Zinc and Wound Healing: A Review of Zinc Physiology and Clinical Applications

Our understanding of the role of zinc in normal human physiology is constantly expanding, yet there are major gaps in our knowledge with regard to the function of zinc in wound healing. This review aims to provide the clinician with sufficient understanding of zinc biology and an up-to-date perspective on the role of zinc in wound healing. Zinc is an essential ion that is crucial for maintenance of normal physiology, and zinc deficiency has many manifestations ranging from delayed wound healing to immune dysfunction and impairment of multiple sensory systems.While consensus has been reached regarding the detrimental effects of zinc deficiency on wound healing, there is considerable discord in the literature on the optimal methods and true benefits of zinc supplementation. 

Zinc, a trace element, is the most abundant intracellular metal and the second most abundant in the body overall after iron. The essential role of zinc in growth was first discovered in 1869 in the fungus Aspergillus niger.¹ In 1926 zinc was found to be endogenously present in human tissues and it was suggested that it possibly served crucial biological roles.^2,3 A significant zinc-biochemistry discovery occurred in 1939 when erythrocyte carbonic anhydrase, the enzyme responsible for the rapid and reversible conversion of carbon dioxide and water to bicarbonate and protons, was shown to require zinc for enzymatic activity.⁴ Another landmark discovery was of the “zinc finger domain” in proteins, a highly conversed sequence allowing for the interaction of proteins with nucleic acids.⁵ Using a bioinformatics approach encompassing genomics, proteomics, and zinc-protein interactions, researchers have identified more than 3000 unique human zinc proteins, suggesting that more than 10% of the human genome encodes zinc proteins.^6-8

Transport, storage, and sensing zinc. The 3000 known zinc proteins are essential in enzymatic and structural roles, transport and storage, DNA repair, replication, and translation.⁸ Given the overwhelming importance of zinc in innumerable physiologic processes, there must be specific mechanisms in place to ensure sufficient intracellular zinc concentrations. More than 3 dozen proteins regulate intracellular zinc concentrations, including the 14 members of the ZRT/IRT-like protein (ZIP) family (SLC39A) that function to increase intracellular zinc concentrations and the 10 members of the zinc transporter (ZnT) family (SLC30A) that decrease intracellular zinc concentrations.⁹ These transporters are responsible for the movement of zinc into the cytosol via the plasma membrane and to various intracellular compartments. In addition, the metallothionein (MT) family of proteins is a class of cytosolic proteins responsible for binding free zinc. The expression of ZIP and ZnT transporters is heavily regulated transcriptionally, translationally, and posttranslationally.^10-12

While there is a fairly comprehensive understanding of zinc transport, far less is understood about cellular zinc sensing. The only known eukaryotic zinc (II) ion sensor is metal-responsive element binding transcription factor-1 (MTF-1). It is believed to sense zinc levels through a pair of 6 zinc fingers with an affinity for zinc lower than that of other zinc fingers — thus allowing it to determine elevated zinc levels.¹³ Metal-responsive element binding transcription factor-1 has been established as an essential gene, as deletion is embryonically lethal.¹⁴

Storage and cellular release of zinc is regulated by the MT family of proteins, of which humans have more than 12 types. Metal-responsive element binding transcription factor-1 controls the expression of the majority of the MTs. Under conditions of increased cellular zinc concentrations, the expression of MTs is increased, and as a result, the cell is capable of binding more zinc, thus decreasing total free zinc.¹⁵

Zinc physiology and role in health. Zinc is ubiquitously found in the body, with 85% stored in muscle and bone, 11% in the skin and liver, and the rest in other tissues.¹⁶ Given the 3000 proteins requiring zinc, it should come as no surprise that zinc is crucial in countless physiologic processes; it is essential in growth, immune function, tissue maintenance, and wound healing.¹⁷ Zinc absorption occurs in the duodenum and proximal jejunum and is taken into enterocytes by transporters found on the apical membrane.¹⁸ Citric acid enhances absorption, while iron, fiber, and phytic acid inhibit absorption.^19,20 The greatest physiological requirement of zinc occurs during puberty, coinciding with the period of rapid bone growth. In addition, infants and children, pregnant and lactating women, and the elderly also require increased zinc. ²¹

Zinc deficiency and excess. Unlike many essential vitamins and minerals, there are no dedicated stores of zinc. When deficiency, defined by a plasmic zinc level below 60 µg/dL, exceeds the regulatory capacity of homeostatic mechanisms, clinical symptoms may arise. Zinc deficiency can occur due to inadequate intake, reduced absorption, increased losses, or increased demand.²¹ It can also occur after the use of penicillamine for Wilson’s disease and due to genetic disorders such as Acrodermatitis enteropathica and sickle cell disease.²² Inadequate intake as a result of a zinc-deficient diet or a phytate-rich diet is the most common worldwide cause of zinc deficiency. Individuals most susceptible to zinc deficiency caused by inadequate intake are those with the greatest physiological demand. Elderly populations are also at risk due to age-related decline in absorption and poor diet.²¹ A randomized controlled trial of more than 600 elderly residents of nursing homes found that approximately half of the individuals studied had serum zinc concentrations below normozincemic levels.²³ Much of the literature on zinc deficiency and supplementation has been focused on the geriatric population, specifically because of the high prevalence of morbidities predisposing them to hypozincemia including malignancy, tuberculosis, dermatological disorders, chronic wounds such as arterial and venous ulcers, and chronic renal insufficiency.^24,25

Severe zinc deficiency manifests as bullous-pustular dermatitis, alopecia, diarrhea, weight loss, intercurrent infections, and hypogonadism in males. Unrecognized severe zinc deficiency is fatal.²² The presentation of moderate zinc deficiency includes growth retardation, delayed puberty, hypogonadism in males, rough skin, poor appetite, delayed wound healing, and abnormalities in gustation, olfaction, and night vision. Mild zinc deficiency may present with oligospermia, weight loss, and hyperammonemia.²²

Zinc toxicity is exceedingly rare, as zinc is considered relatively nontoxic, especially via oral administration. Nonetheless, excessive intake may produce symptoms including nausea, vomiting, epigastric pain, lethargy, and fatigue. Zinc intake exceeding 10x to 20x the Recommended Dietary Allowance of 15 mg per day may induce copper deficiency and symptoms of anemia and neutropenia.²⁶

The PubMed database (https://www.ncbi/nlm.nih.gov/pubmed/) and the Google Scholar database (https://scholar.google.com) were queried for the terms “zinc wound healing,” “zinc deficiency wound healing,” and “zinc supplementation wound healing.” The studies included in this review spanned from 1970 to 2012. Studies were excluded if they lacked any animal or human data and were included if the research contained animal and/or human subjects.

Zinc and wound healing: experimental studies. Much of the current understanding of the role of zinc in wound healing comes from experimental work performed in rats and pigs. During the early inflammatory phase of wound healing, zinc levels are markedly increased. Experiments in the rat model of wound healing have shown that within the first 24 hours after injury, there is a 15% to 20% increase in zinc levels in the wound margin, and this surges up to 30% during further granulation tissue development and epidermal proliferation.²⁷ The early zinc influx is caused by elevated MT expression in keratinocytes at the wound margin, macrophages, and dermal fibroblasts, while later stages of wound healing are associated with decreased zinc levels due to reduced cell division and scar maturation.^27,28

Additional studies of surgical wounds in the rat model revealed that topical zinc treatments reduced wound debris and advanced epithelization.^29-31 Agren³² and Mirastschijski et al³³ have demonstrated that matrix metalloproteinases (MMPs), a class of zinc-dependent proteins, are crucial in wound healing. The ability of MMPs to enzymatically break down collagen fragments is enhanced by the application of zinc oxide, and inhibition of MMP activity significantly delays wound healing.^32,33

Further support for the essential role of zinc in wound healing was demonstrated by a series of experiments in which the rate of surgical wound repair was examined in rats with induced or hereditary zinc deficiency. While rats that were given supplemental zinc had improved surgical wound repair, rats with either hereditary or nutritionally induced zinc deficiency had impaired surgical wound healing.^31,34 Zinc-deficient rats fed supplemental zinc have increased levels of zinc in their wounds, and the healing proceeds normally.³⁴ While supplemental oral zinc did not confer a benefit to normozincemic rats, a 12-day treatment of topical zinc oxide was constructive in the treatment of full-thickness excisional wounds in both hypozincemic and normozincemic animals.³⁵

Researchers have further studied the role of zinc oxide in wound healing through the use of domesticated pigs. ^36,37 In normozincemic pigs, the application of topical zinc oxide resulted in a 30% promotion of healing in both partial-thickness and full-thickness wounds.^37,38 In contrast to zinc oxide, topical zinc sulfate provided no benefit to wound healing.³⁶ In fact, application of higher levels of zinc sulfate (>15 mmol/L) significantly impaired epithelialization and induced dermal inflammatory response.³⁶

Zinc and wound healing: clinical studies. During the acute-phase response to both surgical trauma and infection, zinc concentrations are decreased in the blood and increased in the liver.^39-41 Research suggests MTs play a role in this redistribution, as MT-knockout mice do not display this stereotypical response when challenged with lipopolysaccharide (LPS), a component of the outer membrane of gram-negative bacteria, which elicits strong immunological responses.^39,40,42

Wilkinson and Hawke⁴³ performed a systematic literature review using data from the Cochrane Wound Group to probe whether oral zinc supplementation was beneficial in the healing of chronic leg ulcers. They examined randomized controlled trials and controlled clinical trials involving the use of zinc for the treatment of leg ulcers. They were unable to come to definitive conclusions regarding the use of oral zinc sulfate for the treatment of chronic venous or arterial ulcers.⁴³ The authors suggested a need for a more thorough examination to determine whether oral zinc sulfate supplementation is beneficial in zinc-deficient patients with chronic leg ulcers.⁴³

While 2 studies^44,45 agree with Wilkinson and Hawke⁴³ regarding the paucity of data supporting the benefit of oral zinc supplementation in patients other than those who are zinc deficient, they argue that topical zinc oxide is not only more effective in wound healing, but more broadly applicable to patients, regardless of their zinc status.⁴⁴ Agren reports a double-blind trial of 37 patients with leg ulcers and low serum zinc levels in which patients receiving topical zinc oxide had increased wound healing, increased reepithelialization, decreased rates of infection, and decreased rates of deterioration of ulcers compared to patients who did not receive topical zinc oxide.⁴⁴ While this study involved a relatively small cohort of patients, the results warrant larger randomized controlled trials to better understand the benefit of topical zinc oxide in wound care.

Several studies have examined the use of zinc oxide as a potent debridement agent. Topical zinc oxide has been shown to be an effective debriding agent for pressure ulcers and diabetic foot ulcers.^45,46 In addition, topical zinc oxide has been shown to be a useful debridement agent in the management of burns.⁴⁷ Given that burn patients are hypozincemic and have delayed wound healing, it should not be assumed that normozincemic individuals would display the same response to zinc oxide treatment.^48,49 Larger studies are warranted to evaluate the broader applicability of topical zinc oxide in wound healing. 

Zinc is an essential trace element with innumerable critical physiologic, enzymatic, and structural functions. Given the importance of zinc in numerous biologic processes, it is unsurprising that the ion’s homeostatic concentrations are tightly regulated. Cytosolic zinc levels are coordinated by families of zinc importers, exporters, and cytosolic zinc binding proteins: the ZIP, ZnT, and MT
families, respectively.

While zinc toxicity is rare and relatively benign, zinc deficiency is a global health issue with more than 2 billion people at risk for dietary deficiency. Zinc deficiency may present with a broad symptomatic range, from nausea to impaired growth, gustation, olfaction, night vision, and wound healing. 

The observation of poor wound healing in zinc-deficient individuals lead to a flurry of research in an attempt to both characterize the role of zinc in wound repair and to develop therapeutic approaches to enhance the rate of healing. Oral zinc supplementation has failed to confer any advantage in wound healing rates. However, topical zinc oxide has been shown to improve the rate of wound healing in patients, regardless of their zinc-status. In contrast, topical zinc sulfate is unable to promote wound repair across a wide range of doses.

Zinc is an exceedingly crucial ion in countless cellular and biochemical processes. More than 3 dozen transporters and cytosolic proteins (ZIPs, ZnTs, MTs) work in unison to maintain tight homeostasis of free zinc ion concentrations. Zinc deficiency has numerous clinical manifestations including the impairment of wound healing. Much of the research in the field stems from rat and porcine models, and only a handful of studies, including some randomized controlled trials, have been performed in humans. Both animal and human studies suggest the benefits of topical zinc oxide application in zinc-deficient and normozincemic individuals, but the findings of the studies are attenuated by small sample sizes^{31,34-38,43-45} Further research in the application of supplemental zinc in wound healing is particularly essential, as zinc and zinc products are relatively inexpensive and fairly ubiquitous in the clinic and may offer tangible benefits to patients. 

From the Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ; and Rutgers New Jersey Medical School, Division of Plastic and Reconstructive Surgery, Newark, NJ

Address correspondence to:
Mark S. Granick, MD
New Jersey Medical School-UMDNJ
90 Bergen St, Suite 7200
Newark, NJ 07103
mgranickmd@njms.rutgers.edu

Disclosure: The authors disclose no financial or other conflicts of interest.