Plasmonic nanostructures have found increasing utility due to the increased popularity that surface-enhanced Raman scattering (SERS) has achieved in recent years. SERS has been incorporated into an ever-growing list of applications, with bioanalytical and physiological analyses having emerged as two of the most popular. Thus far, the transition from SERS studies of cultured cells to SERS studies involving tissue has been gradual and limited. In most cases, SERS measurements in more intact tissue have involved nanoparticles distributed throughout the tissue or localized to specific regions via external functionalization. Performing highly localized measurements without the need for global nanoparticle uptake or specialized surface modifications would be advantageous to the expansion of SERS measurements in tissue. To this end, this work provides critical insight with supporting experimental evidence into performing SERS measurements with nanosensors inserted in tissues. We address two critical steps that are otherwise underappreciated when other approaches to performing SERS measurements in tissue are used. Specifically, we demonstrate two mechanical routes for controlled positioning and inserting the nanosensors into the tissue, and we discuss two means of focusing on the nanosensors both before and after they are inserted into the tissue. By examining the various combinations of these steps, we provide a blueprint for performing SERS measurements with nanosensors inserted in tissue. This blueprint could prove useful for the general development of SERS as a tool for bioanalytical and physiological studies and for more specialized techniques such as SERS-optophysiology.

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