Sustained (rh)VEGF₁₆₅ release from a sprayed fibrin biomatrix induces angiogenesis, up-regulation of endogenous VEGF-R2, and reduces ischemic flap necrosis

This study investigated (1) the release of recombinant human vascular endothelial growth factor ([rh]VEGF₁₆₅) from an in vitro fibrin matrix, (2) the effects of (rh)VEGF₁₆₅ released from an in vivo fibrin matrix on ischemic flap necrosis in the rat dorsal skin flap model, and (3) the effects of (rh)VEGF₁₆₅ released from an in vivo fibrin matrix on VEGF-R2 expression in transgenic VEGF-R2/luc mice. In vitro fibrin matrices were spiked with (rh)VEGF₁₆₅ and demonstrated (rh)VEGF₁₆₅ release over 88 hours with 66% recovery. Ischemic dorsal flaps were treated with a fibrin sealant (FS), FS spiked with (rh)VEGF₁₆₅, or left untreated. Flaps treated with FS spiked with (rh)VEGF₁₆₅ showed greater viability than controls as measured by planimetric analysis. Immunohistochemical analyses revealed stronger neovascularization than that exhibited by controls. Transgenic mice implanted with FS spiked with (rh)VEGF₁₆₅ had significant increases in VEGF-R2 expression relative to controls at days 5-13 after implantation. Conclusions drawn from this work are that (1) (rh)VEGF₁₆₅ is released from an in vitro fibrin matrix at clinically appropriate times, (2) (rh)VEGF₁₆₅ increases the viability of tissue flaps in vivo, and (3) (rh)VEGF₁₆₅ induces the expression of VEGF-R2 expression. This work demonstrates the clinical ability of sprayed FS to locally deliver growth factors to ischemic tissue of patients.