Today, synthetic nanopore devices are the subject of intense investigation as intriguing candidate devices for high-speed non-enzymatic interrogation of individual biological macromolecules. Such functionality is required for example in order to sequence individual DNA fragments of unknown composition at high speeds. While many theoretical aspects regarding macromolecule translocation physics and novel readout schemes are presently under investigation by several NIH-funded groups, the practical utilization of nanopores in sequencing systems also requires large arrays of nanopores working in parallel, each of these connected to high-sensitivity electronic amplifiers/detectors. Such degree of parallelism and systems integration is necessary in order to achieve significant improvements in throughput compared with today's state-of-the-art massively-parallel enzymatic sequencing by synthesis schemes (SBS) (such as those offered by 454 Life Sciences which reports high-fidelity sequencing of bacterial genomes at 20 Mb/day). To illustrate the need for arrays one may consider for example, a 100- nanopore array with average nanopore translocation rate of 100b/ms/pore could in principle sequence fragments at (high-fidelity, 100 repeats) rates of 10 Gb/day, allowing an entire human genome to be sequenced in a day, 500 times faster than SBS.
The aims of this proposal are (a) the development of highly-integrated arrays of nanopores that can be fabricated by lithographic methods along with on-chip silicon-based electronic circuits and circuit techniques that amplify and isolate their various electrical signals, and (b) the exploration of a dipole sensing methodology which in principle can distinguish signals from each of the DNA bases. A quadrature capacitance sensor will be incorporated in some of the fabricated nanopores. Arrays of nanopores will be constructed on silicon substrates using a self-aligned compositional approach. Quadrature dipole moment detectors will be constructed that yield a signal independent of the rotation of the DNA molecule relative to the electrodes.
