Integrating Flexible Electronics and Optogenetics for Real-Time Arrhythmic Profiling of Engineered Heart Tissues

About This Grant

Project Summary: Genetic heart disease is associated with heart failure and arrhythmias, which can lead to significant morbidity and mortality. Small animal models of genetic heart disease often fail to capture the clinically relevant features of the disease. Patient- and gene-specific therapies, such gene therapy, gene editing, and exon skipping are making their way into the clinic and are in development. In many cases, genetics has provided a clear understanding of underlying patient-specific disease mechanisms by linking a patient’s disease to a specific gene variant. However, individualized therapeutic strategies lag behind this understanding. Recognizing the limitations of animal models, the FDA Modernization Act 2.0 (2022) and subsequent FDA regulatory guidance (2024) now allow for the use of non-animal models including cell- and organoid-based models to assess therapeutic and efficacy. Patient-specific human induced pluripotent stem cells (hiPSCs) can now be readily created from patient cells such as those obtained via a standard blood draw. These cells can then be differentiated in heart-like cells to created hiPSC-derived cardiomyocytes (hiPSC-CMs), offering an platform to test personalized, genotype-specific therapies for heart disease in vitro. HiPSC-CM models can be further improved by using them to create heart-like tissues in the dish, known as engineered heart tissues (EHTs). Commercial platforms now support the creation of these tissues, and contractility measurements can be obtained non-invasively, enabling therapeutic assessment. However, arrhythmia assessments in EHTs remain limited due to the need for specialized optical equipment, the use of toxic contraction inhibitors such as blebbistatin, the need for voltage-sensitive dyes, and the terminal nature of current experimental protocols, which restrict the ability to track therapeutic effects over time. We have recently developed an electromechanically monitored EHT (emEHT) platform that enables simultaneous measurement of contractility and field potentials. This platform leverages flexible electronics technology to noninvasively and concurrently detect electrical signals and assess tissue forces. We have previously demonstrated the ability to simulate arrhythmias using electrophysiology protocols adapted from the clinic with this system. This proposal aims to develop a next-generation emEHT platform capable of simultaneously assessing action potentials and calcium transients in a non-invasive, non-terminal format through the integration of flexible electronics embedded with optical microsensors. Additionally, we aim to develop the molecular tools necessary to leverage this emEHT platform, including the stable expression of genetically encoded voltage and calcium sensors. The platform will be validated against traditional optical mapping techniques and tested using hiPSC-CMs derived from an arrhythmic form of cardiomyopathy. The development of this platform holds transformative potential for assessing arrhythmia propensity in EHTs, ultimately enabling the evaluation of the functional consequences of genotype-specific cardiovascular therapeutics in the dish.