Short-Term Nicotine Improves Experimental Flap Survival: Implications for Different Findings in Experimental Flap Models

Background and Objectives: The effects of nicotine on wound healing and flap survival remain controversial. While smoking is associated with increased flap complications, emerging evidence suggests that nicotine may exert dose- and duration-dependent effects. This study aimed to investigate how short-term, low-dose nicotine affects flap survival and to evaluate its potential role in oxidative stress and ferroptosis. Materials and Methods: Twelve adult male BALB/c mice were randomly assigned to either a control group or a nicotine-treated group, with six mice in each group. Nicotine, at a dose of 2 mg/kg, was given subcutaneously for fourteen days before flap surgery. This treatment continued for seven days after the surgery. A dorsal random-pattern skin flap model was established in all animals. The flap necrosis area was assessed on postoperative day 7 using planimetric analysis. Serum and tissue glutathione peroxidase 4 (GPX4) levels and serum malondialdehyde (MDA) levels were measured. Histopathological evaluation included epithelialization, microvascular density, neovascularization, fibroblast density, and inflammatory cell infiltration. Results: Nicotine treatment significantly reduced flap necrosis compared with the control group. Histopathological analysis demonstrated significantly increased epithelialization and microvascular density in the nicotine-treated group, whereas no significant differences were observed in neovascularization, fibroblast density, or inflammatory cell infiltration. Biochemical analyses revealed no significant differences in serum or tissue GPX4 levels or serum MDA levels between the groups. Conclusions: Short-term nicotine administration enhanced flap survival, correlating with increased epithelialization and microvascular density, while not significantly affecting markers of oxidative stress or ferroptosis. These results imply that the positive impact of nicotine on flap viability might be largely attributable to vascular processes rather than pathways involving oxidative stress.