Studies have shown for over 100 years that malnutrition impairs wound healing [11–14]. The impairment exists with total protein/calorie (marasmus) malnutrition or with protein (kwashiorkor) malnutrition. Simply, if one holds nutritional support at the time of wounding, a marked impairment in tensile strength will result within 1–2 weeks [15]. The clinical significance of malnutrition relates to the risks of complications with surgery such that if a patient has lost weight from a malignancy or from an inability to eat, then there is a much higher risk for dehiscence. The hidden side of this healing impairment is that altered healing could lead to a bowel anastomosis leak which in turn may lead to an abscess. Since the metabolic reserve is reduced in the elderly, this complication of failing to heal often leads to sepsis, multiple organ dysfunction syndrome, and ultimately death. The clinician can reduce complications by assessing the nutritional status of the elderly and providing supplemental nutrition prior to surgery. In addition, an aggressive approach to perioperative nutrition may make the difference between normal healing without complications and a rocky course and ultimate death.

There are some vitamins and micronutrients that influence tissue repair. Vitamin C is essential for the hydroxylation of proline or lysine in the formation of normal procollagen triple helices [16]. When there is a deficiency, collagen is not properly produced, and people may suffer from scurvy. Since there is a balance between collagen formation and breakdown during the maturation phase of scar formation, recently healed wounds may break down. In addition, vitamin A has been found to augment tissue repair [17, 18]. Several minerals such as zinc [19, 20] and copper [20] are essential for normal healing, and when they are deficient, problems may result. We have noted that patients with subnormal copper levels have impaired healing of their burn wounds [21]. A deficiency in arginine may also lead to altered tissue repair [22].

Diabetes mellitus is a major cause of healing problems in people of all ages [23–25]. Since the disease is seen more commonly in the elderly, it is important to know its impact on tissue repair. Some statistics are important to emphasize its impact on the development of chronic wounds. Twenty percent of hospital admissions in diabetes are related to wound healing problems. Twenty-five percent of diabetic patients will have a foot ulcer during their lifetimes, and 50 % of all nontraumatic amputations are related to diabetes mellitus. A common scenario is that a diabetic patient will not notice a pebble in their shoe due to their impaired sensation. This will create a small wound that goes unnoticed, and eventually a wound is noticed and not properly treated. When the patient finally seeks care, the wound is infected with purulence tracking up the fascial planes of the foot. This patient often presents with cellulitis or invasive infection that leads to an amputation.

Even if a wound is detected, early tissue repair is significantly impaired. As an example, Margolis reviewed several clinical trials that tested treatments for diabetic ulcers [26]. He collected the “controls” which received “standard” treatment. What he found was that only 31 % healed within 20 weeks of aggressive therapy. It is likely that the two-thirds that did not heal stayed open for the remainder of their lives. There are several reasons why tissue repair is impaired in patients with diabetes mellitus [23–25]. First of all, peripheral vascular disease is increased in this population. Diabetics not only suffer from macrovascular disease but also from microvascular disease where there is thickening of the capillary basement membrane. This microvascular disease leads to impaired delivery of oxygen and nutrients from an increase in edema and impaired diffusion. This process also impairs leukocyte migration into the wound. If the patient suffers from renal disease, healing is inhibited further by uremia and its resulting edema [27].

The second factor that contributes to alter healing in diabetes mellitus is its tendency to cause peripheral neuropathy. Loss of sensation progresses from distal to proximal so that the feet are usually involved first. As stated earlier, people with neuropathic feet do not sense injury, and thus minor injuries tend to worsen or fail to recognize that they are injured. We have recently reviewed our 10-year experience with diabetics who burn their feet [28]. It is common for them to walk outside on hot pavement or try to warm their “cold” feet with hot water or by placing them near heaters. We admitted 68 patients with burns to their feet during that period, and the incidence is increasing. As for other types of diabetic wounds, the patients admitted for burns to their feet tended to have prolonged hospital stays and frequent graft failure. Another often unrecognized consequence of neuropathy is that the foot loses its normal feedback to maintain the arch. The foot thus tends to flatten which leads to increased pressure on the first or second metatarsal head. The classic diabetic foot ulcer is a wound that is on the plantar surface on the first or second metatarsal head. The final consequence of neuropathy is that with loss of normal sympathetic innervation, the skin loses its ability to sweat and thus tends to dry and crack. These cracks may lead to a site for infection. Patients should be tested for neuropathy using a 10-g Semmes Weinstein monofilament, 128-hertz tuning fork, vibration perception threshold testing, or a good neurologic exam for sensory loss [29].

There is an increased risk for infection for wounds that form in the diabetic patient. It is well known that hyperglycemia leads to an impaired ability to fight local infection and that avoiding wide swings in glucose levels improve [30]. There are also studies that suggest that leukocyte migration and function is impaired. The inability to fight infections predisposes diabetics to a higher risk for amputations. In addition, there are several metabolic factors that may contribute to impair healing that are covered in other reviews [25, 31]. One interesting concept is that hyperglycemia may lead to deposition of glucose byproducts known as advanced glycosylation end-products (AGES) in the tissues. There are “receptors for advanced glycosylation end-products” (RAGES) that detect these products of hyperglycemia and stimulate an inflammatory response. One theory is that activation of RAGES may lead to the chronic inflammatory state (“metabolic syndrome”) of diabetes mellitus and obesity [32]. This chronic inflammatory state may also contribute to impaired tissue repair.

Since healing is impaired in diabetic patients, it is essential that prevention efforts are made to prevent a wound from developing. The Wound Healing Society has published guidelines for the treatment and prevention of diabetic wounds, and new guidelines should be published in 2016 [33, 34]. All clinicians who treat diabetes mellitus should discuss the risks of foot ulcers with their patients. Diabetics should inspect their feet daily and be extremely careful with the care of their nails. Podiatrists are extremely helpful in these matters. Diabetics with neuropathy should always wear well-fitted shoes and be especially vigilant after the first few days of wearing new shoes. Any new wound should be treated aggressively and early. People with diabetes mellitus should always avoid walking outside while barefoot and never warm their insensate feet with any heated agent. Once a wound develops, they should be treated with something that “off-loads” the pressure point on the wound (metatarsal head). “Total contact casts” have been found to be effective [35]. Studies suggest that topical growth factors or skin substitutes may be effective, but they are extremely costly [36–38]. Vascular disease should be treated if present. Unfortunately, our success with treating these wounds is only marginal, so prevention is essential. Anyone who is fortunate to heal a diabetic foot ulcer should practice extra precautions because the recurrence rate is up to above 50 %. Those patients should wear protective footwear and have daily inspections of their feet for the rest of their lives [39–41].

Wound healing involves the recruitment and rapid proliferation of many different cell types. It makes sense, then, that any drug that impairs rapid proliferation of cells alters tissue repair. Unfortunately, the strategy for dealing with many diseases includes suppressing the inflammatory response, which also requires rapid proliferation of cells. Steroids have been known for decades to impair tissue repair, and their use should be minimized if possible to allow for better healing [42, 43]. The treatment of cancer also involves the killing of rapidly proliferating malignant cells so it is also obvious that chemotherapy agents [44, 45] or radiation [46, 47] impairs tissue repair. In the advent of neoadjuvant therapy (chemotherapy and/or radiation) combined with surgery, it is clear that one must be extremely careful with the healing of these patients. One must optimize their nutritional status if they are to undergo these combined treatments. There are very few agents that augment healing in these situations, but vitamin A has been shown to at least partially reverse impairments due to steroids or radiation [17, 18]. Growth factors may also play a role in improving healing, but these are based on animal studies [48–54].

Neurologic diseases do not impair wound healing, but they do predispose the elderly to the risk of developing wounds. Dementia leads to forgetfulness and risky behavior that may lead to injury. The person may forget to turn off stoves or fail to practice safe techniques for self-care. People with dementia have a more difficult time with cleanliness and maintaining a diet and thus may not clean wounds and tend to be more malnourished. Neuropathies have previously been mentioned as a risk for many types of wounds. Any loss of sensation clearly predisposes a person to pressure sores, since pain is the main warning sign of chronic pressure. Tremors may predispose the elderly to spills and an inability to quickly react to a dangerous situation. Incontinence may lead to maceration of the skin which in turn increases the risks for abrasions or tears with moving. Seizures are risky in people who cook or around hot items since during the seizure they will not react to an injury. People who seize while cooking or bathing frequently sustain very deep burns.

Pressure ulcers may develop at any age, but they are commonly manifested in the elderly as they develop reduced ability to move or after the development of neuropathy [55–61]. These wounds are found in around 10 % of inpatients. The pathophysiology is simple; any pressure on the skin and underlying tissues of greater than 30 mmHg that persists for a prolonged period of time can lead to enough ischemia to create a pressure ulcer. Normally, pressure produces pain which leads to a shift in the body to redistribute the pressure to another area. When we sleep we are constantly and subconsciously moving. Even intoxicated people will move to prevent these wounds. When people lose sensation, such as after paralysis, or when so ill that they are unable to move (such as in an intensive care unit), they are prone to pressure ulcers. Nurses play a major prevention role by rolling patients from side to side. Not uncommonly, however, pressure ulcers develop where bony prominences create pressure. The classic sites are in the presacral region and the occiput and on the heels. There are scoring systems that grade the severity of pressure ulcers that are useful for documentation. Pressure ulcers are staged as 1 when the skin is intact but just reddened for a prolonged period, 2 when the skin has been broken, 3 when the ulcer has become full thickness, and 4 when the wound tunnels into deeper tissues [61, 62]. The wound management becomes more difficult with increasing severity. The usefulness of this paradigm has been recently challenged [63]. It is unclear of the relevance of a stage 1 ulcer, and the pathophysiology varies between stage 2 and stage 3 or 4 ulcers. Stage 2 ulcers result from damage from the “outside in,” and higher staged ulcers are produced from the “inside out.” Irrespectively, the staging system is helpful for documentation and management strategies.

The factors that predispose the elderly to pressure ulcers include the loss of padding with aging, malnutrition, loss of sensation, thinner skin, and incontinence. People with more fat are slightly more protected. Like all wounds, prevention is essential with frequent shifting of the patient, frequent inspection, maintaining normal nutrition, preventing maceration, and getting people out of bed. One recommendation that may reduce presacral ulcers is to leave the head of the bed as flat as possible, but this recommendation is in conflict with recommendations to minimize ventilator-associated pneumonia (keeping the head of the bed at 30°) [64]. The use of special padding in hospital beds may also assist with the reduction of these ulcers [65]. The Braden Score is the most commonly used screening method to determine the risk for pressure ulcers [66]. The score is based on six parameters: sensory perception, moisture, activity, mobility, nutrition, and friction/shear. Pressure ulcers have become such an important issue that they have been declared a “never event” that requires documentation and monitoring in hospitals. The Centers for Medicare and Medicaid Services (CMS) has set up guidelines that result in fines of up to $10,000 per day if compliance is lacking. Once a pressure ulcer develops, it is very difficult to heal. Clearly, one must eliminate pressure from that area, but it is often difficult to prevent people from bearing weight on bony protuberances. Studies suggest that pressure sores may have improved healing with growth factors [67, 68]. Frequently, plastic surgeons will perform various myocutaneous flaps to try to cover these wounds, but once they develop, they have a high incidence of recurrence. If there is no closure after a prolonged period, then surgical closure is recommended.

These ulcers are the result of ischemia that results from vascular insufficiency [57, 58]. In fact, pure arterial insufficiency ulcers are rare, but usually tissue hypoxia contributes to the failure to heal in wounds caused by other etiologies. It is clear that hypoxia leads to impaired tissue repair. Since peripheral vascular disease is a major problem in the elderly (around 30 % of people over 75 years), it is important to remember that if a wound lacks a blood supply (or oxygen), then it will not heal. One of the major indicators for operating on peripheral vascular disease is for a “limb at risk” from failing to heal. The elderly should have a proper assessment of their pulses if they have a wound that does not heal. Other signs of peripheral vascular disease include loss of hair, shiny and dry skin, mummified or black toes, devitalized soft tissue with a moist or dry crust, thickened toenails, purple skin color with dependency, and cool skin. As a rough rule, if the region around the wound has a transcutaneous partial pressure of oxygen (PtcO₂) of less than 40 mmHg, it will have difficulty healing, and if the level drops below 20 mmHg, then healing will not occur. Revascularization will often remedy this problem. All lower extremity wounds must be evaluated for an adequate blood supply in order to treat them. Simple ankle/branchial indices are helpful, but the assistance of Doppler studies is also helpful. Once an arterial ulcer has formed, there are really only two options for treatment – revascularization or amputation. Vascular surgeons are experts in the evaluation and treatment of peripheral vascular disease and should be consulted as necessary. Prevention of arterial ulcers really involves all of the standard means of reducing atherosclerosis – cessation of smoking, reducing hyperlipidemia, exercise, and others. Unfortunately, once one leg requires revascularization of an ulcer, then there is a 20 % chance of the other leg developing an arterial insufficiency ulcer [69].

These wounds are not a sole problem of the elderly but are important to discuss in this chapter. Advanced venous disease, manifested by edema, pigment changes (lipodermatosclerosis), and ulceration, affects 2.5 million people per year in the United States and cost around 3 billion dollars in 1997 [59, 60, 70–73]. The predisposing problem for these ulcers is venous valvular insufficiency that usually results from deep venous thrombosis. The loss of valves leads to ambulatory venous hypertension that interferes with local blood flow to the distal lower extremities. The classic venous stasis ulcer occurs above the medial malleolus with a surrounding hyperpigmented region. As for all venous insufficiency, edema contributes to the problem. With a column of blood coursing from the heart to the feet, there is a large amount of venous pressure that tends to interfere with capillary blood flow. The resulting increase in hydrostatic pressure leads to increased capillary leak and more edema. Any edema creates a greater distance for nutrients to travel from the capillaries to the cells and an increased risk for local hypoxia. Local capillary leaks tend to deposit fibrin which may lead to further hypoxia and impaired nutrient delivery or may “trap” leukocytes leading to persistent inflammation. The actual mechanism of the creation of the wound is not clearly known. There are many theories that need to be proven or disproven [74].