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Diabetic foot ulcers are a leading cause of hospitalization. A reduced formation of new vessels and capillaries is responsible for the poor wound healing observed in diabetes. Adenosine A2A receptor plays a central role in modulating angiogenesis. PDRN (polydeoxyribonucleotide) is a DNA derived drug that engages adenosine A2A receptors. In experimental studies PDRN improved the skin repair process and enhanced wound-breaking strength in diabetic animals. This effect was supported by a marked increase in the expression of Vascular Endothelial Growth Factor (VEGF), a master regulator of angiogenesis that is impaired in diabetes-related wound disorders. The healing-promoting effect was abrogated by adenosine A2A receptor antagonist DMPX. PDRN beneficial effects were confirmed in a clinical trial. Diabetic patient with Wagner grade 1 or 2 ulcers were randomly assigned to receive placebo (n=106) or PDRN (n=110) for 8 weeks. The drug was injected daily by intramuscular route (5.625 mg in a 3 ml, vial) for 5 day/week and by perilesional route (5.625 mg, in a 3 ml vial) 2 day/week for 8 weeks. The treated group nearly doubled the rate of complete healing of difficult-to-heal diabetic foot ulcers compared to placebo as early as 8 weeks after start of treatment. This study is one of the largest trial ever carried out in diabetic patients with poor diabetic skin repair that points out a dramatic efficacy of PDRN in improving hard-to-heal chronic diabetic foot ulcers and confirms the role of adenosine A2A receptor in\ diabetes related waound healing disorders.