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The desire to translate biosensors for real time molecular monitoring has intensified due to the commercial success of 2-week continuous glucose monitors. However, a common limitation for emerging biosensors is that their lifetimes are often too short for commercially expected benchmarks of at least 3-day and ideally 2-week operation. Electrochemical sensors remain the preferred format of biochemical sensing thanks to their low cost, size, weight, and power requirements for mobile deployment. When exposed to biological fluid, all electrochemical sensors require a blocking layer to protect the electrode surface from fouling and redox interferents. Traditional blocking layer approaches rely on self-assembled monolayers which are often fragile to biological interferents like proteins and require specific electrode materials to improve their stability. Presented here is an evaluation of ultra-thin inorganic oxide and nitride films as an alternative to self-assembled monolayer blocking layers. Specifically, silicon oxide, silicon nitride, and aluminum oxide films were deposited by electron beam evaporation or atomic layer deposition at thicknesses of several nanometers to mimic the electrical capacitance of a conventional monolayer blocking layer. These oxide films were characterized over 7-days and demonstrated to provide poor protection against interfering redox currents from dissolved ferricyanide (150 - 300 µA/cm2) and oxygen reduction interference (30 - 60 µA/cm2). The oxide films were then used as a blocking layer in an electrochemical aptamer sensor using the previously published aptamer for phenylalanine. The phenylalanine sensor showed a binding affinity stronger than found in literature, but a reduced signal gain (∼ 20 % change in methylene blue redox current compared to the expected 50 % previously published on gold). It is speculated and supported by literature that these oxide and nitride films gradually dissolve over periods of days in an aqueous environment. Results further show that if lower quality oxide or nitride films are used, they may be more stable, but at the cost of initially higher in currents. While oxide and nitride films fail to improve upon the performance of thiol-blocking layers on gold electrodes, they may provide utility in some applications by allowing for alternate electrode materials and surfaces to be used instead of traditional self-assembled monolayers on gold electrodes. 

The first in-human demonstration of aptamer sensors is reported; these have the potential to enable continuous molecular monitoring beyond glucose. 

Electrochemical aptamer-based sensors offer reagent-free and continuous analyte measurement but often suffer from poor longevity and potential drift even with a robust 3-electrode system. Presented here is a simple, software-enabled approach that tracks the redox-reporter peak in an electrochemical aptamer-based sensor and uses the measurement of redox peak potential to reduce the scanning window to a partial measure of redox-peak-height vs. baseline (~10X reduction in voltage range). This same measurement further creates a virtual reference standard in buffered biofluids such as blood and interstitial fluid, thereby eliminating the effects of potential drift and the need for a reference electrode. The software intelligently tracks voltammogram peak potential via the inflection points of the rising and falling slopes of the measured redox peak. Peak-tracking-derived partial scanning was validated over several days and minimized electrochemically induced signal loss to <5%. Furthermore, the peak-tracking approach was shown to be robust against confounding effects such as fouling. From an applied perspective in creating wearable biosensors, the peak-tracking approach further enables use of a single implanted working electrode, while the counter/reference-electrode may utilize a simple gel-pad electrode on the surface of the skin, compared to implanting working, counter, and reference electrodes conventionally used for stability and reliability but is also costly and invasive. Cumulatively, peak-tracking provides multiple leaps forward required for practical molecular monitoring by extending sensor longevity, eliminating potential drift, simplifying biosensor device construction, and in vivo placement for any redox-mediated sensor that forms parabolic-like data. 

Electrochemical biosensors promise a simple method to measure analytes for both point-of-care diagnostics and continuous, wearable biomarker monitors. In a liquid environment, detecting the analyte of interest must compete with other solutes that impact the background current, such as redox-active molecules, conductivity changes in the biofluid, water electrolysis, and electrode fouling. Multiple methods exist to overcome a few of these challenges, but not a comprehensive solution. Presented here is a combined boron-doped diamond electrode and oil–membrane protection approach that broadly mitigates the impact of biofluid interferents without a biorecognition element. The oil–membrane blocks the majority of interferents in biofluids that are hydrophilic while permitting passage of important hydrophobic analytes such as hormones and drugs. The boron-doped diamond then suppresses water electrolysis current and maintains peak electrochemical performance due to the foulant-mitigation benefits of the oil–membrane protection. Results show up to a 365-fold reduction in detection limits using the boron-doped diamond electrode material alone compared with traditional gold in the buffer. Combining the boron-doped diamond material with the oil–membrane protection scheme maintained these detection limits while exposed to human serum for 18 h.