(1) Background: The treatment of peripheral arterial disease (PAD) is focused on improving perfusion and oxygenation in the affected limb. Standard revascularization methods include bypass surgery, endovascular interventional procedures, or hybrid revascularization. Cell-based therapy can be an alternative strategy for patients with no-option critical limb ischemia who are not eligible for endovascular or surgical procedures. (2) Aims: The aim of this narrative review was to provide an up-to-date critical overview of the knowledge and evidence-based medicine data on the position of cell therapy in the treatment of PAD. The current evidence on the cell-based therapy is summarized and future perspectives outlined, emphasizing the potential of exosomal cell-free approaches in patients with critical limb ischemia. (3) Methods: Cochrane and PubMed databases were searched for keywords "critical limb ischemia and cell therapy". In total, 589 papers were identified, 11 of which were reviews and 11 were meta-analyses. These were used as the primary source of information, using cross-referencing for identification of additional papers. (4) Results: Meta-analyses focusing on cell therapy in PAD treatment confirm significantly greater odds of limb salvage in the first year after the cell therapy administration. Reported odds ratio estimates of preventing amputation being mostly in the region 1.6-3, although with a prolonged observation period, it seems that the odds ratio can grow even further. The odds of wound healing were at least two times higher when compared with the standard conservative therapy. Secondary endpoints of the available meta-analyses are also included in this review. Improvement of perfusion and oxygenation parameters in the affected limb, pain regression, and claudication interval prolongation are discussed. (5) Conclusions: The available evidence-based medicine data show that this technique is safe, associated with minimum complications or adverse events, and effective.

Clinic of Angiology Faculty of Medicine Comenius University in Bratislava 813 72 Bratislava Slovakia

Department of Applied Mathematics Faculty of Electrical Engineering and Computer Science VSB Technical University of Ostrava 708 00 Ostrava Czech Republic

Department of Surgery University Hospital Ostrava 708 52 Ostrava Czech Republic

Department of Surgical Studies Faculty of Medicine University of Ostrava 703 00 Ostrava Czech Republic

Faculty of Medicine University of Ostrava 703 00 Ostrava Czech Republic

Institute of Imaging Methods Faculty of Medicine University of Ostrava 703 00 Ostrava Czech Republic

Radiodiagnostic Institute University Hospital Ostrava 708 52 Ostrava Czech Republic

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Signaling pathways in cutaneous wound healing