Project Summary Cardiac diseases remain the leading cause of human morbidity and mortality. Cardiac microtissues/organoids built from human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) provide promising platforms for disease modeling and long-term treatment (e.g., through transplantation). However, recapitulating the intricate environment of the human heart, especially the global cell maturity, has proven challenging in vitro. One primary hurdle is the lack of consistent delivery of oxygen and nutrients to the deep-layer tissue, leading to unbalanced tissue development that eventually impairs the full functional maturation for precision studies. Existing artificial vascular systems are either confined to planar substrate or limited in resolution, falling short of the spatial coverage and resolution in the capillary network of a living organ for efficient media delivery. Moreover, no concurrent sensing network and bioelectronic data analytics are available to provide real-time and comprehensive assessment (e.g., link to molecular cell mechanisms) of the delivery effect across the 3D tissue. To fill in the gaps, we aim to develop an ultra-flexible and stretchable bioelectronic microarchitecture that integrates a capillary-like network for efficient media delivery and a tissue-like sensing network for tissue-state feedback. The system will be seamlessly integrated with cardiac microtissues to improve tissue development. We will also translate the real-time physiological feedback to molecular cell mechanisms to enable comprehensive quantification of the delivery effect. To realize the goals, Aim 1 will focus on constructing the flexible bioelectronic microarchitecture, optimizing the converged delivery and sensing functions, integrating the system in cardiac microtissues, and evaluating the interfacing intimacy and media delivery efficiency. Aim 2 will focus on the comprehensive analysis and optimization of delivery effect, through the multiple efforts of performing long-term electrical recording, employing in situ electro-sequencing to combine 3D spatial transcriptomics with electrical recording, and using analytics to connect functional phenotypes to molecular cell mechanisms. The success of this work will provide a transformative platform for improving cardiac tissue engineering. This platform can be readily translated to other tissue systems for improving function and development.