Unlocking “hidden” modes: A new physics-driven approach to label-free cancer cell phenotyping

Early detection and accurate typing of cancer are critical for improving patient survival rates. While traditional pathology remains the gold standard, it often requires complex sample processing and chemical staining. In a study published in the journal PhotoniX, researchers from the State Key Laboratory of Millimeter Waves at Southeast University and the Zhongda Hospital of Southeast University have unveiled a new "label-free" screening method. They have developed a sub-terahertz biosensor that leverages the physical concept of "band folding" to distinguish cancer cells based on their unique dielectric properties.

The Challenge: Sensing the Microscopic with Long Waves Sub-terahertz waves (0.1–10 THz) are highly attractive for biomedical sensing because they are non-ionizing (safe for biological tissues) and highly sensitive to water and biomolecules. However, a significant physical hurdle has existed: the wavelengths of sub-terahertz waves are much larger than the micron-sized cells they need to detect, resulting in weak interactions that make it difficult to capture detailed cellular information.

The Solution: Unlocking "Hidden Modes" To overcome this limit, the research team led by Professor Tie Jun Cui proposed a novel solution rooted in solid-state physics: superlattice band folding.

Traditional metamaterial sensors typically operate with only a few sparse resonant modes, which limits the amount of information they can retrieve. The team designed a honeycomb superlattice structure and introduced precise periodic perturbations—essentially breaking the structural symmetry. This operation acts like a key, "unlocking" a high density of "hidden modes" (electromagnetic states that normally cannot interact with free-space waves) and folding them into the radiative region where they can be detected.

"This mechanism could enable rapid differentiation of cancerous phenotypes from the normal counterparts," the authors state in the paper. The result is a sensor that provides a continuous, high-density spectral fingerprint in the 200–250 GHz range, significantly enhancing the ability to probe biological samples.

Experimental Validation: Distinct "Dielectric Fingerprints" The team validated the technology by testing three different cell types: normal mesenchymal stem cells (MSCs), and two types of cervical cancer cells with different degrees of malignancy (HeLa and CaSki).

The experiments showed that the sensor could clearly distinguish between the three. As the malignancy of the cells increased, the sensor detected distinct shifts in the transmission spectra. Crucially, the researchers bridged the gap between physics and biology to explain why this works. Using histopathology and atomic force microscopy, they confirmed that malignant cells possess a denser accumulation of intracellular biomass (such as proteins and nucleic acids) and enlarged nuclei compared to normal cells. This "crowded" cellular architecture leads to a higher effective permittivity, which the sub-terahertz sensor detects as a unique signal.

Future Outlook: This work establishes a direct link between microscopic cellular pathology and macroscopic electromagnetic response. By offering a label-free, non-destructive, and rapid way to phenotype cells, this technology holds promise for the development of future diagnostic devices for early cancer screening and intraoperative assessment.

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