High-precision optoelectronic heart-on-a-chip platforms for investigating human cardiac physiology and drug development

心脏病是世界范围内死亡的主要原因。开发用于量化和评估人类心脏对外部刺激（例如药物）的反应的芯片上心脏技术对于确定心脏病的有效治疗至关重要。当前系统的局限性包括对器官水平生理学和分析方法的模仿不足，这些分析方法阻止在延长的时间段内连续监测心脏行为。该项目旨在解决这些挑战，并通过开发自动化系统，将心脏切片培养组件与传感器和致动器阵列集成在一起，用于器官水平心脏生理学的慢性片上评估，从而大大扩展了芯片上心脏技术的前景。这将使心脏病机制的研究和促进药物筛选。该项目的成果将广泛影响和改变工程生物医学系统和器官芯片技术的发展，用于药物筛选和疾病建模应用。该项目将为本科生和研究生，特别是来自代表性不足背景的学生提供生物电子学和心脏生理学的跨学科教育和研究培训机会。教育K-12学生和当地社区的外展活动将展示心脏芯片演示套件和暑期项目。该项目的目标是开发可扩展的心脏芯片平台，该平台允许自动培养人类器官型心脏切片，并在细胞和组织水平上对人类心脏生理学进行实时连续的芯片上多参数分析及其在药物筛选中的应用，这超出了最先进的生物医学技术的能力范围。该项目依赖于两名在材料、微细加工、生物电子学、生命科学和心脏生理学方面具有互补专业知识的研究人员。具体的研究重点包括：（1）开发高密度单细胞空间分辨率传感器和致动器，用于基本心脏特性的无串扰映射和调制;（2）设计可扩展的自动化芯片上心脏平台，以支持人类器官型心脏切片的长期培养和人类心脏组织生理学的连续芯片上电学和光学映射;（3）通过测试抗癌药物的急性和慢性心脏药物反应和心脏毒性来评估芯片上的心脏系统。该项目将创建具有变革性的芯片心脏系统，从根本上扩大实验选择，提高保真度，简化人类心脏病研究和临床前药物筛选的操作。该奖项反映了NSF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。

Heart disease is the leading cause of mortality worldwide. Development of heart-on-a-chip technologies to quantify and evaluate the response of human heart to external stimuli such as drugs is of critical importance for determining effective treatments for heart disease. Limitations of current systems include insufficient mimicking of organ-level physiology and analysis methods that prevent continuous monitoring of heart behaviors over extended time periods. This project seeks to address those challenges and greatly expand the landscape for heart-on-a-chip technologies by developing automated systems integrating heart slice culture components with arrays of sensors and actuators for chronic on-chip assessing of organ-level cardiac physiology. This will enable study of heart disease mechanisms and facilitate drug screening. The outcomes of this project will broadly impact and transform the development of engineered biomedical systems and organ-on-a-chip technologies for drug screening and disease modeling applications. The project will provide cross-disciplinary education and research training opportunities in bioelectronics and cardiac physiology to undergraduate and graduate students, especially students from underrepresented backgrounds. Outreach activities to educate K-12 students and local communities will showcase heart-on-a-chip demonstration kits and summer programs.The goal of this project is to develop scalable heart-on-a-chip platforms that allow automated culture of human organotypic heart slices and real-time continuous on-chip multiparametric analysis of human cardiac physiology at cellular and tissue levels and their applications in drug screening, which lie outside of the capabilities of state-of-the-art biomedical technologies. This project relies on two investigators with complementary expertise in materials, microfabrication, bioelectronics, life sciences, and cardiac physiology. Specific research foci include: (1) developing high-density single-cell spatial resolution sensors and actuators for crosstalk-free mapping and modulation of essential cardiac properties; (2) designing scalable automated heart-on-a-chip platforms to support chronic culture of human organotypic heart slices and continuous on-chip electrical and optical mapping of human cardiac tissue physiology; (3) assessing the heart-on-a-chip systems by testing acute and chronic cardiac drug responses and cardiotoxicity of anti-cancer drugs. This project will create transformative heart-on-a-chip systems that will fundamentally expand the experimental options, improve the fidelity, and simplify the operation in investigating human heart disease and preclinical drug screening.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.