A Nanotechnology-Based Wearable Biological Sensor for Continuous Monitoring of Inflammatory Immune Diseases

医疗保健是我们现代社会每天见证快节奏和令人大开眼界的技术进步和示范的领域。特别是，建立在机械柔性基板上的可穿戴生物传感器具有很大的前景，可以实现微创、即时的人体健康监测。这尤其适用于那些需要持续护理的人，包括卧床不起的病人和新生儿病人。然而，目前的可穿戴传感器只能测量少量的物理参数，因此缺乏在实验室环境中操作的传统生化技术所提供的通用性、特异性和灵敏度。本研究旨在开发一种基于纳米技术的可穿戴生物传感器设备平台，该平台可以附着在口腔防护器的曲面上，能够以高精度、灵敏度和特异性连续监测唾液中炎症免疫紊乱生物标志物蛋白的浓度水平。这种传感器平台最终可以转化为广泛的临床应用，以定制阻断体内炎症因子的免疫疗法。这项研究的技术消除了传统临床测试所面临的漫长的测量前置时间和劳动强度，有可能提供精确监测个体免疫状态的手段，这满足了治疗全身免疫疾病的“精确（或个性化）医学”的迫切需要。在这个项目中，首席研究员（pi）将与Ecotek实验室的Young Xplorer项目合作，为K-12学生提供传感器纳米制造的课后实践研究经验。该计划将允许pi参加由科学-技术-工程-数学（STEM）协会组织的会议，如西班牙裔专业工程师协会（SHPE），推进西班牙裔，奇卡诺人和美国原住民科学协会（SANCAS）协会和女性工程师协会（SWE）。激发未被充分代表的少数民族学生对基于纳米技术的生物传感器设备的兴趣，并邀请他们参加由pi主办的夏季研究机会计划（SROP）。细胞因子是一种重要的生物分子，在免疫系统的复杂功能相互作用和反应中起着媒介和调节剂的作用。量化细胞因子可以监测免疫反应，为传染病、癌症、自身免疫性疾病、过敏移植和药物发现提供临床和免疫学上有用的信息。本研究的目标是建立一种集成设备技术，通过使用可穿戴式无标签细胞因子生物传感器，实现对免疫状态的连续监测。随着本研究的完成，本研究将建立将结构均匀、高密度纳米等离子体生物传感器阵列和原子薄半导体光电探测器器件层战略性集成到机械柔性通用微系统平台上所需的纳米级器件制造技术。它还将提供基本的设备物理知识，这对于最大限度地提高传感器的可集成性、灵敏度、响应速度、分析物可检测性、生物/光信号转导效率以及设备在曲面上机械变形下的通用性至关重要。用于全柔性器件的独特生物传感方案采用(1)生物调谐纳米等离子体光吸收共振位移和(2)二维半导体过渡金属二硫化物（TMDC）结构的高响应，高量子效率光电子转换。因此，该设备有望实现无标签、连续、同步、微创检测4种关键唾液细胞因子生物标志物，在护理点环境中具有前所未有的检测水平（检测限（LOD） 1 pg/mL ~ 50fM）和响应速度（10分钟）。该传感器的响应速度相当于比常规金标准临床试验缩短20-100倍以上的总分析时间。本研究有望开发出首个基于分析物-受体结合免疫分析机制的可穿戴光电子生物传感器技术，该技术广泛适用于多种蛋白质疾病标志物的检测。

Healthcare is the field in which our modern society is witnessing rapid-paced and eye-opening technological advancements and demonstrations on a daily basis. In particular, wearable biological sensors built on a mechanically flexible substrate hold great promise to enable minimally invasive, point-of-care human health monitoring. This especially applies to those who need constant care, including bedridden and neonatal patients. However, current wearable sensors only allow for measuring a handful of physical parameters, thus lacking versatility, specificity, and often sensitivity offered by conventional biochemical techniques operated in a laboratory setting. This research aims to develop a nanotechnology-based wearable biological sensor device platform that can be attached onto the curved surface of a mouth guard and enables continuous monitoring the concentration levels of inflammatory immune disorder biomarker proteins in saliva at high accuracy, sensitivity, and specificity. This sensor platform could be eventually translated to wide clinical use to tailor the immune therapy blocking inflammation-causing agents in the body. Eliminating the long measurement lead-time and labor intensiveness that conventional clinical tests suffer from, the technology coming out of this research has the potential to provide the means to precisely monitor the immune status of an individual person, which meets the urgent need for 'Precision (or Personalized) Medicine' curing systemic immune disorders. In this program, the principal investigators (PIs) will collaborate with the Ecotek lab's Young Xplorer program in order to offer after-school hands-on research experiences in sensor nanofabrication to K-12 students. This program will allow the PIs to participate in conferences organized by Science-Technology-Engineering-Mathematics (STEM) societies, such as Society of Hispanic Professional Engineers (SHPE), Advancing Hispanics, Chicanos, and Native Americans in Science (SANCAS) Society, and Society of Women Engineers (SWE), to stimulate the interests of underrepresented minority students in nanotechnology-based biological sensor devices and solicit their participation in the Summer Research Opportunities Program (SROP) hosted by the PIs. Cytokines are key biomolecules acting as mediators and modulators of the complex functional interactions and responses of the immune system. Quantifying cytokines allows immune responses to be monitored, providing clinically and immunologically useful information related to infectious diseases, cancer, autoimmune diseases, allergy transplantation, and drug discovery. The goal of this research is to establish an integrated device technology that enables continuous monitoring of the immune status by using a wearable label-free cytokine biological sensor. With the proposed study completed, this research will establish nanoscale device fabrication techniques required for strategically integrating structurally uniform, high-density nanoplasmonic biological sensor arrays and an atomically thin semiconducting photodetector device layer onto a mechanically flexible common microsystem platform. It will also provide fundamental device physics knowledge critically important to maximize sensor integrability, sensitivity, response speed, analyte detectability, biological/photo signal transduction efficiency, and versatility of the device under mechanical deformations on a curved surface. The unique biosensing scheme used for the fully flexible device employs (1) biologically tuned nanoplasmonic light absorbance resonance shifts and (2) high-responsivity, high-quantum-efficiency photoelectronic conversion by two-dimensional semiconducting transition metal dichalcogenide (TMDC) structures. As a result, the proposed device is expected to enable label-free, continuous, concurrent, minimally-invasive detection of 4 key salivary cytokine biomarkers at unprecedented levels of detectability (limit-of-detection (LOD) 1 pg/mL ~ 50fM) and response speed ( 10 min) in point-of-care settings. This sensor response speed is equivalent to a total assay time more than 20-100 times shorter than that of the conventional gold standard clinical test. This research holds great promise to develop the first wearable photoelectronic biological sensor technology based on the analyte-receptor binding immunoassay mechanism, which is broadly applicable to detection of a wide variety of protein disease markers.