Effect of Locally-Administered Pioglitazone on the Survival of Dermal Skin Flaps in an Experimental Study on Rats

Background Distal necrosis remains a common limitation of random-pattern skin flaps due to progressive decline in perfusion and ischemia-reperfusion injury. Pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, has anti-inflammatory effects, but systemic administration may be limited by adverse effects. This study evaluated whether local pioglitazone delivery improves the survival of a random-pattern dorsal skin flap in rats. Materials and methods Sixteen female Wistar rats were allocated into two groups (n=8/group). A cranially based random-pattern dorsal skin flap was elevated in all animals. In the treatment group, pioglitazone was injected subcutaneously into the flap immediately after elevation; the control group received no additional intervention. Flaps were monitored daily, and animals were euthanised on postoperative day eight. Distal flap tissue was harvested, fixed in 10% formalin, processed, and evaluated by Hematoxylin and Eosin (H&E) staining. Necrosis was quantified histologically. Normality was assessed using the Shapiro-Wilk test, and group comparisons were performed using an independent-samples t-test. Severity categories were compared using Chi-Square and Fisher's exact test. Results Necrosis values followed normal distribution (Shapiro-Wilk p=0.106). Group variances did not differ significantly (Levene F =2.207, p=0.160). Mean necrosis was higher in controls (0.825 ± 0.065) than in pioglitazone-treated flaps (0.706 ± 0.102), with a statistically significant between-group difference (t=2.780, p=0.015, 95% CI 0.027-0.210). Categorically, controls exhibited predominantly severe necrosis (seven out of eight) whereas pioglitazone-treated flaps were predominantly moderate (six out of eight), necrosis category differed significantly by group (Pearson χ² = 6.349, df = 1, p=0.012; Fisher p=0.041). Conclusions Local subcutaneous pioglitazone administration significantly reduced distal histological necrosis and shifted outcomes toward less severe injury in a stringent random-pattern dorsal flap model, supporting further investigation of localised pioglitazone as an adjunct to improve flap viability while minimising systemic exposure.