Abstract
The first part of this review focused on the essential biological features of human skin, their origins and cellular relationships as a basis for understanding nutritional requirements in health and disease (see Vol 13(19;Tissue Viabil Suppl): S22-S28). The second part will discuss the importance of a good, well-balanced diet sufficient in proteins (amino acids), fats, carbohydrates, vitamins and minerals in the management of skin wounds. Evidence is drawn from clinical trials, case studies of patients with known genetic deficiencies affecting dietary metabolism and metabolic studies. Experimental studies in laboratory animals have provided limited information on the role of nutrient deficiencies in wound repair. There is still an urgent need for prospective controlled studies on the importance of key nutrients at principle phases in the wound- healing cascade and how uptake and metabolism is regulated by growth factors, cytokines and hormones.
Key words: Skin and skin disorders * Nutrition and diet * Wounds * Genetic disorders
Current focus on wound-bed preparation in the management of chronic wounds focuses upon re-establishing the ‘balance of growth factors, cytokines, proteases and their natural inhibitors as found in acute wounds’ (Schultz et al, 2003). At the meeting of the European Tissue Repair Society and Wound Healing Society in 2002, the expert working group summarized the clinical components of wound- bed preparation and the cellular environment at each stage. Although the authors of the report recognized the importance of water/ moisture balance, changing pH and oxygen tension in wound care, they failed to appreciate the importance of correct nutrient balance in the wound as an essential feature of the wound environment (Schultz et al, 2003). Earlier experimental evidence demonstrated that as wounds heal (acute wounds at least), requirements for different nutrients change to reflect the needs of building materials for enzymes and structural syntheses (Lansdown et al, 1999).
Table 1 lists the main nutrients currently known to fulfil roles as structural components, enzyme co-factors or physiological mediators in skin repair and regeneration.The evidence is drawn from epidemiological studies in populations with traditional dietary habits, case studies with patients with known genetic disorders of nutrient uptake, reports of nutrient deprivation and experimental studies. Although experimental animals do have greatly differing dietary needs from humans, they have proved useful in demonstrating how certain toxic factors in the diet can block the uptake and availability of key minerals, vitamins or amino acids, thereby impairing wound repair or leading to reduced tensile strength in re- epithelialized tissues.
Table 1. Essential nutrients for a healthy skin and repair following injury
Other metals like lead, aluminium, mercury and cadmium may be identified in the skin of some people through environmental or topical exposure (Lansdown, 1995, 2000). These have no nutritional role and occur in the tissues as contaminants. Nickel and chromium are regarded as trace metals in human nutrition but their precise role in metabolic processes is not -well defined (Lansdown, 1995). Chromium may have a multifactorial role but available evidence suggests that it interacts with insulin in glucose metabolism. The role of nickel in metabolic processes is also poorly understood, but it is implicated in cell-membrane function, regulation of prolactic release, blood flow and nucleic acid metabolism. Both metals fulfil the criteria that they are essential in some way (albeit at exceedingly low concentrations) for a fundamental physiological process in the human body.
As part of its protective role, the skin serves to eliminate toxic substances and excess quantities of essential trace minerals through the hair of sweat (i.e. iron, zinc, sodium). Silver may be deposited in the skin following ingestion of silver nitrate or colloidal silver as an oral mouthwash or to treat gastrointestinal infections (Tomi et al, 2004;Van Hasselt et al, 2004). Resulting skin discolorations (argyria) are cosmetically undesirable, but the silver sulphide deposits are of no nutritional role and are nontoxic (Lansdown and Williams, 2004). Some silver absorbed from sustained silver-release wound dressings may interact with trace metals like zinc, copper and calcium. This may advance reepithelialization (Lansdown et al, 1997).
Essential nutrients for skin wound repair
Proteins and amino acids
Proteins and amino acids constitute the largest portion of the human diet and form the main building blocks for tissue growth, cell renewal and repair systems following injury (Munro, 1974). In a tissue like the skin, with its high metabolic rate, regular replacement of cells and functional requirements as a protective shield, deficiencies in proteins and specific amino acids like cysteine, proline, etc. will adversely influence homeostasis and healing in wounds, leading to thin, fragile skin with reduced tensile strength. Nitrogen balance is a critical feature of wound repair, and protein synthesis must increase at wound sites during the repair process if normal healing is to occur (Levenson and Demetriou, 1992). An imbalance or deficiency in certain amino acids has singular effects on protein synthesis and healing, as it does on growth (Levenson and Demetriou, 1992).
Discussion of the needs for proteins and specific amino acids in isolation is difficult in view of the intricate relationships that exist with other nutrients. Protein uptake, metabolism and usage is dependent on the availability of vitamins and trace metals as co- factors in metabolizing enzymes (e.g. copper in lysyl oxidase, zinc in metalloproteinases, etc).
In well-nourished patients, the skin requires adequate amounts of protein and amino acids for:
* Ribonucleic acid (RNA) and deoxyribose nucleic acid (DNA) synthesis
* Collagen and elastic tissue formation
* Nutrition of the immune system
* Epidermal growth and keratinization.
Kwashiorkor (protein-calorie malnutrition common in Third-World countries) is one of the most prevalent causes of protein-energy malnutrition in impoverished societies (Miller, 1989). It is more widely linked to deficiencies in trace metals, vitamins and essential amino acids (Prasad and Oberleas, 1976). Erythema, cracking and scaling, discoloration, inflammation, susceptibility to damage and impaired wound repair reported in cases of kwashiorkor are part of a more general reduction in body health. Although ethically undesirable these days, kwashiorkor-like symptoms have been produced experimentally in young baboons fed protein-energy deficient diets (Coward and Whitehead, 1972). These animals exhibited sparse hair, oedema and flaky paint-like skin lesions resembling those seen in severely malnourished children in Uganda. Marasmus is a similar wasting condition related to protein malnutrition and skin ulceration and hyperkeratinization (scaling) are reported (Miller, 1989).
In patients subject to prolonged protein malnutrition, the skin becomes thinner and wrinkled as epidermal and dermal cell renewal systems decline, and immune resistance to bacterial infection is reduced. Protein-energy malnutrition in diabetic patients is an added risk for limb or digit amputations (Kay et al, 1987; Eiieroth et al, 2004). Numerous experimental studies with generalized protein deficiencies, reduction in specific amino acids, and known amino- acid antagonists have shown impaired angiogenesis, decreased rates of wound contraction, impaired re-epithelialization and low tensile strength (Alvarez et al, 1982; Levenson and Demetriou, 1992).
In wound repair, protein and amino-acid deficiencies are manifest in events in all of the four principle phases in healing (haemostasis, inflammation/granulation tissue formation, cell proliferation, tissue reorganization and ‘normalization’). Collagen synthesis is particularly sensitive to proline deficiency (Bailey, 1978), but insufficiencies in cysteine, cystine, methionine, argentine, tyrosine, histidine and glycine are additional causes of delayed wound healing. Fortification of diets with amino acids can be a means of solving some nutritional problems associated with wound healing (Altschul, 1974). This area is in urgent need of clinical research.
Carbohydrates
Carbohydrates are the principle source of energy for the human body with the high energy releasing pentose-phosphate shunt mechanism being vital in sustaining the high metabolic activity needed in proliferating epidermal cells, especially during re- epithelialization and regeneration (Coulton, 1977). Fibroblasts also seem to be sensitive to glucose deficiencies; concentrations of at least 1.8mM/l were shown to be necessary for stimulating growth and proliferation in culture media (Han et al, 2004). Glucose concentrations in normal human sera vary greatly but available figures suggest that the normal range is 3.9-6.7 mM/1 rising to 4.4- 8.3 mM/1 for people over 70 years of age. Appreciably lower levels of 0.6-5.9 mM/1 or even 0.3-1.2 mM/1 have been recorded in chronic wound patients (Trengrove et al, 1996; James, personal communication, cited by Han et al, 2004). This suggests that the glucose enhancement may be clinically attractive in the treatment of non-healing wounds. Personal observations h\ave shown that epidermal cells in the hyperplastic epidermis following reepithelialization are frequently rich in glycogen granules.
Diabetes has special significance in human skin -wounds. Foot and leg ulcers in diabetic patients show a high incidence of nonhealing and susceptibility to infection, peripheral neuropathy and necrosis leading to possible amputation (Edrnonds and Foster, 2000). Infections with Staphylococcus aureus and Candida albicans are more common in diabetic patients and may in part contribute to the wound indolence (Eneroth et al, 2004). Otherwise, the mechanisms underlying impairment in wound healing in diabetic patients are complex, probably involving circulatory problems, hyperglycaema and osmotic changes, disturbances in vitamin A and zinc metabolism, growth factor imbalances, acidosis and inflammatory changes.
The complexities in diabetic wound healing have been revealed through a large number of experimental studies using streptozotocin- induced diabetes in the rat (Goodson and Hunt, 1977; Barr and Joyce, 1989). In human diabetes, particular attention is given to the vascular pathology involving the proliferation of endothelial cells and obstruction of arterioles, venules and capillaries (Huntley, 1982; Sibbald and Schachter, 1984). Eneroth et al (2004) examined the possibility of using nutritional supplementation to improve the healing patterns in diabetic wounds in a blind clinical trial. Patients with diabetes mellitus and foot ulcers of at least 4-weeks dviration were given oral dietary supplementation with Fortimel (Nutrica AB) daily for 6 months. Although the authors experienced some practical difficulties in this approach and made some interesting observations, they were not able to demonstrate that the dietary intervention significantly improved wound repair.
Fats
Fats and fatty acids provide additional sources of energy in the human. Fats provide building blocks for many components of epidermal and dermal tissues, as well as sources of energy in cell proliferation, maturation and homeostasis (Skog and Jgerstad, 1998). Clinical reports on the influence of fatty-acid deficiency in wound repair are not numerous, but experimental evidence in rats suggests that it can impair wound healing (Hulsey et al, 1980). Certain unsaturated fatty acids like linoleic acid and arachidonic acid which are necessary in inflammatory reactions and prostaglandin synthesis, are not synthesized naturally in the human body and are derived from the diet. Evening primrose oil is a well known source of gamma-linoleic acid.
Fats and fatty acids contribute to wound healing in the following ways:
* Cell membrane synthesis
* Phospholipids in the epidermal barrier layer
* Inflammatory reactions
* Synthesis of intercellular matrix.
Vitamins
Metabolic research has shown that the human body relies on at least 20 vitamins or vitamin-like substances for normal health and physiological functions (Widdowson and Mathers, 1992). Many are low molecular weight substances required by tissues at low concentrations. Excess concentrations of some, like vitamin A, are toxic and can have detrimental effects on the skin and its appendages.
Vitamin A: this is a fat-soluble substance derived from carotene in green vegetables which shows a predilection for epithelial tissues. In its active form – retinol, it plays a central role in epidermal cell proliferation and maturation through binding to cell surface receptors. It enters into a complex sequence of events in normal skin, involving intercellular adhesion, communication and transcription of messenger-RNA (Chytil, 1984). Additionally, vitamin A may interact in the regulation of numerous enzyme systems involved in glycoprotein and glycolipid synthesis, prostaglandins production and cell membrane metabolism (Matter et al, 1980).
Excess vitamin A is harmful and can be a cause of irritation with scaling and roughness of the skin, dry fragile hair and a variety of metabolic changes, some of which are relevant in treating damaged skin (Cunliffe and Miller, 1984). Although vitamin A analogues have been widely researched as possible therapies for a range of skin ailments ranging from idiopathic hyperplasia, acne, photo-damaged tissue, and skin cancers in recent years, none seem to have been clinically suitable or sufficiently safe for patients (Moy et al, 1985; Kotrajaras and Kligman, 1993).
Vitamin A is required for wound healing, possibly in promoting the early inflammatory response and infiltration of macrophages, monocytes and fibroblasts leading to angiogenesis and collagen formation. As expected, vitamin A at appropriate concentrations is essential for epidermal cell growth and re-epithelialization, even though its regulation is unclear. Experimental evidence indicates that a derivative of vitamin A (trans-retinoic acid) can enhance the epidermal growth response through epidermal growth factors (EGF) and transforming growth factor-beta (TGF-β) (Tong et al, 1990), but much research is urgently needed in this area (Saurat, 1988). A detailed review on the pharmacology, clinical and laboratory work on vitamin A and its analogues is provided by Cunliffe and Miller (1984).
Vitamin A can influence dermal growth and excess retinoate inhibits the production of collagen and fibroblasts in culture (Bailley etal, 1990).
Vitamin B complex: the vitamins of the vitamin B complex are variously implicated in the metabolism of all major food requirements in the human patient. Normal body requirements are provided by a diet replete in dairy produce, vegetables, fish and cereals (Lansdown, 2003-2004). Deficiencies are likely to be manifest more through a general reduction in body health and this will reflect on the outward condition of the skin and its responses to normal wear-andtear and injury.
Vitamin C: (ascorbic acid) deficiency is probably best known as a cause of scurvy. The biochemistry of vitamin C in the human body is complex, but in the skin at least, its role in metabolism of trace metals (calcium, magnesium, iron) is relevant. Vitamin C serves several essential roles in wound healing in the skin (Ringsdorf and Cheraskin, 1982; Lansdown, 200Ib, 2002b) (Table 2).
Table 2. The role of vitamin C in wound healing in the skin
The first report showing that hypovitaminosis C was a cause of impaired wound repair was that of Lanman and Ingalls in 1937, but competent and clinically relevant studies did not appear until several years later when hypovitaminosis became linked to defects in the uptake and metabolism of essential amino acids (phenylalanine, tyrosine and praline) required in collagen production, metal ion metabolism, and enzyme activation (Levine, 1986). Current views are that hypovitaminosis manifests by inflammation of hair follicles, coiled hairs on the arms and back, possible bleeding, swollen gums and low serum concentrations (normal range 17-94 mM/1), should be indicative of dietary supplementation. This should be 300-1000 mg/ day given orally in addition to protein-rich food (Levine, 1986).
The role of hypovitaminosis C on wound healing has been extensively researched experimentally in the guinea pig which is naturally scorbutic (unable to synthesize ascorbic acid). Defective fibroblast responses, collagen defects and abnormal scar tissue formation have been reported (Wolbach and Howe, 1926; Bourne, 1944;Abercrombie et al, 1956).Vitamin C plays a major role in the natural defences of the body against infectious agents. Low resistance in patients low on vitamin C has been attributed to the factors listed in Table 3.
Proline and hydroxyproline metabolism were affected through dysfunction of iron-dependent enzyme systems (Lansdown, 200Ib). Clearly, vitamin C is an important aspect of nutrition in wound management particularly when local concentrations quickly become depleted in skin injuries including burn wounds.
Vitamin D: closely associated with the uptake and metabolism of calcium in the body and the action of dietary phosphate, calcitonin and parathyroid hormone (Lansdown, 2002b).The skin is of unique importance in human physiology as it is a principle site for synthesis and storage of vitamin D and its release into the circulation. Vitamin D is synthesized in the presence of sunlight with UV-radiation (wavelength 290-320 nm). The daily need for vitamin D in an adult person is estimated to be 400 iu (Matsuoka et al, 1988). Long-term irradiation might be expected to lead to excessive levels of vitamin and toxic complications associated with high calcium (headaches, anorexia and diarrhoea).
Vitamin E: interacts metabolically with selenium in controlling the metabolism of unsaturated fatty acids required for energy production in the human body (Green and Bunyan, 1969; Putnam and Comben, 1987). As such, it is presumed to fulfil the following main functions:
* An anti-oxidant protecting unsaturated fats from degradation
* Unspecified functions in general metabolism other than as
an anti-oxident (Green and Bunyan, 1969).
The selenium-dependent enzyme glutathione oxidase interacts with vitamin E in inhibiting the breakdown of fattyacid components of cell membranes and ensures stability in tissues (Putnam and Comben, 1987).
While the exact role of vitamin E or its analogues in the skin is ill defined in human wounds, inhibition in the peroxidation of fatty acids has been shown experimentally to promote the expression of a vascular endothelial growth factor and to advance repair in diabetic wounds (Altavilla et al, 2001). Other evidence has been seen to show that vitamin E interacts with other growth factors involved in collagenesis, immune responsiveness and graft rejection. Ehrlich et al (1972) actually claim that vitamin E can inhibit collagen formation and wound repair, but it is unclear at the moment how much vitamin is required for normal growth and repair and what levels in the human body are detrimental. Prospective assessments on theimportance of fruit and vegetable consumption on the health and vitality of a study of 271 adults have substantiated the view that increases in vitamins C and E through beneficial diets may stimulate the physical health status of socioeconomically deprived adults (Steptoe et al, 2004), and by inference will improve responses to injury.
Table 3. Factors attributed to low resistance in patients low in vitamin C
Vitamin K: a fat-soluble substance derived from vegetable foods, and may be synthesized by bacteria in the intestine. In human nutrition, vitamin K has a special importance in haemostasis with vitamin-deficient patients becoming susceptible to haemorrhages, impaired wound repair, and infection (Goskowicz and Eichenfield, 1993; Jenkins et al, 1998; Oehme and Rumbeiha, 1999). Although the importance of vitamin K is not well documented in the dermatological literature, biochemical studies have demonstrated its critical role in activating key proteins in the haemostatic phase, particularly those involved in the production of prothrombin and the clotting factors VII, IX and X. Thus, circulating levels of vitamin K will be significant in the haemostatic phase of wound healing and probably the release of growth factors. Patients with burn injuries exhibit multiple risk factors for development of vitamin K deficiency, including malabsorption, limited enterai uptake, antibiotic therapy and surgical procedures Qenkins et al, 1998). These authors demonstrated a direct relationship between the serum vitamin K level and prothrombin time (vitamin K dependent clotting factors) in 48 burned children. Patients with malabsorption syndromes or dietary vitamin K deficiency may be treated with oral doses of about 10mg/ day of the water-soluble analogue – menadiol sodium phosphate (British Medical Association and Royal Pharmaceutical Society of Great Britain, 2004). Phytomenadione is given to neonatal cases of hypovitaminosis (British Medical Association and Royal Pharmaceutical Society of Great Britain, 2004).
Table 4. Minerais in the nutrition and physiology of the human skin
Anticoagulants used as quick-acting rodenticides (for use in pest control) impair the availability of vitamin K in the body and its ability to stem bleeding.They inhibit the formation of essential clotting factors and damage blood capillaries (Oehme and Rumbeiha, 1999). Oral vitamin Kl (phytomenadione) can be used as an antidote, or in severe cases, patients may require blood transfusion (Jenkins et al, 1998; British Medical Association and Royal Pharmaceutical Society of Great Britain, 2004).
Minerals
At least 16 minerals and trace elements are now known to be important for the health of the human body (Underwood, 1971). Table 4 shows the principle minerals necessary for maintenance of characteristic skin appearance and its functional roles of protection, thermoregulation, homeostasis and excretion, as well as tissue repair following injury (Lansdown, 1995). A detailed analysis by Lansdown and Sampson (1997) of the actions and interactions of metal ions of nutrient status shows their importance to be:
* As structural components of cells or intracellular fluids
* Components or co-factors of key metalloenzyme systems
* Electrolytes and physiological components in the function of epidermal cells, skin glands and cell membrane exchange.
The importance of metals in biological systems in humans, experimental animals and cells in defined media has attracted considerable attention over many years, and the scientific literature on the subject is enormous. In the present review, the nutrient roles of key metals will be reviewed with special reference to their function in skin injury, outward signs and manifestations of deficiency, and possible therapeutic means of treatment.
Calcium
Calcium is the most intriguing metal in the human body and possibly the most difficult to analyse. Not only is calcium the most abundant mineral nutrient with at least 99% of the total body content residing in the skeleton and muscle mass (Lansdown, 2002b), but also it is present as a structural component, enzyme co-factor and growth factor/regulator in many soft tissues, including the skin. Although its central role in the growth and function of normal skin is well documented, its importance in wound healing is frequently overlooked as a feature of management (Lansdown, 2002b).
Calcium gradients are best illustrated with reference to the epidermis, where an exceedingly low calcium concentration in cells of the basal layer is held to promote proliferation. Although the inherent mechanism is not fully understood, there is a progressive increase in calcium concentrations in the post-mitotic maturing cells of the stratum spinosum up to and including the granular layer which is rich in keratohyalin granules and represents the terminal phase in keratinocyte maturation. In normal skin, this is a ‘cut off point for calcium; no calcium can be demonstrated in the stratum corneum under normal circumstances. Most of the early studies were conducted in murine (pertaining to rodents) skin aided by sophisticated techniques in histochemistry and molecular biology, but the observations are entirely relevant to human skin (Lansdown, 2002b).
All living cells in the skin are sensitive to environmental calcium concentrations with keratinocytes being at least 100 times more sensitive than fibroblasts in cell culture (Menon and Elias, 1991). In each case, local calcium concentrations serve to up- regulate calcium-binding proteins on cell membranes and activate intercellular calcium metabolism. At least 50 calciumbinding proteins involved in this process have been identified on cell membranes (e.g. cadherin), intercellular fluids and matrices (e.g. calbindin, calmodulin) and subcellular constituents. At the moment, little is known concerning the regulation of calcium metabolism in normal skin physiology and little appears in the literature concerning the distribution of the calcium-binding proteins in wounded tissue. However, a sharp rise in calcium follows wounding and this persists throughout the healing period and into the normalization phase (Lansdown et al, 1999). Further studies are necessary to determine the mechanism promoting this rise in calcium and the possible involvement of parathyroid hormone, calcitonin and phosphate levels.
If calcium is so important in normal skin physiology and the mere act of wounding is sufficient to disturb local concentrations and gradients, should a nurse consider calcium management in skin care? Calcium is not well absorbed through the skin except in the case of injury and to the authors knowledge the only wound care preparation currently available releasing calcium ion into the wound bed is calcium-sodium alginate and related products (e.g. Kaltostat, ConvaTec). Calcium ions released through ion exchange with sodium in wound exudates contribute in haemostatsis as factor IY The alginate fibres hydrate and are eventually absorbed into the tissue with minimal local reaction as they are ’tissue friendly’ (Lansdown and Payne, 1994). Nothing is presently published to show whether, or to what extent, this free calcium ion is absorbed into wounded tissue and contributes to re-establishment of calcium gradients or other cellular modulators. A lot has yet to be explained regarding the role of calcium in wound repair and how it might be controlled in wound management.
Zinc
Zinc is an essential trace element in all living cells in animal and plant systems (Kaulin, 1869). In human cells, it is a component of at least 70 major enzyme systems, notably those involved in nucleic-acid synthesis, collagenesis, inflammatory reactions, immune responses, and in the metalloproteinases prevalent in early wounds (Lansdown, 1996). Zinc concentrations are naturally highest in tissues undergoing active proliferation including the skin, intestinal mucosa and testis, and functional development of these organs is a good indication of sufficiency in zinc (Prasad and Oberleas, 1976; Lindemann and Mills, 1980; Strain et al, 1996).
Many different views have been expressed on the roles of zinc in human skin physiology including its role in the stabilization of cell membranes, maturation and growth, mobilization of vitamins (especially A and C) and carbohydrate metabolism. Zinc concentrations in the skin tend to be proportional to levels of mitotic activity, thus at least six times more zinc is seen in the epidermis than dermis in normal skin (Henzel et al, 1970). Following acute injury, local zinc concentrations rise by at least 15% and stay high through inflammation and proliferation and into the normalization phase (Lansdown et al, 1999).
The inherent regulatory mechanisms for tissue zinc concentration are not known but are likely to involve the cystine-rich protein – metallothionein (Lansdown, 2002a). This binds zinc, copper, selenium and a variety of non-nutrient metals like gold, silver, cadmium and mercury. By implication, excess levels of these non-trace metals in the circulation or in the wound environment can interfere with the metabolism of essential trace metals and their role in wound repair (Lansdown and Sampson, 1996; Lansdown et al, 1997, 2001). Zinc is applied topically as a mild antiseptic and anti-inflammatory agent in wound therapy; it induces the formation of metallothionein and binds to it. Histochemical demonstration of metallothionein provides a good marker for zinc activity in a tissue (Lansdown et al, 1997; Lansdown, 2002a).
Clinical evidence for the value of zinc in wound management is provided by the rare lethal mutation – acrodermatitis enteropathica (Moynahan, 1974).The condition manifests early in life and affected children exhibit characteristic symptoms of erythema, dermatitis, alopecia, hypogonadism, exceptionally thin skin, failure to thrive and impaired wound repair (Moynahan, 1974). The causation of this hypozincaemia is no\t fully understood. Originally, it was attributed to an inherent defect or toxic material (oligopeptide) in the gut affecting zinc absorption; zinc ion was irreversibly bound or ‘chelated’ by this material and not available for uptake. An alternative and more plausible explanation is that of an inherent defect in the absorptive apparatus in the mucosal cell. Early clinical treatments for acrodermatitis-like symptoms included injection of the drug diodoquin. Although diodoquin was effective in increasing blood zinc, its toxic action on the retinal epithelium of the eye (also seen with related drugs like chloroquin) precluded its therapeutic acceptability. Oral zinc sulphate tablets proved to be a safer and satisfactory alternative.
Further illustrations of zinc deficiency are highlighted in the classical studies of Prasad in Egypt and the Middle East (Prasad, 1978). These workers documented evidence of severe hypozincaemia in populations feeding high-fibre diets rich in histidine, phytate and proteins that bind zinc (Prasad, 1966; Pories et al, 1967; Prasad and Oberleas, 1976). Oral zinc sulphate was used successfully in treatment of these and other cases of dermatitis linked to dietary zinc malabsorption, which can arise not only through substances present in the diet, but also through drugs (e.g. penicillamine), toxic metals (cadmium, mercury, etc.), and gastrointestinal infections (Shakespeare, 1982; Lansdown and Sampson, 1996; Lansdown et al, 2001). In the chronic wound situation, it is not known to what extent defects in the metabolism of zinc underlie non-healing syndromes, or indeed whether oral or topical administration of zinc is beneficial.
Hair and serum analyses can give a good idea of the zinc status in the body, where up to 20% is located in the skin and its appendages (20-678 g/g dry weight) (Molokhia and Portnoy, 1969). Estimates of serum or tissue zinc vary greatly according to the date of the work and the accuracy of the analytical method used, but Halstead et al (1974) analysed 26 reports and concluded that normozincaemia was in the range 70-130 g/100 ml and that this decreases with advancing age. Oral zinc therapy has been used to treat cases of hypozincaemia but topical zinc oxide creams would seem to be a suitable and safe alternative for topical wound therapy. Pories et al (1967) recorded that 150mg oral zinc sulphate reduced the healing time of pilonidal cysts by up to 60%. Zinc absorption from medicated bandages has been shown to be 5 g/cm^sup 2^ per hour over 48 hours. Numerous zinc preparations are available for topical use including water-based pastes, creams and emollients in amphiphilic vehicles, to improve local zinc concentrations, but care has to be taken in the amount applied. Excessive amounts of zinc may impair calcium-related events, possibly leading to retarded healing (Heng et al, 1993). This has to be demonstrated clinically.
In experimental studies, a 1% zinc oxide cream was shown to advance the healing of open skin wounds without complication (Lansdown, 1993). Zinc was absorbed percutaneously (it is better from lipid solvents than aqueous solvents) and penetrates epidermal cells leading to increased mitosis and more rapid reepithelialization. Wounds remained free of infections through the mild antiseptic properties of zinc ion.
Copper
Copper was recognized as an essential trace element in all living cells as long ago as 1816 (Bucholz, 1816) but is now known to be a co-factor for many key enzyme systems. Copper has many similarities to zinc in human nutrition and physiology and like zinc it induces and binds metallothionein. Characteristic features of copper deficiency include hair and nail defects, reduced skin thickness through impaired collagen and elastic tissue synthesis, reduced immunological reactivity, and lowered resistance to infection.
Biochemical studies indicate that copper metabolism is intimately linked to that of iron, such that anaemia is a frequent manifestation of deficiency (hypocuprinaemia) (Hart et al, 1928). In skin physiology, lysyl oxidase necessary in the ‘cross-linking’ of collagen and elastic tissue fibres, is probably the best known of the cuproenzymes (Kagen and Li, 2003). Local copper concentration increases in wound sites, commensurate with the demand for the metal in systems like lysyl oxidase, prolyl oxidase, etc. involved in collagen formation in scar tissue. The inherent regulation of copper absorption, involvement in the carrier-protein caeruloplasmin, and serum concentration is not known but conceivably, cytokines, growth factors and other modulators in the wound bed are implicated.
Copper deficiencies in humans and other species are rare but manifest in terms of dietary deficiencies or inherited defects in intestinal absorption. Illustrations include ataxia and swayback in farm animals, Wilson’s disease, and Menke’s ‘kinky hair’ syndrome (Goodman et al, 2004). In Menke’s disease, the X-linked inherited copper deficiency syndrome is a cause of impaired keratin formation in hair papillae. Affected infants exhibit retarded growth and show clinical symptoms of cytochrome oxidase, lysyl oxidase, tyrosinasae and other cuproenzyme deficiencies. Blood vessel formation is reduced.
Intestinal absorption of copper is influenced by other trace elements including zinc, molybdenum, iron, manganese, cobalt and nickel, and may be inhibited by penicillamine and drugs and food additives that bind the free ion. Excess copper is voided in hair, nails and aged keratinocyte sloughed from the skin surface; ‘green hair’ is a sign of excessive copper in the diet and the hair as a route of detoxification (Verbov, 1990; Tosti et al, 1991; Turnlund et al, 2004). Penicillamine is a powerful chelator of trace metal ions and should be avoided in patients with skin wounds (Shewmake et al, 1988; Gosling et al, 1995). Any rapid depletion of essential trace metals is predictably a cause of chronicity and patient discomfort. In the case of copper, low circulating levels are known causes of impaired skin woundhealing with reduced tensile strength in re-epithelialized tissue attributable to defective collagen and elastic tissue formation (Shewmake et al, 1988; Gosling et al, 1995).
Iron
Iron is characteristically linked to the formation of haemoglobin and in the uptake and metabolism of oxygen radicals.The outward appearance of the skin and its appendages provide a useful guide to the iron status of the body. Although less well documented in the dermatological and woundhealing literature, iron performs a large number of fundamental roles in intracellular metabolism in most cells involved in normal skin physiology and those which adopt a special responsibility in wound repair (keratinocytes, fibroblasts, neutrophils) (Sato, 1991; Lansdown, 200Ia).
The iron content of the human body is estimated to be 3-5 g, with recommended daily intake 91-2 mg varying greatly according to the state of health and age of the individual (Scrimshaw and Young, 1976). Intestinal absorption of iron is influenced by substances present in the diet -which chelate free ion, but vitamin C is important in all aspects of iron metabolism. Deficiencies of iron and/or vitamin C are diagnosed through hair loss, inflammatory changes in the hair follicle and interfollicular skin, abnormal keratinization and impaired wound healing (tensile strength) (Green et al, 1968; Lansdown, 200Ib). Vitamin C supplementation is recommended as a therapy for pressure ulcers, particularly those associated with haemolytic anaemia (Ringsdorf and Cheraskin, 1.982). Iron uptake following topical application in intact skin is probably low; most of the iron required in skin physiology and repair systems will be provided from the plasma pool, with some being recycled (and conserved) within the tissue.
The highest iron content in human skin occurs in those areas with highest vasculature and highest cell turnover. Although most of the iron content is present in the dermal tissues, epidermal cells, hair papillae, sweat glands and melanocytes are also sensitive to iron levels (Sato, 1991). Severe iron deficiency occurring in patients with anaemia is recognized not only by general malaise but also skin irritancy, eczema, nail deformities (Beau’s lines) and hair loss (Handfield-Jones and Kennedy, 1988; Lansdown, 200Ib). Loss of skin ‘tone’, reduced resistance to infection and impaired wound healing are complications. The role of ferro-enzymes in proliferating tissue and skin physiology has been reviewed in detail elsewhere (Lansdown, 2001 a,b).
Iron fulfils the following basic requirements in mammalian skin (Brock, 1984):
* Oxygen transport
* Oxidation-reduction processes
* Mitochondrial respiration.
These are appreciated through cell ‘turnover’, nucleic-acid synthesis, cell-membrane stability and cell viability.Transferrin is the principle iron-binding carrier protein and conditions that reduce its availability or effectiveness (toxic metal ions, chelating agents, etc.) will reflect in iron-deficiency syndromes.
Iron deficiencies through malnutrition, disease or inherited conditions are a potential cause of impaired wound repair mainly through defects in oxygen supply to repairing tissues. Collagen formation in scar tissvie is impaired as is the ability to withstand the effects of local infections (Knighton et al, 1981; Bullen and Griffiths, 1999). Neutrophils and macrophages infiltrating wound sites show a high affinity for iron and their cell membranes are well adapted to absorb (phagocytose) irontransferrin complexes. This profound ability to absorb iron in the wound bed enables the neutrophils to deprive bacteria of an essential ‘growth factor’. Patients deficient in macrophages or neutrophils exhibit a marked reduction in resistance to infective organisms and their immune function is also less than normal.
Oxygen
Oxygen is a prerequisite for normal growth, physiological function and me\tabolism in most tissues in the human body – the skin is no exception (Tandara and Mustoe, 2004). In wound healing, the role of oxygen, tissue vascularity and signalling growth factors and gene expression have received considerable attention in recent years; as such it is well appreciated now that whereas the function and regeneration of certain tissues (epidermal cells) is dependent upon appropriate oxygen gradients, other tissues respond to hypoxic situations (angiogenesis, macrophages). Thus, Falanga et al (2002) demonstrated that low oxygen tension stimulates collagen synthesis and transcription of several genes. Human fibroblasts are sensitive to local oxygen tensions in vitro and respond to activation through growth factors (especially transforming growth factor-beta). It seems that the hypoxia present in the early wound provides the necessary stimulus for collagen synthesis, angiogenesis and scar tissue formation. Further, as wound healing progresses from one state to another in the healing cascade, so requirements for oxygen change.
Hyperbaric oxygen is a therapy used in chronic wound therapy. It is considered to be an important adjunct in the management of diabetic ulcers, ischaemic wounds and major surgery (Zamboni et al, 2003; Niinikoski, 2004). It is recommended for the treatment of problem wounds that fail to respond to traditional medicine and surgical techniques.
The most obvious effects of hyperbaric oxygen therapy are listed in Table 5 (Niinikoski, 2004).
Table 5. The obvious effects of hyperbaric oxygen therapy
Niinikoski (2004) recommended exposing patients to oxygen pressures of 2-2.5 ATA for 90 minutes once or twice daily, and that transcutaneous oximetry provides a convenient means of assessing levels of oxygen diffusion and tissue oxygenation. Hyperbaric oxygen can provide a cost-effective means of improving oxygen tension in indolent wounds, providing a more favourable environment for repair and regenerative systems to proceed (Heyneman and Lawless-Liday, 2002).
Water
The relevance of water as a nutrient is frequently over looked in wound care even though considerable attention is given to the selection and application of hydrofibres, alginates, hydrocolloids and polyurethane-containing dressings to control wound moisture and regulate gaseous exchange (Bale and Harding, 1991; Thomas and Loveless, 1991; Scherr, 1992; Banks et al, 1994; Robinson, 2000).
George Winter in the early 1960s provided much impetus to the study of water relations in the skin and the healing acute wound, control of wound exudates, and provision of a suitably moist environment for wound closure and re-epithelialization (Winter, 1962, 1964). (It is unfortunate that much of the information that he provided on role of water control in the acute wound has inappropriately been applied to human chronic wounds which differ substantially.) He demonstrated using a porcine model that re- epithelialization progressed more rapidly in a moist environment under a semipermeable dressing than under exposed or fully occluded wounds (Figure 1). Hydration with adequate oxygenation favours cell proliferation and migration along the chemotactic gradients provided by metal ions (zinc and calcium), growth factors and cytokmes, whereas dehydration promotes keratinization and hardening of the epidermis and possibly necrosis in exposed dermal tissues, obstrvicts re-epithelialization (Lansdown, 1985a,b). In practice, wounds that dry out tend to become cracked and painful for a patient, and are more prone to infection with aerobic bacteria and fungi (Keye, 2002).
Under normal conditions, water control in intact skin is the function of the epidermal layer of phospholipids (stratum lucidum). This provides a form of ‘water-proofing’ while limiting the penetration of materials coming into contact with the skin surface. On the practical side, removal of natural phospholipids through washing in soaps and lipid solvents greatly enhances water uptake, hydration of deeper epidermal tissues, and susceptibility to infection (Grasso and Lansdown, 1972; Idson, 1978). In the maturation of keratinocytes of the stratum spinosum, cysteine molecules aggregate in pairs and release a molecule of water in the production cystine (see Figure i).This process proceeds with successive layers of cells becoming more dehydrated. The surface of the skin normally contains least water, but it is effectively a ‘dead’ tissue. In the case of skin injury, cells of whatever layer exposed to the open environment become dehydrated and hardened to form a protective layer.
As repair mechanisms proceed, water provides (Enoch and Handing, 2003; Schultz et al, 2003):
* A structural component of the cytoplasm of epidermal and dermal cells
* A medium for enzyme-motivated events in regeneration and repair pathways
* An environmental component motivating the migration and maturation of epidermal cells.
Figure 1. Diagrammatic illustration of the influence of dressings upon epidermal cell migration in full-thickness acute wounds. The dressing retains moisture In the wound site and prevents dehydration. Epidermal ceils move laterally. In open wounds dehydration occurs, a hard mass of wound debris and exudate obstructs migrating cells which migrate beneath the ‘scab’ (adapted from Winter, 1962).
Regulation of-water balance in the wound-healing cascade is critical in achieving optimal healing in the acute wound and possibly the chronic wound as well (Winter, 1962, 1964). Although in wound management excessive exudates and wound fluid is frequently undesirable and embarrassing for a patient, excessive water loss is contraindicated as wound healing is delayed and patient comfort is compromised (Katz et al, 1986).
Summary
The present review has examined the available clinical and experimental evidence illustrating the importance of essential nutrients in the development, physiology and functional capacity of the skin and repair systems following injury. Table 6 provides practical guidance in understanding nutrition as a cause of wound repair.
It is entirely reasonable to expect that many wounds which are colloquially ‘stuck’ at some stage in the wound healing cascade, are in fact deprived of one or more essential nutrients or means of adequately metabolizing them. It is incumbent upon the -wound care nurse to appreciate the nature of the deficiency through analysing overt signs and using laboratory resources to analyse key body tissues – hair, nail, blood/serum for evidence of nutritional or metabolic defect. It is possible that cost implications, lack of time, or educational directives are contributory to non-utilization of essential back-up facilities.
Table 6. Practical guidance in understanding nutrition as a cause of impaired wound healing
The importance of any nutrient in the general health of the skin and its appendages is dependent not on the actual quantity supplied in the diet but in the amount delivered and ‘available to’ the epidermal cells that need it. This nutrient availability may be influenced by the factors listed in Table 7.
Correction of a nutritional defect identified as a potential cause of impaired wound may involve dietary attention, or intraparenteral injections (trace metals, vitamins). Appropriate preparations of vitamin complexes, trace meta preparations and dietary supplements are readily available commercially with recommendations for administration and monitoring. Alternatively, topical application of nutritional supplements like zinc may be administered, either in the form of medicated bandages (e.g. Zincaband, SSL Laboratories), creams or emollients. Substances applied topically are absorbed more readily by intact skin at least from amphiphilic vehicles with fat and water solubility (Grasso and Lansdown, 1972).
Evidence is presented to illustrate that impaired wound healing in older people is in part attributable to nutritional causes. As the body ages, so mechanisms for maintaining trace metals and sensitivities to vitamins, fats, and amino acids decline. Zinc levels are lower. Defects in the synthesis and stability of lipids in cell membranes and the epidermal barrier function render the skin more susceptible to dehydration and defects in repair processes dependent upon a suitably moist environment.
Table 7. Factors influencing nutrient availability
Understanding nutritional factors as a cause of indolence in skin wound repair is complex. Nutrients exhibit a large level of interaction and interdependency, with defects in the availability of some substances having a knock-on effect in the uptake and usage of others.The importance of the nutritionally balanced diet is illustrated with reference to mineral metabolism. The composition of the diet and the presence of substances like plant fibre, drvigs and environmental containments may influence absorption of nutrients and contribute to retarded wound repair. Suitable enquiries into a patient’s dietary habits and nutritional preferences may yield important clues as to why that patients wounds are failing to heal and how the attending nurse can provide inexpensive and practical help.
Nutrition should be considered as an essential feature of wound bed preparation. Unavailability or inability to use a particular nutrient through some inherited condition or disease state may represent the elusive ‘block’ in the progression of events of the wound healing profile of chronic wounds re-emphasized by the expert committee of the Wound Healing Society in its reference to wound bed preparation (Schultz et al, 2003). Clearly, a lot of further research is still required to give the practising nurse unequivocal markers for nutrient deficiencies in wound management, and acceptable treatments for their relief.
KEY POINTS
* It is impractical to consider nutrients individually in the human body; nutrients interact to a great extent in health and disease, particularly minerals and vitamins.
* Pr\oteins and amino-acids form the main building blocks for tissue growth, cell renewal and repair systems following injury.
* Fats provide building blocks for many components of epidermal and dermal tissues and as well as sources of energy in cell proliferation, maturation and homeostasis.
* The human body relies on at least 20 vitamins or vitamin-like substances for normal health and physiological functions.
* At least 16 minerals and trace elements are now known to be important for the health of the human body.
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