Animal-based experimental models in dry eye research: Current approaches and limitations

Experimental animal models offer simplified yet highly controlled systems that enable the systematic exploration of the biological processes underlying human diseases. In dry eye disease (DED), animal models mimic the clinical and pathological features. A wide spectrum of approaches has been developed depending on the targeted mechanism, including aqueous-deficient, evaporative, and mucin-deficient models. Nevertheless, existing models fail to reproduce the multifactorial and heterogeneous nature of DED. Most models are highly useful for short-term evaluations; however, they are insufficient for long-term studies and fail to mimic the chronic course of the disease. Although aqueous-deficient DED models may be advantageous for inducing a more stable and severe DED phenotype, substantial interspecies variability can markedly influence the outcomes. Variability in the lacrimal apparatus, including divided glandular architecture and the presence of accessory glands, such as nictitating membranes and Harderian glands, may attenuate or compensate for the induced phenotype and limit model robustness. Evaporative DED models offer practical advantages and rapid induction but produce only mild ocular surface changes, not reflecting the chronic form of human diseases. A combination of multiple induction methods may yield more comprehensive and physiologically relevant models. In addition to these challenges, the human-oriented design of most diagnostic tests introduces uncertainties in protocol adaptation, optimal thresholds, and interpretation. This review summarizes the key methodologies, diagnostic considerations, advantages, and limitations of the available DED models, while highlighting persistent gaps that constrain their translational relevance.