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to increase levels of mature collagen.23

Fatty Acids

Lipids are used as nutritional support for surgical or critically ill patients to help meet energy demands

and provide essential building blocks for wound healing and tissue repair. Polyunsaturated fatty acids

(PUFAs), consist mainly of two families, n-6 (omega-6, found in soybean oil) and n-3 (omega-3, found

in fish oil). Although fish oil has been widely touted, effects of omega-3 fatty acids on wound healing

are not conclusive. They have been reported to affect proinflammatory cytokine production, cell

metabolism, gene expression, and angiogenesis in wound sites.24

Vitamins, Micronutrients, and Trace Elements

Vitamins C (L-ascorbic acid), A (retinol), and E (tocopherol) show potent antioxidant and antiinflammatory effects. Vitamin C has many roles in wound healing, and a deficiency in this vitamin has

multiple effects on tissue repair. Vitamin C deficiencies result in impaired healing, and have been linked

to decreased collagen synthesis and fibroblast proliferation, decreased angiogenesis, and increased

capillary fragility. Also, vitamin C deficiency leads to an impaired immune response and increased

susceptibility to wound infection. Similarly, vitamin A deficiency leads to impaired wound healing. The

biological properties of vitamin A include antioxidant activity, increased fibroblast proliferation,

modulation of cellular differentiation and proliferation, increased collagen and hyaluronate synthesis,

and decreased MMP-mediated ECM degradation.25

Vitamin E, an antioxidant, maintains and stabilizes cellular membrane integrity by providing

protection against destruction by oxidation. Vitamin E also has anti-inflammatory properties and has

been suggested to have a role in decreasing excess scar formation in chronic wounds. Animal

experiments have indicated that vitamin E supplementation is beneficial to wound healing, and topical

vitamin E has been widely promoted as an antiscarring agent. However, clinical studies have not yet

proved a role for topical vitamin E treatment in improving healing outcomes.26

Several micronutrients have been shown to be important for optimal repair. Magnesium functions as a

cofactor for many enzymes involved in protein and collagen synthesis, while copper is a required

cofactor for cytochrome oxidase, for cytosolic antioxidant superoxide dismutase, and for the optimal

cross-linking of collagen. Zinc is a cofactor for both RNA and DNA polymerase, and a zinc deficiency

causes a significant impairment in wound healing. Iron is required for the hydroxylation of proline and

lysine, and, as a result, severe iron deficiency can result in impaired collagen production.27 As indicated

above, the nutritional needs of the wound are complex, suggesting that composite nutrition support

would benefit both acute and chronic wound healing. A recent clinical research study examined the

effects of a high-energy, protein-enriched supplement containing arginine, vitamin C, vitamin E, and

zinc on chronic pressure ulcers and indicated that this high-energy and nutrition-enriched supplement

improved overall healing of the pressure ulcer.28 In summary, proteins, carbohydrates, arginine,

glutamine, PUFAs, vitamin A, vitamin C, vitamin E, magnesium, copper, zinc, and iron play a significant

role in wound healing, and their deficiencies affect wound healing. Additional studies will be needed to

fully understand how nutrition affects the healing response.

Obesity

The prevalence of obesity continues to increase among adults, children, and adolescents in the United

States, with more than 30% of adults and 15% of children and adolescents classified as obese in a recent

survey.29 Obesity is well known to increase the risk of many diseases and health conditions, which

include coronary heart disease, type 2 diabetes, cancer, hypertension, dyslipidemia, stroke, sleep apnea,

respiratory problems, and impaired wound healing. Obese individuals frequently face wound

complications, including skin wound infection, dehiscence, hematoma and seroma formation, pressure

ulcers, and venous ulcers.30 An increased frequency of wound complications has been reported for obese

individuals undergoing both bariatric and nonbariatric operations.31 In particular, a higher rate of

surgical site infection occurs in obese patients. Many of these complications may be the result of a

relative hypoperfusion and ischemia that occurs in subcutaneous adipose tissue. This situation may be

caused by a decreased delivery of antibiotics as well. In surgical wounds, the increased tension on the

wound edges that is frequently seen in obese patients also contributes to wound dehiscence. Wound

tension increases tissue pressure, reducing microperfusion and the availability of oxygen to the

wound.32

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Figure 5-15. Cellular mechanisms that impair healing of the diabetic wound.

The increase in pressure ulcers or pressure-related injuries in obese individuals is also influenced by

hypovascularity, since poor perfusion makes tissue more susceptible to this type of injury. In addition,

the difficulty or inability of obese individuals to reposition themselves further increases the risk of

pressure-related injuries. Moreover, skin folds harbor microorganisms that thrive in moist areas and

contribute to infection and tissue breakdown. The friction caused by skin-on-skin contact invites

ulceration. Together, these factors predispose obese individuals to the development of impaired wound

healing.

In addition to local conditions, systemic factors also play an important role in impaired wound

healing and wound complications in obese patients. Obesity can be connected to stress, anxiety, and

depression, all situations that can cause an impaired immune response.

The function of adipose tissue used to be considered as primarily caloric storage. However, more

recent findings have documented that adipose tissue secretes a large variety of bioactive substances that

are collectively named adipokines. Both adipocytes as well as resident macrophages in adipose tissue

are known to produce bioactive molecules including cytokines, chemokines, and hormone-like factors

such as leptin, adiponectin, and resistin. Adipokines have a profound impact on the immune and

inflammatory response.33 The negative influence of adipokines on the systemic immune response seems

likely to influence the healing process, although direct proof for this is lacking. Impaired peripheral

blood mononuclear cell function, decreased lymphocyte proliferation, and altered peripheral cytokine

levels have been reported in obesity. Importantly, many of the obesity-related changes in peripheral

immune function are improved by weight loss.34

Diabetes Mellitus

Diabetes affects hundreds of millions of people worldwide. Diabetic individuals exhibit a documented

impairment in the healing of acute wounds. Moreover, this population is prone to develop chronic

nonhealing diabetic foot ulcers (DFUs), which are estimated to occur in 15% of all persons with

diabetes. DFUs are a serious complication of diabetes, and precede 84% of all diabetes-related lower leg

amputations.35 The impaired healing of both DFUs and acute cutaneous wounds in persons with diabetes

involves multiple complex pathophysiological mechanisms (Fig. 5-15). DFUs, like venous stasis disease

and pressure-related chronic nonhealing wounds, are always accompanied by hypoxia.36 A situation of

prolonged hypoxia, which may be derived from both insufficient perfusion and insufficient

angiogenesis, is detrimental for wound healing. Hypoxia can amplify the early inflammatory response,

thereby prolonging injury by increasing the levels of oxygen radicals.37 Hyperglycemia can also add to

the oxidative stress when the production of reactive oxygen species exceeds the antioxidant capacity.38

The formation of advanced glycation end products under hyperglycemia and the interaction with their

receptors are associated with impaired wound healing in diabetic mice as well.39 High levels of

metalloproteases (MMP) are a feature of DFUs, and the MMP levels in chronic wound fluid are almost

60 times higher than those in acute wounds. This increased protease activity supports tissue destruction

and inhibits normal repair processes.40

Several dysregulated cellular functions are involved in diabetic wounds, such as defective T-cell

immunity, defects in leukocyte chemotaxis, phagocytosis, and bactericidal capacity, and dysfunction of

fibroblasts and epidermal cells. These defects are responsible for inadequate bacterial clearance and

delayed or impaired repair in individuals with diabetes.41

As mentioned above, hypoxia contributes to the compromised healing of DFUs, and diabetic wounds

exhibit inadequate angiogenesis. Several studies that have investigated the mechanisms behind the

decreased restoration of vasculature in diabetic wounds have implied that endothelial progenitor cell

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mobilization and homing are impaired, and that the level of VEGF, the primary proangiogenic factor in

wounds, is decreased in the diabetic state.42 Stem-cell–based therapies aimed at inducing endothelial

progenitor cells or bone marrow–derived multipotent stem cells have shown a promising outcome in

diabetic nonhealing wounds, both in animals and in clinical trials.43 In animal studies, therapeutic

restoration of VEGF has been shown to improve repair outcomes significantly.44

The neuropathy that occurs in diabetic individuals probably also contributes to impaired wound

healing. Neuropeptides such as nerve growth factor, substance P, and calcitonin gene-related peptide are

relevant to wound healing, because they promote cell chemotaxis, induce growth factor production, and

stimulate the proliferation of cells. A decrease in neuropeptides has been associated with DFU

formation. In addition, sensory nerves play a role in modulating immune defense mechanisms, with

denervated skin exhibiting reduced leukocyte infiltration.45

In summary, the impaired healing that occurs in individuals with diabetes involves hypoxia,

dysfunction in fibroblasts and epidermal cells, impaired angiogenesis and neovascularization, high levels

of MMP, damage from reactive oxygen species and advanced glycation end products, decreased host

immune resistance, and neuropathy.

Medications and Dietary Supplements

Glucocorticoid Steroids. Systemic glucocorticoids, which are frequently used as anti-inflammatory

agents, are well known to inhibit wound repair via global anti-inflammatory effects and suppression of

cellular wound responses, including fibroblast proliferation and collagen synthesis. Systemic steroids

cause wounds to heal with incomplete granulation tissue and reduced wound contraction.46

Glucocorticoids also inhibit production of HIF-1, a key transcriptional factor in healing wounds.47

Beyond effects on repair itself, systemic corticosteroids may increase the risk of wound infection. While

systemic corticosteroids inhibit wound repair, topical application produces quite different effects.

Topical low-dosage corticosteroid treatment of chronic wounds has been found to accelerate wound

healing, reduce pain and exudate, and suppress hypergranulation tissue formation in 79% of cases.

While these positive effects are striking, careful monitoring is necessary to avoid a potential increased

risk of infection with prolonged use.48

Nonsteroidal Anti-Inflammatory Drugs. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as

ibuprofen are widely used for the treatment of inflammation and rheumatoid arthritis and for pain

management. Low-dosage aspirin, due to its antiplatelet function, is commonly used as a preventive

therapeutic for cardiovascular disease, but not as an anti-inflammatory drug.49 There are few data to

suggest that short-term NSAIDs have a negative impact on healing. However, the question of whether

long-term NSAIDs interfere with wound healing remains open. In animal models, systemic use of

ibuprofen has demonstrated an antiproliferative effect on wound healing, resulting in decreased

numbers of fibroblasts, weakened breaking strength, reduced wound contraction, delayed

epithelialization,50 and impaired angiogenesis. The effects of low-dose aspirin on healing are not

completely clear. Clinical recommendations suggest that, to avoid antiplatelet effects, individuals should

discontinue NSAIDs for a time period equal to 4 to 5 times the half-life of drugs before surgery. Thus,

the majority of surgical patients do not have significant NSAID activity at the time of wound repair. The

exception may be those cardiac patients who must be maintained on low-dose aspirin due to severe risk

of cardiovascular events. In terms of the topical application of NSAIDs on the surfaces of chronic

wounds, the local use of ibuprofen foam provides moist wound healing, reduces persistent and

temporary wound pain, and benefits chronic venous leg ulcer healing.

Peripheral Vascular Disease

Total disease prevalence based on objective testing has been evaluated in several epidemiologic studies

and is in the range of 3% to 10%, increasing to 15% to 20% in persons over 70 years.51 Peripheral

vascular disease (PVD) is an independent risk factor for subsequent ulceration and limb loss in diabetes.

It is present in 50% of patients with diabetic foot ulcer (DFU), a proportion that may be increasing.

Those with DFU and peripheral arterial disease (PAD) are less likely to heal and more likely to require

amputation compared to patients without PAD. It is therefore essential that PVD is identified in all

patients with diabetes.

Patients with PVD commonly suffer from chronic toe and foot sores, cramping leg muscles when

walking or numbness, weakness or heaviness in the muscles. Other PVD symptoms include:

Numbness in the extremities

Weakness and atrophy of calf muscles

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A feeling of coldness in legs or feet

Changes in the color of the feet: feet will turn pale when elevated and turn dusky red when in the

dependent position

Hair loss over the dorsum of the feet, thickening toenails

Painful ulcers and/or gangrene in tissue, typically in the toes

Pathophysiology: The etiology of ulceration in diabetic patients with PVD is multifactorial distal

polyneuropathy (motor, sensory, and autonomic), abnormal foot anatomy, functional changes in the

microcirculation in the presence of PVD, lead to abnormal loading or trauma of the poorly perfused

painless neuropathic foot. Infection in the foot exponentially increases the demand for oxygen, which in

PVD is unmet. Healing is impaired also due to impaired humoral immunity and abnormal inflammatory

responses.52

Traditional wound care algorithms include aggressive detection of PAD and treatment with

revascularization for all patients with PVD and lower extremity wounds – in order to prevent limb

amputation. The Transatlantic Inter-Society Consensus (TASCII) criteria for critical limb ischemia is a

commonly used method for revascularization. When the TcPO2 is >30 mm Hg, the ankle-brachial index

(ABI) and the TASC II definition of critical limb ischemia predict wound healing and should be key

factors in considering conservative therapy. New strategies are being developed to diagnose PVD in

patients with diabetes, referring those presenting with a new foot ulcer to a multidisciplinary team, so

that appropriate interventions help preserve the limb.

Stress

Stress has a great impact on human health and social behavior. Many diseases – such as cardiovascular

disease, cancer, compromised wound healing, and diabetes – are associated with stress. Numerous

studies have confirmed that stress-induced disruption of neuroendocrine immune equilibrium is

consequential to health.53 The pathophysiology of stress results in the deregulation of the immune

system, mediated primarily through the hypothalamic–pituitary–adrenal and sympathetic–adrenal

medullary axes or sympathetic nervous system.54

Studies in both humans and animals have demonstrated that psychological stress causes a substantial

delay in wound healing.55 Caregivers of persons with Alzheimer’s and students undergoing academic

stress during examinations demonstrated delayed wound healing.56 The hypothalamic – pituitary–

adrenal and the sympathetic–adrenal medullary axes regulate the release of pituitary and adrenal

hormones. These hormones include the adrenocorticotrophic hormones, cortisol and prolactin, and

catecholamines (epinephrine and norepinephrine). Stress upregulates glucocorticoids and reduces the

levels of the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α at the wound site. Stress also reduces

the expression of IL-1α and IL-8 at wound sites – both chemoattractants that are necessary for the initial

inflammatory phase of wound healing.57 Furthermore, glucocorticoids influence immune cells by

suppressing differentiation and proliferation, regulating gene transcription, and reducing expression of

cell adhesion molecules that are involved in immune cell trafficking.58 Cortisol functions as an antiinflammatory agent and modulates the Th1-mediated immune responses that are essential for the initial

phase of healing. Thus, psychological stress impairs normal cell-mediated immunity at the wound site,

causing a significant delay in the healing process.59

Stressors can lead to negative emotional states, such as anxiety and depression, which may in turn

have an impact on physiologic processes and/or behavioral patterns that influence health outcomes. In

addition to the direct influences of anxiety and depression on endocrine and immune function, stressed

individuals are more likely to have unhealthy habits, which include poor sleep patterns, inadequate

nutrition, less exercise, and a greater propensity for abuse of alcohol, cigarettes, and other drugs. All of

these factors may come into play in negatively modulating the healing response.

Cigarette Smoking

It is well known that smoking increases the risk of heart and vascular disease, stroke, chronic lung

disease, and many kinds of cancers. Similarly, the negative effects of smoking on wound healing

outcomes have been known for a long time.60 Postoperatively, patients who smoke show a delay in

wound healing and an increase in a variety of complications such as infection, wound rupture,

anastomotic leakage, wound and flap necrosis, epidermolysis, and a decrease in the tensile strength of

wounds.61 In the realm of oral surgery, impaired healing in smokers has been noticed both in routine

oral surgery and in the placement of dental implants.62 Cosmetic outcomes also appear to be worse in

smokers, and plastic and reconstructive surgeons are often reluctant to perform cosmetic surgeries on

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