Use of Proteoglycan-Genes to Engineer Vascular Tissue

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DESCRIPTION (provided by applicant): One of the major limitations in vascular tissue engineering is the failure of the engineered tissue to form functional and intact elastic fibers. Recent work in our laboratory has found that by genetically engineering arterial smooth muscle cells to overexpress a specific isoform of the extracellular matrix proteoglycan, versican, elastic fibers form in vitro and in vivo when the transduced cells are seeded into injured arteries. We hypothesize that this technology can be used to create blood vessel substitutes and vascular grafts with intact and functional elastic fibers. To address this hypothesis, this proposal has the following specific aims: 1. Optimize the gene delivery system so that optimal levels of expression can be achieved in a controlled fashion to maximize elastic fiber formation. 2. Create "sheets" of engineered cells in vitro with intact elastic fibers to be used to form small diametric tubes which exhibit maximal elastogenic properties. 3. Assess the feasibility of seeding engineered cells onto micro-fiber based biodegradable polymer scaffolds wrapped around a frame to create layers of smooth muscle cells interspersed with functional elastic fibers and; 4. Determine if integrating these elastic fiber generating cells into collagen based tubular scaffolds will result in the formation of tubes with appropriate tensile strength and elastogenic properties. The overall goal of this application is to create a vascular medial layer that possesses an appropriate mixture of extracellular matrix components that mimic the natural vessel and contain intact and functional elastic fibers.