Different gene delivery systems were developed in this dissertation to promote tissue regeneration by regenerative in vivo gene therapy. A local virus delivery method was developed using a lyophilized adenovirus formulation to restrict viral vector delivery in and around biomaterials. This strategy may reduce the dispersion of virus to avoid unwanted systemic infection and decrease the viral concentration within scaffolds. We also determined that virus bioactivity can be preserved for long-term storage using this method, which allows freeze-dried adenoviruses to be incorporated with biomaterials as a pre-made construct to be use at the time of surgery. This delivery has been applied to successfully repair not only critical-sized craniofacial defects, but also osteonecrosis caused by radiation therapy.

To enhance the spatial control of gene delivery, two different strategies were established to effectively bind viral vectors on scaffold surfaces. Avidin-biotin and antibody-antigen interactions were used to mediate virus immobilization. By binding viral vectors to biomaterials, only cells that adhered and proliferated on scaffolds would be transduced to express bioactive signals. Furthermore, a wax masking technique was introduced to control the bioconjugation on defined regions of biomaterials for spatially controlling transgene expression.

In order to broadly apply the immobilized gene delivery methods to different biomaterial scaffolds, chemical vapor deposition (CVD) polymerization was utilized to functionalize inert biomaterial, poly-&egr;-caprolactone (PCL), surfaces for immobilization of cell-signaling viruses. This surface modification was able to be performed on 2-D and 3-D structures. Through these controlled gene delivery systems, bioactive factors may be precisely expressed to engineer distinct tissue interfaces.