Stimulating angiogenesis by gene transfer approaches offers the hope of treating tissue ischemia which is untreatable by currently practiced techniques of vessel grafting and bypass surgery. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF-2) are potent angiogenic molecules, making them ideal candidates for novel gene transfer protocols designed to promote new blood vessel growth. In this study, an ex vivo gene therapy approach utilizing cell encapsulation was employed to deliver VEGF and FGF-2 in a continuous and localized manner. C(2)C(12) myoblasts were genetically engineered to secrete VEGF(121), VEGF(165) and FGF-2. These cell lines were encapsulated in hollow microporous polymer membranes for transplantation in vivo. Therapeutic efficacy was evaluated in a model of acute skin flap ischemia. Capsules were positioned under the distal, ischemic region of the flap. Control flaps showed 50% necrosis at 1 week. Capsules releasing either form of VEGF had no effect on flap survival, but induced a modest increase in distal vascular supply. Delivery of FGF-2 significantly improved flap survival, reducing necrosis to 34.2% (P < 0.001). Flap vascularization was 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 implanted capsules. These results demonstrate that FGF-2, delivered from encapsulated cells, is more efficacious than either VEGF(121) or VEGF(165) in treating acute skin ischemia and improving skin flap survival. Furthermore, these data attest to the applicability of cell encapsulation for the delivery of angiogenic factors for the treatment and prevention of tissue ischemia
We describe a new animal model designed to assess the impact of ischemia on wound healing. Eight patterns of arterial lesion in the limb were first tested in 24 Wistar rats. Resection of the external iliac artery down to the femoral artery at the level of the knee was chosen as the reference model and performed on the left limb of 45 rats; the right limb was used as the control. Skin wounds measuring 1.2 x 0.8 cm were created on both feet. Ischemia was assessed by blood flow measurement, which decreases dramatically in the ischemic limb. A significant delay in wound closure with a decrease in wound contraction was observed in the ischemic limb. Myofibroblast quantification showed a significant delay in appearance as well as a decrease in the number of these cells in the ischemic wound. Vascular endothelial growth factor-A appearance and evolution were qualitatively similar in both situations. However, collagen type I mRNA was markedly decreased in ischemic granulation tissue 10 days after wounding. These findings suggest that decreased wound contraction plays an important role in delayed ischemic wound healing, probably due to reduced myofibroblast development and activity.
Survival of arterialized venous flaps is optimized by using smaller-caliber veins for inflow and reserving larger-caliber veins for outflow. This regulates inflow and avoids high blood pressure, and arterialized venous flaps behave as physiologic flaps do, by not relying on neovascularization for survival.
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