Cardiovascular diseases caused by the loss or dysfunction of cardiomyocytes (CMs) are the leading cause of death and affect millions of people worldwide. Tissue engineering holds great promise for the repair of injured hearts but requires the engineering of functional tissue constructs. Some of the key limitations of current cardiovascular tissue engineering approaches include the inability to generate cell-laden and cell- adhesive biomaterials, engineer vascularized tissues, and mimic the biological complexity and microarchitecture of cardiac tissues. To address these challenges, we aim to combine innovative microscale technology and advanced biomaterials (i.e. hydrogels) to create cell-laden hydrogels and develop 3D vascularized cardiac tissue constructs with controlled physical and biological properties. We will primarily use natural-based photocrosslinkable hydrogels (gelatin methacrylate, GelMA) to develop highly organized 3D vascularized networks. Specifically, we will co-culture endothelial cells (ECs) and mesenchymal stem cells (MSCs) within the patterned hydrogel construct and induce MSCs differentiation toward smooth muscle cells and develop biomimetic vasculature with controlled geometrical features and biological characteristics. Then, we will encapsulate cardiomyocytes within another layer of hydrogel and combine it with the pre- developed vascularized networks to generate cardiac tissue constructs with variable configurations and controlled complexities. Through the triple-culture of CMs with aligned ECs and MSCs, we will extensively study the biological properties of the tissue construct. In addition, we will test the functionality of the developed vascularized construct under cyclically stretched conditions. Finally, we will assess the functional properties of the engineered cardiac tissue construct in vivo. Achievements in this project will be important for cardiovascular tissue regeneration where the matrix material properties and configuration play an important role in maintaining native structural architecture of cardiac and vascular tissues. In addition, the developed constructs can be used as an integrative platform for drug cytotoxicity studies.
