Despite significant advances in the surgical and medical management of congenital heart disease, congenital cardiac anomalies remain a leading cause of death in the newborn period. Most severe forms of congenital heart disease require surgical intervention. Complications arising from the use of currently available prosthetic materials in the form of vascular grafts, patches, or replacement heart valves are a leading source of morbidity and mortality after congenital heart surgery. Currently available prosthetic materials such as polytetrafluoroethylene are a significant source of thromboembolism, have poor durability due to neointimal hyperplasia, are susceptible to infection, and perhaps most importantly lack growth capacity, which results in the need for additional operations as children outgrow their prosthetics. The development of better biomaterials with growth potential could substantially improve the outcomes of children requiring congenital heart surgery by reducing the number of graft-related complications and enabling earlier definitive surgical repair without risk of serial re-operation. Tissue engineering offers a potential solution to this vexing problem. Using tissue engineering methods, bioprosthetics can be made from an individual's own cells creating a living material with excellent biocompatibility and the ability to grow, repair, and remodel. The goal of this application is to optimize the design of an improved vascular graft for use in congenital heart surgery. Using the tissue engineered vascular graft (TEVG) as a model for bioprosthetics specifically developed for use in congenital heart surgery, we will rationally design an improved TEVG based on the mechanisms underlying vascular neotissue formation. We will focus our work on the role of host-derived macrophages on vascular neotissue formation, which we have previously demonstrated are critical to neovessel formation and the primary determinants of long-term graft function. We will use murine models to investigate the cellular and molecular mechanisms underlying the role of macrophages in the formation of TEVG stenosis, and then, based on our discoveries, rationally design strategies for optimizing neotissue formation, neovessel function, and TEVG performance. Finally we will validate these strategies using a humanized mouse model. This work will complement our ongoing clinical studies evaluating the use of TEVG in congenital heart surgery and facilitate the development and translation of this promising technology from the bench to the bedside.
Congenital cardiac anomalies are the most common birth defect and a leading cause of death in the newborn period. The most effective treatment for congenital cardiac anomalies is reconstructive surgery. Unfortunately, complications arising from the use of currently available vascular conduits are a significant cause of postoperative morbidity and mortality. The development and translation of a tissue-engineered vascular graft, created from an individual's own cells, with the ability to grow and remodel, holds great promise for advancing the field of congenital heart surgery and improving the outcomes of infants requiring surgical intervention.
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