The aim of this research effort is to leverage the unique capabilities of our recently developed sub-nanometer precision transmission electron beam ablation lithography (TEBAL) to demonstrate that the precise integration of solid-state nanopores with nanoelectrodes, nanochannels and other nanostructures will address key obstacles that must be overcome to achieve nanopore-based low-cost high-speed sequencing of chromosomal length DNA molecules, and the resultant medical and scientific benefits enabled by this technology. Fast and low cost full genome DNA sequencing will allow, for example, major improvements in the understanding, diagnosis, treatment and prevention of disease, and significant advances in evolutionary research and the understanding of cellular operation. This project will build on the remarkable progress towards nanopore-based DNA sequencing over the past decade, and it is planned to continue the tradition of sharing results, techniques and nanopore devices with the research community so that the work carried out will make the maximal contribution to advancing the state of the art. It is expected that the nanopore-nanoelectrode devices produced will seed further work by other groups on a variety of transverse electrode sensing methodologies and nanoelectrode-based single DNA molecule manipulation, which will contribute to the achievement of a nanopore-based """"""""$1000 genome sequencer"""""""". This development (R21) project will begin work on the long term goals described above by demonstrating the improvements that can be achieved using nanopore devices with integrated nanoelectrodes and nanochannels. Beyond developing reliable nanopore-nanoelectrode devices, the unique aspects of the proposed work include the integration of geometrically more complex electrode patterns to manipulate DNA motion, and the integration of these devices with microfluidics and a fluorescent microscope setup to allow tracking of DNA molecules, so that they can be actively transported to the nanopore. The specific tasks are to show that: * DNA molecule length can be measured more accurately by transverse sensing with nanoelectrodes * the translocation speed of double stranded DNA can be reduced by applying forces via nanoelectrodes * by constraining DNA molecules, length measurement resolution improves for longer molecules * individual DNA molecules can be selected, transported to a nanopore and translocated through it These objectives will be accomplished in several steps. The required nanopore-nanoelectrode, nanopore-nanochannel and microfluidics devices will first be fabricated and characterized (some of this has already been achieved). Next, experiments with these devices will be conducted to evaluate their performance and identify problems. Finally, several cycles of device refinement and further experiments will resolve these problems and improve device performance to optimal levels, so that achievement of the objectives can be demonstrated. PROJECT

Public Health Relevance

This research aims to achieve much faster and lower-cost DNA sequencing by developing a nanotechnological sensor. This sensor works just like picking out the knots on a string by running it through one's fingers, except the string is a million times thinner! It will enable major improvements in the understanding, diagnosis, treatment and prevention of disease, by allowing us to determine the underlying genetic causes and symptoms, detect these rapidly and accurately in patients, and treat them appropriately.

National Institute of Health (NIH)
National Human Genome Research Institute (NHGRI)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Special Emphasis Panel (ZHG1-HGR-N (M1))
Program Officer
Schloss, Jeffery
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Schools of Arts and Sciences
United States
Zip Code
Parkin, William M; Balan, Adrian; Liang, Liangbo et al. (2016) Raman Shifts in Electron-Irradiated Monolayer MoS2. ACS Nano 10:4134-42
Balan, Adrian; Chien, Chen-Chi; Engelke, Rebecca et al. (2015) Suspended Solid-state Membranes on Glass Chips with Sub 1-pF Capacitance for Biomolecule Sensing Applications. Sci Rep 5:17775
Niedzwiecki, David J; Lanci, Christopher J; Shemer, Gabriel et al. (2015) Observing Changes in the Structure and Oligomerization State of a Helical Protein Dimer Using Solid-State Nanopores. ACS Nano 9:8907-15
Rodríguez-Manzo, Julio A; Puster, Matthew; Nicolaï, Adrien et al. (2015) DNA Translocation in Nanometer Thick Silicon Nanopores. ACS Nano 9:6555-64
Balan, Adrian; Machielse, Bartholomeus; Niedzwiecki, David et al. (2014) Improving signal-to-noise performance for DNA translocation in solid-state nanopores at MHz bandwidths. Nano Lett 14:7215-20
Venta, Kimberly; Shemer, Gabriel; Puster, Matthew et al. (2013) Differentiation of short, single-stranded DNA homopolymers in solid-state nanopores. ACS Nano 7:4629-36
Venta, Kimberly; Wanunu, Meni; Drndi?, Marija (2013) Electrically controlled nanoparticle synthesis inside nanopores. Nano Lett 13:423-9
Merchant, Chris A; Drndic, Marija (2012) Graphene nanopore devices for DNA sensing. Methods Mol Biol 870:211-26
Healy, Ken; Ray, Vishva; Willis, Lauren J et al. (2012) Fabrication and characterization of nanopores with insulated transverse nanoelectrodes for DNA sensing in salt solution. Electrophoresis 33:3488-96
Saha, Kamal K; Drndic, Marija; Nikolic, Branislav K (2012) DNA base-specific modulation of microampere transverse edge currents through a metallic graphene nanoribbon with a nanopore. Nano Lett 12:50-5

Showing the most recent 10 out of 16 publications