Cardiovascular disease creates a critical need for durable, biocompatible vascular grafts. This project focuses on the development of synthetic tissue-engineered blood vessels using advanced biomaterials designed to replicate the mechanical and biological properties of native vessels. Fabricated grafts will be implanted in vivo to assess patency, integration, and functional performance under physiological conditions. Following explantation, multi-omics analyses (transcriptomics, proteomics) will be performed on the excised grafts to characterize cellular responses, tissue remodeling, and host–material interactions. Scaffold design will be optimized to promote endothelialization, smooth muscle organization, and hemocompatibility while maintaining mechanical integrity. This biomaterial-based approach aims to provide off-the-shelf, immunocompatible vascular grafts with translational potential, while the in vivo and omics data will generate mechanistic insight into graft-host interactions. Successful development could transform vascular repair strategies, offering scalable, readily available solutions that improve long-term patient outcomes in cardiovascular interventions.