Nutrition and wound healing

This paper reviews evidence that suggests malnutrition exists among the sick population in hospital and at home, a situation that has not improved in 20 years. It examines the consequences of malnutrition in broad terms and its effect on wound healing. The role of specific nutrients for wound healing is discussed, and finally the barriers which prevent nurses from delivering adequate patient nutrition are exposed.     

General principles of wound healing

Wound healing is a complex process involving different biologic and immunologic systems. Despite improvements in diagnostics and therapy, wound failures remain a clinical problem. The approach to a nonhealed wound is an interdisciplinary challenge that should not be underestimated. Better understanding of the complex wound-healing cascade helps our approach to wound healing and its possible failure. Manipulations of the involved immunologic features offer future therapeutic strategies.     

Nitric oxide regulates wound healing

Nitric oxide (NO) synthesis occurs during wound healing, but its role has not been defined. To study the effect of NO on wound repair, S-methyl isothiouronium (MITU, a competitive inhibitor of NO synthase) was administered at a dose of 10, 50, and 100 mg/kg body weight/day, using intraperitoneally implanted miniosmotic pumps. Groups of 10 male Balb/C mice underwent a dorsal skin incision and polyvinyl alcohol sponges were inserted subcutaneously. The animals were sacrificed 10 days postwounding and wound breaking strength and hydroxyproline content of sponges, an index of reparative collagen deposition, were determined. Some sponges were used to harvest wound fluid and infiltrating cells, which were then incubated overnight with or without 1 mM MITU. Nitrite and nitrate, stable end products of NO, were measured in wound fluid and in wound cell culture supernatants. Continuous intraperitoneal infusion of MITU significantly decreased wound fluid nitrite/nitrate concentrations in a dose dependent manner (P < 0.01). Inhibition of wound NO synthesis by 100 mg MITU/kg/day was paralleled by lowered wound collagen accumulation (P < 0.01) and wound breaking strength (P < 0.01). In vitro NO synthesis by wound cells obtained from animals treated with 100 mg MITU/kg/day was not significantly different from controls (12.6 +/- 1.2 vs 10.7 +/- 0.6 nmole NO2 + NO3/microgram DNA), reflecting the reversible inhibition of NO synthase by MITU. However, NO production was equally inhibited in wound infiltrating cells by the in vitro addition of MITU (83% vs 85%, respectively). These data suggest that nitric oxide synthesis is critical to wound collagen accumulation and acquisition of mechanical strength.     

Nutritional aspects of cancer-related fatigue

OBJECTIVE: Recent studies suggest an involvement of the obese (OB) gene and its product leptin in the regulation of body fat. Since adults with growth hormone deficiency (GHD) have a high body fat mass which can be normalized with recombinant human (rh) GH therapy, we investigated whether GH influences serum leptin directly or indirectly via its lipolytic effect. DESIGN: Fourteen adults with GHD were treated with subcutaneous injections of rhGH given every evening for 52 weeks. Serum leptin, fat mass and body fat percentage were measured at baseline and after 4 and 52 weeks of treatment. METHODS: Serum leptin was measured with a commercially available RIA. Total body water was determined by dilution of deuterium. Fat free mass was estimated by assuming a hydration of 73%. Fat mass was estimated by subtracting fat free mass from weight. RESULTS: At baseline, serum leptin levels were exponentially related to body fat percentage (r = 0.88; P < 0.0005). rhGH treatment for 4 weeks did not significantly influence serum leptin levels, whereas treatment for 52 weeks significantly decreased serum leptin levels (15.6 +/- 2.9 to 10.8 +/- 2.1 micrograms/l; P = 0.020). Fat percentage was significantly decreased after 52 weeks of treatment (37.6 +/- 2.1 to 33.8 +/- 2.5%; P < 0.0005). The decrease in serum leptin could largely be explained by the decrease in body fat percentage, whereas the relation between leptin and body fat percentage did not change. CONCLUSIONS: The influence of GH on serum leptin in indirect, via its effect on body fat percentage.     

Nutritional aspects of neuromuscular diseases

Evidence suggests that individuals with DMD have reduced skeletal development, including decreased linear growth and bone mineral density, compared to normal subjects. Despite their reduced muscle mass, a high percentage of DMD patients are overweight. Body composition measurements can assist with monitoring changes in fat mass and skeletal muscle mass as the disease progresses. Weight management in overweight DMD patients is indicated because excess adiposity burdens mobility and breathing, but only one study in two DMD patients has documented that weight reduction can be done safely. In the latter stages of the disease most DMD subjects become underweight because of an acceleration in skeletal muscle protein degradation relative to its synthesis. Studies of energy, protein and branched chain amino acid supplementation in DMD have yielded promising but inconclusive results, and more well-designed studies are needed in this area. Although there is currently no cure for DMD, studies on the role of nutritional therapy in increasing the quality of life in these patients are urgently needed. Studies in adults with various SP-NMDs indicate a reduction in fat-free mass and an increase in fat mass relative to controls. The newly developed method of air displacement plethysmography for measuring body composition is ideally suited for SP-NMD subjects because it requires very little effort and the measurement procedure is relatively fast. Dual energy x-ray absorptiometry technology has been proposed for distinguishing myogenic from neurogenic SP-NMDs from calculation of the fat-to-lean soft tissue ratio, which is higher in patients with myogenic muscular atrophy. Studies on the energy metabolism of ambulatory SP-NMD subjects indicate that their basal metabolic rate is either similar to or slightly lower than controls, but 24-hour energy expenditure is about 25% lower than controls. This reduction in 24-hour energy expenditure is due to a reduction in physical activity in SP-NMD. Studies examining the roles of energy expenditure, physical activity, and diet in the development of adiposity and risk for secondary chronic diseases in SP-NMD subjects are currently underway.     

Fetal tissue repair and wound healing

The fibrosis and scar formation that characterize adult wound healing are also the cause of clinical problems; scar contracture, hypertrophic scar, and pulmonary and hepatic fibrosis are only a few examples. Studies of fetal wound healing can provide an insight into the initiation and regulation of a scarless repair process akin to regeneration. Studies of fetal repair have already suggested mechanisms that might favorably alter adult healing. Topical application of hyaluronic acid to wounds in adult diabetic rats leads to enhanced epithelial migration. It has been recognized that the addition of TGF-beta to fetal wounds causes an adultlike healing response with fibrosis and inflammation. A subsequent study using neutralizing antibody to TGF-beta in adult wounds showed enhanced healing with a more normal dermal architecture with fewer macrophages, fewer blood vessels, and less collagen. As our understanding of regenerative tissue repair increases, the opportunities to modulate adult fibrotic conditions should expand.     

Specific nutritional factors in wound healing

Provision of a nutritionally complete diet provides the optimum environment for recovery and healing. Clinical research and experience suggest that several nutritional factors may be associated with impaired wound healing, including vitamin C, vitamin A, vitamin E, zinc, protein, and individual amino acids. Studies have shown that supplementing specific nutrients to patients who are not clinically deficient has little effect on pressure ulcer healing. Inexpensive, nontoxic nutritional supplements may not harm the patient, however, some nutritional supplements are expensive or potentially toxic. Before routine use of these nutrients can be justified, further research is required.     

The importance of nutrition in wound healing

Nursing Standards recent Focus on Nutrition campaign raised some uncomfortable issues about nurses' knowledge of wound healing. We continue the theme here, with a review of the importance of good nutrition for effective wound healing.     

Effect of norepinephrine on gastric wound healing

Lavage of the stomach with norepinephrine has been suggested as a temporary means of controlling upper gastrointestinal tract bleeding. The effect of norepinephrine on the healing of a standard gastric incision in the rat was studied using irrigation topically. When compared with those rats in the control study that were irrigated with a saline solution alone, no significant difference was found in the tensile strength, local inflammatory response or synthesis of new collagen, as determined by the hydroxyproline-proline ratio. There would appear to be no adverse effect on gastric wound healing as a result of preliminary irrigation of the gastric mucosa with norepinephrine given topically in a concentration of 16 milligrams per liter.     

Acute surgical wound care. 2: The wound healing process

The first article in this series on acute surgical wound care traced the history of surgical wound care from primitive dressings and techniques of closure used in the past to the present-day approaches. It also outlined the classification of acute surgical wounds (Vol 7(18): 1101-6). This second article describes the four stages of wound healing in acute surgical wounds, using clinical slides to illustrate the wound healing process. General factors, such as age, nutrition and medication, and local factors, including a moist environment, blood supply and wound infection, will be discussed to demonstrate their importance in promoting optimum wound healing.     

Metalloproteinase inhibitors and wound healing: a novel enhancer of wound strength

BACKGROUND: Wound strength is a balance between collagen synthesis and degradation. The role of collagen breakdown in wound healing is still not well understood. We investigated the role of collagenases (metalloproteinases [MMPs]) in wound healing in using GM6001, a novel inhibitor of MMPs. METHODS: We used the dorsal skin incision model with implantation of polyvinyl alcohol sponges. Twenty male Sprague-Dawley rats were randomly assigned to receive either GM6001 (10 mg/kg body weight) or 2 mL saline subcutaneously. Ten days after operation the animals were killed and fresh wound breaking strength, scar and sponge hydroxyproline content, and collagen type I gene expression in sponges were assayed. In addition, the inflammatory response and the wound fluid cytokine (tumor necrosis factor-alpha [TNF-alpha] and transforming growth factor-beta 1 [TGF-beta 1]) profile were studied. RESULTS: GM6001 significantly increased wound strength (422 +/- 59 vs 302 +/- 33 g, P < .05), whereas scar collagen content did not differ. In the sponge granulomas the inflammatory infiltrate, the collagen content, and the collagen type I gene expression were all significantly decreased by GM6001. CONCLUSIONS: Inhibition of MMP activity during acute wound healing enhances wound strength even though new collagen synthesis and the inflammatory response are significantly decreased. This could be achieved by decreasing collagen turnover or increasing collagen maturation and crosslinking, or both.     

Angiogenesis in wound healing and tumor metastasis

Formation of new blood vessels is essential for several physiological and pathological events, e.g. embryogenesis, wound healing and tumor growth and metastasis. In order to increase the insight into the mechanisms of angiogenesis we have visualized the different components of the microvasculature in human wounds and tumors by immunohistochemistry on the light and electronmicroscopic level. For this purpose, antibodies recognizing distinct markers for human endothelial cells, pericytes and basal lamina were used on freshly frozen or paraformaldehyde-fixed tissue samples. In terms of efficacy, the PAL-E antigen is highly specific for blood vessel endothelium. Its sensitivity is less than other endothelial markers, such as von Willebrand factor and CD 31, as it is not expressed in arterioles. Within the context of the microvasculature alpha-smooth muscle actin and the HMW-MAA chondroitin sulphate proteoglycan are useful markers for pericytes. Type IV Collagen and Laminin can be visualized consistently in the microvascular basal lamina. During the formation of granulation tissue in wound healing a heterogeneity of the expression of endothelial and pericyte markers is found. In the least matured zone in granulation tissue of decubitus lesions and experimental skin wounds microvessels already contained both endothelial cells and pericytes, suggesting a role for both cell types in the early steps of angiogenesis. Regarding the tumor microvasculature, antibodies to von Willebrand factor often failed to stain capillaries, that did show expression of the other endothelial markers studied. Broad staining in pericytes was found for the HMW-MAA chondroitin sulphate proteoglycan. In contrast, these cells only locally expressed alpha-smooth muscle actin. Staining of the basal lamina components Type IV Collagen and Laminin within tumors was not restricted to the microvasculature. Therefore, antibodies recognizing endothelial markers, particularly PAL-E and BMA 120, are preferable as tools to visualize the tumor microvasculature. In accordance with the situation in granulation tissue of wound healing the broad presence of pericytes in the microvasculature of human tumor suggests an involvement of this cell type in tumor angiogenesis. Recent immunohistochemical studies on human tumor lesions indicated that a high number of microvessels adjacent to the tumor as a measure of tumor angiogenesis is an unfavorable prognostic factor in cutaneous melanoma, mammary carcinoma and non-small cell pulmonary carcinoma. This new application of immunohistochemistry represents a valuable, clinically relevant adjunct to the repertoire of the surgical pathologist.     

The conjunctiva in corneal epithelial wound healing

BACKGROUND/AIMS: During the healing of corneal epithelial wounds with limbal involvement, conjunctival epithelium often migrates across the denuded limbus to cover the corneal surface. It is believed that, over a period of time, conjunctival epithelium covering the cornea assumes characteristics of corneal epithelium by a process referred to as conjunctival transdifferentiation. The purpose of this study was to examine, clinically, the fate of conjunctival epithelial cells covering the cornea and to assess the healing of corneal epithelial wounds when the conjunctival epithelium was removed or actively prevented from crossing the limbus and extending onto the cornea. METHODS: 10 patients with conjunctivalisation of the cornea were followed for an average of 7.5 months. Five patients in this group had their conjunctival epithelium removed from the corneal surface and allowed to heal from the remaining intact corneal epithelium. In another four patients with corneal epithelial defects, the conjunctival epithelium was actively prevented from crossing the limbus by mechanically scraping it off. RESULTS: The area of cornea covered by conjunctival epithelium appeared thin, irregular, attracted new vessels and was prone to recurrent erosions. Conjunctivalisation of the visual axis affected vision. Removal of conjunctival epithelium from the cornea allowed cells of corneal epithelial phenotype to cover the denuded area with alleviation of symptoms and improvement of vision. It was also established that migration of conjunctival epithelium onto corneal surface could be anticipated by close monitoring of the healing of corneal epithelial wounds, and prevented by scraping off conjunctival epithelium before it reached the limbus. CONCLUSION: This study shows that there is little clinical evidence to support the concept that conjunctival transdifferentiation per se, occurs in humans. "Replacement" of conjunctival epithelium by corneal epithelial cells may be an important mechanism by which conjunctival "transdifferentiation" may occur. In patients with partial stem cell deficiency this approach can be a useful and effective alternative to partial limbal transplantation, as is currently practised.