PROJECT SUMMARY Tissue engineered vascular grafts (TEVGs) have demonstrated potential to revolutionize cardiovascular care, with multiple grafts now in clinical trials in children and adults. Yet, there remains a pressing need to optimize these grafts to improve outcomes and enable wide-spread usage. In this proposal, we build upon a strong foundation of prior findings but introduce an innovative multi-fidelity computational-experimental approach that promises to accelerate greatly the development of improved TEVGs. Although the proposed approach is general with broad applicability, we will focus on one particular application – TEVGs for congenital heart surgery – to refine the approach and illustrate its utility. Specifically, we will use a pre-clinical juvenile ovine model to collect the longitudinal data needed to develop and inform novel multiscale computational models that will be melded to describe the in vivo development of a neovessel from an implanted biodegradable polymeric scaffold. Our approach will be informed by data from three initial, non-optimal designs, then used to identify via formal methods of optimization preferred microstructural scaffold parameters and an overall geometry that optimizes in vivo function. Particularly novel will be our ability to account for normal developmental changes in the lamb vasculature and coupling of cell signaling, growth and remodeling, and 3D hemodynamics in a novel multi-fidelity, multiscale workflow that allows optimization of desired biological and physiological outcomes. To achieve these goals, we propose three Specific Aims: 1) To quantify normal vascular development and performance of three baseline TEVG designs in a lamb model; 2) To develop and employ a novel multiscale fluid-solid-growth (FSG) simulation framework to optimize TEVG design; 3) To validate the model-identified optimal TEVG design in a longitudinal large animal study. Our team is uniquely positioned for success, combining expertise in animal models of congenital heart disease, development of TEVGs and their clinical translation, finite element simulations of cardiovascular hemodynamics and biomechanics, modeling vascular growth and remodeling, and identifying and modeling mechanisms of mechanobiology. Our approach is innovative in that we will 1) meld macro (organ) level simulations of cardiovascular biomechanics with micro level simulations of vascular cell signaling, 2) develop a novel, generally applicable paradigm for model-driven optimization of tissue engineered structures that provides control over outcomes, and 3) facilitate clinical translation of TEVGs with improved performance. Successful completion of this study will be significant in multiple ways – not only will it result in a new (optimal) design of a TEVG for use in the Fontan surgical procedure, performed in children born with single ventricle congenital heart defects, it will also establish a novel computational-experimental paradigm in cardiovascular tiss...