The Effect of Combined Ultrasound and Electric Field Stimulation on Wound Healing in Chronic Ulcerations

Introduction. Ultrasound and electric stimulation are known therapies for the treatment of chronic ulcerations. Combined modulated ultrasound and electric field stimulation (CUSEFS) have never been studied as a single modality. The authors evaluate the results of CUSEFS (BRH Medical Ltd, Jerusalem, Israel) on a variety of wound types in a number of clinics. Methods. This retrospective analysis looked at ulcers treated with CUSEFS in 4 clinics. Wounds were evaluated by an independent assessor and data was evaluated by an independent statistician. Of the 300 wounds treated with the CUSEFS device, only those classified as diabetic foot ulcers (DFUs) or venous leg ulcers (VLUs) were evaluated. A treatment was deemed successful if the wound was 50% closed within 4 weeks. Subjects were then followed to see if their wounds completely closed within 16 weeks. Results. Of the 27 DFUs treated, 59.3% (16) achieved 50% closure within 4 weeks. Of the 38 VLUs treated, 71.1% (27) achieved 50% closure within 4 weeks. It was found that variables such as gender, size of the wound at presentation, and longevity of the wound had no bearing on the outcome. The age of the patient had an effect on the outcome of the VLUs. The wound healing trajectory was supported in that there was a significant difference in the achievement of total closure between those subjects who had a successful trial and those who did not. Conclusion. Combined modulated ultrasound and electric field stimulation has a place as adjunct therapy that aids wound healing and provides an effective noninvasive treatment option.

Amultitude of healing modalities have been attempted for treatment of chronic nonhealing wounds and ulcerations. Chronic wounds and ulcers are defined as those existing for more than 3 weeks without healing or achieving increased structural or functional integrity.¹ According to Hermans,² internal or underlying forces that lead to gradual lesion formation are ulcers, while trauma or lesions formed by external forces are considered wounds. 

Wound healing typically occurs via primary or secondary intention within 2 weeks.³ Wounds are considered chronic when measurements do not decrease by approximately 10% per week or by 50% in a month.³ The larger and deeper the wound, the less chance it has at healing in a short period of time.³ Wound healing phases include inflammation, proliferation, and tissue remodeling, including an abundance of cell types. Soluble mediators, keratinocytes, nerve cells, fibroblasts, extracellular matrix components, and a variety of leukocytes are some of the cell types included in wound healing.⁴

The inflammatory phase begins in the first 24 hours and can last a few days, with the formation of platelet aggregation and hemostasis. Platelet alpha-granules release their contents, including cytokines and platelet-derived growth factor (PDGF). Platelet-derived growth factor promotes revascularization, wound contraction, and granulation tissue production. Cellular relations and chemotaxis allow for the progression of wound healing into the next phase, proliferation, which includes epithelialization. In this phase, which can last for weeks, fibroblasts reorganize a collagen matrix and allow for the reformation of structural integrity and neovascularization.³ Lastly, tissue remodeling occurs, which can persist from months to years, including wound contraction, replacement of type III collagen with type I collagen, and ultimately increased tensile strength. Fibroblasts convert to myofibroblasts, collagen is remodeled by matrix metalloproteinases, and a stable epithelial structure is fabricated.³  

Treatment of chronic wounds benefits from ultrasound therapy by increasing local blood flow in the wound and periwound area, stimulation of angiogenesis, increased vascular permeability, cellular protein synthesis, and improved collagen substance and configuration.^5-8 Electrical stimulation therapy assists in wound healing by affecting the electrochemical wound process. Intact skin has a transepithelial potential, with the skin surface containing a negative charge from chloride ions and the dermis maintaining a positive charge via sodium ions. Ulcerations and wounds lead to abnormalities in the transepithelial potential, which may promote wound healing. Chronic wounds lose the electrical currents and, hence, have decreased healing. Electrical stimulation therapy reintroduces the currents and assists with the healing process.^8-10

Yao et al¹¹ evaluated nonhealing neuropathic diabetic foots ulcers (DFUs) treated with ultrasound for a period of 5 weeks. Ultrasound was applied to different treatment groups: 1) 3 ultrasound treatments per week, 2) 1 ultrasound treatment per week, and 3) control group without ultrasound treatment. The study found that the group treated 3 times per week had significant wound area reduction in weeks 3, 4, and 5. No statistical difference existed between the second and third groups. The study found that ultrasound was effective in treating chronic neuropathic diabetic foot ulcerations partly by reducing proinflammatory cytokines and enhancing tissue regeneration, with increased ultrasound usage leading to better results.¹¹

Baker et al¹² studied electrical stimulation waveforms on healing rates of diabetic patients with ulcerations. Patients receiving asymmetric biphasic waveforms had significantly increased healing rates of nearly 60% compared to the control with no electrical stimulation. Similarly, Peters et al¹³ evaluated high voltage, pulse galvanic electrical stimulation on DFUs, finding that 65% of patients in the group treated with stimulation had enhanced wound healing compared to the placebo group with no electrical current therapy.

Institutional review board approval was received to perform a retrospective analysis of patients treated with combined ultrasound and electric field stimulation (CUSEFS) (BRH A2 device, BRH Medical, Jerusalem, Israel). Four centers were selected. The data for patients treated between July 2013 and September 2014 was collected from the wound management system devices used to treat them and given to an independent assessor. More than 200 files were reviewed and filtered in the following way to achieve an evaluable group. First, only patients whose ulcers were categorized as DFUs or VLUs were included. Figures 1, 2, 3, and 4 represent typical wounds treated with CUSEFS. Second, any subject who did not receive a minimum of 8 treatments given twice weekly for 4 weeks, as per the manufacturer’s treatment protocol, except for those who achieved total closure prior to that time, were excluded. Patients who were excluded for this reason were contacted and surveyed for the cause of their stopping treatment with CUSEFS. None of these patients stopped treatment due to adverse events. Finally, 3 more subjects were excluded from statistical evaluation because their age was more than 2.5 standard deviations from the average, making them statistical outliers.

Those subjects who were evaluable were divided into a DFU group and a VLU group. Patients diagnosed with diabetes were included only if their HbA1C was < 10.0. Patients in the DFU group were excluded if they had an ankle brachial index < 0.5. In the VLU group, patients were excluded if they had a diagnosis of a known or active venous thrombus in the area being treated. Smokers were not excluded from evaluation. Patient demographics, including age and gender, were evaluated. Ulcers were evaluated for size at presentation and the longevity of the wound prior to commencement of treatment with CUSEFS. Once CUSEFS was initiated, no changes to prior treatments were allowed. Patients were allowed to continue with any treatments they had been receiving prior to initiation even though they had been deemed failures. This was used as a built-in control. In the DFU group, treatments ranged from debridement and offloading to wound care with advanced wound dressings, not including biologics. For the VLU group, debridement, as necessary, was performed and all patients were treated with 3-layer compression dressings as they had been prior to CUSEFS initiation. Combined ultrasound and electric field stimulation was performed twice weekly for 25 minutes each visit. An independent assessor evaluated wound photographs and performed the planimetry such that all measurements were carried out by a single individual. This was deemed important so that attention to details, such as characterizing wound edges or areas of epithelialization, were standardized across all measurements. The wound management system device utilized for the CUSEFS features an integrated digital planimetry system. The assessor manually traced the wound edges and the software calculated the wound surface area (Figures 5 and 6). Wound measurements were recorded for the initial visit as well as at visit 8, which occurred at 4 weeks from the beginning of the study. Patients who achieved total wound closure prior to 8 visits were photographed and evaluated at their last visit. Patients whose ulcers closed 50% or more during the 4 weeks were judged a success. Both treatment successes and failures, defined those whose wounds closed less than 50% in 4 weeks, were followed to evaluate if they achieved wound closure by 16 weeks of treatment. Some patients continued to receive treatment, but data was not formally collected past 16 weeks, which was deemed the end of the study period. 

The data was analyzed with descriptive statistics and regression analysis was performed according to the subjects’ age, gender, ulcer longevity, and size of ulcer at presentation. Reports of total wound closure by 16 weeks were further evaluated to see if there was a difference between wounds that closed 50% during the 4 weeks as compared to those that did not.

Table 1 represents the overall results of this study. There were 26 patients with DFUs and 36 patients with VLUs. In the DFU group, 16 (59.3%) exhibited 50% closure during 4 weeks of treatment, and in the VLU group, 27 (71.1%) exhibited 50% closure within 4 weeks.

In the DFU group there were 17 males and 9 females. In the VLU group there were 15 males and 21 females. There was no difference in the effect of gender on the results of the study (Tables 2 and 3) (DFU group P > 0.05; VLU group P > 0.05).

The average age of the subjects in the DFU group was 81.5 years (Range: 63-104 years), and in the VLU group the average age was 77 years (range: 59-96 years). There was no significant effect of age on achieving a successful result in the DFU group (P > 0.05). In the VLU group, age was a significant predictor of achieving 50% closure within 4 weeks (P < 0.05) (Tables 4 and 5).

The size of the wounds at initiation of the trial ranged from 0.19 cm² to 9.47 cm². In the VLU group the wounds ranged from 0.27cm² to 38.57cm² at presentation. There was no significant effect of size of the wound on successful outcome in either the DFU or the VLU groups (P > 0.05) (Tables 6 and 7). Size of the wound at initiation of the trial had a significant effect on achieving total closure within 16 weeks in the DFU group (P < 0.05) but not in the VLU group (P > 0.05) (Tables 8 and 9).

The wounds in the DFU group were treated on average for 27.4 weeks (range: 4-112 weeks) prior to initiation of the trial with CUSEFS. In the VLU group, wounds were treated on average for 28 weeks (range: 8-160 weeks) prior to initiation of CUSEFS treatment. There was no significant difference on wound longevity prior to initiation of CUSEFS treatment on achieving a successful result of 50% closure within 4 weeks (P > 0.05) or on achieving total closure within 16 weeks (Tables 10, 11, 12, 13).

The 3 patients who were analyzed separately because of their young age all achieved wound closure of more than 50% within 4 weeks and 2 of the 3 achieved total closure within 16 weeks. A successful outcome of 50% closure within 4 weeks significantly predicted total closure within 16 weeks in both the DFU (P < 0.05 one tailed) and the VLU (P < 0.001) groups (Tables 14 and 15).

While both ultrasound therapy and electric stimulation have been in use for more than a century, their combination as a single therapy in the field of wound care has never been evaluated. These modalities have wound healing factors that complement and supplement each other. The wound management system device used in this study not only combines the 2 modalities but modulates them both individually and in combination during the treatment period. This modulation is both in intensity and, specifically in the electric stimulation, directional. This not only alters the overall effect on the cellular structures but modifies the directions of cellular and subcellular aggregation. The wound management system device provides ultrasound frequencies ranging from 1.0-3.0 MHz with an intensity ranging from 0.0- 2.0 W/cm². The electrical field stimulation interferential beat frequency ranges from 0-250 Hz. The modulation that occurs during the treatment is built into the software and this provides a multitude of therapeutic intensity and frequency combination during the therapy session to capture more of the benefits of each individual combination. For instance, ultrasound is known to stimulate fibroblasts to create collagen and also to lay the new collagen in a more ordered pattern, resulting in a better weave for epithelialization. Electric stimulation is known to pull the fibroblasts and resultant collagen taut, resulting in an even stronger weave. The resultant combination of the 2 therapies is a more ordered and tighter collagen weave.

While the results of the investigation were significant and positive, it is interesting that confounding factors such as age, initial size of the wound, and the longevity of the wound prior to treatment had no effect on outcome. The only exception to this was the effect of age on healing rates in VLUs. It is interesting to note that the effect was only in the initial stage of the evaluation of 50% closure within 4 weeks, but not in achieving total closure within 16 weeks. One possible explanation for this is the more systemic changes being effected by the CUSEFS, which does eventually get activated but does so at a slower pace. These generalized effects are not part of the healing in DFUs and, therefore, the authors saw no effect of age on DFU healing rates.

The study also supported the concept of wound healing trajectories. Wounds that healed between 25%-50% within 4 weeks would progress to achieve total closure, as seen in Steed and colleagues²⁴ and Cardinal and coauthors.²⁵ Wounds that achieved a 50% closure within 4 weeks had a greater likelihood of achieving total closure and at a faster rate than those that did not reach that endpoint. This was true even after the subjects who achieved 100% closure during the first 4 weeks were removed from the 16-week analysis.

This study shows a CUSEFS device has a positive effect on stimulating wound healing in chronic ulcerations both in matters of chronicity and quality of the healing. Although further evaluation is necessary and a randomized controlled trial would be needed, the results of this study certainly indicate CUSEFS is an excellent adjunct modality and that the combination of ultrasound and electric field stimulation in the modulated way performed by this device has a significant synergistic effect on wound healing. The negative correlation with the wound healing trajectory shown by this study is likely due to the small sampling and should be evaluated on a larger group.

Affiliations: Department of Vascular Surgery, Beilinson Medical Center, Petach Tikva, Israel; Diabetic Foot Service, Shaarei Zedek Medical Center, Jerusalem, Israel; Yale New Haven Hospital, New Haven, CT; Private Practice, Lodi, NJ; Lander College, Department of Psychology, New York, NY

Correspondence:
Jonathan I. Rosenblum, DPM
Shaarei Zedek Medical Center
12 Bayit Street
Jerusalem 91031, Israel
diabfootman@gmail.com 

Disclosure: The authors disclose no financial or other conflicts of interest.