Role of Percutaneous Transluminal Angioplasty for Wound Healing and Dynamics of the Microbial Community in Patients With Type 2 Diabetes and Diabetic Foot Syndrome

The planned study is a monocentric, randomized, and controlled clinical trial. Study participants will be randomized in a 1:1 ratio into two groups: one receiving early PTA ("immediate PTA", within 48 hours after diagnosing a hemodynamically relevant chronic leg artery stenosis) and the other receiving elective PTA (standard of care). Baseline and all follow-up examinations will be performed identically in both groups, except for the timing of PTA. Although the study is unblinded for both participants and physicians due to practical feasibility, blinding will be applied during the data analysis phase. This will involve separate analysis of primary and secondary endpoints by interventionists (physicians or clinicians) and data analysts to minimize bias. Aside from the timing of PTA, baseline and follow-up examinations will be conducted uniformly across both groups. These examinations will focus on the severity and healing process of the foot ulcer. If complications in wound healing occur in the elective group, a crossover to the "immediate" PTA group will be implemented. Thus, for each participant, the treatment of peripheral arterial disease (PAD) and diabetic foot ulcers (DFU) will follow established guidelines and will be monitored and documented by specialized staff during clinical follow-ups and study visits. During the visits, investigators will not only focus on the diabetic foot ulcers but will also consider each participant's overall health. In this context, the investigator will first aim to improve renal retention parameters through sufficient hydration, taking cardiac function into account. In cases of severe renal insufficiency, guideline-based selective angiography with PTA standby using CO2 angiography may be performed, as this method does not affect kidney function.

Baseline characterization The participant's complete medical history, as well as information on current and previous medications, is obtained during the initial clinical evaluation. Additionally, data on lifestyle factors (such as smoking, alcohol consumption, diet, physical activity, mental health, erectile function, symptom severity, pain, self-management, diabetes distress, erectile dysfunction, and diabetes burden), as well as social status, are collected. A physical examination is performed, which includes determining whether venous or neuropathic triggers should be considered in addition to the ischemic etiology of the ulcers. Anthropometric measurements, retinopathy screening, wound swabs, and sampling of deep tissue material from the wound bed for microbiome DNA sequencing are also carried out. Additional proteomic and metabolomic analyses of the wound biofilm are planned. Routine laboratory chemistry testing will be performed regularly during the study visits, and the duration of diabetes and ulcer will also be recorded.

Wound documentation Wound documentation and clinical measures are performed to monitor existing ulcerations using a 3D camera with an AI-based wound analysis system (Curevision®, Munich, Germany) to objectively assess wound healing progress. The system analyzes wound dimensions (length, width, area, and depth) and wound bed tissue (granulation, fibrin, and necrosis), providing consistent, non-operator-dependent data. The wound is assessed according to the WIfI (Wound, Ischemia, and foot Infection) and Wagner (Armstrong) classification criteria, as recommended by current interdisciplinary guidelines. Tissue involvement, including possible osteomyelitis, is investigated by X-ray, computed tomography, or magnetic resonance imaging if clinically indicated. Wound documentation will be conducted at each follow-up visit until wound closure is confirmed.

Perfusion measurement Duplex/Doppler ultrasound of the leg arteries, along with Doppler frequency analysis, is performed alongside ankle-brachial and toe-ankle index measurements. Segmental pulsoscillography is used to locate the site of vascular occlusion and evaluate perfusion pressure, serving as a monitor for critical limb ischemia. Measurement of arterial perfusion at rest and perfusion reserve is achieved using occlusion plethysmography. In the subsequent duplex ultrasound, the anatomy of the peripheral arteries is assessed. Later in the course, these examinations determine the patency of the revascularized vessel segment, the degree of stenosis by peak flow velocity determination, and intimal hyperplasia. Furthermore, flow-dependent dilatation of the femoral artery is also examined using duplex sonography. Of note, in cases of severe renal insufficiency, carbon dioxide angiography may be employed for selective angiography. Oxygen saturation of the foot will be analyzed using a spectroscopic camera, and control measurements will be performed by assessing the hands.

Assessment of Microvascular Complications Diabetic Sensorimotor Polyneuropathy (DSPN) is commonly prevalent in Diabetic Foot Syndrome (DFS) and is assessed using the Neuropathy Disability Score (NDS), based on the modified Toronto Consensus criteria. An NDS score ≥ 3 points is considered pathological. AI-based fundus photography is performed using a non-mydriatic camera (DRS Plus, Centervue®, Padua, Italy) to screen for diabetic retinopathy and macular degeneration. Utilizing confocal imaging technology, the camera provides high-quality retinal images without the need for pupil dilation. Additional complications, such as diabetic kidney disease, are assessed through urinary albumin and creatinine levels, and the estimated glomerular filtration rate (eGFR) is calculated based on cystatin C and creatinine levels.