Cold atmospheric plasma as an effective method to treat diabetic foot ulcers: A randomized clinical trial

Our results indicate that three sessions of CAP treatment per week, for three consecutive weeks, accelerate wound healing in diabetic foot ulcers, accompanied by an immediate but brief reduction of bacterial load. To the best of our knowledge, this is one of the few reports that study the effect of CAP in diabetic ulcers. Previous basic and clinical findings also support the effect of CAP in support of wound healing18. A starting point for such research is the well-known broad-spectrum bactericidal effect of CAP18,19,20. In this respect, a rich protein medium such as a wound interface is not affecting the efficacy of the direct treatment of CAP21. Subsequent basic studies suggest that CAP also directly stimulates the regeneration of damaged tissue on the wound surface22. Chronic wounds included diabetic foot ulcers, characterized by wound infections, accumulation of liquid and necrotic tissue, excessive tissue neogenesis, increased release of proteinases and cytokines, and disturbed synchronicity of the different stages of healing23. Poor blood supply to the wound bed, as well as neuropathy, exacerbated the healing process in diabetic ulcers24. A prolonged inflammatory phase, induced by increased concentration of interleukins and cytokines, delays wound closure25. CAP could balance the quality of the inflammatory reaction by decreasing cytokine production and increasing the formation of anti-inflammatory mediators such as IL-10, TGFβ, IL-813. It is assumed that CAP modulates and restores the enzymatically (or non-enzymatically) eliminated nitrogen species (RNS/RONS) or radicals, essential for wound healing16,26. CAP also induces cell proliferation and neovascularization14,15. However, a selective apoptotic effect of CAP on cytotoxic and T-helper cells, B-lymphocytes, and natural killer (NKT) cells may be involved in regulating the healing process27. The CAP in this study can produce a variety of active oxygen and nitrogen products such as O, OH, O2, NO, H2O2. ROS species are beneficial in the eradication of bacterial load. It has been shown that helium CAP can reduce the staphylococcus aureus biofilms up to five orders of magnitude in five minute treatment28. We also observed an immediate antiseptic effect after five minute CAP exposure. ROS produced by CAP can induce the intercellular ROS in the bacteria. This accumulation in intracellular ROS can interrupt the cellular function and inactive the bacteria29.

Based on these biological premises, clinical trials found the successful treatment of burn wounds, venous ulcers, and chronic ulceration in non-diabetic patients by cold plasma treatment9,10,11,12,30,31,32,33. The assessment of CAP treatment on diabetic wounds was limited mainly to animal studies8,34. In our previous paper8, we showed that CAP promotes wound healing process in diabetic rat ulcers. It is important to note that there are significant differences between animal models and clinical trials, such as the dependency of treatment efficacy on patient care, different wound shapes or sizes, and different healing mechanisms. Similarly, it was reported that plasma enhances the wound-healing rate in diabetic rodents, presumably due to increased levels of TGF-β1, superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT)8,34. We show that clinical outcomes in terms of the fraction of wound healing, indicative of the degree of decreased wound size, were statistically lower for the CAP + SC group compared with the SC group. In reviewing previous published studies, accelerating the effect of plasma on wound closure primarily accompanies reduced bacterial load9,10,11,12. However, in our study, the bacterial wound load was not significantly reduced with CAP three times per week, while the fraction of bacterial load ‘after exposure’ was significantly lower than ‘before exposure,’ with each session indicative of CAP’s short-term antiseptic effect. The high local disinfection quality of plasma treatment immediately after exposure shows that wound bacteria recolonize ten hours after CAP treatment35. Patient care was effective in modulating the infection rate of diabetic wounds, which was not addressed here. The frequency and duration of plasma treatments were used more often than the current protocol, according to most previous reports. Isbary et al. reported a significant reduction (34%) of bacterial load in 38 chronically infected wounds with a five-minute daily treatment, using the first-generation product of a plasma source, MicroPlaSter α (Hounslow, Middlesex, UK)19. They later reported that a two-minute daily treatment with either MicroPlaSter α or the second-generation device, MicroPlaSter β was an effective technique to decrease bacterial load in chronically infected wounds30. They found that three to seven minutes of daily plasma treatment for various etiologies over two weeks led to a greater reduction in width and length, compared to controls12.

Brehmer et al. reported that plasma exposure accelerates wound healing, while it reduces the local bacterial load and pain in patients with chronic leg ulcers, given a treatment protocol of three times per week for eight consecutive weeks10. In another study, plasma treatment of pressure ulcers used plasma once a week for eight consecutive weeks, significantly accelerated the reduction rate of wound size, amount of exudate, wound base, and bacterial load. This effect is prominent after one plasma treatment11. Antibacterial effects and healing times in other studies can be explained by differences in the time-course of plasma treatment, the plasma operator system, such as the working gas composition, distance or driving power, environmental variables, and biological tissue characteristics36. Wound depth, not size10, exhibited the major response to CAP treatment, as it is not effective for deep wounds. In light of this, our inclusion criteria were limited to grade 2 ulcers; we also found that wound healing with CAP is independent of the initial wound size.

The current study did have some limitations. The main investigators collecting and analyzing the data were unaware of the assigned treatment, so having the proper placebo for CAP treatment could reduce the possibility of undermining the blinding effect. In our study, patients with diabetic wounds were included, independent of size, infection, or type of colonized bacteria. All aforementioned factors can influence wound healing, although we did not find any significant association between initial wound size and response to CAP treatment.

We treated all wounds with CAP for five minutes per session, irrespective of size: we moved the nozzle in a particular pattern over the wound surface to not leave untreated areas, but it was preferable to adjust the time for wound size to equalize the beam applied to the ulcer’s surface per unit area. This decision was chosen since the wound sizes and shapes were different in each patient and make it challenging to define a protocol for treatment time. It is also notable to state that the treatment time protocol was obtained by the outcome of a limited preliminary study, which we concluded a 5-minute treatment is promising for our research. Safety and risk estimation of plasma treatment have consistently been questioned in medical research. OES shows that most irradiated UV belongs to the 300 to 400 nm, which is not associated with DNA damage37. The treatment response and side effects of plasma used for wounds should be assessed for a longer period than three weeks. No specific harm was reported in the study. For a more complete understanding of treatment mechanisms, elaboration of the cellular response after plasma therapy would be desirable.

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