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Bioengineering prediction of three-dimensional vascular growth and remodeling in embryonic great-vessel development

Final Report Summary - VASCULARGROWTH (Bioengineering prediction of three-dimensional vascular growth and remodeling in embryonic great-vessel development)

In Europe and in the world, approximately 1 in 100 children are born with a clinically significant congenital heart defect (CHD). In order to survive, severely cyanotic patients require immediate open-heart surgeries as soon as they are born and further interventions throughout their lifetime. In this bioengineering project the present computational cardiovascular (CV) modeling and prediction capability is expanded significantly. We can now simulate the “vascular growth” process quantitatively in the computer both at the microstructure and macroscopic scales. We have shown the distinct genetical pathways driven by blood flow and pressure. These radically new tools will allow surgeons and engineers to design improved reconstructive surgeries before in vivo execution and devices that incorporate the effects of long-term vascular growth and remodeling. Project focused on early embryonic great vessel development and successfully employed a practical animal model in order to validate computational modeling. We were able to change key mechanosensitive genes during embryonic development locally through our new novel microvascular electroporation system. We also created heart defects through mechanical means and selectively repaired them, to demonstrate fetal interventions. This proposal substantially expands the investigation of the biomechanical regulation of AA morphogenesis, including potential arch reversibility or plasticity after epigenetic events, using multimodal experiments in the chick embryo and a range of computational growth models as a proof of principle that biomechanical events can be directly coupled to changes in morphogenesis (and CV biology). Our key innovation is to develop the first in vivo morphomechanics-integrated three-dimensional (3D) mathematical models of great-vessel growth and remodeling that can describe and predict normal growth patterns and abnormal vascular adaptations common in CHD. Changes in gene expression within the AA during normal and altered hemodynamics, is correlated with predictive computational models to identify biologic mechanisms for altered AA morphogenesis. Our multidisciplinary application of bioengineering principles to CHD, using the chick embryo as a model, provided novel insights and paradigms towards our long-term goal to optimize the fetal and post-natal medical and surgical management of children and adults with CHD towards improved CV function, freedom from re-intervention, and improved quality of life.