Delivery of FGF-2 but not VEGF by encapsulated genetically engineered myoblasts improves survival and vascularization in a model of acute skin flap ischemia

Stimulating angiogenesis by gene transfer approaches offers the hope of tre ating tissue ischemia which is untreatable by currently practiced technique s of vessel grafting and bypass surgery. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF-2) are potent angiogenic mo lecules, making them ideal candidates for novel gene transfer protocols des igned to promote new blood vessel growth. In this study, an ex vivo gene th erapy approach utilizing cell encapsulation was employed to deliver VEGF an d FGF-2 in a continuous and localized manner. C2C12 myoblasts were genetica lly engineered to secrete VEGF(121), VEGF(165) and FGF-2. These cell lines were encapsulated in hollow microporous polymer membranes for transplantati on in vivo. Therapeutic efficacy was evaluated in a model of acute skin fla p ischemia. Capsules were positioned under the distal, ischemic region of t he flap. Control flaps showed 50% necrosis at 1 week. Capsules releasing ei ther form of VEGF had no effect on flap survival, but induced a modest incr ease in distal vascular supply. Delivery of FGF-P significantly improved fl ap survival, reducing necrosis to 34.2% (P < 0.001). Flap vascularization w as significantly increased by FGF-2 (P < 0.01), with numerous vessels, many of which had a large lumen diameter, growing in the proximity of the impla nted capsules. These results demonstrate that FGF-2, delivered from encapsu lated cells, is more efficacious than either VEGF(121) or VEGF(165) in trea ting acute skin ischemia and improving skin flap survival. Furthermore, the se data attest to the applicability of cell encapsulation for the delivery of angiogenic factors for the treatment and prevention of tissue ischemia.