Wound healing occurs over 4 phases: (1) hemostasis; (2) inflammation; (3) proliferation; (4) remodeling.
Macronutrients (proteins/amino acids, carbohydrates, and essential fatty acids) provide building blocks and energy for tissue growth, cell renewal, and repair after injury.
Micronutrients (vitamins and minerals) enhance cellular proliferation and maintenance.
Wound healing impediments include local and systemic factors.
The goal of wound care is to optimize the environment through removal of necrotic tissue, foreign debris, bacterial load, and limit the amount of dead space.
To obtain appropriate wound care and nutrition for optimal wound healing, it is important to understand the fundamentals of wound healing. Traditionally there are 4 phases (hemostasis, inflammation, proliferation, and remodeling) without distinct separation between the phases ( Fig. 1 ). The complex interaction and timing of wound healing are critical to understand so as to obtain the best outcome for injured patients. Through a variety of chemical mediators (ie, cytokines, chemokines, growth factors, and inhibitors), the transition from wounding to healing takes place ( Table 1 ).
|Cytokine||Cell of Origin||Function|
|EGF||Platelets, macrophages||Mitogenic for keratinocytes and fibroblasts, stimulates keratinocyte migration|
|FGF||Macrophages, mast cells, T lymphocytes, endothelial cells||Chemotactic and mitogenic for fibroblasts and keratinocytes, stimulates angiogenesis|
|IFNs ( α , β , and γ )||Lymphocytes, fibroblasts||Activate macrophages, inhibit fibroblast proliferation|
|ILs (1, 2, 6, and 8)||Macrophages, mast cells, keratinocytes, lymphocytes||IL-1: induces fever and adrenocorticotropic hormone release; enhances TNF- α and IFN- γ , activates granulocytes and endothelial cells; and stimulates hematopoiesis|
|IL-2: activates macrophages, T cells, natural killer cells, and lymphokine-activated killer cells; stimulates differentiation of activated B cells; stimulates proliferation of activated B and T cells; and induces fever|
|IL-6: induces fever and enhances release of acute-phase reactants by the liver|
|IL-8: enhances neutrophil adherence, chemotaxis, and granule release|
|KGF||Fibroblasts||Stimulates keratinocyte migration, differentiation, and proliferation|
|PDGF||Platelets, macrophages, endothelial cells||Cell chemotaxis, mitogenic for fibroblasts, stimulates angiogenesis, stimulates wound contraction|
|TGF- α||Macrophages, T lymphocytes, keratinocytes||Mitogenic for keratinocytes and fibroblasts, stimulates keratinocyte migration|
|TGF- β||Platelets, T lymphocytes, macrophages, endothelial cells, keratinocytes||Cell chemotaxis stimulates angiogenesis and fibroplasia|
|Thromboxane A2||Destroyed wound cells||Potent vasoconstrictor|
|TNF||Macrophages, mast cells, T lymphocytes||Activates macrophages, mitogenic for fibroblasts, stimulates angiogenesis|
Phases of wound healing
Following tissue injury, the healing process begins with hemostasis as the body’s mechanism to limit hemorrhage. Wounded cell membranes release vasoconstrictors, thromboxane A2 and prostaglandin 2α, promoting clot formation and hemostasis ( Fig. 2 ). As blood vessels constrict, circulating platelets become activated by the exposed collagen and release chemical mediators, promoting further platelet aggregation and activation. The exposed collagen also triggers the clotting cascade to form a fibrin matrix, which serves as the scaffold for the platelet plug and other invading cellular responders (ie, leukocytes, endothelial cells, fibroblasts). The platelet plug and adhesive proteins (fibronectin, vitronectin, and thrombospondin) form a provisional matrix, or fibrin clot. The provisional matrix is crucial for early hemostasis and prevents bleeding hours to days after injury.
Following initial hemostasis, the injured cell membranes release chemical mediators, leading to the inflammatory phase lasting for 4 to 6 days. The inflammatory mediators (ie, prostaglandins) create vasodilation of proximal vessels, allowing for increased cellular response. Cardinal signs of the inflammatory process include erythema, heat, edema, and pain, and should resolve 48 to 72 hours after the wound has occurred. Platelet-derived growth factor and transforming growth factor-β, released by the platelets, are chemotactic for circulating neutrophils (PMNs) and monocytes, triggering them to enter the wound. Interleukin-1, tumor necrosis factor-α, and platelet factor 4 are additional chemotactic signals for PMNs. The endothelial cells adjacent to the wound are activated and form a molecule adhesion with the PMNs. The margination of PMNs along the vessel wall leads to diapedesis, the process of moving through the vascular wall into the wound bed ( Fig. 3 ). PMNs clear the wounded site of bacterial and necrotic debris by releasing proteolytic enzymes. 48 to 96 hours, later circling monocytes are attracted and transformed into macrophages in the area. The macrophages release further cytokines and enzymes for wound healing. The cellular responders during the inflammatory phase promote early granulation tissue formation and tissue debridement, setting the stage for the proliferative phase.
The transition from the inflammatory phase to proliferation occurs on about day 4, and progresses through day 14 ( Fig. 4 ). Primary changes during the proliferation phase include epithelialization, angiogenesis, and granulation.
Epithelialization occurs either at an intact basement membrane or at the wound margin. It is stimulated by epidermal growth factor and transforming growth factor-α, products of activated platelets and macrophages. Fibroblasts synthesize and release keratinocyte growth factors and interleukin-6, which activate keratinocytes to migrate over the wound, creating an early barrier.
Angiogenesis, stimulated by tumor necrosis factor-α, is the formation of new capillaries within the wound bed. The new blood vessels promote blood flow to manage the increased metabolic activity within the wound. Local factors leading to the increase in angiogenesis include low oxygen tension, low pH, and high lactate levels. As a result of angiogenesis, there is increased oxygen availability and immune-mediated cell access to cellular debris and bacterial contaminants for clearance.
Granulation tissue is a dense network of newly formed capillaries and blood vessels, fibroblasts and macrophages, and randomly deposited collagen fibers. The granulation tissue forms as fibroblasts migrate into the wound site from surrounding areas, become activated, synthesize collagen, and proliferate ( Fig. 4 ). The capillaries carry nutrients and oxygen to support the elevated metabolic rate of cellular migration, division, and protein synthesis.
From about day 8 through about 1 year, the wound continues to transform and undergo maturation and remodeling ( Fig. 5 ). Collagen synthesis continues for 4 to 5 weeks following wound formation. Initial collagen is thin and oriented parallel to skin. Over time, the thin collagen is absorbed and thicker collagen is deposited along the skin tension lines, thereby increasing tensile strength. As the remodeling progresses, collagen synthesis and degradation occur to re-create the tissue before injury; however, wound strength never reaches 100%. In fact, at 1 week, 3 weeks, and 3 months (and beyond), wound strength reaches 3%, 30%, and 80% respectively.
The balance between collagen deposition and degradation leads to scar formation. A fine linear scar is the equal balance between the 2 mechanisms. If more collagen is deposited, a hypertrophic scar will form. Adversely, if degradation is greater, wound dehiscence may occur.
The process of wound healing is a complex interaction composed of hemostasis, inflammation, proliferation, and remodeling. Understanding the phases of wound healing will give the surgeon a better understanding of how to optimize the healing process through proper nutrition and wound care management.
The role of nutrition in wound healing
“You are what you eat” is a saying that we are all very familiar with. From time immemorial, healers have known the value of good nutrition and the role it has had in the well-being of their patients. Some 2300 years ago, Hippocrates warned of underestimating the vital role that nutrition played in health and human disease. The healing process results from a complex series of events that involves the immune system working with many other physiologic systems. Digestion, absorption, protein synthesis, caloric needs, protein degradation, and hormonal control are all parameters that play a role in enabling the body to heal itself. As practicing surgeons, we are fortunate that the vast majority of our patients are healthy and usually well-nourished and may be returned to a normal diet in a very short period of time. However, for those patient populations that may be at risk of malnutrition, such as the geriatric, diabetic, and those with impairments in nutrient bioavailability, the clinician must be ready to identify and treat these patients to ensure proper wound healing.
As with all new patients, a thorough history and a physical are conducted. These alone have been found to be 80% to 90% accurate in evaluating patient nutritional status. The addition of multiple or complex biochemical, immune, or anthropometric measurements does not increase greatly the accuracy of nutritional assessment. In fact, some studies indicate that anthropomorphic measurements, such as body mass index and weight loss, are less sensitive markers of malnutrition. Although low body mass index values and recent weight loss are associated with hypoalbuminemia, such measures can miss more than half of patients with protein deficiency. As such, anthropomorphic measures likely are insufficient for identifying patients who might benefit from a laboratory nutritional assessment. However, the clinician has at his or her disposal several nutrition screening tools that can be used rather easily. Validated nutrition screening tools include the Mini-Nutritional Assessment-Short Form (MNA-SF), the Malnutrition Universal Screening Tool (MUST), and the Malnutrition Screening Tool (MST). The MUST nutritional risk screen identifies adults who are underweight and at risk of malnutrition. It has been validated in acute care, long-term care, and in the community. The MST screening tool is valid and reliable for identifying nutrition problems in acute care and ambulatory care. The MNA-SF was revised to a 6-item screening tool and revalidated as a stand-alone screening tool. The tool has 3 cutoff points, allowing clinicians to quickly identify those who are malnourished. The maximum score is 14. Scores of 12 to 14 indicate well nourished, scores of 8 to 11 indicate nutrition risk, and scores of 0 to 7 indicate that the individual is malnourished. The MNA-SF has been validated to identify malnutrition in older adults, age 65 and older, residing in the community or institutional settings. It has an 80% sensitivity specificity and 97% positive predictive value, according to clinical studies.
Currently, there is no standard regimen for testing or monitoring nutritional deficiencies in wound patients. Some researchers suggest that systematic laboratory nutritional assessments and C-reactive protein levels may be appropriate. Moreover, there is a dearth of information for testing local wound nutritional deficiencies outside the research setting.
Protein and amino acids
Proteins provide the main building blocks for tissue growth, cell renewal, and repair after injury. They significantly affect multiple phases of wound healing (hemostasis, inflammation and granulation tissue formation, cell proliferation, tissue reorganization, and normalization) by their roles in RNA and DNA synthesis, collagen and elastic tissue formation, nutrition of the immune system, epidermal growth, and keratinization. With prolonged protein malnutrition, skin becomes thinner and wrinkled and immunity wanes. Diabetic patients with protein malnutrition are at higher risk for amputations.
Dietary proteins that provide all 9 of the essential amino acids are considered complete proteins. Food sources of complete protein include meat, poultry, fish, eggs, milk products, and soybeans. The body needs an adequate supply of essential amino acids, enough nitrogen and energy for the synthesis of the 11 other amino acids. Legumes, grains, and vegetables provide incomplete proteins.
Certain nonessential amino acids become conditionally essential during periods of trauma, such as thermal injury, sepsis, or pressure ulcers. 1-Arginine is 32% nitrogen and in some studies has been shown to increase concentrations of hydroxyproline, which is an indicator of collagen deposition and protein in the wound site. Glutamine has been shown to be used by inflammatory cells within the wound for proliferation and as a source of energy.
With regard to nutrition, the body’s main concern is for adequate energy provided from carbohydrate, protein, and fat. When the total amount of calories consumed is too low, protein from both the diet and the individual’s muscle stores will be used as an energy source, thus increasing the caloric requirements needed to promote anabolism and reverse catabolism.
Carbohydrates provide energy and prevent gluconeogenesis when the body is forced to convert protein stores for energy use. An inadequate supply of carbohydrates can lead to muscle wasting, loss of subcutaneous tissue, and poor wound healing. Grains, fruits, and vegetables with complex carbohydrates are the preferred sources.
Lipids and essential fatty acids
The most concentrated source of energy comes from fats and triglycerides, which provide energy for proliferation and are building blocks for epidermal and dermal tissues. They are important for cell membrane synthesis, epidermal phospholipids, inflammatory reactions, and intracellular matrix synthesis.
Water-soluble vitamins B and C are absorbed into the bloodstream and are excreted if blood concentrations are too high. Although foods do not deliver toxic doses of water-soluble vitamins, large amounts in supplements can reach toxic levels.
Vitamin B complex consists of 8 water-soluble vitamins found in meat, dairy, vegetables, fish, and cereals. Vitamin B complex helps to promote cell proliferation and maintain healthy skin and muscle tone, increase metabolic rate, and enhance immune and nervous system function. Deficiencies in vitamin B can impair wound healing and are associated with several disorders, many of which have skin manifestations. In particular, thiamine is associated with decreased wound healing and breaking strength.
Vitamin C enhances activation of leukocytes and macrophages in the wound bed and is essential for collagen synthesis. A deficiency of vitamin C prolongs the healing time and contributes to reduced resistance to infection. To date, there is no clinical evidence that wound healing is improved by providing mega-doses of vitamin C above the Dietary Reference Intake (DRI of 70–90 mg/d). Good sources of ascorbic acid are citrus fruits, strawberries, tomatoes, potatoes, broccoli, mangoes, and green peppers.
Fat-soluble vitamins A, D, E, and K dissolve in fat and are transported in the body attached to lipids. Unlike water-soluble vitamins, they are stored in the liver and fatty tissue until blood concentrations decline and the body retrieves them from storage.
Vitamin A is responsible for epithelium maintenance and it also stimulates cellular differentiation into fibroblasts and collagen formation. It has also been shown to reverse the anti-inflammatory effects of corticosteroids on wound healing. The administration of vitamin A, topically or systemically, also can correct the impaired wound healing of patients on long-term steroid therapy. This increase of the inflammatory response is thought to occur by an enhanced lysosomal membrane lability, increased macrophage influx and activation, and stimulation of collagen synthesis. These mechanisms still are not well understood, but it is clear vitamin A plays an important role in wound healing. Vitamin A deficiency, which is uncommon, may result in delayed wound healing and increased susceptibility to infection. Good sources of vitamin A are carrots, sweet potatoes, apricots, spinach, and broccoli.
Vitamin D, a fat-soluble vitamin, is involved in calcium uptake and metabolism by inhibiting secretion of calcitonin and parathyroid hormone. Vitamin D is readily obtained from sunlight, fatty fish, whole eggs, beef liver, mushrooms, and fortified foods. Deficiency in vitamin D leads to rickets in children and osteomalacia and osteoporosis in adults. The role of vitamin D in wound healing is unclear.
Vitamin E, another fat-soluble vitamin, serves as an antioxidant role interacting with selenium-dependent glutathione oxidase to inhibit degradation of cell membrane fatty acids. Low levels of vitamin E have been reported in chronic wound patients. In chronic wounds, free radical formation is enhanced because of the inflammatory cascade caused by ischemia, necrotic tissue, and microbial flora. Vitamin E is found in asparagus, avocados, eggs, nuts, and spinach. Supplementation remains controversial. Some reports indicate that vitamin E may impair collagen synthesis and wound healing in animals, whereas other investigators report enhanced healing in irradiated rat skin and patients with post-thrombotic leg ulcers.
Vitamin K, also a fat-soluble vitamin, is present in leafy green vegetables, parsley, kiwi, meat, eggs, and dairy. Vitamin K is needed for posttranslational modification of certain proteins that are mainly required for coagulation and bone metabolism. Deficiency can result in hemorrhage, impaired wound repair, and infection.
Iron is important in hemoglobin formation and oxygen transport, uptake, and metabolism of free radicals, and hydroxylation of collagen precursors. Iron deficiency interferes with healing through tissue hypoxia and decreased bactericidal ability by leukocytes.
Zinc is a cofactor for at least 70 major enzyme systems important in wound healing, including DNA and RNA polymerases, proteases, and carbonic anhydrase. It also liberates vitamin A from storage in the liver and assists in immune function. Many studies have reported significantly lower zinc levels in chronic wound patients compared with presumably healthy controls. Because zinc deficiency impairs wound healing, zinc repletion may increase healing rates; however, there is no strong clinical evidence that oral zinc sulfate aids healing of arterial and venous ulcers. Topical zinc acts as a mild antiseptic and anti-inflammatory agent in wound care, whereas one study demonstrated that 1% zinc oxide cream increased mitosis and reepithelialization rates.
Water is critical for optimal healing. Hydration promotes cell proliferation and migration along chemotactic gradients created by metal ions, cytokines, and growth factors. Dehydration leads to epidermal hardening and dermal necrosis that delays wound healing and adds to patient discomfort.
The wound-healing phase is extremely energy demanding. There is a strong increase in cell proliferation, protein synthesis, and enzyme activity during the healing process that requires energy and building substrates. Normally, these substrates are released from body energy stores and protein reserves; however, undernourished subjects need increased food intake or supplements with high energy and protein density. In addition, basic macronutrients, such as protein or amino acids, carbohydrate, fat and electrolytes, and micronutrients are necessary.
The daily energy requirement of a healthy person is 30 to 35 kcal/kg of body weight, depending on physical activity. In diseases, such as the usual multiple morbidities of a geriatric patient with coexisting wounds, energy intake should be increased to 35 to 40 kcal/kg per day. And although there are studies that support the use of specialized nutritional support in postoperative and wounded patients, this evidence has not been borne out by clinical investigation. Also, the risk complications and increased cost of these specialized nutritional support elements need to be considered as well. Indeed, nutrition and nutritional supplementation in wound care is not yet standard of care and remains controversial.
Preoperative nutritional support is generally recommended for patients with moderate (10%–20% weight loss; serum albumin <3.2 g/dL to >2.5 g/dL) to severe malnutrition (>20% weight loss; serum albumin <2.5 g/dL) and who can tolerate waiting at least 7 days for an elective operation. If intestinal function is maintained in a patient, enteral nutritional support is generally preferred, as it is associated with the maintenance of gut mucosal barrier function, the decreased activation of gut-associated lymphoid tissue, and lower costs of administration than parenteral nutrition. Total parenteral nutrition is reserved for patients with ineffective gastrointestinal function, not compromised oral function.
Serum protein markers are the best way to assess the adequacy of nutritional supplementation, as conventional methods, such as daily weight, may not be accurate in critically ill patients. Although albumin is commonly used as a preoperative marker of nutrition, its half-life of 18 to 21 days precludes its use as an effective daily indicator of improvements in nutritional status. Prealbumin (half-life 3–5 days) and transferrin (half-life 7–10 days) should be monitored weekly in patients receiving enteral or parenteral nutritional support.
In general, it is important to counsel undernourished patients about ways to improve their diets. Providing nutritional supplements in addition to regular food intake seems a logical means of replenishing nutrients and supplying extra nutrients for increased tissue resistance and wound repair.
Nutrition and its role in wound healing has been the subject of intense study and experimentation. New research is pointing to exciting nutritional interventions that will advance not only our understanding, but more importantly, better outcomes for our patients. Without a doubt, poor nutrition leads to poor outcomes, whereas the reverse has a positive effect on wound healing. The clinician must recognize those patients who have poor nutrition or are at risk and address the patient’s needs accordingly to ensure successful wound healing and avoid wound failure.