Nanofluidic systems with integrated nanopores for macromolecular sensing, manipulation and confinement

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The PI's research program, straddling the fields of nanotechnology/science and soft-matter/biophysics, is devoted to developing the field of nanofluidics. Nanofluidic devices are networks of fluid-filled channels on a chip with dimensions ~1-100 nm. Such devices have the ability to analyze and manipulate single-molecules. For example, nanochannels can extend DNA; nanopores can sense DNA electrically. Such single-molecule devices have the ability to perform genomic analysis without requiring molecular amplification, so that analysis could ultimately be performed on a single molecule, single-cell, basis. Such technology would have wide application in biomedical systems possessing extreme cell-to-cell genetic heterogeneity (cancer) and/or few cells are available (e.g. analysis of circulating tumor cells). Hand in hand with application goals, elucidating the behavior of confined macromolecules leads to new device concepts and more effective design. Finally, cells and viruses are inherently confined environments. Artificial' nanofluidic structures can probe confinement over a wide-parameter space and place results from in vivo experiments in a global, physical context. In this proposal we will jointly pursue nanofluidic technology development and fundamental physics exploration of confined polymer systems. In particular, our focus will be on developing a new class of nanochannel devices with integrated nanopores. The nanochanel-pore devices will be used to perform a novel transverse blockade sensing that does not require through-pore translocation, potentially leading to resolution not limited by the molecule diameter, improved translocation control and high multiplexing capability. These devices could lead to a high-resolution DNA electrical mapping ability based on sensing of sequence specific protein labels and DNA modifying/regulatory proteins. In our fundamental research axis, we will explore DNA non-equilibrium dynamics and knot-formation in nanochannels, extending our previous work to extreme confinement regimes and systems with embedded pores. In addition, optical tweezers and nanocavities with integrated pores will be used to study DNA packaging in a nanofluidic “virus,” leading to quantitative measurements critical for advancing understanding of the phage-system and cavity confined polymers. As demonstrated by past outstanding HQP outcomes, this work will lead to a rich multidisciplinary training environment leading to diverse career opportunities in industry and academia. Five HQP will be supported (PDF-1, MSc/PhD-3, MSc-1). HQP will receive training in nanofabrication, single-molecule techniques, quantitative analysis of single-molecule data, nanopore sensing and polymer theory in a multidisciplinary environment supported by collaborations with polymer theorists, biologists, experts in genomics technology and industry.