VASCULAR TISSUE ENGINEERING: RATIONAL DESIGN USING MODELING

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Tissue engineering holds promise for the treatment of cardiovascular disease. For tissue-engineered cardiovascular constructs a nonthrombogenic endothelial cell (EC) surface will be advantageous. Our goal is to establish, for blood-contacting EC surfaces, relationships between pro- and anti- hemostatic properties of ECs that can be preconditioned in vitro, and physiologic responses of thrombosis and vascular healing in vivo. To achieve this goal, the hemostatic properties of constructs variably preconditioned in vitro are being correlated with in vivo outcomes, thereby documenting the utility of rational design. These studies employ baboon endothelial progenitor cells (EPCs) that are readily isolated from whole blood in vitro, and relevant in vivo baboon models of thrombosis and vascular graft intimal hyperplasia. To enhance or inhibit EPC properties that regulate hemostatic functions, EPCs are grown on conventional ePTFE coated with different matrix proteins (collagen or elastin) and subjected to variable hemodynamic preconditioning (static vs. normal shear). Hemostatic, inflammatory, and mitogenic activities that are orchestrated by EPCs are assessed using functional, biochemical, molecular, and histologic assays. We are assessing: 1) thrombus formation in native, non-anticoagulated blood under physiologic flow conditions, and 2) healing of EPC-constructs following surgical placement. It is not our goal to develop an improved vascular graft. Rather, by documenting that cellular preconditioning in vitro can predictably improve outcomes in vivo - a principle that can be extended to other cell types and animal models - these results will validate rational design in general, and encourage studies with other constructs and test beds.