The Multifaceted Properties of Copper and Zinc in Skin Healing.

Copper (Cu) and zinc (Zn) are trace elements required for a multitude of physiological processes, including wound healing, and there has been a long history of including both metal ions in topical skin repair formulations. Wound healing involves complex and dynamic cellular mechanisms in the main phases of platelet hemostasis, inflammation, granulation tissue formation, re-epithelialization, and extracellular matrix remodeling. This process is influenced by the balance in the skin's commensal microbiota, and the risk of microbes becoming pathogenic through migration and colonization of the deeper tissues. We examine the antimicrobial effects of Cu/Zn versus their roles in the innate immune response that prevents the invasion and proliferation of microorganisms and in the cellular mechanisms that promote wound healing. Cu/Zn modulates macrophage polarization, promoting the transition from the pro-inflammatory M1 phenotype to the pro-healing M2 phenotype, which is critical for tissue repair. Both elements also act as cofactors that modulate the activities of important growth factors, mediators, and enzymes, including antioxidant enzymes, such as superoxide dismutase, which have a role in the innate immune response to pathogens and protect cells from oxidative damage, reducing inflammation and promoting healing. These divalent ions stimulate angiogenesis, and the Cu/Zn combination can also modulate integrin expression in keratinocytes, which are needed for re-epithelialization, supporting cellular mobility and differentiation, and enhancing the healing process. The synergistic roles of Cu/Zn in preventing infection while stimulating the skin's natural immune defenses encourage efficient tissue repair after injury. Topical Cu/Zn-containing formulations therefore hold promise for improving wound management.