low-impact fractures, and retards the healing of bone, when fractured, accidentally or electively.

VITAMIN K

Vitamin K is an essential cofactor in the synthesis of prothrombin, and the clotting factors VII, IX, and X are required for the synthesis of calcium-binding protein. In vitamin K deficiency a bleeding diathesis occurs. Parenteral injections of vitamin K can be used to reverse the effects of Coumadin (warfarin sodium). In the presence of liver disease vitamin K may not be able to promote synthesis of adequate amounts of prothrombin.

VITAMIN E

Unlike other vitamins, large doses of vitamin E have been found to inhibit healing, decreasing tensile strength and reducing collagen accumulation.Vitamin E plays an important role in membrane stabilization, neutralizes lipid peroxidation, and limits the levels of free radicals, peroxidases, and other products of lipid peroxidation. This antioxidant activity has been promoted for its antitumor and antiaging effects, but recent studies have not demonstrated a statistical benefit. It is known that supplemental vitamin E increases the risk of bleeding in the perioperative period. Oral supplements should be stopped 1 to 3 weeks before planned elective surgery.

MINERALS

Iron

Like vitamin C, iron is required for proline and lysine hydroxylation. It is also a critical cofactor in the replication of deoxyribonucleic acid (DNA). Iron deficiency anemia will diminish oxygen transport, an effect that will impair oxygen delivery, causing a secondary effect on wound healing and on bacterial killing.

Calcium and Magnesium

Calcium and magnesium are cofactors in protein synthesis and in the function of the collagenase enzyme, which is useful in the remodeling phase of wound healing. Calcium supplements should be considered for all women in the perimenopausal period and for individuals who avoid dairy products. Carbonated beverages impede calcium absorption through their high phosphorus content and may impair bone formation during adolescence and young adulthood, contributing to osteoporosis in later years. Calcium supplements, with vitamin D when appropriate, will facilitate bone healing in the deficient state but are not known to promote healing beyond normal when nutritional status is adequate.

Zinc

Zinc functions as a cofactor for over 70 known enzymes, including ribonucleic acid (RNA) and DNA polymerases and other transferases. Therefore, mitosis is impaired, and the cell proliferation required for normal healing is decreased. Deficiency of zinc results in decreased fibroblast proliferation, decreased collagen synthesis, and delayed epithelialization of wounds. Zinc deficiency is not common, but it may occur in patients with large burns, diffuse sweating, severe trauma, chronic alcoholism, intestinal fistulas, and cirrhosis. Chronic zinc deficiency has been reported in Middle Eastern children and is characterized by short stature, mild anemia, and hypogonadism. Supplemental zinc will not increase wound healing unless zinc deficiency exists.

ROLE OF OXYGEN

No discussion of wound healing would be complete without a review of the role oxygen plays in the process. Oxygen delivery to the healing wound is controlled by multiple factors. Inspired oxygen is transported across the alveolar capillary gradient of the lung, is bound to hemoglobin delivered by the circulatory system, then transmitted across the capillary bed, where it dissolves in the extracellular tissues and thus reaches the point of injury. Respiratory insufficiency, anemia, cardiac insufficiency, peripheral vascular insufficiency, and defects in hemoglobin (including anemia, carboxyhemoglobin, and sickle cell disease) will all adversely affect the healing process. A failure of oxygen delivery is one of the common pathways of the woundhealing impairment associated with diabetes mellitus, irradiation, arteriosclerosis, and chronic infection. Conversely, the rate of healing is a function of arterial oxygen tension through a certain physiological range. Assuming normal oxygen delivery mechanisms are in place, the oxygen tension distributed throughout the wound varies directly with the proximity of the capillary. Close to the wound capillary oxygen tension ranges between 60 and 90 mm Hg. At 150 away from the capillary, oxygen tension approaches zero. Actively dividing fibroblasts are found in close proximity to the capillary, whereas macrophages are the only cells found at the distance where oxygen tension approaches zero. Collagen synthesis requires a partial pressure of oxygen (PaO2) 40 mm Hg pressure. Oxygen is used not only in the energy-requiring processes of protein synthesis and cell replication but also in the biochemical hydroxylation of proline and lysine molecules.

Hyperbaric oxygen (HBO) has been used to increase oxygen tensions in hypoxic, difficult wounds.Treatment of wounds with HBO stimulates fibroblast proliferation and differentiation, increased collagen deposition, and cross-linking, neovascularization, and microbial lysis. Limited clinical data suggest that this modality can be successful in enhancing the healing of poorly healing irradiated or diabetic wounds.

OTHER FACTORS INFLUENCING WOUND HEALING

SMOKING

Smoking has several adverse effects on primary wound healing, as well as multiple effects on systemic wellbeing. Long-term consequences including emphysema, peripheral vascular insufficiency, and carcinogenesis significantly increase the risks of elective or reconstructive surgery. Inhalation of the combustion products of tobacco includes carcinogenic tars, carbon monoxide, and nicotine as the active toxic ingredients.

Nicotine is a stimulant and the primary addicting agent in smoking. Metabolic effects of nicotine include increased platelet adhesion and increased thrombus formation within the microvasculature. Nicotine also directly inhibits keratinocyte migration, prolonging reepithelialization, and inhibits proliferation of red blood cells, macrophages, and fibroblasts, further impairing wound healing.

Associated effects of smoking cause peripheral vasoconstriction, reduce capillary perfusion, increase bleeding, and through carbon monoxide binding shift the oxyhemoglobin curve to the left, reducing oxygen delivery. Hydrogen cyanide is another product of combustion in smoking.The deleterious effect of hydrogen cyanide is on oxidative metabolism and oxygen transport at the cellular level,interfering with cellular respiration. Smoking directly increases matrix metalloproteinase-1 messenger ribonucleic acid (mRNA), a product of dermal fibroblasts that degrades collagen. In addition to increasing degradation of collagen, nicotine reduces production of types I and III collagen by as much as 40%. Normally, collagen represents 70% of the dry weight of the skin. Increased degradation, in combination with reduced production, could be one of the central mechanisms contributing to the thinned, wrinkled skin of smokers’ faces.

Smoking is a significant cofactor in osteoporosis, impairing calcium metabolism, reducing fracture healing, and increasing fracture risks.The combination of toxins, causing direct vasoconstriction, intravascular thrombus, collagen disruption, impaired oxyhemoglobin

dissociation, and oxygen consumption, affects all aspects of the healing process.The carcinogenic activity of smoking is well known in relation to lung cancer but less recognized as a cofactor in both squamous cell and basal cell cancers of the skin.

Smoking is a direct contraindication to several elective procedures, especially facelift surgery, because the risks of skin necrosis, hematoma formation, and scarring create a high probability of an unsatisfactory outcome. Smoking also increases the complication rate of general anesthesia and the risk of postoperative pneumonia. Studies have indicated that smoking cessation, with complete withdrawal at a minimum of 2 weeks before elective surgery, can reverse many of the acute toxic effects of tobacco. Complete cessation will diminish the risk of malignancy.

ALCOHOL

The negative effects of alcoholism and its associated malnutrition have already been mentioned. Alcohol withdrawal continues to carry a significant risk of morbidity and mortality. Recognizing the risk in the preoperative period and initiating the appropriate treatment for delirium tremens will reduce the risk of poor outcomes. Supplemental thiamine and treatment with psychotropic drugs (benzodiazepam, Librium,Thorazine, or other recommended agents) should be used as prophylaxis.

STEROIDS AND ANTI-INFLAMMATORY

DRUGS

Steroids inhibit wound macrophages and epithelial cell migration and reduce essential biochemical processes involved in fibrogenesis, angiogenesis, and wound contraction.VitaminA will reverse the effect of steroids on the inflammatory process and promote epithelial repair. Antiinflammatory drugs such as aspirin and ibuprofen decrease collagen synthesis by up to 45%. The effect is dose dependent and reverses slowly. Stopping aspirin in the preoperative period should be considered 4 to 6 weeks in advance of elective surgery. The list of drugs and supplements, especially over-the-counter medications containing salicylates, should be reviewed with each patient. The inhibitory effect on the inflammatory process is mediated through prostaglandin. Salicylates are also well known to increase bleeding time and risk of hematoma by their activity in reducing platelet stickiness.

LATHYROGENS

Lathyrism was well known among ancient Greeks. Eating the ground pea (Lathyrus odoratus) results in loss

of collagen in tendons and ligaments, as well as fascia. Poisoning leads to giant hernias, knee instability, and vertebral dislocation. The active ingredient is BAPN. The effect is mediated through blockage of the aldehyde intermediates in collagen cross-linking. The strength of the collagen bundles is lost, and tissue integrity is disrupted. Both BAPN and a related lathyrogen, d-penicillamine, have been used as pharmaceutical agents to control scar tissue, to little benefit.

OXYGEN-DERIVED FREE RADICALS

Radiation, ischemia, inflammation, and certain chemicals release oxygen-derived free radicals that are cytotoxic and highly reactive. They cause cellular injury by degrading hyaluronic acid and collagen, destroying cell membranes, interfering with protein enzyme systems, and disrupting intracellular membranes. Oxygen radical scavengers such as superoxide dismutase (SOD) and allopurinol prevent damage from these radicals by blocking xanthine oxidase (XO). Intracellular generation of free radicals is one of the factors contributing to damage associated with aging, reperfusion syndromes, hyperoxygenation syndromes, chemical-induced tissue injury, drug-induced hemolytic anemia, and vitamins A and D deficiency. Blocking these radicals is the goal of many current antiaging regimens and in the salvage of replanted tissues and failing flaps.

AGING

During World War I, Alexis Carell and coworkers noted the correlation between rates of wound contracture and age. Open wounds among 20-year-old patients closed in 40 days.This rate slowed progressively, rising to 56 days in 30-year-olds and 76 days in 40-year-olds. In the burn literature, significant differences in healing and rates of morbidity and mortality correlate with age. Patients over the age of 50 are considered part of the elderly risk group for complications. Factors believed to contribute to this decrease in the rate of healing include reduction in the amounts of connective tissue deposited over time, reduced hydroxyproline accumulation, decreased cellular activity, including reduced numbers of cells present, reduced secretory products, and significantly reduced DNA and RNA synthesis. Epithelial migration is slower.Age is affected by numerous factors other than simply time. Genetic coding, repair, and control of cell replication and repair are among the cellular factors involved. Reduced tolerance to ischemia is also implicated as one of the major factors. Changes in growth hormone production, estrogen and

testosterone levels, and reduced sensitivity to these hormones, among others, result in alterations in body fat/protein ratios, bone density, skin thickness, and vascular reactivity. Although healing does occur, its time scale is altered significantly, and cellular proliferation is reduced in all phases of healing.

Significant features of healing in the aged include (1) reduction in rate of gain of tensile strength and in the absolute value at completion, (2) reduced wound closure rate and bursting strength, (3) delayed start for all cellular events in the course of healing, and (4) reduced cellular proliferation and substance production. Healing in the aged is quantitatively impaired and delayed, but it can be achieved if deficiency states are corrected, general principles of good surgical technique and postoperative management are followed, and associated conditions, such as diabetes, heart disease, and pulmonary insufficiency, are adequately addressed.

Facial skin aging occurs in sun-exposed skin more severely than in non-sun-exposed skin surfaces. Both genetic (intrinsic) and environmental (extrinsic) factors contribute to the changes seen in photodamaged and aged skin. Photoaging is characterized by wrinkles, pigment irregularities, loss of skin tone, loss of resilience, and malignant degeneration. Ultraviolet (UV) radiation increases collagen-degrading MMPs and reduces collagen synthesis. Damage affecting both mitochondrial and genomic DNA affects repair mechanisms in ways that result in loss of collagen and elastin fibers. Furthermore, UV A and B increase elastase activity. Neutrophil production of serine elastase is associated with increased fibronectin breakdown products, which themselves are harmful to tissues. UV damage, causing active cellular and matrix degradation, and chronological aging effects such as reduced cell proliferation and production capacity, are some of the underlying mechanisms of skin aging. The underlying pathogenic agent for much of this damage is believed to be reactive oxygen species that are known to affect growth, differentiation, senescence, and connective tissue degradation. Some of these effects are reversed by topical applications of vitamin A as retinoic acid. Use of effective sunscreen will also protect the skin by inhibiting the production of oxygen radicals. Possible reversal of these age-related effects through manipulation of the wound environment by application of exogenous growth factors has been evaluated extensively but has not yet found a definable role in wound management. Topical cytokines and retinoids have found a role in enhancing skin stability and increasing collagen formation, and may improve

healing characteristics, but they are used most frequently at the present time for their antiwrinkle effects.

HEALING IN SPECIALIZED

CIRCUMSTANCES

SKIN GRAFTS

Healing of skin grafts proceeds in several stages. Additional processes accompany the usual steps of inflammation, proliferation, and maturation. The skin graft that is used may be a thin ( 0.0015 in. thick) split-thickness graft harvested from a remote donor site, a thicker graft ( 0.0015 in. thick), or a fullthickness skin graft. The thinner the graft harvested from a donor site, the more quickly the donor site will heal, with less pigment change and scar formation at the donor area, and more scarring, contraction, and contracture at the recipient site. Full-thickness skin grafts are frequently taken from areas of high skin laxity, permitting closure of the donor area with primary intention. Full-thickness skin grafts typically have a better color match and contract as healing progresses. It is speculated that the amount of dermis transferred with the epidermis in the graft is an important cofactor in quality healing.

The skin graft, when applied to a recipient bed that is free of contamination and has good vascularity, will be nourished for the first 72 hours by a process known as imbibition. The graft adheres to the bed through proper surgical technique (sutures, bolster tie-over dressing, and bulky dressing immobilization) and naturally occurring fibrin glue. Bacteria in the recipient bed, especially staphylococcal species, produce fibrinolytic enzymes that will prevent adherence of the graft, giving it an appearance of “dissolving” within a few days of application. If the graft is properly immobilized, neovascularization brings capillary blood flow directly into the transplanted dermis and epidermis within 72 hours. Take off of the graft is accomplished when capillary ingrowth, fibrinogen fixation, and cellular proliferation in the graft are established.Transplantation of epidermis alone can be done if cultured epidermal cells are used. Commercial production of autologous epidermal cells is now widely available, and homograft epidermal cells cultured from fetal foreskin are also effective and available in many countries, and under certain circumstances in the United States. Conditions where such techniques may be necessary include massive burns, congenital conditions such as epidermolysis bullosa, and autoimmune chronic skin disorders such as

severe toxic epidermolysis necrobioticum. Cultured epidermis is expensive, and current research attempts to find useful applications in chronic skin ulcers, smaller burns, and other such open wounds have yet to be shown to be clinically valuable.

CARTILAGE

The three-dimensional structure of the ear, nose, larynx, and tracheal airway is supported by cartilage. There are three types of cartilage in humans: (1) hyaline cartilage, found in joints, rib cage, and trachea, functions to dissipate loads on bone and in joints; (2) elastic cartilage occurs in the ear, nose, and larynx, providing the semirigid support required by their structure and function; (3) fibrocartilage, found in the intervertebral disks, tendon attachments, and temporomandibular joint, serves to transfer loads between tendon and bone and to cushion joints.

Cartilage consists of a highly organized matrix of primarily type II collagen and proteoglycans and a cellular component, chondrocytes, embedded in a multilaminated capsule. Cartilage contains no lymphatic or blood vessels.Thus small, localized injury results in no bleeding or inflammatory process, and healing is not initiated unless surrounding soft tissues are also injured. Formation of scar tissue following cartilaginous injury results in disorganized bundles of type I collagen, with the result that the shape and structure of the cartilage can be altered. Initial healing in cartilaginous tissue that has been significantly traumatized is similar to the wound healing process of skin that has already been discussed. A cascade of peptides, growth factors, and inflammatory cells characterizes the initial stage. Where the process of cartilaginous wound healing differs from that of skin is in the acute need for a delicate balance between the deposition of scar tissue and the actual regeneration of cartilage. Inflammation and subsequent type II collagen deposition inhibit the regrowth of cartilaginous tissue. Fibrocartilage, as found on the articular surfaces of the temporomandibular joint, has much better regenerative capacity than hyaline cartilage. Fibrocartilage repair is mediated by mesenchymal cells of the adjacent bone marrow, which have greater regeneration abilities than do mature chondrocytes.Thus, because of the proximity to bone marrow, full-thickness cartilage defects of the joint are replaced by fibrocartilage, and par- tial-thickness defects are mainly repaired by depositions of fibrous scar tissue. Hyaline cartilage heals with the initial formation of a fibrocartilage intermediary that is eventually replaced by hyaline. The primary mediator of hyaline regeneration is a mesenchymal cell from adjacent marrow, not chondrocytes.

Maintaining the shape of cartilage is a primary consideration in cartilage repair in the ear, nose, and airway. Careful reapproximation of the structure, splinting for extended periods of time, and minimizing inflammation can result in a satisfactory outcome. Infant cartilage can be retrained and reshaped into aesthetically improved positions with only taping and splinting, correcting such deformities as lop ear and cleft lip nasal distortions if initiated in the perinatal period.

Mature cartilage is much more resistant to reshaping by manipulation. The most common complication of cartilage healing is deformation or warping.This is well illustrated in cases of nasal deviation after trauma or corrective nasal surgery. Even after prolonged splinting of the nose or septum, the cartilage has a tendency to redeviate. Cartilage heals with a fibrous union, leaving the structural integrity impaired in ways that are not yet well understood.

Blunt injury to cartilage may result in subperichondral hematoma. Left untreated, this can result in pressure necrosis of the cartilage. In the ear, this results in subsequent fibrosis and “cauliflower” or “boxer’s” deformity. In the nose, this can result in septal perforation and loss of dorsal support.

Better understanding of healing cartilage will result in improved care for fractures, inflammatory diseases, and diseases of aging, including osteoarthritis and posttraumatic joint disorders.

BONE

Bone is a complex tissue containing many unique cells: osteoblasts (derived from mesenchymal, osteoprogenitor cells), responsible for bone formation; osteocytes, a type of osteoblast surrounded by bone matrix; and osteoclasts (related to the monocyte/macrophage cell line), which are multinucleated cells that direct bone resorption. Just as the healing process described earlier can be divided into stages, bone heals through a sequence of stages: (1) injury, (2) soft callus, (3) hard callus, and (4) remodeling. Understanding the distinct characteristics of bone healing requires knowledge of the physiology of bone, its matrix, and its unique cells. The connective tissue matrix of bone is both inorganic and organic. The organic matrix is similar to dermis, consisting of collagen type I, glycoproteins, and proteoglycans. The inorganic matrix includes mainly calcium salts, predominantly hydroxyapatite. Bones are composed of 92% solid material.The organic component of the bone matrix consists of 98% collagen and 2% glycosaminoglycans and proteoglycans. Blood supply to

the bone is derived from three sources, the periosteum, endosteum, and surrounding soft tissue.

Two specific types of bone exist, membranous and endochondral, both derived from mesenchymal tissues. They are distinguished by the means through which they ossify. Endochondral bone initially forms as cartilaginous tissues at the epiphysis and then ossifies. Membranous bone is formed from preexisting mesenchymal cells that differentiate directly into osteoblasts and that form osteoid material without initial cartilaginous intermediates. Membranous bone includes the skull and most of the facial bones. The long bones of the skeleton are endochondral. Further distinction between bone is made on a morphological basis, cortical or cancellous. Few tissues in the adult human have a better capacity for the regeneration of both form and function than bone. Primary reconstruction by reduction and fixation of fractures will result in the restoration of facial appearance. Fracture or osteotomy stimulates bone regeneration so efficiently that, when completed, the fracture site may be undetectable. Abnormal healing occurs and may result in such exuberant bone formation, malunion if the fragments are misaligned, or nonunion if stable fixation is not achieved. Defects in the facial skeleton do not initiate regenerative growth, and nonunion of improperly immobilized fractures is a common outcome. One reason for the persistence of a defect is an inadequate supply of inducible proteins and growth factors required for osteogenesis, the most important of which is bone morphogeneic protein (BMP). The source of BMP is demineralized bony matrix, something that is deficient in cases of large bony voids. The ingrowth of fibrous tissue from the surrounding connective tissue can mechanically interfere with the process of bony union and impair the healing of bone defects. Finally, a lack of rigid scaffolding across the void inhibits conduction of osteoblasts and osteoclasts into the wound site.

Normal bone healing proceeds through injury and inflammation. Following this initial stage of healing, beginning between 3 and 4 days after injury, bone begins a unique healing process, osteoinduction and osteoconduction, to begin the formation of soft callus. Cells involved in this process include fibroblasts, chondroblasts, and osteoblasts. Mesenchymal cells are transformed into bone cells (osteoinduction) by effects from growth factors, physical signals, and other chemical modulators. Ingrowth of capillaries and osteoprogenitor cells into the fracture site (osteoconduction) arises from adjacent soft tissue and bone, primarily from the periosteum. Migration into the wound by fibroblasts, osteoblasts, and chondroblasts initiates cellular secretions