Abstract
The process of label selection holds significant importance in the field of electrochemical biosensors, as it directly impacts the achievement of low detection limits and a wide dynamic range. To attain these objectives, it is necessary to take into account several aspects, including low electroactive potential, high electron transfer kinetics, and how these molecules attach to electrodes/recognition and/or signaling elements. Nonetheless, the utilization of electroactive labels in electrochemical bioassays, specifically for point-of-care applications, presents challenges when it comes to small molecule detections such as biomarkers or medicines. Furthermore, the setup of the electrochemical biosensors necessitates the utilization of an electrochemical redox reporter, which can be introduced into the solution in large quantities or linked to the recognition elements through covalent bonding. This is widely followed in the majority of the electrochemical sensing platform, where target-recognition elements binding does not generate any noticeable signals. By considering these issues altogether, it can be understood why currently, energy-based electro-recording signals, including hydrogen evolution reaction (HER), oxygen reduction reaction (ORR), and water splitting have motivated many researchers to develop electrochemical bioassays without tailored properties of electroactive labels. The use of these electrochemical
signals decreases the complicated procedure and permits the detection of a wide variety of molecules.
This review aims to provide insight into the relationship between energy-based signals and bioassays, guiding the design of HER/ORR/water splitting-based materials for signal recording in biosensors. These methods oer reagentless and electrochemical redox reporter-free options, which are increasingly attractive for large-scale commercialization of biosensors due to their simplicity, cost-eectiveness, speed, and favorable signal recording compared to traditional electroactive label-based biosensors. The primary goal is to encourage readers to explore new avenues for developing high-performance bioanalytical methods that do not rely on electroactive labels, potentially revolutionizing the field of biosensors and broadening their applications in various domains.



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