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Real-time continuous monitoring of proteins in-vivo holds great potential for personalized medical applications. Unfortunately, a prominent knowledge gap exists in the fundamental biology regarding protein transfer and correlation between interstitial fluid and blood. Additionally, technological sensing will require affinity-based platforms that cannot be robustly protected in-vivo and will therefore be challenged in sensitivity, longevity, and fouling over multi-day to week timelines. Here we use electrochemical aptamer sensors as a model system to discuss further research necessary to achieve continuous protein sensing.

 

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.