**3. Etiology and risk factors**

Peripheral neuropathy and peripheral arterial disease are the most frequent causes of diabetic foot ulcers out of a range of interrelated factors. Diabetic foot ulcer is hence frequently referred to as neuropathic, neuroischemic, or ischemic ulcers. Since the 1990s, ischemic and neuroischemic ulcers have become the most common cause of diabetic foot ulcer, accounting for more than one-third of all cases [14, 15]. This is most likely due to increased awareness of the importance of ischemia in diabetic foot ulcer and its detrimental effects, but it may also be related to improved diagnostic procedures, which could have an impact on recommendations for diagnostic criteria [15, 16]. Between 70 and 83% of diabetic patients with serious soft-tissue infections have polymicrobial at the time of diagnosis [17]. Additionally, chronic diabetic foot ulcer has abnormally high matrix metalloprotease (MMP) levels compared with acute wounds, which promotes tissue disintegration and eventually impedes normal healing processes [18]. Diabetes and long-term smoking both raise the risk of gangrene [19]. Gas gangrene, a rare consequence of diabetic foot ulcers, can occur in people with these persistent non-healing lesions [20]. Gangrene is induced by a decrease in blood flow to the affected tissues, which causes a hypoxic environment and cellular damage from Advanced Glycation End Products, which leads to cell death [21]. Diabetes mellitus (DM) affects wound closure processes, beginning with a reduction in fibrinolysis and an imbalance of cytokines, which produces a change in wound closure [22]. Inadequate re-epithelialization is caused by hyperglycemia, which also inhibits angiogenesis and cell migration. Similarly, inadequate extracellular matrix (ECM) formation by fibroblasts contributes to the issue of inadequate wound healing [23, 24].
