Transistor and Circuit Designs for Real Time Brain Injury Biomarker Detection

 描述：临床上对脑损伤的即时护理和持续监测诊断有着巨大的需求。目前最先进的酶联免疫吸附分析(EL ISA)、表面等离子体共振(SPR)和微悬臂梁都是昂贵的、劳动密集型的、不需要护理的、造成过多的时间延迟、缺乏便携性和/或不是无标签的。一种用于快速、实时检测急性脑损伤生物标志物的电子生物传感器替代方案将填补一个重要的临床空白。在过去的二十年里，有机薄膜晶体管(OTFT)被用于生物传感，但灵敏度不足。虽然纳米线传感器提供了更好的灵敏度，但它们在其他方面可能是不切实际的。因此，发展基于有机或其他宏观薄膜的改进型生物传感器是非常必要的。在这里，我们提出了一种高灵敏度的OTFT传感器平台，使用p通道和n通道有机半导体，基本上可以在大范围、可访问的传感区域内瞬时检测Pg/mL蛋白质水平。在单个传感器芯片中同时使用p沟道和n沟道晶体管能够区分可能的电串扰和/或假阳性 通过将来自两种类型的设备元件的响应与时间相关联来发送信号。当集成到单个逆变器电路中时，这两个晶体管可以形成一个传感器，两者的信号贡献具有协同作用，这是以前用蛋白质从未完成的。我们将使用GFAP作为原型分析仪，以推动向实用和临床相关的实时脑损伤检测和低浓度(40pg/mL)临床灵敏度的需要迈进。电容耦合层和感受器连接的创新将导致这种灵敏度，比以前基于晶体管的传感高出几个数量级。这种以氟聚合物-碳氢分子电介质以及共聚物和树枝状受体连接层为特征的新的覆盖层化学，也可以被应用于替代半导体，包括可溶有机物，以允许更好地印刷器件，以及无机半导体，以允许更好地耐水溶液和生理溶液。探索的提高灵敏度和耐用性的方法将包括：1)确定 氟聚合物-烃材料的最佳厚度和改进的组成，以增加电容，同时保持对水溶液的电阻阻抗；2)通过通过树枝状大分子将抗体连接到偶联基团来增加表面抗体密度；以及3)通过响应结合而催化降解氟聚合物来放大结合诱导的电子变化。最后一种方法在传感器文献中完全是史无前例的，并且可以产生低于pg/m L的灵敏度。

 DESCRIPTION: There is enormous clinical need for immediate point-of-care and continuous-monitoring diagnostics for brain injury. The state of the art ELISA (enzyme-linked immunosorbent assay immunoassay), SPR (surface plasmon resonance) and micro cantilevers are expensive, labor intensive, not point of care, impose excessive time delays, lack portability, and/or are not label-free. An electronic biosensor alternative for rapid, real time acute brain injury biomarker detection would fill an important clinical void. Organic thin film transistors (OTFTs) have been used for bio sensing in the last two decades, but with inadequate sensitivity. While nanowire sensors provide better sensitivity, they can be otherwise impractical. Therefore, it is highly desirable to develop improved biosensors based on organic or other macroscopic thin films. Herein we propose a highly sensitive OTFT sensor platform, using both p-channel and n-channel organic semiconductors, for detecting pg/mL protein levels essentially instantaneously with large, accessible sensing areas. Using both p- and n-channel transistors in a single sensor chip enables discrimination of possible electrical cross-talk and/or false-positive signals by correlating the response versus time from the two types of device elements. When integrated into a single inverter circuit, the two transistors can form a sensor with synergistic signal contributions from both, never before accomplished with proteins. We will use GFAP as the prototype analyst in order to advance progress toward practical and clinically relevant, real-time brain injury detection and the need for low concentration (40 pg/mL) clinical sensitivity. Innovations in capacitive coupling layers and receptor attachment will lead to such sensitivities, orders of magnitude higher than previously demonstrated for transistor-based sensing. This new overlayer chemistry, featuring fluoropolymer- hydrocarbon molecule dielectrics and both copolymer and dendritic receptor-linking layers, can also conceivably be applied to alternative semiconductors, including soluble organics to allow for greater printability of the devices, and inorganic semiconductors to allow for greater chemical resistance to aqueous and physiological solutions. Methods explored to increase sensitivity and durability will include: 1) determining the optimal thickness and improved composition of the fluoropolymer-hydrocarbon material to increase capacitance while maintaining resistive impedance to aqueous solutions; 2) increasing surface antibody density by linking antibodies to coupling groups via dendrimers; and 3) amplifying binding-induced electronic changes by catalytic degradation of the fluoropolymer in response to the binding. This last method is completely unprecedented in sensor literature, and could produce sub pg/mL sensitivities.