Critical limb ischemia is the end-stage manifestation of peripheral arterial disease (PAD), frequently presenting as ischemic rest pain, ulceration, or gangrene. Diabetes mellitus is a major risk factor for lower extremity arterial occlusion, with infrapopliteal arteries most commonly affected. Patients with diabetic foot ulcers (DFUs) have a high prevalence of neurovascular complications, poor healing, and elevated amputation and mortality rates. Large-scale cohort studies indicate that five-year survival after amputation in this population is only about 50%, underscoring the need for more effective therapies.
Endovascular revascularization has become the first-line treatment for diabetic lower limb ischemia. However, despite successful revascularization, persistent microvascular dysfunction and difficult-to-heal ulcers remain common due to chronic inflammation, impaired angiogenesis, and tissue repair deficits. Current advanced wound dressings provide limited benefit and are often costly.
Cold atmospheric plasma (CAP) has emerged as a promising adjunctive therapy, with demonstrated antimicrobial activity-including efficacy against multidrug-resistant organisms-and the ability to promote microcirculation and wound healing. CAP generates reactive oxygen and nitrogen species that disrupt bacterial membranes and may also stimulate tissue regeneration. Preclinical and clinical studies suggest that CAP can accelerate healing in chronic wounds and is well tolerated by patients.
Given these advantages, the present study aims to assess the efficacy and safety of CAP combined with endovascular intervention in patients with diabetic foot ulcers and lower extremity arterial occlusion, to inform future clinical application of this novel technology.
Aged 18-80 years, with a diagnosis of type 1 or type 2 diabetes and diabetic foot ulcer; glycated hemoglobin (HbA1c) ≤ 10%.
Presence of at least one chronic foot ulcer persisting for at least three weeks, with no signs of healing after standard-of-care treatment based on current clinical guidelines. The ulcer must be classified as Wagner-Armstrong grade 1D or 2D (Wagner: superficial ulcer [grade 1] or ulcer extending to tendon [grade 2]; Armstrong: presence of both ischaemia and infection [stage D]).
Documented infrapopliteal arterial stenosis or occlusion by vascular ultrasound and/or CT angiography (CTA), meeting indications for revascularization. All enrolled patients must have received successful infrapopliteal balloon angioplasty, with intraoperative angiography confirming target artery patency.
Provision of written informed consent.
Concurrent treatment of the wound with local vacuum therapy or maggot therapy.
Undergoing dialysis.
Use of local active antibiotics.
Treatment with platelet-rich fibrin.
Parallel
Cold atmospheric plasma (CAP)
DeviceCAP therapy will be administered once daily for the first five days and then every other day thereafter, for a total of 13 sessions. Each session will last approximately 25 minutes, as recommended by the manufacturer. During treatment, the affected limb will be enclosed in a sterile treatment bag, sealed with medical adhesive tape. The CAP device will operate in two sequential modes: a "disinfection mode" delivering ozone-rich (O₃) plasma-activated gas for 20 minutes, followed by a "healing mode" delivering nitric oxide (NO)-rich plasma-activated gas for 5 minutes. All procedures will be performed in accordance with the manufacturer's instructions and the device's standard operating protocol.
Sham Procedure
DeviceParticipants in the placebo group will undergo a sham procedure, in which the electric field required for plasma generation will be disabled, so that no plasma will be produced. Only the operating sounds of the device will be simulated, ensuring blinding for both participants and clinical staff.
Successful infrapopliteal angioplasty
Other interventionAll patients will undergo successful infrapopliteal angioplasty, with less than 30% residual stenosis confirmed by digital subtraction angiography.
Change in ulcer area between groups
The ulcer area (cm²) will be measured daily during the first five days, and every other day for the subsequent eight visits (13 follow-up assessments in total)
Time to 10% reduction in ulcer area
The time from randomization to the first occurrence of a 10% reduction in ulcer area
Time to 20% reduction in ulcer area
The time from randomization to the first occurrence of a 20% reduction in ulcer area.
Time to onset of clinical signs of infection
The time from randomization to the first documented clinical sign of wound infection.
Change in pain score
Change in pain score, assessed by the Visual Analogue Scale (VAS; 0 = no pain, 10 = worst imaginable pain; higher scores indicate greater pain severity)
Change in pain score
Change in quality of life (EQ-5D questionnaire)
Change in quality of life (SF-12 questionnaire)
Incidence of keloid formation
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Shenyang Medical College
Lead sponsor
Ansteel General Hospital
Collaborator
Tsinghua University
Collaborator
