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Gene therapy for cancer holds enormous therapeutic promise, but its clinical application has been limited by the inability to achieve targeted, high-level transgene expression with limited systemic toxicity. The authors have developed a novel method for delivering genes to microvascular free flaps (commonly used during reconstructive surgery) to avoid these problems.During the finite period in which a free flap is separated from the host (ex vivo), it can be perfused with extremely high titers of genetic material through the afferent artery, resulting in efficient transduction of the tissue. Before reanastomosis, unincorporated genetic material is flushed from the flap, minimizing systemic toxicity.In a rodent model using an adenoviral vector containing the lacZ reporter gene, high regional expression of β-galactosidase was achieved in all the different cells in a microvascular free flap. Moreover, no β-galactosidase staining was observed outside of the transduced flap, and viral sequence was undetectable by polymerase chain reaction analysis in other tissues. Further analysis confirmed that high-level transgene expression was precisely localized to the explanted tissue, with no collateral transduction.Targeting gene delivery with minimal systemic toxicity is essential for successful gene therapy. This form of “biological brachytherapy” provides a new opportunity to deliver targeted therapeutic transgenes to patients undergoing reconstructive surgery and allows microvascular free flaps to perform therapeutic and reconstructive functions.