Nanowire Devices for Ultrasensitive, Multiplexed Detection of Cancer Markers

描述（由申请人提供）：该项目的总体目标是开发一种强大的基于硅纳米线的纳米电子传感器技术，用于快速，超灵敏和定量的多路检测癌症标记蛋白。化学合成的硅纳米线可以为可重复的场效应探测器阵列的组装提供所需的均匀性，并且用特定受体修饰这些纳米器件的表面将实现对癌症标志物的实时、超灵敏的电子检测。拟议的研究将涉及四个具体的研究领域。首先，开发一个鲁棒的、可寻址的纳米线传感器芯片和有效的芯片接口。大规模的硅纳米线生长将与晶圆级组装相结合，结果将被优化以产生高效的芯片制造工艺，从而实现良好的器件良率和高效的芯片吞吐量。将开发和验证一种新的芯片接口，使简单的“即插即用”互连到测量仪器。将进行大规模器件表征，以确定纳米线晶体管特性的统计再现性，并优化这些特性。其次，将开发一种可重复的方法，将抗体受体阵列连接到功能性纳米线器件阵列。用于癌症标记的单克隆抗体阵列将使用微阵列连接到纳米线设备阵列，并且受体阵列的保真度和能力将使用荧光和电结合测定来确定。第三，定义纳米线传感器性能的关键因素和限制。对抗体修饰的纳米线器件阵列芯片的系统研究将用于确定关键性能因素，包括(i)器件基线和检测稳定性，（ii）作为缓冲离子强度函数的检测灵敏度，（iii）对假阳性/假阴性反应的选择性和区分，以及（iv）定量浓度分析方法。此外，还将研究纳米线器件阵列中多路检测的限制。第四，确定纳米线器件芯片的特性和血清样品的限制。血清分析中的蛋白质检测限作为离子强度的函数，以及选择性多路检测的限，包括非选择性结合和定量浓度分析的假阳性的区分。所提出的研究具有广泛的意义，(1)可以利用现有的诊断标志物进行癌症的早期诊断和复发检测，(2)可以通过检测和监测新出现的癌症标志物进行高度稳健的诊断和治疗，(3)可以普遍应用于其他人类疾病的早期诊断和监测。

DESCRIPTION (provided by applicant): The overall goal of this project is to develop a robust silicon nanowire-based nanoelectronic sensor technology for rapid, ultra-sensitive and quantitative multiplexed detection of cancer marker proteins. Chemically-synthesized silicon nanowires can provide the uniformity needed for assembly of arrays of reproducible field-effect detectors, and modification of the surfaces of these nanodevices with specific receptors will enable real-time, ultra-sensitive electronic detection of cancer markers. The proposed research will address four specific research areas. First, a robust, addressable nanowire sensor chip and effective chip interface will be developed. Large-scale silicon nanowire growth will be coupled with wafer scale assembly, and the results will be optimized to yield an efficient chip fabrication process that enables good device yield and efficient chip through-put. A new chip interface that enables simple `plug-and-play' interconnection to measurement apparatus will be developed and validated. Large-scale device characterization will be carried out to determine statistical reproducibility of the nanowire transistor properties, and to optimize these properties. Second, a reproducible methodology for linking antibody receptor arrays to functional nanowire device arrays will be developed. Monoclonal antibodies arrays for cancer markers will be linked to the nanowire device arrays using a microarrayer, and the fidelity and competence of the receptors arrays will determine using fluorescence and electrical binding assays. Third, key factors and limits on the nanowire sensor performance will be defined. Systematic studies of the antibody-modified nanowire device array chips will be used to determine key performance factors, including (i) device baseline and detection stability, (ii) detection sensitivity as a function of buffer ionic strength, (iii) selectivity and discrimination against false positive/false negative responses, and (iv) methods for quantitative concentration analysis. In addition, limits for multiplexed detection in the nanowire device arrays will be investigated. Fourth, nanowire device chip characteristics and limits for serum samples will be determined. Protein detection limits in serum analysis as a function of ionic strength, and limits for selective multiplexed detection, including discrimination of false positives from nonselective binding and quantitative concentration analysis will be characterized. The proposed research has broad significance and (1) could enable early stage diagnosis and detection of recurrence of cancer using current diagnostic markers, (2) allow for highly robust diagnosis and treatment by detection and monitoring of panels of emerging cancer markers, and (3) could be generally applied for early stage diagnosis and monitoring of other human diseases. PUBLIC HEALTH RELEVANCE The overall goal of this project is to develop a nanoelectronic sensor technology for rapid, ultra-sensitive and quantitative simultaneous detection of multiple cancer marker proteins. The proposed research has broad significance and promises to (1) enable early stage diagnosis and detection of recurrence of cancer using current diagnostic markers, (2) allow for highly robust diagnosis and treatment by detection and monitoring of panels of emerging cancer markers, and (3) become a general technology for rapid early stage diagnosis and monitoring of human disease.