Another concern for biosensor longevity is chemical and enzymatic attack of the biorecognition element itself (Figure ). In particular for aptamers, processes such as nuclease cleavage, enzymatic methylation, and oxidation of the singlestranded DNA can all potentially degrade the sensor redox tag current and the sensor response over time. We will not spend time discussing enzymatic modification of aptamers in detail here because it is largely aptamer dependent and resolvable, if needed, by chemically modifying the aptamer or providing membrane protection to block nucleases and other enzymes. Lastly, one of the major remaining concerns that extends beyond just aptamer sensors is protein biofouling. Aptamer sensors employing alkylthiolate monolayers on mechanically polished gold typically exhibit a rapid initial 30-50% reduction of redox tag current due to biofouling when scanned in protein rich fluids such as serum. We speculate that this is due to hydrophobic protein domains fouling at defect sites where the inner hydrophobicity of the monolayer molecules is partially exposed (Figure , left plot). Even more problematic, but not previously discussed in the literature, is the reorganization of biofouled protein molecules and the resulting protein interactions with surface immobilized aptamer molecules over multiple days. While these interactions may not significantly impact redox tag and background currents over multiple days, they can constrain the aptamers' ability to move freely and therefore prevent proper sensor response to changes in analyte concentration (Figure , middle and right plots).