An adaptive harmonic AFM probe with enhanced sensitivity for cellular imaging

Accurate classification of cellular images plays an indispensable role in early cancer diagnosis. Based on signal enhancement, harmonic atomic force microscopy (AFM), distinguished by its high resolution, demonstrates unique advantages in rapid acquisition and analysis of cellular images. Traditional harmonic probes are generally designed without sufficient consideration of environmental and sample-induced interference on probe vibration. However, in cellular imaging, environmental perturbations and heterogeneous mechanical properties of samples can significantly compromise imaging quality. To address the challenge of precision imaging in multi-environment cellular studies, we have developed an adaptive harmonic atomic force microscopy (A-HAFM) probe capable of generating stable harmonic signals in both atmospheric and liquid environments, enabling high-resolution cellular imaging and precise cell classification. Experimental studies involving 3600 samples of human cervical epithelial cells and human cervical cancer cells with varying invasiveness (HeLa and SiHa) demonstrated that the A-HAFM probe achieved 52.17% improvement in amplitude response sensitivity compared to conventional AFM, along with 60% enhancement in imaging clarity, with classification accuracy for normal vs cancer cells improved by 7.97% and between cancer subtypes (HeLa/SiHa) increased by 12.73%. By precisely characterizing cellular substructures and identifying physiological signatures, this technology establishes a promising platform for cellular-level diagnosis and therapeutic evaluation of cardiovascular diseases, malignant tumors, and other critical illnesses.