Why Sensors Fail in Biological Samples: Fouling, Blocking, Matrix Effects and Prevention Solutions

Sensors and biosensors designed for biomarker detection in biological samples often suffer from performance loss caused by surface fouling, interface blocking, and matrix interference. Although these effects are frequently discussed separately, in real sensing systems they are strongly interconnected and they determine analytical reliability, especially in body fluids like serum, plasma, whole blood, sweat, and other complex media. This review provides a practical and mechanism-oriented overview of how these processes originate, how they differ, and how they ultimately lead to signal drift, reduced sensitivity, false-positive responses, and shortened sensor lifetime. We first discuss the molecular origins of interface failure, including protein adsorption, conditioning film formation, nonspecific binding, ionic strength effects, pH fluctuations, viscosity-related diffusion changes, and electroactive interferents. The impact of these phenomena is then compared across major sensing platforms, including electrochemical, potentiometric, optical, capacitive sensors, field-effect transistors and wearable biosensors. A central part of this review focuses on practical prevention strategies already employed in real biomarker sensing platforms. These include hydration-driven antifouling coatings, zwitterionic and hydrogel interfaces, post-immobilization blocking with bovine serum albumin, mercaptohexanol and ethanolamine, ionophore and membrane engineering in ion-selective electrodes, hydrophobic solid-contact layers for water-layer suppression, regeneration workflows, membrane and microfluidic pre-treatment, and AI-assisted drift correction. By combining advances in materials engineering, surface chemistry, sample handling, and algorithmic correction, this review highlights strategies to improve sensor stability in complex biological fluids. Overall, it offers a practical guide for developing next-generation low-fouling, drift-resistant, and self-correcting sensing systems for reliable biomarker analysis at the point of care.