Treatment of Chronic Venous Ulcer with Cold Atmospheric Plasma Jet

Abstract

Nowadays, cold atmospheric plasma jet (CAP-jet) shows interesting results in the dermatology sector, particularly focusing on wound healing and antimicrobial properties. The purpose of this case report is to present a nonthermal atmospheric pressure plasma treatment as a novel therapy for venous ulcers. The plasma consists of ionized helium gas that is produced by a high-voltage (4.5 kV) and high-frequency power supply (22 kHz). We here present a 65-year-old man with a slow-healing ulcer on the right lower limb. The CAP was applied to the ulcer twice a week for four consecutive weeks and the patient was followed for 6 weeks. The amount of exudate, ulcer size, and wound grading were determined weekly. The results showed that exudate from the ulcer significantly reduced in the first week after complete treatment, the wound grading of the ulcer improved by the second week, and the size of the ulcer significantly decreased after 2 weeks. The ulcer entirely healed after 4 weeks without any signs of infection. This case study demonstrates that applying CAP-jet can decrease the bacterial load on the ulcer site and stimulate tissue regeneration concurrently. This increases the speed of the healing process.

Introduction

One in five adults in developed countries is affected by chronic wounds such as venous leg ulcers, pressure ulcers, and diabetic foot ulcers [1]. Chronic venous ulcer (CVU) is among the most prevalent types of ulcers of the lower extremity and is particularly prevalent among the elderly. CVUs can last and recur for years, significantly impacting the quality of life [2]. These ulcers are the result of a functional failure of venous valves in the lower limbs, which leads to increased backflow and venous hypertension. Treatment of CVUs is usually a significant challenge in daily clinical practice. Treatment options include compression therapy, dressings, and vascular surgery [3]. CVUs should be properly cared for in order to avoid infections and promote healing.

Cold atmospheric plasma has been introduced as a potential new treatment modality in chronic wound therapy. In physical science, plasma is described as the fourth state of matter. Plasma can be “thermal” and “nonthermal.” Nonthermal cold atmospheric pressure plasma, also known as cold plasma, sources are promising and innovative method in different fields of medicine, from oncology to dermatology [4]. Cold plasma is composed of electromagnetic fields, a certain amount of visible light, free electrons and ions, ultraviolet light, infrared radiation, nitric oxide (NO), reactive oxygen species (ROS), hydroxyl (OH), hydrogen peroxide (H2O2), and atomic oxygen (O) (Fig. 1). These special tissue-reactive species are responsible for the broad biological efficiency of CAP on regenerative cellular processes [5]. In particular, disinfecting as well as pH-modulating effects has been described [6]. A number of studies have demonstrated the effectiveness of CAP in treating diabetic foot ulcer, pressure ulcers, burn wounds, full-thickness cutaneous wounds in healthy and diabetic mice.

Fig. 1.

Components by which physical plasmas can interact with their surroundings.

Plasma treatment has the potential to facilitate wound healing by acidification of the wound milieu, stimulation of proliferation and migration of wound-relating skin cells by its pro-angiogenic effect, activation of integrin receptors on the cell surface, and its antiseptic effects. CAP has significant potential in the dermatology field. It can be used for the treatment of various skin infections, sterilization or disinfection, and also for plasma skin rejuvenation [7, 8]. In this case report, we describe an example of the successful use of CAP-jet as a supportive treatment strategy for CVUs.

Case Report

A 65-year-old man was referred to Razi Skin Hospital at Tehran University of Medical Sciences, Tehran, Iran, with a history of 1-year nonhealing venous ulcer on his right lower limb. He had a known history of hypertension, which was controlled by medical treatment. The color Doppler ultrasound examination of his lower extremities venous system revealed deep vein and perforating insufficiency, while the ankle-brachial index was within normal limits. The patient had been previously using a compression wrap with no improvement. Examination revealed a shallow ulcer with a macerated border and an exudative reddened base. The wound was initially subjected to a standard bacterial tissue culture (Levine wound swab technique) to screen for infection, which resulted in negative results.

The wound was then cleaned with normal saline and debrided manually prior to plasma therapy. The treatment period was composed of 4 weeks of CAP therapy and 6 weeks of follow-up. Patients treated with plasma received a 1 min/cm² plasma application twice a week. A dermatologist evaluated the amount of exudate, the size of the ulcer, and the grading of the wound weekly. To compare the wound size and healing process, a high-quality digital photo was taken, and the wound was measured.

The schematic of the plasma jet is shown in Figure 2. CAP was generated from ionized helium gas in ambient air and driven by a high-voltage (4.5 kV) and high-frequency (22 kHz) power supply. The feeding gas for this study was 99.99% pure helium (He) with six standard lit/min gas flow rates. The CAP-jet contains reactive ROS and reactive nitrogen species, as well as different excited helium states. The distance between the nozzle tip and the wound surface was controlled manually in the range of 3–5 mm with slow movement across the wound surface. During the CAP-jet treatment, no thermal damage and electrical shock were reported.

Fig. 2.

Schematic view and actual helium atmospheric plasma jet.

Initially, the ulcer measured 30.23 cm² in size, and after 2 weeks of treatment both the size and depth of the ulcer had significantly reduced (10.62 cm²) (Fig. 3b). The ulcer was found to improve each week, and the surrounding edges had begun to epithelize. The ulcer was completely healed after 4 weeks (Fig. 3c). There was a significant reduction in wound exudate within the first week. The microbiological examination of the wound revealed the presence of Staphylococcus aureus. However, after 2 weeks of treatment, smear and culture results came back negative. There were no significant side effects reported, and the patient well tolerated the treatment.

Fig. 3.

a–c CVU of a 65-year-old male patient located on the right lower limb with the area 30.23 cm², moderate exudate, and sloughy tissue at the baseline treated with CAP-jet. Wound 2 weeks after the beginning with the area 10.62 cm², no exudate, and granulation tissue. The wound 4 weeks after the start is entirely healed without any signs of infection.

Discussion

To the best of our knowledge, this is one of the few case reports that evaluate the effect of CAP-jet on CVUs. As a result of this report, CAP-jet appears to be an effective and safe treatment modality for CVUs.

CAP has proven antimicrobial, antineoplastic, and anti-inflammatory effects and promotes wound healing [9]. Various factors affect wound healing, both systemically and locally. Factors such as the local infection and the age of the patients can delay wound healing. CAP supported effective re-epithelialization, angiogenesis, and controlling of inflammation. It is believed that (ROS) and nitrogen species generated in plasma play an important role in the plasma and tissue interaction. Haertel et al. [4] reported that the influence of plasma on angiogenesis acceleration is an important physiological process in wound healing. Furthermore, cold plasma accelerated the re-epithelialization of full thickness and burn wounds, as has been reported, respectively, by Nasruddin et al. [10] and Ngo Thi et al. [11]. In several studies, it was reported that topical application of NO significantly accelerated wound healing, followed by promoting re-epithelialization, decreasing inflammation, and increasing angiogenesis [12]. Consequently, NO-containing plasma is suggested as a promising strategy for controlling wound inflammation and improving chronic wound care.

The CAP-jet system used in this study is advantageous because the probe is large and capable of treating a large area compared to other plasma generators. The presence of microorganisms has been recurrently suggested as a predominant factor in delayed wound healing. CAP-jet can also be a valuable supplement to antiseptics in treating wound-resident pathogens.

Here we show that plasma treatment is a novel alternative treatment for CVUs. Based on the results, the time to wound healing can be shortened under CAP-jet therapy in CVUs by reducing the wound size and decreasing the bacterial load. Generally, cold plasma therapy is an effective method for increasing angiogenesis factors and decreasing inflammatory factors; this method helps rapid wound healing in patients with chronic ulcers. CAP treatment is a safe and painless new technique to decrease bacterial load for chronic infected wounds. Our results suggest a possible treatment effect of cold plasma for wound healing in venous ulcers in the future.

Statement of Ethics

The study conforms to the guidelines established by the Declaration of Helsinki. Written informed consent was obtained from the patient for publication of this case report and any accompanying images. Ethical approval was not required for this study in accordance with local/national guidelines.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

No funding was received.

Author Contributions

Babak shokri and Hamidreza Mahmoudi initiated the search. Shirin Samsavar, Hamidreza Mahmoudi, and Maryam Daneshpazhooh performed the study. Shirin Samsavar and Mohammad Reza Khani conducted all parts of the research. Shirin Samsavar wrote manuscript. All authors discussed the result, revised the manuscript, and gave final approval for the manuscript.

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

Funding Statement

No funding was received.