CAREER: Optoelectronic lab-on-a-chip technology for high content automated multiparametric physiological analyses of live cells

体外活细胞（如干细胞）是复制人类（病理）生理的强大模型，可以详细分析细胞功能、细胞作用机制以及对干预和治疗的反应。这些细胞模型的广泛接受，加上它们日益增长的商业可用性和获得患者特异性细胞的便利性，强调了它们彻底改变我们对人体生理学和功能的理解的潜力。然而，迄今为止，随着时间的推移，对这些细胞模型的特性进行全面研究的技术有限，这极大地阻碍了它们在生理学研究、疾病建模和药理学研究中的转化。该项目将解决这些技术挑战，并开发自动化的芯片实验室平台，以全面监测和控制细胞生理学。这将通过材料、器件制造、电路设计、软件开发和系统集成方面的创新来实现。研究结果代表了下一代芯片上实验室健康监测和调制系统的重要步骤。如果成功，结果将大大简化操作，扩大可能性，并在许多生物医学研究项目中创造新的机会，在这些项目中，高度需要减少人类接触的自动化芯片实验室设备。教育活动将与技术发展相结合，通过对女性和代表性不足的学生进行生物电子学研究的多学科培训，介绍光电生物医学系统的新本科课程。推广计划包括讲座和设计教学示范包，以教育K-12学生，以及当地高中生积极参与研究。该项目将开发和验证自动化的芯片实验室平台，该平台允许在标准细胞培养环境中对多个平行活细胞特性及其在有意义的时空精度水平上的相互作用进行直接高含量、实时、多参数的询问。该项目包括三个研究目标：(1)探索用于无串扰电记录、刺激和体外活细胞功能三参数荧光记录的细胞尺度组件。我们将研究这些元件的结构-性能关系，以优化器件性能。将进行光学和电化学建模，以获得对其特性的基本见解；(2)开发紧凑型芯片实验室平台，用于在受控培养条件下对活细胞模型进行自动化、长期、多参数探测。与培养环境完全兼容，有利于处理危险病原体，如COVID-19、有毒物质和放射性物质。先进的硬件和软件设计将能够独立控制每种模式，快速测量和数据分析。这将消除对大量技术专业知识的需求，手动分析生成的高内容数据，大大节省了时间，减少了错误，提高了实验人员的准确性；(3)通过严格的台式测量和诱导多能干细胞来源的神经元的高含量芯片筛选来验证平台。性能将以商业系统为基准进行测试。该项目的技术和新知识将影响广泛的生物医学工程界，包括阐明疾病机制，药物测试，个性化医疗，器官芯片。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。

In vitro live cells such as stem cells are powerful models to replicate human (patho)physiology and enable detailed analysis of cell function, cellular mechanisms of action, and responses to interventions and therapeutics. The widespread acceptance of these cell models, coupled with their growing commercial availability and ease of deriving patient-specific cells, have underscored their potential to revolutionize our understanding of human physiology and function. To date, however, limited techniques exist for comprehensive investigation of the properties of such cell models over time, which greatly impedes their translation for physiology investigations, disease modeling, and pharmacology research. This project will address these technical challenges and develop automated lab-on-a-chip platforms for comprehensive chronic monitoring and control of cell physiology. This will be accomplished via innovations in materials, device fabrication, circuit design, software development, and system integration. The research results represent important steps towards the next generation lab-on-a-chip health monitoring and modulation systems. If successful, the outcomes will significantly simplify the operation, expand the possibilities, and create new opportunities in many programs of biomedical research, in which automated lab-on-a-chip devices with reduced human exposure are highly demanded. The education activities will integrate with the technical developments through multidisciplinary training of female and underrepresented students in bioelectronics research, introduction of new undergraduate courses on optoelectronic biomedical systems. Outreach plans involve lectures and designing pedagogical demonstration kits to educate K-12 students as well as active research participation by local high school students.This project will develop and validate automated lab-on-a-chip platforms that allow for direct high-content, real-time, multiparametric interrogation of multiple parallel live cell properties and their interplay at meaningful levels of spatiotemporal precision inside standard cell culture environment. The project includes three research objectives: (1) explore cellular-scale components for crosstalk-free electrical recording, stimulation, and triple-parametric fluorescence recording of in vitro live cell function. The structure-property relationships of those components will be investigated to optimize the device performance. Optical and electrochemical modeling will be performed to yield fundamental insights into their characteristics; (2) develop compact lab-on-a-chip platforms for automated, long-term, multiparametric probing of live cell models under controlled cultivation conditions. The full compatibility with incubator culturing environment is beneficial for work with dangerous pathogens, such as COVID-19, toxic substances, and radioactivity. Advanced hardware and software designs will enable independent control of each modality, fast measurement, and data analysis. This will eliminate the need of significant technical expertise to manually analyze the high-content data generated, dramatically save the time efforts, reduce error, and improve accuracy for the experimenters; (3) validate the platforms via rigorous benchtop measurements and high-content on-chip screening of induced pluripotent stem cells-derived neurons. The performance will be benchmarked against commercial systems. The technology and new knowledge in this project will impact the broad biomedical engineering community, including elucidating disease mechanisms, drug testing, personalized medicine, organs-on-chip.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.