Biologically Inspired Engineering of Hierarchical Vascular Networks

DESCRIPTION (provided by applicant): There are 1.2 million new or recurrent coronary attacks each year in the U.S, resulting in myocardial infarction or tissue death. The generation of functional cardiac tissue to replace damaged tissue could significantly change the way we currently treat heart disease. Consequently, a robust method of fabricating blood vessels could facilitate growth of larger scale cardiac tissue for treating this increasing burden of disease in America. Our aim in this proposal is to add a vascular network which can supply the cardiac graft with nutrient transport in vitro and be connected to blood supply in vivo. Micro fabrication technologies allow for the spatially precise creation of a cell-instructive environment and will be used to pattern 100 um to 1 mm channels within a graft material. Mimicking physiologic vasculature, the hierarchically organized vascular network of blood vessels will be induced to branch from relatively large (millimeters) to very small (10 um) conduits. Cardiac tissue will be grown around the vessel structure, using a hydrogel encapsulation method. Bioreactors will provide biophysical signaling using a time varying fluid flow regime to mature the blood vessels along with angiogenic cytokines to induce individual capillary sprouting providing transport at the cellular scale. This hierarchical design is particularly important because it creates a specific inlet and outlet for in vitro connectivity and clear ends for surgical anastomosis in vivo, while maintaining a micro vascular network for efficient nutrient delivery. This design bridges the gap between larger scale singular vascular tubes which often lack effective transport to individual cells, and co culture studies with endothelial cells which lack fluid perfusion. The vascular functionality of the cardiac graft will be assessed in vivo an interposition graft in an end to end anastomosis in the rat abdominal aorta. The specific aims of the proposal will be to (1) Use micro fabrication technologies to create a hierarchically designed template for vascular formation, (2) Apply biophysical regulation to induce capillary sprouting, (3) Functionally test the survival and functional perfusion of the cardiac graft in an in vivo rat abdominal aorta model. This project will build upon our laboratory's previous experience and expertise in cardiac tissue engineering with advanced biological micro fabrication techniques, to create a large, perfused cardiac graft that can be used in vivo. We hope that these studies can aid to the overall effort to reduce the national burden of cardiovascular disease, by creating a cardiac patch that can be used for patients suffering from myocardial infarctions and coronary artery disease.