Investigation of the clinical and histopathological effects of topical pentoxifylline application on flep autonomization process in rat back randomized dorsal skin flap

Flaps are used very frequently in the repair of defects that occur in the body due to congenital or acquired reasons. Flap surgery has been performed successfully with increasing knowledge for years. Total or distally started partial necrosis of flaps reduces the success of surgery, causes increased morbidity and mortality rates of patients, hospital costs and loss of labor force. To reduce flap loss, surgical delay method or flap supporting pharmacological agents can be used. Studies on systemic and topical used pharmacological agents continue intensely. Pentoxifylline is a methylxanthine derivate which is nonselective phosphodiesterase inhibitor and causes vasodilatation by relaxing vascular smooth muscle. It also has hemorheological effects; it reduces platelet adhesion and aggregation, increases erythrocyte elasticity and fibrinolysis thus increasing blood fludity. It has antiinflammatory effects, reduces ischemia reperfusion damage. The FDA-approved indication for use of pentoxifylline is intermittent claudication, at the same time due to the mentioned mechanisms of action, it is used systemically to increase flap survival. Systemic side effects limit the use of the drug. In literature, there are many studies on the effects of systemic use of pentoxifylline on flap; there is no study on topical use of pentoxifylline on flap. The study aimed to investigate the effects of the topical form of pentoxifylline on flap survival. In the study 60 5 month old, 250-300 grams female Sprague-Dawley rats were used. Rats were randomly divided into 3 groups. 24 rats were included in each control and experiment-1 groups and 12 rats were included in experiment-2 group. On the back of all rats, caudally based 4 x 3 cm skin flap was made. Until the 5th day of the experiment, vaseline was applied on the flaps of control group and %5 pentoxifylline cream was applied on the flaps of experiment-1 and experiment-2 groups. On the 5th day in all rats, the caudal base of the flap which includes pedicle was cut. On the 5th day, 12 rats from each of the control and experimental-1 groups that applied vaseline for 5 days and %5 pentoxifylline for 5 days were selected. On 8 rats of each group flaps were excised with surrounding tissue for histopathological examination and on 4 rats of each group microangiography was performed, flaps were excised with surrounding tissue and vascularization was examined with contrast on the mammography device. On the 5th day, after cutting the base of the flaps, 12 rats each in all groups, rats in control and experiment-1 groups were followed with vaseline application and rats in experiment-2 group were followed with %5 pentoxifylline cream application. So in rats in control group received vaseline for 12 days; rats in experiment-1 group received %5 pentoxifylline cream for 5 days and vaseline for 7 days; rats in experiment-2 group received %5 pentoxifylline cream for 12 days. On 12th day of the experiment, all rats were photographed and the living and necrosis areas of the flaps were measured. Rats in all groups were sacrified on the 12th day of the study. 8 out of 12 rats in each group, flaps with surrounding tissue were excised for histopathological examination; and on 4 rats of each group microangiography was performed, flaps were excised with surrounding tissue and vascularization was examined with contrast on the mammography device. As a result of this study; on the 12th day the viable areas of flaps were %40.76±7.87 in control group; %95.58±0.99 in experiment-1 group; %100±0 in experiment-2 group. In the contrast microangiography on 5th day; it was seen that vascularization started from the lateral sides to the flap in experiment-1 group and in control group vascularization had not started yet. In the contrast microangiography on 12th day; it was seen that vascularization in experiment-1 and experiment-2 groups wert significantly higher than the control group and vascularization was more in experiment-2 group than experiment-1. In histopathological and immunohistochemical examinations, it has been determined that pentoxifylline significantly increases vascularization and the number of new vessels, epithelization and wound healing; in early stage it reduces inflammation and edema and in late stage it reduces fibrosis. With these results, it was determined that the topical form of pentoxifylline increased flap viability. In clinical use, the beneficial effects of this drug on the flap, which may have gastrointestinal and cardiovascular side effects when used systemic, can be achieved with topical use. Keywords: Flap, Pentoxifylline, Topical, Angiogenesis, Autonomization, Wound Healing