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都在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，建立在机械柔性衬底上的可穿戴生物传感器在实现微创、医疗保健点人体健康监测方面具有很大的前景。这尤其适用于那些需要持续护理的人，包括卧床和新生儿。然而，目前的可穿戴传感器只允许测量少数几个物理参数，因此缺乏通用性、特异性，而且往往缺乏实验室环境下操作的传统生化技术所提供的灵敏度。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，该平台可以附着在护口器的曲面上，并能够以高精度、高灵敏度和高特异性连续监测唾液中炎性免疫紊乱生物标志物蛋白的浓度水平。这个传感器平台最终可能被转化为广泛的临床应用，以量身定做阻止体内致炎物质的免疫疗法。这项研究消除了传统临床测试的长时间测量周期和劳动强度，这项研究产生的技术有可能提供精确监测个人免疫状态的手段，满足治疗全身免疫疾病的精准(或个性化)药物的迫切需求。在这项计划中，首席研究人员(PI)将与Ecotek实验室的Young Xplorer计划合作，为K-12学生提供传感器纳米制造的课外实践研究体验。该计划将允许私人投资机构参加由科学-技术-工程-数学(STEM)学会组织的会议，如西班牙裔专业工程师协会(SHPE)、促进拉美裔、奇卡诺人和美国原住民科学协会(SANCAS)和女性工程师协会(SWE)，以激发未被充分代表的少数族裔学生对基于纳米技术的生物传感器设备的兴趣，并邀请他们参与由私人投资机构主办的暑期研究机会计划(SROP)。细胞因子是重要的生物分子，是免疫系统复杂功能相互作用和反应的介体和调节器。定量细胞因子可以监测免疫反应，提供与传染病、癌症、自身免疫性疾病、过敏移植和药物发现有关的临床和免疫学有用信息。这项研究的目标是建立一种集成的设备技术，通过使用可穿戴的无标记细胞因子生物传感器来连续监测免疫状态。随着拟议研究的完成，这项研究将建立所需的纳米级器件制造技术，以战略性地将结构均匀、高密度的纳米等离子体生物传感器阵列和原子薄的半导体光电探测器器件层集成到机械灵活的公共微系统平台上。它还将提供基本的设备物理知识，对于最大限度地提高传感器的可积性、灵敏度、响应速度、分析物可检测性、生物/光信号传输效率以及设备在曲面上发生机械变形时的多功能性至关重要。用于全柔性器件的独特的生物传感方案采用(1)生物调谐的纳米等离子体光吸收共振位移和(2)通过二维半导体过渡金属二卤化物(TMDC)结构进行的高响应性、高量子效率的光电转换。因此，所提出的设备有望实现对4个关键唾液细胞因子生物标志物的无标记、连续、并发、微创检测，在护理点设置中具有前所未有的可检测性(检测极限(LOD)1 pg/mL~50fm)和响应速度(10分钟)。这种传感器的响应速度相当于总检测时间比传统的金标准临床测试缩短20-100倍以上。这项研究有望开发出第一个基于分析物-受体结合免疫分析机制的可穿戴光电生物传感器技术，该技术可广泛应用于各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.