One to two weeks of wearable continuous glucose monitoring in dermal interstitial fluid for diabetes management is a historical achievement in clinical diagnostics. Unfortunately, glucose monitoring remains an isolated success despite acute needs for continuous measure of many other molecules across the field of human disease management such as in cardiac, fertility, and therapeutic drug monitoring. The major limitation is that electrochemical glucose sensors are enzymatic, thus limiting generalizability to other analytes due to a modest number of oxidoreductase enzymes that could oxidize/reduce analytes of interest. Unlike enzymatic sensors, electrochemical aptamer sensors are affinity-based and broadly generalizable by relying on large oligonucleotide libraries of 10 12 -10 15 possible aptamer sequences, which can be further chemically modified to enhance binding capabilities during selection for a specific target. There are now over a dozen examples of continuous in-vivo aptamer sensor monitoring at nanomolar to micromolar concentration ranges. These early successes place aptamer sensors within a very limited collection of continuous chemical sensors that have been in-vivo demonstrated for clinically oriented applications, including ionselective/ionophore sensors and enzymatic biosensors. Unfortunately, aptamer sensor longevity has remained a significant challenge for the clinical adoption of aptamer sensors, especially when tested in representative in-vivo conditions. Electrochemical aptamer sensors conventionally use a mixed monolayer of redox-tagged aptamers and alkylthiolate passivating molecules chemisorbed onto the surface of a gold electrode (Figure ). These self-assembled monolayers have been shown to rapidly degrade on gold electrodes in blood or serum at a body temperature of 37 °C. The mechanisms of monolayer degradation in complex biofluids have not been fully understood, which has limited the ability to pursue specific approaches to improve sensor longevity. Part of the challenge is that, if there are a plurality of mechanisms rapidly and simultaneously degrading a sensor's monolayer and its biorecognition element, it becomes highly difficult to isolate and observe individual degradation mechanisms in a manner that is representative of the end application in whole biofluid. A recent review by Shaver and Arroyo-Currás 9 concluded that experimental conditions such as elevated temperature, repeatedly applied voltages, and protein-rich biofluids can have a detrimental effect on monolayer integrity, limiting sensor operation to at most a few hours. This mirrors a generally accepted opinion that widely utilized self-assembled alkylthiolate monolayers on gold are too unstable to last more than several days when repeatedly electrochemically scanned and exposed to complex fluids such as raw serum or blood at body temperature.