Electrochemical Control of Plasmonic Nanogaps for Microfluidic Metabolite Sensing

Early-stage disease detection through a simple, non-invasive urine metabolite test could transform the landscape of diagnostics, making affordable, personalised health monitoring a reality. Metabolites in urine offer real-time snapshots of subtle physiological changes during disease progression, but access to this information remains limited by the cost and complexity of existing technologies. A promising alternative is surface-enhanced Raman spectroscopy (SERS), which amplifies weak molecular vibrations by confining light in plasmonic nanogaps to enable highly sensitive, label-free detection. However, limitations in reproducibility, fouling, and flow compatibility continue to hinder its practical application in metabolite sensing. In this thesis, I develop a reproducible, microfluidic SERS platform for high-throughput, in-flow metabolite sensing. The platform is based on the self-assembly of gold (Au) nanoparticles with cucurbit[n]uril (CB[n], n=5-8), a rigid molecular scaffold that precisely defines and stabilises sub-nanometre plasmonic hotspots. The stabilising influence of CB[n] enables the integration of electrochemical control of the nanogap environment to enhance molecular detection and to regenerate the substrate by removing bound molecules while preserving hotspot architecture. To achieve this, I introduce two complementary electrochemical regeneration strategies that rapidly restore nanogaps, extending SERS to real-time flow-injection and chromatographic detection, including metabolite sensing in urine. To understand what governs the reproducibility and robustness of nanogap regeneration, I spectro-electrochemically probe Au surface chemistry in situ. Here, I identify a covalent Au-Cl surface adlayer as a key intermediate that stabilises nanogap architecture and enables effective scaffold rebinding. Beyond regeneration, this same Au-Cl species also mediates surface transformations during Au nanoparticle growth, demonstrating its broader relevance in interfacial Au chemistry. The insights from this thesis deepen our understanding of dynamic Au surfaces and provide a mechanistic basis for improving the reliability and reusability of SERS platforms in complex, real-world sensing environments.