Metasurface-Enhanced Infrared Spectroscopy for Quantitative Molecular Sensing: A Proof-of-Concept Study for Therapeutic Drug Monitoring.

Therapeutic drug monitoring (TDM) is the clinical practice of measuring specific drugs at designated intervals to maintain a constant concentration in a patient's bloodstream. However, detecting clinically relevant levels (typically in the μg/ml range) remains challenging outside the laboratory, as current analytical methods use elaborate sample preparation protocols and complicated measurement procedures. Here, we present a metasurface-assisted Fourier-transform infrared approach using dried samples that enhances molecular absorption by aligning their vibrational modes with the metasurface resonance; the metasurface supports a guided-mode resonance that hybridizes with the vibrational frequency of the drug molecule, thereby increasing the effective absorbance significantly. The metasurface topology also promotes ordered drug crystallization in regions with the strongest light-matter interaction, further contributing to the absorption enhancement. Using this design, we are able to consistently detect phenytoin in serum below the therapeutic range of 10-20 µg/ml by achieving a limit of detection of 1.4 μg/ml, which is limited by the drying process. This proof of concept for TDM at concentrations in the sub-clinical level highlights the significant potential for metasurface-enhanced spectroscopy and offers a path toward compact, high-performance infrared sensors for healthcare applications.