Precise detection of single particles and bio-sensing applications on quartz crystal microbalance using non-linear resonance behavior

Ultrasensitive mass detection is essential across various fields, including environmental monitoring, biosensing, and medical diagnostics. Quartz crystal microbalance (QCM) and nanoelectromechanical system (NEMS) sensors are widely utilized, yet NEMS approaches are hindered by issues of stability and reproducibility, whereas QCMs face fundamental physical limitations in enhancing sensitivity. To address the limitations of current sensing technologies, we demonstrate that increasing the driving force applied to the QCM induces non-linear resonance, and that utilizing the abrupt amplitude drop occurring at this non-linear resonance enables mass detection down to 100 fg. Unlike conventional linear QCM operation, our method significantly enhances mass sensitivity by exploiting amplitude-drop behavior in the non-linear regime, without requiring additional surface functionalization or device modification. We validated this sensing strategy through the detection of micro/nanoparticles and protein-antibody interactions, successfully achieving single micro/nanoparticle detection and reaching a detection limit of 100 fg. Notably, this method enables reliable single micro/nanoparticle detection with high reproducibility. This sensing approach provides a simple yet powerful platform that overcomes key limitations of traditional QCM systems. With the potential for real-time biomolecular diagnostics in aqueous environments and future integration with microfluidic chips, our approach represents a promising strategy for ultra-sensitive mass detection.