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

主要研究者：Cao，Hung提案编号：1652818心脏病是发达国家死亡的主要原因，这是由于未能充分替换因血凝块或其他形式的阻塞而导致的血流损失而受损的心室心肌（心脏壁）。 这种失败归因于成年哺乳动物心室心肌细胞（CM =心肌细胞）分裂和再生失去的心肌的能力有限。 相比之下，斑马鱼心脏完全再生后，20%的心室去除，从而提供了一个遗传上易于处理的模型系统心脏再生的调查。 虽然已经使用免疫组织化学以及DNA和蛋白质分析对斑马鱼心脏进行了广泛评估，以研究心脏发育和再生中不同信号传导途径的作用，这被认为与开发哺乳动物再生疗法有关，但目前的方法无法阐明该过程的进展（即，再生）的相同样品随时间的变化。 该项目的目标是建立在PI在镇静动物中获得高质量（有利的高信噪比）心电图（ECG）信号的能力的基础上，提供革命性的基于聚合物的无线设备，用于在心脏再生的自由游泳斑马鱼模型中长期采集内在ECG。 更广泛的社会利益包括承诺1）实现新型心脏治疗; 2）减少药物筛选的成本和时间; 3）为患者和健康人群提供众多舒适的基于贴片的医疗可穿戴设备。 将研究与教育活动相结合，旨在帮助缩小工程教育与生物医学研究之间的差距，包括努力1）激励和培养不同学科和水平的学生接受高等教育和生物工程职业; 2）通过教师直接和间接地培养K-12学生，通过扩大知识，在最先进的高科技，3）将严谨研究中使用的尖端技术转化为直接支持社会的真实的世界设备; 4）吸引来自工程、科学和医学的多学科人员来解决尚未解决的生物工程挑战; 5）建立国际合作，交流创新，解决水质等全球性问题。与哺乳动物心脏不同，由于成年心肌细胞（CM）分裂和增殖的能力有限，在缺血诱导的梗死后心肌再生能力有限，斑马鱼（Danio rerio）心脏在20%心室切除后完全再生。 该项目的中心主题在于应用柔性和可伸缩的微电子技术和无线电力传输技术，在自由游泳的斑马鱼模型中进行心脏再生研究。 该项目涉及三个里程碑：1）开发柔性和可拉伸的微电极阵列（MEA）膜，用于在心脏再生的斑马鱼模型中长期记录心电图（ECG）：四个直径约200 um的工作电极将放置在心脏附近，一个参考电极将位于身体上。 2)设计和实施无线系统（“ECG护套”），包括无线供电（电感耦合或超声）和数据通信，用于在生物调查下对圆形水箱中自由游动的鱼（同时监测多条鱼）进行远程和连续的心电监测。 3)利用该系统研究斑马鱼心肌再生相关基因的作用（具有由截肢或低温方法诱导的损伤的多个mu样模型），具有向人类的潜在翻译，并证明用于i）药物筛选的翻译潜力（斑马鱼将接受影响心脏活动的众所周知的药物治疗，例如胺碘酮和维拉帕米）和ii）用舒适的（柔性和可伸展的）和不显眼的基于贴片的装置（例如，ECG、EEG、EOG、EMG和血压）。 开发的技术将能够长期（长达2个月）记录特定心肌部位的ECG，从而唯一确定研究区域的整体功能，而不会产生镇静作用。哺乳动物心脏几乎没有再生能力的传统观点现在受到最近的动物和人类研究的质疑，其中新的CM可能来自现有的CM和祖细胞或干细胞。在斑马鱼研究中发现特定基因对心脏再生的作用，将提出激活人类心脏有限再生能力的方法，从而对潜在的心脏疗法持乐观态度。

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.