Quartz Crystal Microbalance-Based Biosensor for Rapid and Ultrasensitive SARS-CoV-2 Detection

The COVID-19 pandemic highlighted the urgent need for rapid, sensitive, and affordable diagnostic tests, especially in resource-limited settings. While RT-qPCR remains the gold standard for SARS-CoV-2 detection, it is expensive and requires specialized equipment. Antigen-based tests, though faster, lack sufficient sensitivity. Therefore, there is a pressing need for a platform that combines the rapidity of antigen tests with the sensitivity of molecular tests. In this work, we address this problem by developing a Quartz Crystal Microbalance (QCM) biosensor for the rapid detection of SARS-CoV-2 nucleocapsid proteins. We designed a QCM biosensor with polyethylene glycol (PEG)-based surface functionalization, which significantly improves sensitivity and specificity. The platform achieved a detection limit of 53.3 TCID50/mL and a sensitivity of 0.263Hz/ TCID50 /mL, with results available in approximately 15minutes. Cross-reactivity tests with Influenza A demonstrated its high specificity for SARS-CoV-2. Comprehensive surface characterization using Scanning Electron Microscopy (SEM), Digital Holographic Microscopy, and Raman Spectroscopy confirmed the stability and integrity of the functionalized sensor surface. The platform is cost-effective, scalable, and designed for ease of use in resource-limited settings. This work presents the first open-source QCM biosensing platform for SARS-CoV-2 detection that combines high sensitivity, rapid results, and affordability. It offers a deployable solution for COVID-19 diagnostics, particularly in underserved regions, and is adaptable for future pandemic preparedness.