Inverse surface-enhanced spatially offset Raman spectroscopy (SESORS) through a monkey skull

The use of nanoparticles in nanomedicine has received increasing interest. However, in vivo detection of nanoparticles using optical techniques is still a formidable challenge. Detecting surface-enhanced Raman scattering (SERS)labeled nanoparticles through thick tissue is crucial due to its large number of potential applications in the field of disease diagnostics and monitoring. As gold nanoparticles are becoming an important nanoprobe and nanosensor platform for SERS in vivo applications, accurate detection and quantitation of these particles has become even more important. Conventional optical methods, however, are typically limited in obtaining SERS signals at the surface level, due to the attenuation caused by the highly scattering and absorbing tissue. Herein, we utilize spatially offset Raman spectroscopy to overcome this depth limitation and obtain specific spectrochemical signatures of SERS-labeled nanoprobes, such as gold nanostars, beneath thick material and bone. The efficacy of this method, referred to as surface-enhanced spatially offset Raman spectroscopy is demonstrated through the detection of layer-specific and subsurface SERS signals beneath three different substrates: (a) 4-mm tissue phantom, (b) 4-mm paraffin film, and (c) 5 mm bone of a macaque skull. Additionally, we show the possibility of recovering the pure SERS signal that belongs to a specific layer within a two-layer system using scaled subtraction.