Heart failure and arrhythmias are the major clinical manifestations of genetic forms of cardiomyopathy, which can be life-threatening and cause significant morbidity and mortality in these diseases. New patient/genotype-specific therapies are in development and clinical testing for different forms of cardiomyopathy, however small animal models insufficiently capture the clinically relevant patient disease phenotypes and genotypes. Patient-specific human induced pluripotent stem cells (hiPSCs) can be created from readily available adult cells (e.g., blood, skin, or urine cells) and differentiated in heart-like cells, cardiomyocytes (hiPSC-CMs), offering opportunities to evaluate new treatments in a human cardiomyocyte context. While hiPSC-CM models are promising for disease modeling and drug testing, the cells are immature and often produce non-physiologic outputs. Engineered heart tissues (EHTs) can be created by casting hiPSC-CMs into hydrogel matrices, supported by flexible posts, to create tissue-like structures in the dish. EHTs improve cell maturity and provide access to physiologic outputs like force of contraction. Arrhythmia modeling in EHTs, has proven more challenging and has only been accomplished by invasive, terminal experiments requiring specialized dyes and imaging equipment. The project aims to optimize the application of flexible electronics technology to EHT culture conditions so that contractility and field potential can be evaluated as electrical and mechanical activity simultaneously and noninvasively for indefinite time periods. This platform will enable personalized drug testing like genetic correction strategies, which are currently in development. We developed a prototype device employting this technology, which we named electromechanically-monitored EHTs (emEHTs). We present demonstrating that emEHTs function to capture tissue strain and field potential on an array of sensors. We propose to further validate this technology by characterizing device function from fabrication to long-term culture, employing a standard product development quality improvement process to ensure consistent device quality and outputs. To allow for more generalized adoptability, a graphical user interface will be developed for collecting and analyzing device output. We will further validate this technology with advanced imaging characterization of calcium and membrane voltage of emEHTs. Pharmacologic studies that assess both contractility and arrhythmogenicity will be conducted to demonstrate potential for drug testing and screening. Previously collected and reprogrammed hiPSCs from patients harboring mutations in genes known to be highly arrhythmogenic will be assessed using emEHTs to demonstrate the potential of modeling genetic forms of cardiomyopathy. This project will be co-led by an interdisciplinary team of cardiovascular researchers and bioengineers with skill sets in clinical cardiology, arrhythmia modeling, cardiovascular genetics, and microfabrication. Successful completion of this project will result in a well-validated working emEHT platform for use by scientists with experience in hiPSC culture and differentiation methods.
|Effective start/end date||4/1/23 → 3/31/25|
- National Heart, Lung, and Blood Institute (1R33HL168758-01)
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