Electrical Activation of Wound-Healing Pathways

Abstract

BACKGROUND: Effective wound healing has been a lasting and challenging topic in health care. Various strategies have been used to accelerate and perfect the healing process. One such strategy has involved the application of an exogenous electrical stimulus to chronic wounds with the aim of stimulating healing responses. THE PROBLEM: The biology of electric stimulation to instigate healing, however, is very poorly understood. How does electric stimulation induce healing responses? BASIC/CLINICAL SCIENCE ADVANCES: Recent research shows that the electric fields (EFs) activate multiple signaling pathways that are critical for wound healing. Importantly, the EFs provide a powerful, sometimes an overriding, directional signal for cell migration in wound healing. Unlike other stimuli, EFs have the intrinsic property of being directional. The EF-directed cell migration (electrotaxis/galvanotaxis) appears to be a consequence of EF-induced polarized signaling of epidermal growth factor receptors, integrins, and phosphoinositide 3 kinase/Pten, and may be mediated by protein kinase C, intracellular Ca(2+), and cyclic adenosine monophosphate (cAMP). Because directional cell migration is a key component in wound healing, galvanotaxis may represent an important mechanism of wound healing. CLINICAL CARE RELEVANCE: With the constantly enlarging diabetic and aging population, chronic or nonhealing wounds pose increasing health and economic problems, and currently there is no effective therapy available. Electric stimulation activates important intracellular signaling pathways that are polarized in the EF direction, resulting in enhanced and stimulated directional cell migration. Electric stimulation offers a novel approach to achieve better and accelerated wound healing. CONCLUSION: Experimental evidence suggests a significant role of endogenous EFs in cell migration in wound healing. Most importantly, EFs are a very powerful signal to direct cell migration. Electric stimulation therefore may represent a promising and unique strategy to induce cell and tissue growth in a directional manner, to enhance wound healing, and to achieve better wound healing.

Figure 1

Electrical activation of wound-healing pathways. Schematic diagram shows the generation of the endogenous wound electric signals and the electrical activation of some important signaling pathways for cell migration and wound healing. (A) Injury breaks the epithelial barrier and induces endogenous wound electric fields (EFs). Electric stimulation can also be exogenously applied; (B) extracellular EFs may activate epidermal growth factor receptors (EGFRs), vascular endothelial growth factor receptors (VEGFRs), and integrins; (C) polarized activation of membrane receptors induces asymmetric intracellular signaling, notably extracellular-signaling regulated kinase 1/2 (ERK1/2), phosphoinositide 3 (PI3) kinase/Akt, Rac, and protein kinase C (PKC) to induce downstream cascades; (D) the orchestration of the polarized intracellular signaling results in directional cell migration and proliferation, and perhaps directional nerve growth and new blood vessel formation. These effects may lead to improved wound-healing response.