Ultrasensitive cell surface stress biosensor based on magnetic-stress-electrical coupling

Surface stress, as an indicator of cellular state, responds to morphological changes, signaling, and disease processes, and is therefore highly significant for early diagnosis and precise disease monitoring. However, cell surface stress can become very subtle when the external stimulus is weak. Detecting these weak stress signals with high sensitivity to enable reliable and precise biosensing is thus an essential challenge. Here, we report a surface-stress biosensor based on multiphysics coupling that demonstrates label-free electrical detection of trace cell populations (as few as 20 cells·mL^-1) and is applicable across diverse adherent cell types. The differing surface stresses generated by various cells on the biosensor surface were amplified by incorporating ferromagnetic materials and applying an external magnetic field. The chip employs interdigitated electrodes and a non-floating thin-film design to ensure that weak electrical signals from the densely packed palladium-nanoparticle film can be detected while minimizing the influence of the film's weight on biosensor performance. The biosensor provides a wide detection range from 200 to 2 × 10⁴ cells·mL^-1, with high sensitivity and a detection limit as low as 20 cells·mL^-1 for normal human hepatocyte (L02) and human hepatocellular carcinoma cells (HepG2) after treatment with sorafenib. Moreover, we further elucidate the principle of magnetic sensitization through theoretical calculations. This work represents a significant advancement in high-sensitivity biosensing for the personalized treatment and management of hepatocellular carcinoma and provides insights into novel in-vitro diagnostic strategies.