Physiological conditions can alter the performance of electrochemical sensors through complex interactions arising at the tissue matrix and electrode interface. Understanding this relationship is a prerequisite to the eventual deployment of these sensors in vivo. Herein, we investigate the ability of energy dispersive X-ray (EDX) analysis to monitor silicone oil levels within carbon paste electrodes (CPE). We correlate these findings with scanning electron microscopy (SEM) images and cyclic voltammetry (CV) data. EDX analysis reported significant variations in silicone oil content when the CPE was immersed in protein (bovine serum albumin (BSA)), lipid (phosphatidylethanolamine (PEA)), surfactant (Triton®X (TX)) and brain tissue over a 28-day period. Moreover, the greatest effect occurs within the first 24 h of exposure. Protein adsorption appears to hinder the X-rays emitted during SEM imaging resulting in reduced silicone oil measured by EDX. SEM images and voltammetric profiles support this finding. Brain tissue homogenate appears to reduce silicone levels at a slower rate than PEA and TX which corroborates voltammetric data. Notwithstanding this, the surface morphology determined by SEM imaging suggests comparable surface alterations for the three treatments over the 28 days. Finally, we report the impact that continuously cycling CPEs in protein and lipid has on the silicone oil content. There was a significant improvement recorded over a 3.5h period when compared to EDX analysis performed on CPEs stored in the solutions for the same period. Collectively, the data provided within support the utility of EDX analysis as a valid and simple surface analytical technique that can be employed to follow the removal of silicone oil from CPEs.