Cardiomyocytes derived from patient-specific induced pluripotent stem cells (hiPSCs) provide a promising source for customized cell therapy, drug screening and toxicology assays. Specifically, the use of novel bioengineering approaches to generate 3-dimensional (3D) functional heart tissues made of hiPSC-derived cardiomyocytes (hiPSC-CMs) may improve retention and survival of the transplanted cells at the injury site and enhance their therapeutic actions. However, for the cardiac tissue-engineering field to advance toward clinical applications, the in vitro structural and functional maturation, and in vivo vascularization and functional integration need to be significantly improved compared to the current state of the art. As such, the main goal of this proposal is to explore the potential of select in vitro and in vivo conditions to improve structural organization, functional maturation, and vascularization of hiPSC-CMs within a 3D engineered cardiomimetic environment. Specifically, we will test the hypothesis that optimized cellular composition and biophysical stimulation regimes applied to bioengineered hiPSC-CM tissue patches will act synergistically to yield the most rapid vascularization, optimal survival, and functional maturation following their i vivo implantation. The specific aims of the proposal are to: 1) Vary and explore the effects of specific cellular (cardiac and vascular) formulations on the function of hiPSC-CM tissue patches, 2) Investigate the roles of in vitro applied electrical-only, mechanical-only, and combined electromechanical stimulation in the structural, molecular, and functional maturation of hiPSC-CM tissue patches, and 3) Determine the effect of electromechanical stimulation and time of implantation on the vascularization and function of hiPSC-CM tissue patches in nude mice in vivo. With the completion of these studies we plan to (i) provide new mechanistic insights regarding the roles of cellular composition and biophysical stimulation in engineered cardiac tissue function, maturation, and vascularization and (ii) generate superior human cardiac tissue patches for future applications in drug development, disease modeling, and cell-based cardiac therapies.