Electrical Stimulation: Can It Help Facilitate Wound Closure?

While there are varied modalities available to help manage stubborn wounds, this author suggests that electrical stimulation may play an adjunctive role. Accordingly, he reviews the current literature, theories and practical application of electrical stimulation in wound care.

   As the field of wound care progresses clinically from a focus on the gross and cellular levels to a better understanding of the subcellular and biochemical levels, our approach to treatment has progressed from passive dressing modalities to advanced wound care products including mechanically driven wound care modalities. Mechanical wound care products incorporate physical modalities including pressure, ultrasound, radiofrequency and electrical stimulation.

   As our understanding of the inner workings of cells increases, we begin to try to manipulate cells in the most positive way to induce quicker and better wound healing. The best of these modalities not only alter the structure of the cells involved but also induce the biochemical actions that cause healing. The ultimate goal is not only to heal the current wound but also to generate healing so the tissue is in such a condition as to minimize the risk of ulceration recurrence.

   The “current of injury” and exogenous mimicking of the phenomenon for wound care is not a new concept. Ojingwa finds reference to the use of electric stimulation as far back as the 17th century. He relates the use of an electrostatically charged gold leaf to enhance the healing of smallpox lesions.1

   Barker and colleagues observed that wounds in the skin induce an instantaneous current flow out of the wound (driven by the transepithelial potential difference). This establishes a steady direct current (DC) electromagnetic field at the wound of up to 200 mV/mm that persists until re-epithelialization is complete.2 This translates into the fact that in the presence of a wound, our skin battery leaks its electric potential until such time as the wound heals.

   This electric field is important for generating a natural biological galvanotaxis, which draws cells and neural tissue to the wound to generate healing. In a chronic wound, this electromagnetic field is disrupted and therefore inhibits cellular regeneration. If electrical signals play a role in the stimulation of wound repair, then one could expect that exogenous application of an electrical current to chronic wounds could mimic the body’s bioelectrical currents and enhance tissue healing processes.

   Cruz and co-workers found the current of injury varied in specific ways during the regeneration process with the current ceasing to flow as healing completes or stalls.3 Foulds and colleagues, in demonstrating the “skin battery,” showed that a voltage is consistent across the epidermis.4 They note that the outer surface of the skin is negatively charged with respect to the positively charged dermis.

A Guide To The Theoretical Basis Of Electric Stimulation

   While the mechanism by which electric stimulation changes the cellular environment is still unknown, researchers have put forth a number of hypotheses. Bourguignon and colleagues propose that electric stimulation affects the cells simply by inducing a local increase in temperature, which generates a localized increase in cellular metabolism.5

   While this is interesting, it does not account for the significant increase in proliferation and in healing rates in comparison with other heating modalities. Numerous studies have focused on localized warming of the wound area with results that were not as impressive as those with electric stimulation.

   Another theory is that electric stimulation causes a change in pH in the wound area. While pH has become an area of research of late in wound care, not enough is known to be able to attribute the increase in healing to this reason.

   A third possibility is that the electrodes themselves are shedding metal ions into the wound area, thereby affecting cellular biosynthesis. Bourguignon and co-workers discount this theory.6 I would also discount this theory.5 While this may explain the increase in high voltage pulsed current (HVPC) electric stimulation where the electrodes are in the wound bed, it does not explain the dramatic increase in healing rates even when one only places the electrodes in the periwound area.

   Binder suggests that electric stimulation may not be causing an electrochemical reaction but rather be triggering an electrophysiologic response in the cells including membrane-related events such as gating of ion channels or activating membrane-bound enzymes.6 Tsong and colleagues have supported this hypothesis, showing that an electric field can stimulate membrane bound ATPases.7

What You Should Know About Electric Stimulation Devices

   There are four basic types of electric stimulation devices: low intensity direct current (LIDC), HVPC, alternating current (AC) and transcutaneous electrical nerve stimulation (TENS).

   The LIDC is a continuous monophasic waveform with a current kept at a low voltage. The HVPC is defined as having a waveform of paired pulses with a long interval between the pulses. The AC is characterized by symmetrical biphasic pulses using low voltage and amperage. The TENS is also an alternating current in a lower frequency than standard electric current. The major treatment protocol difference between AC and TENS in comparison to LIDC and HVPC is that in the latter two, one places the electrodes inside the wound. In contrast, with AC and TENS, the physician places the electrodes on intact skin in the periwound area.

A Closer Look At Cellular And Biochemical Changes Triggered By Electrical Stimulation

   Yang and colleagues observed a change in the cell shape and cytoskeleton reorganization in mouse fibroblasts when they were exposed to a low intensity direct current.8

   While Kincaid and co-workers have shown electric stimulation to have a bacteriocidal effect in wound care, there is much debate as to how much of a dose of electrical stimulation is required to produce that effect.9 Cooper and Erickson showed that in vitro epidermal cells, cell clusters and cell sheets demonstrated galvanotaxis in migrating toward the cathode.10,11

   Zhou and colleagues found the electrical stimulation activated VEGF production and release, causing a reduction in localized ischemia on a cellular level.12

   Orida and co-workers showed that macrophages migrated toward the anode while Fukushima and colleagues showed that neutrophils migrate to both the anode and cathode.13,14 Weiss and colleagues showed that after application of electric stimulation, there was a reduction in mast cells, which are over-represented in numerous fibrotic disorders.15

   Bourguignon and colleagues reported that HVPC of fibroblasts led to increased DNA production and protein synthesis.5 They did not observe this effect during treatment but rather upon the completion of each treatment cycle. Protein synthesis peaked at two hours post-treatment. The DNA synthesis was less uniform with the peak occurring anytime from two through 24 hours post-treatment. I believe (and I am currently involved in research to this end) that the reason for this diversity is related to the chronicity of the wound itself.

   Bourguignon also reported that this effect was maximized based on proximity to the cathode.5 It is also important to note that when researchers employed higher electrical intensities, both protein and DNA synthesis decreased, showing that there may be a dose response. Weiss and colleagues showed that in cultured fibroblasts stimulated with pulsed current, there was a six-fold increase in the expression of receptors for transforming growth factor-β with respect to control fibroblasts.15

Other Pertinent Insights

   While the in vitro research suggests that electric stimulation would be an effective adjunct therapy in many types of chronic ulcers, until 2003, most controlled research focused on the effect of electric stimulation on pressure ulcers.

   Houghton and colleagues performed a randomized controlled trial in 2003 to evaluate the efficacy of HVPC electric stimulation on diabetic foot ulcers as well as vascular ulcers due to either arterial or venous insufficiency. They found an almost twofold healing rate in comparison to the sham-treated legs in all three types of ulcers.16

   Feedar and co-workers showed that providing electrical stimulation for 60 minutes per day, five to seven times per week was enough to enhance tissue healing.17 They also found that altering the frequency of the pulse rate during the duration of treatment was beneficial. They felt the higher pulse rate was detrimental to the newly healed tissue.

Case Study: When A Patient Presented With An Ischemic Ulcer

   A 78-year-old male presented for an office visit with a Wagner grade 1-2C ischemic ulcer on the posterior left calf. The ulcer had been present for two months. The ulcer was ovoid and was 5 cm wide by 16 cm long. The necrotic black eschar was stuck to the underlying tissue and was painful to the touch.

   Previous treatment included the use of silver dressings and hydrogels, as well as repeat debridement. When the patient presented to us, his main complaint was pain in the area as well as a fear of the gangrene spreading.

   We took cultures from the necrotic tissue and nothing of note grew out. Biopsy of the wound revealed necrotic tissue with gangrene and minimal mitotic activity as well as no vascularization of the superficial tissue.

   We sought to moisten the wound edges so the wound would loosen and enable easier and more painless debridement. To accomplish this, we decided to keep the tissue in a constantly moisturized environment with a thick layer of hydrogel. To accelerate healing, we surrounded the wound on its medial and lateral edges with the LifeWave BST device (High-Tech Medical Devices, Ltd.), creating a field that ran transverse to the wound. We explained to the patient that the electrical stimulation was likely not to have much obvious added value for the first 14 days.

   We changed the patient’s dressings and electrodes every two days with constant monitoring for the development of infection. At day 14 the wound edges had loosened considerably. We were subsequently able to perform debridement and the post-debridement wound size was 4.3 cm by 14 cm. The patient came to the clinic for weekly visits including debridement.

   At four weeks, the wound was 40 percent closed with healthy soft epithelium where the ulcer had been. At seven weeks, the wound was 88 percent closed. At nine and a half weeks, the wound was totally closed with healthy epithelium where the wound had been. The patient related no pain on palpation of the area and there was full ankle range of motion.

In Conclusion

   Mechanical treatment modalities are the wave of the future in the field of wound care. Many of the modalities are modern adaptations of historic treatments. Electric stimulation has been around for almost 300 years. In the last 30 years, multiple modalities of this treatment have emerged.

   Although very few randomized controlled trials have been conducted, especially in the field of diabetic foot ulcers, the clinical compilation of reported cases is impressive. From both this and my clinical experience, electric stimulation is a very good adjunctive therapy in wound care.

Dr. Rosenblum is the Director of the Diabetic Foot Service at the Shaarei Zedek Medical Center in Jerusalem. He is the Medical Director for the Mamlam (Advanced Treatment) Clinic Chain, which specializes in emerging wound care technologies. He also serves as a research and development consultant to many med-tech start-ups in Israel and Europe.

References:

1. Ojingwa JC, Isseroff RR. Electrical stimulation of wound healing. J Invest Dermatol 2003 Jul; 121(1):1-12. 2. Barker AT, Jaffe LF, Vanable JW Jr. The glabrous epidermis of cavies contains a powerful battery Am J Physiol 1982; 242(3): R358-R366. 3. Cruz NI, Bayron FE, Suarez AJ. Accelerated healing of full thickness burns by the use of high voltage pulsed galvanic stimulation in the pig. Ann Plast Surg 1989; 23(1):49-55. 4. Foulds IS, Barker AT. Human skin battery potentials and their role in wound healing. Br J Dermatol 1983 Nov; 109(5):515-22. 5. Bourguignon GJ, Bourguignon LY. Electric stimulation of protein and DNA synthesis in human fibroblasts. FASEB J 1987; 1(5):398-402. 6. Binder SA. Applications of low and high voltage electrotherapeutic currents. In Wolf SL (ed.): Electrotherapy. Churchill Livingstone, New York, 1981, pp.1-24 7. Tsong TY, Astumian RD. Absorption and conversion of electric field energy by membrane bound ATPases Bioelectrochem Bioenerg 1986; 15:457-476 8. Yang WP, Onuma EK, Hui SK. Response of C3H/10T1/2 fibroblasts to an external electric field stimulation. Exp Cell Res 1984; 155(1):92-104. 9. Kincaid CB, Lavoie KH. Inhibition of bacterial growth in vitro following stimulation with high voltage, monophasic, pulsed current. Phys Ther 1989; 69(8):651-655. 10. Cooper NS, Schliwa M. Electrical and ionic control of tissue cell locomotion in a DC electric field. J Neurosci Res 1985; 13:223-244 11. Erickson CA, Nuccitelli R. Embryonic fibroblast motility and orientation can be influenced by physiological electric fields. J Cell Biol 1984; 98(1):296-307. 12. Zhou M, Bai H, Wang E, et al. Electrical stimulation directly induces pre- angiogenic responses in vascular endothelial cells by signaling through VEGF receptors. J Cell Sci 2004; 117:397-405. 13. Orida N, Feldman JD. Directional protrusive pseudopodia activity and motility in macrophages induced by extracellular electric fields. Cell Motil 1982; 2(3):243-256. 14. Fukushima K, Senda N, Inui HM, et al. Studies on galvanotaxis of human neutrophilic leukocytes and methods of its measurement. Med J Osaka Univ 1953; 4:195-208. 15. Weiss DS, Eaglestein WH, Falanga V. Exogenous electric current can reduce the formation of hypertrophic scars. J Dermatolo Surg Oncol 1989; 15(12):1272-1275. 16. Houghton PE, Kincaid CB, Lovell M, et al. Effect of electrical Stimulation on chronic leg ulcer size and appearance Phys Ther 2003; 83(1):17-28. 17. Feedar JA, Kloth LC, Gentzkow GD. Chronic dermal ulcer healing enhanced with monophasic pulsed electric stimulation. Phys Ther 1991; 71(9):639-649. Additional Reference 18. Gardner SE, Frantz RA, Schmidt FL. Effect of electrical stimulation on chronic wound healing: a meta-analysis. Wound Rep Reg 1999; 7(6):495-503.