Cold atmospheric plasma (CAP) is a partially ionized gas generated at near-body temperature. It has drawn attention in wound care because it delivers reactive oxygen and nitrogen species, electric fields and ultraviolet light to tissue without thermal injury. Diabetic foot ulcers (DFUs) are a logical target: they are slow to heal, frequently colonized by bacteria, and a leading precursor to lower-limb amputation. This article reviews what randomized trials and recent reviews actually show.
How cold plasma is thought to work
Laboratory work suggests that the reactive species produced by CAP have antimicrobial effects and may modulate inflammation and stimulate cell migration and angiogenesis. These mechanisms are biologically plausible, but mechanistic findings do not by themselves show that ulcers heal faster in patients. Clinical trials are needed to answer that question, and in DFUs they remain few and small.
The German randomized trial
The most widely cited trial is by Stratmann and colleagues (JAMA Network Open, 2020). It was a prospective, randomized, patient-blinded, placebo-controlled study at two clinics in Germany. Wounds were randomized to eight applications of argon-based CAP or eight sham applications, both on top of standard care. Sixty-five wounds from 45 patients were enrolled, and 62 wounds (31 per group) were analyzed.
At the end of therapy, the remaining wound area was 30.5% in the plasma group versus 55.2% in the placebo group (P = .03), and the time to a 10% area reduction was shorter with plasma. Importantly, the authors reported no significant differences in clinical signs of infection or in microbial load between groups, and no therapy-related adverse events. The final assessment occurred only days after the last treatment, so durable healing and complete closure were not the focus of the results. Baseline median wound area also differed between groups (2.82 cm² versus 1.32 cm²), which is a reminder that small trials can be affected by imbalance despite randomization.
Evidence from Iranian trials
Amini and colleagues (Journal of Diabetes & Metabolic Disorders, 2020) randomized 44 patients, 22 per arm, to standard care alone or standard care plus a helium plasma jet applied for five minutes, three times weekly for three weeks. The abstract reports significantly lower expression of inflammatory markers (including IL-1, IL-8, interferon-gamma and TNF-alpha) and reduced bacterial load after plasma treatment, and concludes the jet was effective for wound healing. A related randomized trial from the same research setting, by Mirpour and colleagues (Scientific Reports, 2020), likewise examined CAP in DFUs. Notably, the bacterial-load signal in this trial contrasts with the German trial, where no microbial difference was seen, illustrating how device type, gas, dosing and concomitant antibiotic use may change results.
What systematic reviews can and cannot say
Systematic review activity is growing. A protocol for a meta-analysis of CAP for DFU healing was registered by Li and colleagues (BMJ Open, 2023), and a systematic review and meta-analysis of randomized trials of CAP added to standard wound care was published online by Matija and colleagues (International Journal of Lower Extremity Wounds, 2025). Because the total number of randomized participants across the field is only in the tens to low hundreds, pooled estimates are likely to carry wide uncertainty, and readers should consult the full texts for effect sizes and certainty ratings rather than relying on headline conclusions.
Interpreting the evidence
Several limitations are shared across the trials. Sample sizes are small, treatment protocols differ (argon versus helium, different session numbers and durations), follow-up is short, and outcomes such as complete wound closure, recurrence and amputation have not been established. Plasma devices are also heterogeneous, so results with one platform may not transfer to another. Finally, CAP has been studied as an adjunct. It does not replace the foundations of DFU care: offloading, debridement, infection control, assessment and treatment of ischemia, and glycemic management.
Key takeaways
Cold atmospheric plasma has a plausible biological rationale and a favourable short-term safety record in small randomized trials, with some evidence of faster early wound-area reduction. Effects on bacterial load are inconsistent between studies, and evidence for complete healing, durability and limb-level outcomes is lacking. Larger, longer, adequately powered trials with standardized protocols are needed before CAP can be considered an established DFU therapy.
References
- Stratmann B, Costea TC, Nolte C, et al. Effect of Cold Atmospheric Plasma Therapy vs Standard Therapy Placebo on Wound Healing in Patients With Diabetic Foot Ulcers: A Randomized Clinical Trial. JAMA Network Open. 2020;3(7):e2010411.
- Amini MR, Sheikh Hosseini M, Fatollah S, et al. Beneficial effects of cold atmospheric plasma on inflammatory phase of diabetic foot ulcers; a randomized clinical trial. Journal of Diabetes & Metabolic Disorders. 2020;19(2):895-905.
- Mirpour S, et al. Cold atmospheric plasma as an effective method to treat diabetic foot ulcers: A randomized clinical trial. Scientific Reports. 2020.
- Li Z, et al. Effect of cold atmospheric plasma therapy on wound healing in patients with diabetic foot ulcers: protocol for a systematic review and meta-analysis. BMJ Open. 2023;13(4):e066628.
- Matija D, Ivan D, Andrea CG, et al. Cold Atmospheric Plasma Therapy for Diabetic Foot Ulcers: A Systematic Review and Meta-Analysis of Randomised Controlled Trials. International Journal of Lower Extremity Wounds. 2025.
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