Transistor and Circuit Designs for Real Time Brain Injury Biomarker Detection

 描述：有巨大的临床需求，即时床旁和连续监测诊断脑损伤。现有技术的ELISA（酶联免疫吸附测定免疫测定）、SPR（表面等离子体共振）和微量分析仪是昂贵的、劳动密集型的、不是护理点的、强加过多的时间延迟、缺乏便携性和/或不是无标记的。用于快速、真实的时间急性脑损伤生物标志物检测的电子生物传感器替代物将填补重要的临床空白。有机薄膜晶体管（OTFT）在过去二十年中已用于生物传感，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，非常需要开发基于有机或其它宏观薄膜的改进的生物传感器。在本文中，我们提出了一种高灵敏度的OTFT传感器平台，使用p沟道和n沟道有机半导体，用于检测pg/mL蛋白质水平，基本上是即时的，具有大的，可访问的传感区域。在单个传感器芯片中使用p沟道晶体管和n沟道晶体管两者使得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。当集成到一个逆变器电路中时，这两个晶体管可以形成一个传感器，两者都有协同信号贡献，这在蛋白质中是前所未有的。我们将使用GFAP作为原型分析师，以推进实际和临床相关的实时脑损伤检测以及低浓度（40 pg/mL）临床灵敏度的需求。电容耦合层和受体附着的创新将导致这种灵敏度，比先前基于晶体管的感测所证明的高几个数量级。这种新的覆盖层化学，具有含氟聚合物-烃分子交联以及共聚物和树枝状受体连接层，也可以想象地应用于替代半导体，包括可溶性有机物以允许设备的更大的可印刷性，以及无机半导体以允许对水溶液和生理溶液的更大的耐化学性。探索增加灵敏度和耐久性的方法将包括：1）确定 含氟聚合物-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）通过经由树枝状聚合物将抗体连接到偶联基团来增加表面抗体密度;和3）通过响应于结合的含氟聚合物的催化降解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是完全前所未有的，并且可以产生低于pg/mL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.