Tip-Enhanced Raman Scattering: Principles, Instrumentation, and the Application to Biological Systems

Tip-enhanced Raman scattering (TERS) is a near field technique that has revolutionized molecular imaging. New developments in the technology and methodologies have recently seen unprecedented improvements in spatial resolution. This article outlines the basic theory of TERS, highlighting some of the pivotal studies in the field. This article starts with an explanation on how TERS is able to surpass the limitations of classical Raman spectroscopy such as diffraction limit and the small Raman scattering cross-section to generate signal enhancement at nanometer resolution. This article then describes three physical phenomena including localized plasmon resonance, optical nanoantenna resonance, and the lightening rod effect to explain the enhancement generated in a TERS experiment. In the second part of this article, the application of TERS for investigating biological molecules and subcellular components is discussed along with the important methodological considerations when recording measurements of these biological complex systems. Finally, a number of pivotal studies investigating the structure of DNA, proteins, peptides, and single cells are highlighted.