Title

 

Authors

P. Lo Giudice¹, A. De Rosa¹, F. Borsini<sup>1

1</sup>Research and Development, Sigma-Tau S.p.A., Pomezia, Rome, Italy

 

Abstract

Skin flaps are frequently used in plastic and reconstructive surgeries to repair large skin defects and deep wounds formed from injuries, surgeries, ulcerations, or congenital defects. Nevertheless insufficient arterial supply and inadequate venous drainage can lead to distal skin flap ischemia and necrosis (Robinson et al, 1996). It was recently reported that propionyl-l-carnitine (PLC) improves post ischemic flow recovery and revascularization by promoting dilative arteriogenetic remodeling in a ischemic hindlimb rabbit model (Stasi et al, 2010). Authors report that PLC reduces endothelial NADPH oxidase related ROS production, increases NO availability and reduces expression of cytokines markers of endothelial activation such as VEGF and ICAM-1. These properties of PLC, could be utilized to facilitate “therapeutic angiogenesis” i.e. for the treatment or prevention of pathological clinical situations characterized by local hypovascularity such as tissue regeneration. The aim of the present study was to assess if PLC could be effective in promoting “therapeutic angiogenesis” in the model of skin flap in which angiogenesisis on the basis of healing processes. Male Wistar rats 13-14 weeks old (200-225 g) were anesthetized by intraperitoneal pentobarbital sodium injection (60 mg/kg). Hair was shaved from the dorsal surface. A caudally based dorsal skin flap was elevated from the scapulas to the iliac crest for 10 x 3 cm, and then sutured back into its original site. Rats were randomized into two groups of 15 rats each; one group received oral PLC at the dose of 100 mg/kg/day, the other served as control. Administration of PLC started just after flap creation. The extent of skin flap survival is directly related to the formation of new vessel and is considered a direct measure of the amount of angiogenesis (Kane et al, 2001). Angiogenesis was quantified by measuring the extent of survival flap and monitored by serial assessment of blood flow (BF) in the flap by a scanning laser Doppler perfusion imaging just before, immediately after surgery, and at postoperative days 2, 4, 6, and 8. After the last blood flow recording the necrotic areas were planimetrically measured in blind. No infection or mortality was observed throughout the experimental processes. Laser Doppler imagining of flap in vehicle-treated rats showed that BF dropped as soon as the flap was made. Serial measurements of BF indicate that ischemia was followed by a blood flow restoration in the proximal and medial part of the flap. On the contrary, in the distal part skin perfusion further decreased and remained very low even on days 6 and 8 leading to necrosis. Necrotic skin of vehicle-treated rats measured 1,297 ± 97 mm². PLC-treated animals showed a significantly faster recovery of BF and a higher flap viability, indeed the area of necrotic skin was significantly less than that of vehicle-treated rats (770 ± 80 mm², p < 0.01). Present results show that PLC improves skin flap viability. Angiogenesis is on the basis of healing processes in this type of lesions, indeed in the skin flap model, the distal segment of the flap progressed through ischemia to necrosis and developing of new vessels are required to provide blood flow to the flap. The faster recovery of blood flow and the increased flap viability observed suggests that PLC supporting the formation of new blood vessels reduces the extension of necrotic skin. Even if additional studies are required to evaluate these effects in humans, these findings provide experimental support to use PLC for enhancing skin flap viability and promoting the healing of wounds in clinical settings.
 
Robinson et al (1996), Atlas of Cutaneous Surgery Vol. 1. Saunders Co: Philadelphia. p. 400.
Stasi et al (2010), Arterioscler Thromb Vasc Biol 30: 426-35
Kane et al (2001), Br J Pharmacol 132: 1631−38