A comprehensive scoping review of methodological approaches and clinical applications of tear fluid biomarkers

Tear fluid is an emerging source of disease biomarkers, drawing attention due to its quick, inexpensive, and non-invasive collection. The advancements in detection techniques enable the measurement of ultra-low biomarker levels from small sample volumes typical of tear fluid. The lack of standardized protocols for collection, processing, and analysis of tear fluid remains a significant challenge. To address this, we convened the Tear Research Network Review Taskforce in 2022 to review protocols from the past three decades, providing a comprehensive overview of the methodologies used in tear fluid biomarker research. A total of 1484 articles published from January 1974 to May 2024 from two electronic databases, Embase and Ovid MEDLINE, were reviewed. An exponential increase in the number of articles on tear fluid biomarkers was observed from 2015 onwards. The two most commonly reported collection methods were; glass capillaries (45.2%), and Schirmer's strips (25%), with glass capillary tube collection remaining the most frequent method until 2019, when Schirmer's strips became the leading method. Most articles analyzed tear fluid proteins (65%) and focused on a single analyte (32.3%). In recent years, an increase was observed in the type and number of examined analytes. The differences in the reported methodologies and protocols underscore the need for standardization and harmonization within the field of tear fluid biomarkers to minimize methodological differences and reduce variability in clinical outcomes. Consistent and detailed reporting is essential for improving the reproducibility and validity of tear fluid studies, in order to advance their potential clinical applications.