Development of Scanning Ion-Conductance Microscopy Based Tip-Enhanced Raman Spectroscopy in Liquid Environments

The ability to conduct nanoscale imaging and in situ chemical analysis in liquid environments can greatly benefit biological and soft materials research. Scanning ion-conductance microscopy (SICM) is one of the most popular non-contact techniques for imaging and manipulating living cells and soft substrates in their native environments, using ionic current feedback to enable gentle and precise mapping. On the other hand, tip-enhanced Raman scattering (TERS) has achieved label-free, molecularly specific nanoscale characterization via plasmonic enhancement provided by the probe tip. Recent developments in both techniques have made it possible to combine SICM with TERS. The resulting hybrid SICM-TERS can enable simultaneous, correlated mapping of topography in liquid environments. This review provides an overview of SICM and TERS leading up to the development of SICM-TERS, including their respective principles, instrumental developments, and current state of the art. Additionally, it discusses how combining these two techniques enables new opportunities for real-time, minimally invasive investigations of dynamic biological processes and complex interfacial phenomena under native conditions. As probe durability and multimodal microscopy integration improve, SICM-TERS is expected to take a more versatile role in correlative nanoscale imaging in the future. This will have a major impact on nanomedicine, biology, and materials research.