HYPOTHESIS: Tissue flaps are commonly used for surgical reconstruction, especially over difficult wounds and in breast reconstruction. Complications due to inadequate flap perfusion are a source of morbidity, and in the lower extremity, can result in amputation. METHODS: We evaluated the ability of PDGF-B and FGF2 plasmid DNA, formulated in a Type I collagen matrix, to promote tissue survival in a rat transverse rectus abdominis muscle (TRAM) flap model based on the inferior deep epigastric artery. In the absence of any therapeutic, only ~24% of flap tissue survives in this model. The DNA/matrix formulations were delivered subcutaneously into the skin paddles 7 days prior to flap elevation, and tissues were harvested 7 days later. RESULTS: Our studies reveal dramatic increases in overall vascularity after treatment with both PDGF-B and FGF2 plasmid DNA; however, only PDGF-B increased flap survival (130% increase at 228 mg plasmid DNA/cm2 vs. controls; p<0.01). Transdermal spectral imaging demonstrated an increase in patent vessels supporting bloodflow in flaps treated with PDGF-B plasmid DNA versus the FGF2 transgene. CONCLUSIONS: Matrix-enabled gene therapy may therefore provide an effective, non-surgical approach to promote flap survival and is well suited for such surgical applications where transient therapeutic transgene expression is desired.