An Electronic-Sensing & Magnetic-Modulation (ESMM) Biosensor for Phagocytosis Quantification for Personalized Stratification in Pathogenic Infections

拟议研究的目标是一个生物传感器平台，以量化人类血细胞对抗病原体的先天能力（一种称为吞噬作用的现象）。了解血细胞的吞噬活性对于确定我们的免疫系统（身体的自然防御）杀死病原体的有效性至关重要，这可能导致对高风险个体进行分层。目前的临床仪器不足以以快速、自动化的方式进行吞噬监测，并且需要大量的工作人员培训、手动样品处理、长等待时间和每次测试的巨大成本。为了解决这一未满足的需求，本项目将设计和制造一种生物传感器，只需一滴血就能定量吞噬作用。该项目是微纳传感，生物医学工程，生物电子学，微流体学，机器学习和疾病诊断的核心。在所提出的微流体生物传感器中，血细胞将与功能化的微珠（模仿病原体）相互作用并执行吞噬作用。微流控装置内的不同磁场配置将相应地调节细胞的流体行为，这反过来将使用构建在芯片上的微电极来识别和量化。该生物传感器将推动生物医学和设备研究，并将具有巨大的潜力，有利于人类的健康。该项目将培养生物电子学，微流体学和机器学习领域的本科生和研究生。该项目还将使拟议的研究纳入PI的教育工作。此外，国际和平组织的外联活动将包括通过教育讲座吸引K-12学生、当地卫生保健行业和公众，并在网上提供这些讲座，以广泛传播知识。该提案将使下一代体外诊断平台的开发成为可能，该平台配备了集成在微流体芯片中的电子传感磁调制（ESMM）模块，以量化人类血细胞杀死病原体的能力。免疫系统激活对病原性感染的应答的异质性对于制定治疗患者的正确临床应答策略至关重要。量化血细胞杀死病原体的天然能力，即，吞噬作用对于证明个体对抗病原体的反应的有效性至关重要。此外，工程化/调节吞噬活性的能力将极大地改善感染患者的治疗结果。该项目旨在开发一种新型的个性化生物传感器，不仅能够量化吞噬能力，而且还将确定适当的治疗方法，以提高吞噬细胞杀死病原体的能力。该生物传感器配备有微流体、用于电子感测的微电极和四极磁配置以调节芯片上的血细胞行为。血细胞将与抗体缀合的磁性颗粒相互作用，并将在芯片上执行吞噬作用。此外，拟议的生物传感器将配备使用机器学习的实时数据分析，以提高传感器性能。所提出的传感器将能够对感染患者的免疫反应进行分层，仅需要一滴全血即可快速获得结果（TOR）。将使用患者临床样本对传感器进行基准测试。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。

The objective of the proposed research is a biosensor platform to quantify the innate ability of human blood cells to combat pathogens (a phenomenon known as phagocytosis). Knowing phagocytic activity of blood cells is critical to determine the effectiveness of our immune system (body’s natural defense) to kill the pathogens potentially leading to stratify the high-risk individuals. Current clinical instruments are inadequate to perform phagocytosis monitoring in a rapid, automated way and requires extensive staff training, manual sample processing, long wait times, and huge cost per test. To address this unmet need, this project will design and fabricate a biosensor capable of quantifying phagocytosis requiring only a drop of blood. The project is at the nexus of micro-nano sensing, biomedical engineering, bioelectronics, microfluidics, machine learning and disease diagnostics. In proposed microfluidic biosensor, blood cells will interact with the functionalized microbeads (mimicking pathogens) and perform the phagocytosis. Different magnetic field configurations within microfluidic device will modulate the cells fluidic behavior accordingly which will in turn be identified and quantified using micro electrodes built on chip. The proposed biosensor will advance biomedical and device research and will have great potential to benefit human healthcare. This project will train undergraduate and graduate students in the fields of bioelectronics, microfluidics, and machine learning. The project will also enable the integration of proposed research into PI’s educational efforts. Further, PI’s outreach activities will include engaging K-12 students, the local health-care industry, and the general public through educational lectures and making them available online for broad dissemination of knowledge. The proposal will enable the development of a next generation in-vitro diagnostic platform equipped with Electronic-Sensing & Magnetic-Modulation (ESMM) modules integrated in a microfluidic chip to quantify the human blood cells ability to kill pathogens. The heterogeneity of the immune system activation in response to pathogenic infections is critical to strategize the correct clinical response to treat the patients. Quantifying blood cells natural ability to kill pathogens i.e., phagocytosis is critical to demonstrate the effectiveness of individual’s response in combating pathogens. Further, the ability to engineer/ modulate the phagocytic activity will tremendously improve the therapeutic outcomes for the infected patients. This project aims to develop a novel personalized biosensor capable of not only quantifying the phagocytic ability but also will determine appropriate therapeutics to improve phagocytes ability to kill the pathogens. The biosensor is equipped with microfluidics, microelectrodes for electronic sensing, and quadrupole magnetic configuration to modulate the blood cells behavior on-chip. Blood cells will interact with antibody conjugated magnetic particles and will perform phagocytosis on-chip. Furthermore, the proposed biosensor will be equipped with real-time data analysis using machine learning to improve the sensor performance. The proposed sensor will enable stratification of immune response of infected patients requiring only a drop of whole blood with a rapid time to result (TOR). Sensors will be benchmarked with patient clinical samples. Sensor will have the capability to be used at the point-of-care at multiple health-care settings.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.