? ? We are evaluating the biological efficacy of a robust vascular tissue engineering technology, with the goal of generating sufficient pre-clinical data to perform a clinical safety and efficacy study in patients after the completion of this award. Over the past decade, we have developed strategies for vascular tissue engineering that are generalizable across multiple species, including human. However, several aspects of the current engineered grafts will require modification before this technology can be feasibly translated into the clinic. Recent advances in stem cell biology and biomaterials capabilities, as well as some recent insights into engineered vessel mechanics, make it possible for us to modify our current engineered graft model and make it suitable for clinical application. In the five years of this award, we will harness our combined expertise in vascular graft engineering (Niklason), vascular surgery (Lawson), endothelial biology (Niklason, Lawson, Pober), biomaterials processing (Burghouwt), cryopreservation (Song), and FDA regulatory processes (Hellman) to make important, substantive progress on this complex problem. Our overall approach is to employ decellularized engineered matrices as our vascular graft substrate. By using allogenic decellularized matrices, we should avoid serious immune consequences that can be observed with xenogeneic matrices. By using selected porcine (or human) cells to generate mechanically robust engineered grafts and then decellularizing these tissues, we will produce immune-tolerated matrices that have appropriate mechanics for arterial implantation. We will seed engineered extracellular matrices with endothelial cells (EC) or their progenitors (endothelial progenitor cells, or EPC), and we will systematically compare the relative thrombogenicity of these two cell types. We will evaluate both differentiated EC and EPC because obtaining EPC from blood or marrow may be more clinically feasible than obtaining EC from a vascular biopsy. Since this tissue engineering paradigm works equally well with both porcine and human cells, results in the porcine model system will guide parallel in vitro experiments using human cells. Lastly, we will develop enabling platform technologies for translation to the clinic. Specifically, we will develop a GMP-manufactured scaffolding having targeted degradation properties to enhance graft mechanics. In addition, we will optimize cryopreservation strategies for acellular and recellularized grafts, so that tissues can be produced and then transferred or stored for clinical use. (End of Abstract) ? ? ?
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