Wireless implantable optoelectronic arrays for untethered high performance cardiac monitoring and modulation

危及生命的心血管疾病，包括心力衰竭和心律失常（心律失常）对生活质量、发病率和死亡率有重大影响。在美国，仅室性心律失常每年就造成30万例心脏性猝死。有效的治疗和诊断方法的发展需要对心力衰竭和心律失常复杂的潜在病理生理有详细的了解。然而，这受到现有的实验性心血管电生理技术的限制。这个多学科项目将开发下一代无线多功能光电阵列工具，用于心脏监测和调制。这种技术对心脏的发育、结构和功能研究至关重要。它将导致心血管疾病发病机制的新见解，并促进各种类型心律失常和心力衰竭的治疗/诊断选择的发展。这个多学科项目将与教育/推广活动相结合，包括将该项目的成果应用于乔治华盛顿大学教授的各种课程中，为来自不同学科项目的本科生提供实践研究培训，并直接吸引代表性不足的K-12学生。该项目的成果也将用于乔治华盛顿大学大学预科暑期浸入式课程，以提高未被充分代表的高中生对生物医学工程的兴趣。目前的心脏电生理研究通常是基于心肌细胞或移植心脏的急性体外和离体实验。对清醒、行为自由的动物进行慢性体内心血管研究，将为了解心血管疾病的复杂发病机制提供一些最大的机会。该项目的目标是开发无线、植入式光遗传调制和电传感阵列，为自由行为的动物受试者的基础和转化心血管研究提供重要的新机会。本项目包括三个研究目标：(1)开发具有优异电化学、光学和机械性能的细胞级柔性透明微电极阵列，用于高分辨率电生理。利用微电极阵列研究慢性疾病模型将探索有效的生物相容性封装策略。(2)设计由透明微电极阵列和微尺度无机发光二极管组成的无线、皮下植入、多功能、多位点微系统，用于同时进行无串扰电生理记录和光遗传调制。(3)在自由运动小鼠模型中，通过研究特定心肌细胞和多位点起搏策略在室性心律失常终止和心力衰竭中的作用来验证微系统。该设备的无线特性将最大限度地减少与光纤电缆和电线相关的传统系绳、有线技术的不利影响（例如运动伪影、严重的组织损伤等）。拟议的工作将建立在主要研究人员在创新材料，生物电子设备制造，电路设计和心血管生理学方面的专业知识之上。多功能植入式阵列工具将为心血管研究社区提供目前无法获得的技术平台，用于自由运动动物心血管生理学的基本工作原理的慢性研究，并允许临床医学治疗/诊断方法的未来发展。该项目将揭示设计高性能细胞尺度透明微电极阵列的关键参数，为构建微创无线多功能生物电子接口提供多种方法，并为心血管生理学研究提供重要的新见解。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Life-threatening cardiovascular diseases including heart failure and heart rhythm disorders (arrhythmias) have significant impact on the quality of life, morbidity, and mortality. Ventricular arrhythmias alone are responsible for 300,000 sudden cardiac deaths in the United States per year. The development of effective therapeutic and diagnostic approaches requires detailed understanding of the complex underlying pathophysiology of heart failure and arrhythmias. However, this is limited by available experimental cardiovascular electrophysiology technologies. This multidisciplinary project will develop the next generation of wireless multifunctional optoelectronic array tools for cardiac monitoring and modulation. Such a technology is critical for developmental, structural, and functional cardiac studies. It will lead to new insights in cardiovascular disease pathogenesis and facilitate the development of therapeutic/diagnostic options for various types of arrhythmias and heart failure. This multidisciplinary project will be integrated with educational/outreach activities, including adopting the results of this project into various courses being taught at the George Washington University, hands-on research training for undergraduate students from different disciplinary programs, and directly engaging underrepresented K-12 students. Results from this project will also be used in The George Washington University Pre-College Summer Immersion Program to boost underrepresented high school students' interests in biomedical engineering.Current cardiac electrophysiology research is often based on acute in vitro and ex vivo experiments using cardiomyocytes or explanted hearts. Chronic in vivo cardiovascular studies on awake, freely behaving animals will offer some of the greatest areas of opportunity for understanding the complex pathogenesis of cardiovascular diseases. The goal of the project is to develop wireless, implantable optogenetic modulation and electrical sensing arrays to enable significant new opportunities for basic and translational cardiovascular studies with freely behaving animal subjects. This project includes three research objectives: (1) Develop cellular scale flexible transparent microelectrode arrays with superior electrochemical, optical, and mechanical properties for high-resolution electrophysiology. Efficient biocompatible encapsulation strategies will be explored for studying chronic disease models using the microelectrode arrays. (2) Design wireless, subdermally implantable, multifunctional, multisite microsystems consisting of transparent microelectrode arrays and microscale inorganic light-emitting diodes for simultaneous crosstalk-free electrophysiological recording and optogenetic modulation. (3) Validate the microsystems by studying the roles of specific cardiomyocytes and multisite pacing strategies in ventricular arrhythmias termination and in heart failure in freely moving mouse models. The wireless features of the devices will minimize adverse effects (e.g. motion artifacts, severe tissue damages, etc.) of conventional tethered, wired techniques associated with fiber optic cables and electrical wires. The proposed work will build upon the principal investigators' expertise in innovative materials, bioelectronic device fabrications, circuit designs, and cardiovascular physiology. The multifunctional implantable array tools will offer cardiovascular research community currently unavailable technological platforms for chronic research into the basic operating principles of cardiovascular physiology on freely moving animals and allow future development of therapeutic/diagnostic approaches in clinical medicine. The project will reveal the key parameters in designing high performance cellular scale transparent microelectrode arrays, provide versatile approaches for constructing minimally invasive wireless multifunctional bioelectronic interfaces, and demonstrate important new insights in cardiovascular physiology research.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.