CAREER: Wireless Flexible Micro-sensors to Monitor Cardiac Phenotypes in Zebrafish Models of Heart Regeneration

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PI: Cao, HungProposal #: 1652818Heart diseases are the leading cause of death in the developed world due to failure to adequately replace lost ventricular myocardium (heart wall) damaged by loss of blood flow due to blood clots or other forms of obstruction. This failure is attributed to the limited ability of adult mammalian ventricular cardiomyocytes (CMs = heart muscle cells) to divide and regenerate the lost myocardium. In contrast, zebrafish hearts fully regenerate after 20% ventricular removal and thus provide a genetically tractable model system for heart regeneration investigations. While the zebrafish heart has been extensively assessed using immunohistochemistry and DNA and protein analyses to study the roles of different signaling pathways in cardiac development and regeneration, which is thought to have relevance for developing mammalian regeneration therapies, current approaches cannot elucidate the progress of the process (i.e., regeneration) of the same samples over time. The objective of this project, which builds on the PI's demonstrated ability to obtain quality (favorable high signal to noise ratio) electrocardiogram (ECG) signals in sedated animals, is to provide revolutionary polymer-based wireless devices for long-term acquisition of intrinsic ECG in freely swimming zebrafish models of heart regeneration. Broader society interests include the promise 1) to enable novel cardiac therapy; 2) to reduce cost and time of drug screening; and 3) to pave the way for numerous comfortable patch-based healthcare wearables for both patients and healthy populations. Integration of research with education activities are designed to help close the gap of engineering education and biomedical research, including efforts to 1) inspire and train students from different disciplinary and levels to follow higher education and a bioengineering career; 2) to nurture K-12 students directly and indirectly through their teachers by broadening knowledge in state-of-the-art hi-technology applied in bioengineering and medical research; 3) to translate cutting-edge technologies used in rigorous research to real world devices directly supporting society; 4) to engage multidisciplinary personnel from engineering, science and medicine to tackle unmet bioengineering challenge; and 5) to establish international collaborations to exchange innovations as well as to address global issues such as water quality.Unlike mammalian hearts, which have limited ability to regenerate myocardium after ischemia induced infarct due to the limited capacity of adult cardiomyocytes (CMs) to divide and proliferate, zebrafish (Danio rerio) hearts fully regenerate after 20% ventricular resection. The central theme of this project lies in the applications of flexible and stretchable microelectronics and wireless power transfer to carry out heart regeneration studies in freely swimming zebrafish models. The project involves three milestones: 1) Development of flexible and stretchable micro-electrode array (MEA) membranes for long-term recording of electrocardiogram (ECG) in zebrafish models of heart regeneration: Four working electrodes approximately 200 um in diameter will be placed near the heart and a reference electrode will reside on the body. 2) Design and implementation of a wireless system (an "ECG Jacket") including wireless powering (inductive coupling or ultrasound) and data communication for remote and continuous electrocardiac monitoring of freely swimming fish (multiple fish monitored simultaneously) in a circular tank under biological investigations. 3) Deploying the system to elucidate the roles of specific genes towards myocardium regeneration in zebrafish (multiple mutant-like models with injuries induced by either amputation or a cryogenic approach) with potential translations to humans and to demonstrate the translational potentials for i) drug screening (zebrafish will be treated with well-known drugs that affect cardiac activity, e.g. amiodarone and verapamiland) and ii) physiological monitoring in humans with comfortable (flexible and stretchable) and unobtrusive patch-based devices (e.g., ECG, EEG, EOG, EMG, and blood pressure) in the home setting. The technologies developed will enable long-term (up to 2 months) ECG recordings of specific myocardial sites and thus uniquely determine the overall functionality of the area under investigation without effects of sedation. The conventional view of mammalian hearts as having virtually no regenerative capacity is now questioned by recent animal and human studies, in which new CMs may arise from existing CMs and progenitor or stem cells. The discovery of specific genes' roles towards heart regeneration in zebrafish studies would suggest methods to activate limited regenerative capacity in the human heart, garnering optimism about potential cardiac therapies.