Abnormal wound healing

Impaired wound healing

A variety of local and systemic factors are implicated in abnormal wound healing, which impair tissue regeneration by interrupting each of the stages of wound healing. Physical impediments to wound closure may delay or prevent healing, such as the presence of foreign bodies or neoplasm; hematomas and seromas commonly cause failure of skin grafts. Excessive tension on a wound or surrounding edema may compress the vascular supply and lead to ischemia; recent data also implicate mechanical tension as a leading cause for hypertrophic scar formation [68]. Therapeutic radiation and repetitive trauma are also well-known detriments to wound healing. A summary of the classic factors that are known to impair wound healing is listed in Table 2.

Delivery of oxygen is especially important in the healing wound, and a variety of insults can disturb wound healing by evoking hypoxia. In addition to providing a substrate for ATP synthesis in aerobic cell metabolism, large quantities of oxygen are used by neutrophils for superoxide radical generation in oxidative killing. Furthermore, molecular oxygen itself is toxic to anaerobic microorganisms. Wound oxygenation is determined by blood perfusion, hemoglobin dissociation, local oxygen consumption, fraction of inspired oxygen, hemoglobin content, arterial oxygen tension, circulating blood volume, cardiac output, arterial inflow, and venous

Table 2. Local and systemic factors that impair wound healing. Adapted from [69]

drainage [70]. Disruption of vascular supply and depletion of oxygen can lead to wound hypoxia, which has been associated with systemic diseases such as connective tissue disorders and microvascular disease in diabetes mellitus. Tobacco smoking produces similar effects through nicotine-induced vasoconstriction and displacement of oxygen on hemoglobin with carbon monoxide [5].

Infection is another classic adversary of proper wound healing. Bacterial counts that exceed approximately 105 organisms per gram of tissue will generally not heal by any means, including flap closure, skin graft placement, or primary intention [71]. The introduction of early excision and grafting for burn wounds has virtually eliminated burn wound sepsis, which was historically a leading cause of burn mortality. Endotoxin produced by gram-negative bacteria stimulates phagocytosis and collagenase expression, which contributes to matrix degradation and destruction of normal tissue. Bacteria are also known to accelerate protease production in macrophages (such as MMPs) while inhibiting protease inhibitor expression. This effect leads to increased matrix destruction and degradation of growth factors, which are characteristics of chronic non-heal- ing wounds [72].

Nutritional status has a profound effect on wound healing as well. Serum albumin is thought to be one of the most accurate predictors of surgical morbidity and mortality, with levels below 2.1g/dL associated with poorer outcomes [73]. Protein replacement has been shown to enhance wound healing [74], as has supplementation with the amino acids arginine, taurine, and glutamine [75, 76]. Whereas patients with large burns characteristically have albumin levels below 1.0g/dL, there has been no conclusive demonstration that exogenous albumen will improve outcomes. Nevertheless, all efforts should be made to provide early enteral nutrition and to modulate the metabolic state. Some data suggest that the catabolic state can be modulated by propranolol in children [77], as well as by oxandrolone in children and adults [78,79].

Vitamin C (ascorbic acid) is an essential cofactor in proline and lysine hydroxylation during collagen synthesis, and supplementation of 100–1,000 grams per day may improve wound healing [76]. Vitamin A (retinoic acid) is required for wound epithelial-

ization, maintenance of normal epithelium, proteoglycan synthesis, and normal immune function. Oral retinoid therapy is well known to counteract the detrimental effects of corticosteroids on wound healing, possibly through promotion of TGFand IL-1 signaling [80]. Vitamin K deficiency will impede clot formation and hemostasis, while vitamin D is required for bone healing and calcium metabolism. Finally, vitamin E supplementation may serve an important role as an antioxidant in trauma patients. Early administration of vitamin E has been shown to reduce the incidence of organ failure and the length of ICU stay in critically ill surgical patients [81].

The dietary minerals associated with adverse wound healing are zinc and possibly iron. Zinc is an essential cofactor in RNA and DNA polymerases, and a deficiency can inhibit granulation tissue formation [82] and delay wound healing [83]. Supplementation with zinc was also reported to improve wound healing [75]. Iron is also a cofactor in DNA synthesis as well as proline and lysine hydroxylation. Although the role of iron in normal hematopoiesis is well established, chronically anemic patients do not appear to suffer from delayed wound healing [5, 84]. Selenium deficiency is known to cause hair and skin abnormalities in humans and rodents, though it has not been implicated in abnormal wound healing. Recent evidence has implicated selenoproteins in keratinocyte function and cutaneous development [85]. Based on the importance of hair follicles and keratinocytes in wound epithelialization, it may prudent to assume that adequate selenium is necessary for proper wound healing.

Hypertrophic scars and keloids

Hypertrophic scar and keloids are the prime examples of proliferative scars, which are characterized by excessive collagen deposition. Whereas these two morphological aberrations can be difficult to differentiate, keloids are defined as scars that grow beyond the periphery of the original wounds and hypertrophic scars represent raised scars that remain confined to the boundaries of the original wound. Keloids rarely regress with time; hypertrophic scars frequently regress spontaneously. Keloids appear to have a strong genetic component, with more prevalence in dark-skinned patients of

African, Asian, or Latin American descent. Hypetrophic scars, in contrast, are the result of prolonged inflammation and maybe frequently preventable [5]. Hypertrophic scars also tend to occur in pigmented individuals; they are more common in young people and rarely occur in the aged. Interestingly, they often develop in areas of the body where contraction occurs and rarely form on the scalp or the palms and soles.

In light of its potent effect on fibroblast proliferation and collagen deposition, it is perhaps not surprising that TGFplays a central role in proliferative scarring. Increased levels of the TGF- 1 isoform have been found in both keloids and hypertrophic scars [86]. Likewise, antibodies to TGFisoforms have been found to reduce fibrosis in hypertrophic scars [87]. Novel therapies for hypertrophic and keloid scars are in development that target ECM synthesis and fibroblast proliferation [88].

Chronic non-healing wounds

Dysfunction of normal wound healing processes leads to chronic wounds. In particular, chronic wounds appear to have sustained inflammation with less matrix production. Chronic wounds exhibit higher levels of cytokines such as IL-1, IL-6, and TNF- , with reduced levels of essential growth factors such as EGF and PDGF [14]. Higher levels of MMP-1, MMP-2, MMP-8, and MMP-9 have been demonstrated, with reduced levels of MMP inhibitors [89]. These non-healing wounds are prone to developing squamous cell carcinoma, originally reported in burn wounds by Marjolin. Marjolin ulcers tend to be very aggressive and should be highly suspected with non-healing burn wounds. Therapy includes complete local extirpation of the cancer with negative margins and lymphatic mapping [90]. Other conditions such as osteomyelitis, pressures sores, venous stasis ulcers, and hidradenitis have also been associated with wound malignancies [5]. Patients with impaired skin integrity due to burn injuries are at increased risk for decubitus ulcers, which constitute a closely monitored hospital-acquired complication.

A variety of burn dressings and skin substitutes are employed in the treatments of acute burns, which are listed in Tables 3 and 4 respectively.