The use of zinc in wound healing has been studied for its cellular and molecular mechanisms in modulating the healing process. A 2017 review article discusses zinc's role in this context, highlighting its importance in wound healing through two lenses, the consequences of zinc deficiency and the potential benefits of topical and systemic zinc supplementation. Zinc deficiency is linked to delayed healing, and it is suggested that addressing it can lead to improved outcomes, especially in at-risk patients. A typical treatment approach includes a loading dose of 10–30 mg and a daily maintenance dose of 2.5-5 mg. However, the effects of zinc supplementation in individuals without deficiency are less well-defined, with limited high-quality studies available. For instance, some evidence suggests that oral zinc does not enhance healing in patients with arterial or venous ulcers, while one meta-analysis indicates that topical zinc oxide (6-15%) improved healing in chronic venous leg ulcers, though findings were derived from small and low-quality studies. [1]
In wound care, zinc therapy is suggested to be beneficial for zinc-deficient patients due to the loss of zinc during injury. Common formulations include topical zinc sulfate (ZnSO4) at a 3% concentration, known for its antioxidant properties, as well as 1% zinc chloride and insoluble zinc oxide, which offers prolonged zinc release and enhances healing. Zinc oxide also aids in collagen degradation in necrotic wounds and induces mRNA expression of metallothionein, contributing to its anti-UV protective effects. For severe burn patients, a typical regimen involves daily zinc supplementation of 22 mg or more. Recent advancements in zinc oxide nanoparticle technology show promise for wound treatment due to their effective cell penetration and immunomodulatory and antimicrobial properties. Nevertheless, the authors emphasize that further research into the pharmacodynamics and toxicology of these nanoparticles is crucial before they can be widely implemented. [1]
Zinc is an essential trace element with critical physiological, enzymatic, and structural functions, tightly regulated by families of zinc importers, exporters, and binding proteins. To further understand the role of zinc in wound healing, another 2017 review discussed biological functions regulated by zinc and its role in wound management. Physiological processes involving zinc have been predominantly identified in experimental animal models including rats and pigs. Results from these studies have shown that zinc is markedly increased during the first 24 hours post-injury, peaks during epithelial proliferation, and is attributed to elevated metallothionein (MT) expression in wound margin keratinocytes, macrophages, and dermal fibroblasts. While topical zinc oxide application was shown to promote healing in animals with and without a zinc deficiency, topical zinc sulfate showed no benefits and even impaired healing at higher concentrations. [2]
Clinical studies indicate that while oral zinc supplementation lacks definitive evidence for healing chronic leg ulcers, topical zinc oxide demonstrates increased wound healing and reepithelialization in patients with and without low serum zinc levels. Additionally, zinc oxide serves as an effective debridement agent for pressure ulcers, diabetic foot ulcers, and burns. However, due to the limited sample size, more extensive research is needed to fully understand its applications and benefits across various patient populations. While zinc toxicity is rare, zinc deficiency affects over 2 billion people globally, leading to symptoms such as impaired growth, taste, smell, night vision, and poor wound healing. The study authors concluded that the use of oral zinc supplementation and topical zinc sulfate does not improve wound healing rates, whereas topical zinc oxide enhances healing regardless of the patient’s zinc status. Overall, further studies are needed to explore the therapeutic potential of zinc in wound care. [2]
In order to assess the efficacy of zinc supplementation in patients with pressure injuries, a 2020 meta-analysis evaluated seven studies (N= 473 patients) that compared zinc supplementation to a control nutrition intervention. The zinc therapies used in the intervention groups included specific nutrition approaches, protein-lipid-zinc oral formula, compound sulfadiazine zinc, sulfadiazine zinc ointment, silver zinc cream, and zinc oxide oil. The analysis found a significant improvement in healing rates for the intervention group compared to the control group, with a relative risk of 1.44 (95% confidence interval 1.01 to 2.06; p= 0.043; I2= 19.3%). Additionally, all included studies showed significant improvement in Pressure Ulcer Scale for Healing scores of pressure injuries. Based on these findings, it was suggested that zinc therapy may potentially promote wound healing and should be considered for patients during pressure injury treatment. [3]
Zinc as a topical formulation for the acceleration of wound healing has been explored in both ex vivo and in vitro models for its antimicrobial and anti-inflammatory properties. Among these, a 2021 human ex vivo model study evaluated the efficacy and mechanism of ZnSO4 in epidermal wound healing exhibited in healthy volunteers (N= 30) with suction blister wounds. This randomized, double-blinded, three-arm trial compared topical zinc gel (1.4%), gel placebo, and distilled water applied to induced wounds once daily for 4 days before biopsy and immunohistochemistry analysis. Results suggested that topical ZnSO4 increased keratinocyte migration and Zn-dependent matrix metalloproteinase-1 (MMP-1) expression of the neoepidermis (new skin growth over wound) but not in any other epidermal compartment. Additionally, MT was shown to be upregulated in the neoepidermis and non-epithelialized wound beds. This leads to the possibility that ZnSO4 topical application enhances MMP-1 expression leading to cell migration and MT upregulation, resulting in anti-inflammatory processes on the wound surface. Notably, no significant differences were seen between treatment groups on neoepidermis formation on day 4 prior to biopsy. [4]
As zinc is one of the key metal ions involved in wound healing that promotes protein synthesis, cell division, and immune function regulation, several recent animal studies have evaluated the efficacy of zinc via in vivo and in vitro testing. One study investigated the use of a topical arginine and zinc controlled-release hydrogel on wound recovery rate for 13 days in a mice model. By day 13, wounds treated with the zinc combination hydrogel were nearly completely healed (96.59%) when compared to a blank control group (68.61%). An additional mice model study tested topical zinc nanocomposites for antimicrobial efficacy and rate of wound healing. Zinc nanocomposites were tested for antibacterial properties in pathogens commonly seen in acute and chronic wounds with low inhibitory activity overall. Zinc nanocomposite-treated mice showed faster wound healing at day 7 (73%) and complete wound closure by day 10 of treatment. Another study tested multiple sprayable hydrogel systems for sustained release of multi-metallic ions (calcium, copper, and zinc) at a wound site and assessed for wound healing efficacy in a rat model. The zinc-containing hydrogel spray showed rapid wound healing within 6 days of treatment, increased collagen deposition and angiogenesis at wound site compared to the multi-metallic ion-free hydrogel; these findings are limited by the use of other endogenous metallic released by the body during wound healing. Overall, study results show potential benefits for topical zinc use in wound care management but require further testing for safety and clinical outcomes in humans. [4], [5], [6], [7]