Beyond Self-Assembly: Bioorthogonal ‘Click’ Chemistry Strategies for Robust Electrochemical Interfaces in Wearable Biosensors

Electrochemical biosensors integrated into wearable devices have revolutionized the technology in terms of health monitoring and diagnostic systems. However, when it comes to moving the devices from the laboratory to real-world environments, a critical problem emerges with the interface. The problem, in essence, is that biorecognition elements tend to lose their activity, delaminate, and drift when exposed to various environmental stresses. The traditional methods for the immobilization of the biorecognition elements result in receptors with random orientations, hydrolytically unstable bonds, and batch-to-batch variability, regardless of the method, including physisorption or non-selective covalent attachment, like using EDC/NHS. This review is organized around a comparative question: which limitations of classical immobilization strategies (physisorption, self-assembled monolayers used as passive anchoring platforms, and EDC/NHS coupling) can be resolved by click chemistry, which can be resolved by mechanistic features? Accordingly, CuAAC, SPAAC, IEDDA, and thiol-ene/yne photoclick reactions are discussed, not as an isolated catalog of ligations, but as complementary solutions to specific interfacial failure modes, including random bioreceptor orientation, hydrolytically vulnerable attachment, poor batch reproducibility, catalyst sensitivity, and the difficulty of functionalizing soft polymeric or textile substrates. In this framework, click chemistry is treated as a deterministic interface-engineering strategy that enables defined covalent fixation, programmable probe density, and improved mechanical and electrochemical robustness under wearable operating conditions.