(verbatim from the proposal): The long-term objective of this proposal is to develop tissue engineered vascular grafts suitable for small diameter applications using novel hydrogel scaffold materials and genetically modified vascular cells. The scaffold materials that we will use are photopolymerized hydrogel materials containing bioactive moieties such as cell adhesion peptides and immobilized growth factors. The mechanical properties, such as the elastic modulus, of the hydrogel scaffold materials can be widely varied by changing the polymer molecular weight and crosslink density. We will utilize tubular constructs consisting of layers of endothelial and/or smooth muscle cells in the hydrogel scaffolds. The cells seeded into the scaffolds can be genetically modified ex vivo to improve tissue performance, e.g. better thromboresistance by transfection with nitric oxide synthase or better mechanical properties by transfection with crosslinking enzymes such as lysyl oxidase. Mechanical conditions experienced by cells during tissue growth will contribute significantly to the final properties of the tissue engineered construct. To investigate the influence of the mechanical environment on tissue formation of engineered vascular grafts, we will design a pulsatile flow bioreactor than can simulate the mechanical conditions experience in vivo. Tissue engineered constructs will be exposed to different levels of physiological flow with control over both the wall shear stress and cyclic strain. We will investigate the effects of a dynamic mechanical environment on properties of engineered tissues including cell orientation, morphology, and proliferation; extracellular matrix synthesis, crosslinking, and organization; and expression of vasoactive genes.
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