Bioprosthetic tissue valves have enjoyed increased application in recent years because of their superior hemodynamic performance, but remain indicated only for the older patients because of their inevitable structural degeneration that is accelerated in younger, more active patients. Mechanical prosthetics rarely fail structurally, but instead suffer from clotting risks that necessitate the use of anticoagulation medication. Endothelial cells line all blood contacting surfaces and provide a natural regulation of coagulation. We have developed novel engineering strategies that enable endothelial cells to seed and remain adhered to the surfaces of prosthetic valves even within ultra-high fluid shear stresses. These monolayers express natural anticoagulant phenotypes under shear stress, and exhibit nearly 1000 fold less platelet activation compared to the current surface preparations. We are designing novel mechanical valve prosthetics that take advantage of this technology, and expanding their evaluation in ex vivo and in vivo contexts. We are also pursuing the adaptation of this technology to other cardiovascular applications.