Elsevier

Bioelectrochemistry

Volume 146, August 2022, 108108
Bioelectrochemistry

Non-contact electrical stimulation as an effective means to promote wound healing

https://doi.org/10.1016/j.bioelechem.2022.108108Get rights and content

Highlights

  • NCES provided by self-made device could be expediently applied to cells/animals.

  • NCES device parameters were chosen via the simulation analysis of EF distribution.

  • Growth-promoting effect of NCES on HaCaT cells was more obvious than that on HDFs.

  • NCESs of about 54 and 84 mV mm−1 accelerated the wound healing rate of model mice.

Abstract

Electrical stimulation has been demonstrated to have beneficial effects in skin tissue repair. However, most electrical stimulations are applied with percutaneous electrode, which is prone to causing serious trauma. Using non-contact electrical stimulation (NCES) is expected to reduce the potential risk. In this study, NCES was expediently exerted by a self-designed practical device. Electrode plates of 10-cm spacing with appropriate side lengths of 21 and 30 cm were selected by EF distribution analysis for applying NCES to cells and mice, respectively, and the real EF strengths were measured. The change of loading voltage which had no effect on the regular pattern of EF distribution could be used as a single factor to explore the effect of NCES on wound healing. It was subsequently demonstrated that 53 mV mm−1 NCES facilitated the migration and proliferation of HaCaT cells and HDFs in vitro, and the M2-type polarization of macrophages. Moreover, 54 and 84 mV mm−1 NCESs accelerated the wound healing rate of model mice from the perspective of reducing scarring, enhancing collagen synthesis and increasing angiogenesis in vivo. The promoting role of NCES in wound healing showed the potential to initiate new possibilities for the clinical treatment of skin tissue injuries.

Introduction

Physical stimulation plays such an important role in tissue repair that Du et al. [1] proposed that external physical stimulation is the additional “fourth element” to the three traditional components of tissue engineering. Common physical stimulations include mechanical, electrical, magnetic and optical stimulations [1], [2], [3], [4]. The process of tissue regeneration is complicated; even for the skin wound healing, it also involves inflammatory reactions, immune responses, granulation, epithelialization and vascularization, as well as the regeneration of hair follicle and nerve endings [5]. These processes require a set of complex signals from cells, macrophages, and the extracellular matrix to induce regeneration of defective tissue and achieve functional recovery [6]. Clinically, various physical stimulations such as ultrasound [7], electric [8], and infrared [9] have been applied to accelerate wound repair.

As one of the most commonly used and effective methods, electrical stimulation was applied in wound healing initially based on the discovery of endogenous electric field (EF) present in the wound [10]. Since DuBois-Reymond measured the naturally occurring electric currents at human skin wounds in 1843 [11], the generation mechanism of endogenous has gradually become clear. When a wound that disrupts the epithelial barrier occurs, it will short-circuit the trans-epithelial potential maintained by the directional transmission of ions (e.g. Na+ and Cl-) by polarized epithelial cells. Then a wound EF will be generated when the potential at the wound drops to negative relative to that underneath the unwounded epidermis which is far away from the wound [10], [12], [13]. In 1950s-1970s, a great number of clinical therapeutic effects made electrical stimulation therapy attract researchers' attention, which laid an important foundation for the wide acceptance and application of electrical stimulation for wound treatment [14], [15], [16], [17]. It was reported that the treatment of chronic ischemic skin ulcer with 200–1000 mA direct current stimulation achieved satisfactory therapeutic effect [18]. During the following decades, with the in-depth study of the action mechanism and the development of power supply equipment, electrical stimulation fully demonstrated its superiority in promoting the healing of wounds, especially the hard-to-heal wounds in clinic. [19], [20], [21]. Janković and Binić [22] reported that the electrical stimulation accelerated the ulcer healing and greatly alleviated the suffering of patients; after electrical stimulation, the wound areas reduced by 82% compared to 46% of control group within the same duration. Wirsing et al. [23] achieved complete wound healing of 47 patients with hard-to-heal wounds by using 1.5 μA electric current stimulation.

However, as the most used form of electrical stimulation for wound healing and skin tissue regeneration, electrical current stimulation often requires transdermal electrodes, which not only demands disinfection to avoid infection, but also could cause secondary damage to the wound [24], [25], [26]. Even for non-invasive transcutaneous electrical stimulation, the usage of patch electrodes needs to avoid the wound area, and the long-term or concentrated loading of current is easy to cause burns [15], [27]. In addition, the electrode patch may also cause allergies and other symptoms. In pursuit of safety and convenience, capacitive coupling EF as a non-contact electrical stimulation (NCES) has been used to efficiently improve the effect of electrical stimulation therapy [26]. Capacitive coupling EF, which is normally generated between two parallel electrified metal electrode plates [28], [29], can form as uniform EF in a certain space. Although the efficacy of NCES in promoting tissue repair has not been widely verified, the researches of capacitive coupling EF in bone and cartilage tissue repair have been well performed [29], [30], [31], [32]. Griffin et al. [30] proved that 10 mV mm−1 capacitive coupling electrical stimulation could increase the invasion and proliferation of human bone marrow mesenchymal stem cells. It was reported that capacitive coupling EF as low as 4 mV cm−1 increased the proliferation of chondrocytes [32]. The potential application of uniform capacitive coupling EF in promoting wound healing is worthy of further and wider studying.

In this study, the effects of capacitive coupling EF as a NCES on the growth of wound healing were investigated in detail. NCES could be conveniently applied to cells or animals compared with the above researches, and EF distribution analysis and animal experiments were performed to further explore the effects of NCES. Specifically, a self-designed practical device for applying NCES was fabricated and the influences of square electrode plate side length and loading voltage on NCES under the plates spacing of 10 cm were evaluated by analyzing the EF distribution with COMSOL Multiphysics 5.4 software. Subsequently, taking 5, 10, 15, and 20 V NCESs at the plates spacing of 10 cm as the experimental groups, the real EF strengths were measured, and the migration and proliferation of human epidermal keratinocyte cell line (HaCaT) cells and human dermal fibroblasts (HDFs), the differentiation of human leukemia cell line (THP-1) cells, as well as the polarization of macrophages were evaluated. Full-thickness wound healing models on mice backs were utilized to investigate the wound healing ratio, vascularization level and collagen secretion under NCES. It is showed that the cell migration, proliferation, and wound healing ratio were greatly impressed under 54 and 84 mV mm−1 NCESs, indicating the potential of NCES in the clinical treatment of skin tissue damage and achievement of tissue regeneration.

Section snippets

Device fabrication

As shown in Scheme. 1A, a self-designed device providing NCES was fabricated for cell culture and animal experiments. It consists of a direct current regulated power (DH1719A-4, Dahua, Beijing, China), two square copper electrode plates, a Teflon base and two wires. The two electrode plates are connected to the positive and negative poles of the direct current regulated power through wires. The rectangular Teflon base was designed hollow in the center part, and five slots with an interval of

EF distributions between square electrode plates at different side lengths

In order to select electrode plates with suitable size, spatial EF distributions between the electrode plates at the side lengths of 1–50 cm were analyzed, in which plate side lengths of 3, 12, 21 and 30 cm were chosen as the typical representatives. The EF distributions of longitudinal sections and cross sections were presented in Fig. 1A. At the spacing between two electrode plates of 10 cm and the loading voltage of 10 V, it was found that the EF distribution between square electrode plates

Conclusions

In this study, the exploration to the feasibility of NCES means and its influence on promoting wound healing was successfully achieved by using a self-fabricated device. The simulation results supported that the side length of square electrode plates greatly affected EF distribution. When the spacing between two electrode plates is fixed at 10 cm, the longer side length is more favorable for the device to provide more uniform NCES. The electrode plates with the appropriate side lengths of 21

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This study was supported by funds from National Natural Science Foundation of China (NSFC) Research Grants (61871014, 52072015, 31971238, 52071008, U20A20390, 11827803), and it as also supported by National Key R&D Program of China (2017YFC0108505, 2017YFC0108500) and Beijing Natural Science Foundation (7191006).

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