Surface second harmonic generation (SHG) is a coherent, nonlinear optical technique that is well suited for investigations of biomolecular interactions at interfaces. SHG is surface specific due to the intrinsic symmetry constraints on the nonlinear process, providing a distinct analytical advantage over linear spectroscopic methods, such as fluorescence and UV-Visible absorbance spectroscopies. SHG has the ability to detect low concentrations of analytes, such as proteins, peptides, and small molecules, due to its high sensitivity, and the second harmonic response can be enhanced through the use of target molecules that are resonant with the incident (ω) and/or second harmonic (2ω) frequencies. This review describes the theoretical background of SHG, and then it discusses its sensitivity, limit of detection, and the implementation of the method. It also encompasses the applications of surface SHG directed at the study of protein-surface, small-molecule–surface, and nanoparticle-membrane interactions, as well as molecular chirality, imaging, and immunoassays. The versatility, high sensitivity, and surface specificity of SHG show great potential for developments in biosensors and bioassays.

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