? The ultimate goal of this project is a completely biological artificial artery (bioartificial artery) that is suitable as a small diameter vascular graft, such as for use in coronary bypass. We will build upon our two major discoveries: (1) when neonatal smooth muscle cells (SMCs) are entrapped in fibrin gel formed as a tube around a nonadhesive rod, the SMCs contract the gel around the rod, causing the fibrin fibrils and SMCs to become circumferentially aligned. As the SMCs subsequently degrade the fibrin, they produce extensive cross-linked collagen and elastic fibers, which also are circumferentially aligned. This remodeling provides the construct with tensile mechanical properties approaching values of arterial tissue; (2) endothelial cells cultured from blood can be expanded to 10A8 cells in less than six weeks, the expansion occurring from a putative circulating marrow-derived angioblast.
In Specific Aim 1, we will compare the properties of remodeled fibrin gel tubes prepared with neonatal SMCs (rat, pig, and human) under the static culture condition used to date with tubes subject to cyclic distension, imparting a mechanical signal expected to increase tissue growth as we found in collagen gel-based tubes, and controlled transmural flow of culture medium, minimizing gradients of soluble factors and potentially leading to increased and near-uniform tissue growth.
In Aim 2, we will study the properties of bioartificial arteries, the remodeled fibrin/SMC constructs described above plus an endothelium generated using traditional late-stage seeding of the tubular construct with the blood outgrowth endothelial cells (BOECs) noted above, including their adhesion strength in pulsatile flow at physiological shear stress and their state of activation. Once such constructs have been validated in vitro we will proceed with testing the viability, patency, and hemocompatibility properties in animal models. The bioartificial artery will be implanted into the aorta of the rat, first in the syngeneic setting and subsequently in the """"""""allogeneic"""""""" setting (with respect to the SMCs; autologous BOECs will be used). A similar allogeneic study will subsequently be performed in the pig. We will also fabricate bioartificial arteries from human SMC and BOECs, so that these results should be directly relevant for a future clinical study. ? ? ?
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