Low-cost active CMOS biochips for whole genome analysis

描述(由申请人提供)： 这项研究计划寻求将硅微电子学与遗传分析相结合，以开发具有解决整个基因组信息内容的潜力的先进诊断平台。拟议的技术由完全集成的微电子仪器组成，这些仪器提供一系列感应点或像素，每个感应点或像素都旨在检测独特的核酸序列或遗传标记。这种格式与现在建立的高通量cDNA和寡核苷酸微阵列的众多用途相兼容，包括基因表达研究、基因分型、突变鉴定和比较基因组学。该器件与传统的“滑动”微阵列的不同之处在于，分析物检测、模数转换和其他功能通过行业标准的互补金属氧化物半导体(CMOS)电路直接集成在芯片上。将开发两种类型的检测技术：荧光和电子。芯片上的荧光检测消除了对宏观、外部光学的需要，并保持了与当今流行的诊断方案的连续性。用于荧光诊断的CMOS微阵列将能够进行时间分辨测量，将以两种新的方式加以利用：(I)激发脉冲和数据收集阶段的时间分离，从而允许在没有集成光学过滤器的情况下运行；(Ii)由染料之间的荧光寿命差异驱动的多色诊断。电子检测将推进无标签诊断，这种诊断不需要分析物标记，并且可以就地和实时监测样品。在最初的可行性阶段，将对两种电气方法进行对比：(I)直接测量伴随杂交而来的阻抗变化；(Ii)基于在与cmos兼容的结构中实现的晶体管阈值电压变化的场效应激励方法。随后，将基于最有希望的方法制造功能齐全的CMOS仪器，以及相关的信号处理和数据分析电路。此外，这项工作将探索杂交热力学的芯片上电子控制的前景，以期开发特定于应用的操作模式(例如，用于基因分型)。为了提供未来的可访问性，器件设计将保持与低成本cmos制造的最大兼容性。将廉价的微电子技术应用于高通量基因分析，如果实现大规模生产，有望显著降低临床成本以及基因组学、药物基因组学和相关领域的研究应用。

DESCRIPTION (provided by applicant): This research program seeks to integrate silicon microelectronics with genetic analyses to develop advanced diagnostic platforms with potential to address the information content of entire genomes. The proposed technology consists of fully-integrated microelectronic instruments that present an array of sensing sites or pixels, each of which is designed to detect a unique nucleic acid sequence or genetic marker. This format is compatible with the numerous, now established uses of high-throughput cDNA and oligonucleotide microarrays including gene expression studies, genotyping, mutation identification, and comparative genomics. The proposed devices differ from conventional "slide" microarrays in that analyte detection, analog-to-digital conversion, and other functions are integrated directly on-chip via industry-standard complementary-metal-oxide-semiconductor (CMOS) circuitry. Two types of detection technologies will be developed: fluorescent and electrical. Fluorescence detection on-chip eliminates need for macroscopic, external optics and maintains continuity with today's prevalent diagnostic protocols. CMOS microarrays for fluorescence-diagnostics will be capable of time-resolved measurements, to be exploited in two novel ways: (i) temporal separation of excitation pulse and data collection stages, thus allowing operation without integrated optical filters and, (ii) multicolor diagnostics driven by difference in fluorescence lifetimes between dyes. Electrical detection will advance label-free diagnostics that do not require analyte labeling and that can monitor samples in-situ and in real time. Two electrical approaches will be contrasted in an initial feasibility phase: (i) direct measurement of electrical impedance changes accompanying hybridization and, (ii) a field effect actuation method based on shifts in threshold voltage of a transistor realized in a CMOS compatible structure. A fully-featured CMOS instrument, with associated signal processing and data analysis circuits, will be subsequently fabricated based on the most promising approach. Moreover, the effort will explore prospects for on-chip electronic control of hybridization thermodynamics, with view to developing application-specific operational modes (e.g. for genotyping). To provide for future accessibility, device design will maintain maximal compatibility with low-cost CMOS fabrication. Application of inexpensive microelectronic technology to high-throughput genetic analyses, if realized at mass production scales, promises significant reductions in costs for clinical as well as research applications in genomics, pharmacogenomics, and related fields