Quartz crystal microbalance biosensors for clinical biomarker detection: Advances in biorecognition, immobilization, and signal enhancement strategies.

Quartz crystal microbalance (QCM) sensing provides label-free, real-time detection of surface-associated changes and has gained increasing attention for biomedical biomarker detection. This review examines advances in QCM biosensors reported between 2020 and 2025, focusing on biorecognition elements, receptor immobilization, signal-enhancement strategies, and factors limiting clinical translation. Recent studies demonstrate the detection of diverse disease-associated targets in biologically relevant media, with antibodies remaining the predominant biorecognition elements and covalent coupling the most frequently employed immobilization strategy. Signal enhancement is achieved through three principal routes: increasing the mass coupled to the sensor, increasing the effective surface area for target capture, or increasing the intrinsic sensitivity of the resonator. Nanoparticle-based approaches dominate current signal-enhancement strategies, while surface nanostructuring and high-frequency QCM provide alternative routes to improved sensitivity. However, low limits of detection alone do not establish clinical utility. Viscoelastic and hydration effects, biofouling, measurement variability, sensor regeneration, sample requirements, and limited validation in clinical specimens remain important challenges. Greater standardization of experimental procedures and reporting, together with clinically relevant validation and advances in sensor interfaces, fluidics, and data analysis, will be essential for translating QCM biosensors from proof-of-concept studies toward robust clinical and point-of-care applications.