The objective of this research is to create a nanoscale system that achieves ultra-rapid, high-resolution analysis of biomolecules such as nucleic acids and proteins. The approach is based on a combination of nanopore device fabrication, predictive physics-based diagnostic algorithms to control biomolecule transport in the device, and integration of these subsystems to demonstrate high-speed biomolecule analysis with much higher resolution than currently possible.
Intellectual Merit: This work addresses the challenge of developing nucleic acid and protein sequencing platforms that achieve orders-of-magnitude savings in time and cost. This is essential to transform current understanding of the genetic basis of disease and thereby revolutionize many areas of medicine and biotechnology. This work takes an integrated approach to the critical issues of device fabrication and high-performance operation. It combines a wafer-scale process (based on advanced electron-beam and atomic layer deposition techniques) to fabricate the first reproducible arrays of engineered nanopore devices, with a novel computational diagnosis platform that couples hierarchically detailed simulation engines and mathematical algorithms to adaptively refine the nanopore device performance for ?single-nucleotide? resolution.
Broader Impact: This program will develop interdisciplinary and diverse science and technology manpower by training three graduate and nine undergraduate students across five engineering and science disciplines, enhanced by collaborations with national laboratories. Three of the undergraduate trainees will be recruited from underrepresented minorities by active collaboration with a campus program for creating research opportunities for underrepresented minorities. The project will develop hands-on modules for undergraduate, graduate, and continuing education courses in circuit diagnosis, nanofabrication, and nanosystems.
Radically new biomolecule analysis platforms are essential for achieving the desired transformational developments in understanding genetic susceptibility to disease, genome variation among individuals, drug response, and rapid response to pathogenic threats. For example, many areas of medicine, biotechnology, and biology will be revolutionized by the capability to sequence human and other mammalian-size genomes for less than US $1,000 in a period of hours to days. The emergence of prototype ‘Engineered Nanopore Devices’ (ENDs) holds great promise as an ultra-rapid biomolecule analysis platform for a number of applications including DNA sequencing. Two critical and interrelated challenges in realization of END-based biomolecule analysis platforms are: (1) Development of a process for fabricating reproducible arrays of high-quality ENDs; and (2) Understaning and controlling biomolecule transport in ENDs to obtain much higher sensor resolution – ultimately to ‘single-nucleotide’ levels - than currently known. To address these challenges, this project took a unique integrated approach as embodied in two core innovations: (1) Development of a reproducible electron-beam lithography and atomic layer deposition processes to fabricate END arrays; and (2) Creation of a computational system for describing and understanding DNA transport through ENDs. Our results in this project, as embodied in several journal publications, conference presentations, a book chapter, and a granted US patent, have contributed substantially towards bring END-based biomolecule analysis systems closer to reality. Our project was based upon a combination of concepts from nanoscale materials/device processing, experimental and computational biophysics, sensor diagnosis, and circuit testing. It developed two graduate researchers with strong multidisciplinary training who are ready to be absorbed by US industry and academia. This program involved intensive cross-training of researchers (across five different engineering and science Schools at Georgia Tech) in nanoscale device fabrication, biomolecule transport simulations, circuit diagnosis methodologies, and bioanalytical measurements, thus leading to a synergistic creation of knowledge with significant scientific and technological ramifications. Our fundamental research was disseminated to a broad science and engineering community via peer-reviewed publications, conference presentations, and a book chapter; whereas the applied aspects generated intellectual property in the form of a US patent. The results of this project were used to develop course modules for undergraduate/graduate courses in nanoengineering and nanofabrication.
