The broad goal of our research is the design of materials that control the distribution and release of DNA from the surfaces of biomedical materials and devices. The safe, efficient, and controlled delivery of DNA to cells presents a formidable challenge and an obstacle to the clinical success of gene therapy. Conventional materials do not meet the technical or clinical demands of this rapidly growing field, particularly for applications that require release from surfaces or the predictable administration of multiple gene sequences. Degradable polymer matrices can be engineered to sustain the release of plasmid DNA using strategies similar to those previously developed for the delivery of proteins. However, these bulk materials lack the sophistication required to control the distribution of plasmid (or multiple plasmids) near the surface of the material. We have developed degradable multilayered materials that provide nanometer-scale control over the incorporation and subsequent release of polyanions, including DNA. This proposal is based on the hypothesis that multilayered polymer assemblies incorporating plasmid DNA can be used to direct the release of DNA to cells growing on the surfaces of these materials. The following Specific Aims are designed to exhaustively evaluate this hypothesis. They are: 1) To incorporate plasmid DNA into hydrolytically degradable polyelectrolyte films using a layer-by-layer approach, 2) To characterize the physical and chemical erosion profiles of plasmid-containing films and establish the structural integrity of released DNA, and 3) To evaluate functional DNA-containing films as substrates for cell attachment and as platforms to direct the transfection of adherent cells. Sophisticated new materials that control the distribution and release of plasmid DNA from the surfaces of biomedical materials will have a profound impact on the development of localized gene therapies and the continued advance of gene therapy into the clinic.
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