Biological Applications Specific Integrated Circuits for Genomic Analysis.

The turn of the 21st century ushered in a new era for genomic based sciences. Ever since the discovery of the deoxyribonucleic acid (DNA) as the master instruction coding block inside virtually every living cell, great efforts and discoveries in the fields of genomics have skyrocketed, punctuated by the completion of Human Genome Project in 2003. At the same time we also witnessed the advent and rapid advance of modern semiconductor, in particular complementary metal-oxide-semiconductor (CMOS) technologies. There are particular areas in which the advancement of one field, in this case genomics, can benefit handsomely from integration with a more developed technology such as CMOS. This thesis describes two projects in which advanced CMOS technologies are leveraged to promote advancements in genomic sciences. The first project describes the design of a custom field-programmable gate array (FPGA) for the simulation of gene regulatory networks. As the field of genomics shifts its focus from genotyping to phenotyping, understanding the underlying gene regulatory networks in a behavioral or systematic manner becomes an increasingly important task. Simulating gene regulatory networks can be very computationally intensive, especially with complex models and large systems. Simple custom circuits, built from passive and active semiconductor devices, can be used to efficiently model and simulate complex gene regulatory networks using a mix of analog and digital computation. Here a typical FPGA architecture combined with fairly simple, specialized and configurable computational elements is employed. A working prototype built using 0.18 microm CMOS technology demonstrates the feasibility, efficiency and potential of such a system. Some variations of simple synthetic gene regulatory networks are simulated as examples. The second project incorporates the design, characterization, and demonstration of an array of CMOS active pixel sensor (APS) designed for integrated fluorescence sensing applications in genetic diagnostics and instrumentations. The 64 x 64 array is fabricated in a standard mix-signal 0 18-microm CMOS process with an integrated, programmable signal integration period for time-gated, time-resolved fluorescence spectroscopy. It is sensitive to photon densities as low as 8 x 106 photons/cm2 with 64-point averaging and, through a differential pixel design, has a measured impulse response of better than 800 ps. The sensor array can be employed as an integrated, active microarray platform, as well as a high-frame-rate imager for fluorescence lifetime imaging microscopy (FLIM). The functionality of the array is verified through calibrated intensity and lifetime measurements of a novel class of fluorescent molecules---semiconductor quantum dots (QDs). In addition, new techniques in probe immobilization and analyte labeling in conjunction with QDs are developed to demonstrate the array as a viable technology for a low-cost, high-throughput integrated active microarray plateform. Experiments using physiological samples in a gene expression profiling study demonstrate the platform as a potential application in point-of-care medicine.