Wound Repair and Extremely Low Frequency-Electromagnetic Field: Insight from In Vitro Study and Potential Clinical Application

Abstract

Wound healing is a complex, staged process. It involves extensive communication between the different cellular constituents of various compartments of the skin and its extracellular matrix (ECM). Different signaling pathways are determined by a mutual influence on each other, resulting in a dynamic and complex crosstalk. It consists of various dynamic processes including a series of overlapping phases: hemostasis, inflammation response, new tissue formation, and tissue remodeling. Interruption or deregulation of one or more of these phases may lead to non-healing (chronic) wounds. The most important factor among local and systemic exogenous factors leading to a chronic wound is infection with a biofilm presence. In the last few years, an increasing number of reports have evaluated the effects of extremely low frequency (ELF) electromagnetic fields (EMFs) on tissue repair. Each experimental result comes from a single element of this complex process. An interaction between ELF-EMFs and healing has shown to effectively modulate inflammation, protease matrix rearrangement, neo-angiogenesis, senescence, stem-cell proliferation, and epithelialization. These effects are strictly related to the time of exposure, waveform, frequency, and amplitude. In this review, we focus on the effect of ELF-EMFs on different wound healing phases.

Keywords: ELF-EMF; fibroblasts; healing; keratinocytes; non-healing wounds; wound.

Figure 1

Molecular mechanisms of ELF-EMFs’ effects on cell function. ELF-EMFs open voltage-dependent calcium channels, causing interference in cell differentiation with Ca²⁺ influx into cells. It is well documented that Ca²⁺ ions affect activity-dependent gene expression, and this effect is mediated by signaling pathways activating Ca²⁺-responsive DNA regulatory elements. Decreasing antioxidants concentration has a defense mechanism against free radicals. The ELF-EMFs could also induce the production of oxygen (O₂) in the cellular environment, which plays a major role in oxidative damage that, subsequently, led to biomolecular damage, DNA double strand breaks, DNA/RNA damage, and cell death.

Figure 2

The chronic wound shows the presence of infection and biofilm formation, a hyperproliferative and nonmigratory epidermis, and an inflammatory state with an increase in inflammatory cells (neutrophils and macrophages) not properly functioning. Fibroblasts and keratinocytes become senescent while there is a reduction of angiogenesis, stem cell recruitment and activation, and ECM remodeling. ELF-EMFs has been shown to regulate the inflammatory response, induce senescence of fibroblasts, and keratinocytes through increased proliferation and migration. The regulation of MMP and collagen synthesis improves the ECM microenvironment. Proangiogenic and vasculogenic activity support cells with nutrition and oxygen. The role on biofilm and infection is still controversial.