Biomarkers in tear fluid have attracted much interest in daily healthcare sensing and monitoring. Recently, surface-enhanced Raman scattering (SERS) has enabled highly sensitive label-free detection of small molecules. However, a highly stable straightforward tear assay with superior sensitivity is still under development in tear collection and analysis. Here we report a plasmonic Schirmer strip for on-demand, rapid, and simple identification of biomarkers in human tears. The diagnostic strip features gold nanoislands directly and evenly formed on the top surface of cellulose fibers, which maintain a hygroscopic nature for an efficient collection of tear production as well as provide plasmonic enhancement in SERS signals for identification of tear molecules. The uric acid in human tears was quantitatively detected at physiological levels (25-150 μM) by using SERS. The experimental results also clearly reveal a strong linear correlation between uric acid level in both human tears and blood for gouty arthritis diagnosis. This functional paper strip enables noninvasive diagnosis of disease-related biomarkers and healthcare monitoring using human tears.

The quantitative label-free detection of neurotransmitters provides critical clues in understanding neurological functions or disorders. However, the identification of neurotransmitters remains challenging for surface-enhanced Raman spectroscopy (SERS) due to the presence of noise. Here, we report spread spectrum SERS (ss-SERS) detection for the rapid quantification of neurotransmitters at the attomolar level by encoding excited light and decoding SERS signals with peak autocorrelation and near-zero cross-correlation. Compared to conventional SERS measurements, the experimental result of ss-SERS shows an exceptional improvement in the signal-to-noise ratio of more than three orders of magnitude, thus achieving a high temporal resolution of over one hundred times. The ss-SERS measurement further allows the attomolar SERS detection of dopamine, serotonin, acetylcholine, γ-aminobutyric acid, and glutamate without Raman reporters. This approach opens up opportunities not only for investigating the early diagnostics of neurological disorders or highly sensitive biomedical SERS applications but also for developing low-cost spectroscopic biosensing applications.

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High-throughput small-molecule assays play essential roles in biomedical diagnosis, drug discovery, environmental analysis, and physiological function research. Nanoplasmonics holds a great potential for the label-free detection of small molecules at extremely low concentrations. Here, we report the development of nanoplasmonic paper (NP-paper) for the rapid separation and ultrasensitive detection of mixed small molecules. NP-paper employs nanogap-rich silver nanoislands on cellulose fibers, which were simply fabricated at the wafer level by using low-temperature solid-state dewetting of a thin silver film. The nanoplasmonic detection allows for the scalable quantification and identification of small molecules over broad concentration ranges. Moreover, the combination of chromatographic separation and nanoplasmonic detection allows both the highly sensitive fluorescence detection of mixed small molecules at the attogram level and the label-free detection at the sub-nanogram level based on surface-enhanced Raman scattering. This novel material provides a new diagnostic platform for the high-throughput, low-cost, and label-free screening of mixed small molecules as an alternative to conventional paper chromatography.

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