From Fundamentals to Applications: Harnessing Digital Chemistry for Nanopore Sensor Development

Nanoscale materials and devices have attracted a significant research effort recently as they are promising for applications in the medical, environmental, forensic, and energy sectors. An exciting and emerging nanoscale device is the ion current rectifying nanopore sensor. These sensors offer high sensitivity label-free detection of even non-electrochemically active analytes using electrochemical means. This promising technology is hindered by a limited understanding of the intricacies of the transduction mechanism. A purely experimental investigation of these fundamentals is highly challenging as techniques to experimentally probe the interior ionic behavior of the nanopore are not currently available, while the more readily measurable electrochemical signal is a superimposition of highly coupled physical phenomena (such as electroosmotic flow, electric migration, diffusion, electrostatics, and surface charge dynamics) making it extremely difficult to delineate individual mechanisms. Furthermore, throughput of these devices is low, therefore, experimental designs requiring a large number of samples or repetitions is often not feasible. In this thesis, experiments are used in conjunction with finite element analysis to further the practical understanding of the preparation, the fundamental understanding of the ion transport, and the device optimization of nanopore sensors, and in particular of nanopipettes. The reaction of nanopipette silanization is investigated, as it is the most common crosslinking platform used for the immobilization of probes, and yet is seldom discussed in nanopipettes. The reproducibility and stability of silane layers, as well as the throughput of the process, and associated problems such as nanopipette blockage/dewetting and nanopipette filling, have been discussed. Vapor-phase deposition was offered as an effective way to mitigate these issues. In addition, the behavior of ion current rectification inversion was investigated, and finite element analysis revealed the link to tip-localized ion enrichment and to the positional migration of said ion enrichment. The behavior of the protons and of the surface charge density was also investigated using a model that considers the enrichment/depletion of protons and the surface protonation/deprotonation reactions. It was revealed that the surface charge is highly non-linear and is sensitive to many nanopipette parameters. The models used for these fundamental investigations were experimentally validated through the qualitative comparison of trends with those observed in experiments. Finally, a model capable of considering the device-to-device variance of nanopipette sensors was developed and experimentally validated, allowing computations to offer experimental guidelines on improving the device geometry, as well as allowing computations to be used to find the geometric and operating conditions that can offer the highest sensitivity to an analyte. This thesis has furthered the practical understanding of these nanopipette sensors, as well as highlighted fundamental ion transport dynamics, and provided a framework for the computational optimization of nanopipettes and other nanoscale devices.