Surface-Enhanced Raman Scattering Nanoendoscope for Quantification of a Protein Released under Physiological Stimulation in Brain Tissue

A surface-enhanced Raman scattering (SERS) biosensor with minimal invasiveness and high spatial resolution has been developed as a nanoendoscope to detect changes in protein concentrations at specific sites in biological tissues. While generally applicable to various tissues or proteins, the SERS nanoendoscope is demonstrated for the quantitative detection of S100β, an astrocytic protein whose plasmatic levels are known to vary in several neuropathologies such as Alzheimer’s disease, schizophrenia, Down syndrome, Parkinson’s disease and epilepsy, but for which intratissular levels have not been locally monitored, demonstrating key attributes of the SERS nanoendoscope. The SERS nanoendoscope is fabricated with densely and well-dispersed deposited gold nanoparticles modified with anti-S100β primary antibody on pulled optical fibers with a tip diameter of 700 nm, conducive to noninvasive and regiospecific detection of the S100β protein in different regions of mouse brain slices under different physiological stimuli with micrometer resolution. Quantification was performed ex vivo using SERS-active nanotags with secondary antibodies with detection limits of 5 and 7 nM in phosphate-buffered saline solution and mouse brain slice, respectively. Various physiological stimuli were then applied ex vivo to wild-type and S100β-knockout mouse brain slices to demonstrate the SERS nanoendoscope under physiological conditions. The average concentration of S100β was increased to 27, 45, and 48 nM upon N-methyl-d-aspartate, electrical, and optogenetic stimulation, respectively, statistically higher than all controls, demonstrating the ability of the SERS nanoendoscope to quantify protein release in biological tissues.