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

这项拟议的研究的目标是建立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)杀死可能导致高危人群分层的病原体的有效性至关重要。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、手动样本处理、漫长的等待时间和巨大的每次测试成本。为了解决这一未得到满足的需求，该项目将设计和制造一种生物传感器，该传感器能够量化吞噬作用，只需一滴血。该项目涉及微纳传感、生物医学工程、生物电子学、微流体、机器学习和疾病诊断等领域。在所提出的微流控生物传感器中，血细胞将与功能化的微球(模仿病原体)相互作用，并执行吞噬作用。微流控器件内不同的磁场配置将相应地调制细胞的流体行为，这些行为将利用芯片上构建的微电极进行识别和定量。提出的生物传感器将促进生物医学和设备研究，并将具有巨大的潜力，造福于人类健康。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能够融入到国际和平协会的教育工作中。此外，PI的外展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普通公众，并使其在网上可用于广泛传播知识。该提议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控芯片中的电子传感和磁调制(ESMM)模块，以量化人类血细胞杀死病原体的能力。免疫系统在应对病原体感染时激活的异质性对于制定正确的临床反应来治疗患者至关重要。量化血细胞自然杀灭病原体的能力，即吞噬作用，是证明个体反应在对抗病原体方面的有效性的关键。此外，设计/调节吞噬细胞活性的能力将极大地改善感染患者的治疗结果。本项目旨在开发一种新型的个性化生物传感器，不仅能够量化吞噬细胞的吞噬能力，而且可以确定合适的治疗方法来提高吞噬细胞杀灭病原体的能力。该生物传感器配备了微流体、用于电子传感的微电极和四极磁配置来在芯片上调节血细胞的行为。血细胞将与抗体结合的磁性颗粒相互作用，并在芯片上执行吞噬功能。此外，提出的生物传感器将配备使用机器学习的实时数据分析，以提高传感器的性能。建议的传感器将使感染患者的免疫反应分层，只需滴一滴全血，结果迅速(TOR)。传感器将以患者临床样本为基准进行基准测试。传感器将有能力在多个医疗保健环境的护理点使用。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.