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
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