Zinc—Minerals similarly play important roles in enzymatic regulation. Hundreds of zinc-containing enzymes are involved in wound healing and are required in tissue repair, growth, antioxidant capacity, and immune function.1,24 Zinc is specifically critical to collagen, DNA, RNA, and protein synthesis, as well as cellular proliferation.4 Zinc deficiency has been encountered in the setting of chronic wounds with extensive drainage, decreased dietary intake, or excessive gastrointestinal losses.25 Although many studies exist evaluating the utility of zinc supplementation on wound healing, many are confounded by multinutrient supplementation. No studies to date support zinc supplementation when zinc deficiency is absent. Patient assessment for medications or conditions that may impact zinc metabolism should be completed. Importantly, zinc supplementation can interfere with the absorption of other cations, so excessive supplementation should be avoided.1
Amino Acids for Wound Healing
Arginine—Arginine is an essential amino acid that serves as a substrate for cellular proliferation, collagen deposition, and lymphocyte function.8,26,27 Arginine serves as the biologic precursor for nitric oxide (NO), a substrate that has important wound healing properties. Nitric oxide metabolites have been shown to positively regulate wound repair while NO metabolites are reduced in wound environments in diabetic ulcerations.28,29 Arginine also is a proline precursor, an essential building block for collagen synthesis,6,30 and a stimulator of growth hormone and T cells.30,31 Animal studies have suggested L-arginine supplementation may reverse impaired NO synthesis in diabetic wounds.28 A single randomized trial assessing differing doses of arginine supplementation on stage II or stage IV pressure ulcers noted an almost two-fold improvement in healing time.32 However, human studies have not shown increased rates of re-epithelialization of skin graft donor sites when provided oral or parenteral arginine supplementation.33 Inadequate data currently exist to support regular arginine supplementation for all types of wounds, and no safe dose of daily arginine intake has been established.
Glutamine—Similarly, glutamine supplementation has been proposed to accelerate wound healing due to its role as a primary metabolic fuel source for rapidly proliferating cells such as epithelial cells and fibroblasts.8 Glutamine is thought to induce expression of heat-shock proteins and protect against inflammatory and infectious wound complications.34 Additionally, glutamine is thought to increase tissue insulin sensitivity, which may prove beneficial in wounds, as topical insulin previously has been shown in animal and human models to promote healing.35 Glutamine is thought to play a role in the inflammatory phase of wound healing via superoxide production, leukocyte apoptosis, and phagocytosis.6,34,36 Unfortunately, numerous randomized trials on glutamine supplementation have resulted in conflicting evidence confounded by multisupplementation within the same trial.37,38 A double-blind, randomized, controlled trial of 270 participants assessed the effect of oral supplementation with arginine, glutamine, or β-hydroxy-β-methylbutyrate vs control in the healing time of diabetic foot ulcerations. Significant differences in wound closure time at week 16 were only identified in participants with low albumin levels (≤40 g/L) who were supplemented (50.8%) vs the control group (34.9%; P=.0325) and in those with poor limb perfusion (ankle-brachial index of <1.0) who were supplemented (60.3%) vs the control group (39.3%; P=.0079).39 Ongoing clinical trials evaluating the effects of glutamine supplementation on differing wound types will hopefully shed light on the efficacy of supplementation.
Final Thoughts
Wound healing is multifactorial and should consider the health status and medical comorbidities of each patient treated. We propose an individualized approach to wound healing that includes exploration of specific macronutrient and micronutrient deficiencies, as malnutrition has been associated with wound chronicity and serves as a modifiable risk factor to improve healing.2 The evidence backing specific nutrient supplementation in patients with deficiencies is strong and should be considered in patients with chronic wounds. Adequate caloric intake and protein content should be recommended for most wound patients; however, excessive protein intake has not been beneficial in wound healing. The data behind specific amino acid and vitamin supplementation are limited at this time. As with other therapeutics, there is likely an appropriate dose for supplementation that has not yet been elucidated. Consideration of wound type, size, depth, exudate, and underlying cause are important to optimize healing and tailor nutritional supplementation to each patient. We hope future studies will illuminate the complementary role of dietary intake and nutrient supplementation for the treatment of chronic nonhealing wounds.