Caterina Gagliano

Dry eye disease (DED) is a complex, multifactorial condition in which oxidative stress is increasingly recognized as a recurrent feature of ocular-surface dysfunction and as a signaling hub linking environmental stress, organelle dysfunction, innate immunity, and regulated cell death. Mitochondrial and endoplasmic-reticulum dysfunction, failure of endogenous antioxidant systems, and increased production of reactive oxygen species (ROS) can occur in response to tear hyperosmolarity, desiccating stress, aging, and other injuries. These changes activate redox-sensitive signaling pathways such as Nrf2/Keap1, SIRT3–TXNIP–NLRP3, and SLC7A11/GPX4, linking mitochondrial injury and lipid peroxidation to inflammasome activation, ferroptosis, pyroptosis, and epithelial barrier disruption. Damage to the tear film causes persistent inflammation that further damages the ocular surface. This narrative review examines oxidative stress in DED through the lens of redox checkpoints rather than a single pathogenic mechanism. We incorporate up-to-date evidence on organelle stress, antioxidant signaling, innate immune activation, and regulated cell death, and discuss their crosstalk to highlight therapeutically actionable nodes. We focus on newer redox-modulating and mitochondria-targeted strategies, while critically considering the overrepresentation of preclinical evidence, the limited validation of oxidative biomarkers, and the translational barriers that currently keep mechanism-based antioxidant therapy out of routine clinical care for patients with diverse clinical phenotypes of DED.

Glaucoma causes progressive damage to the optic nerve, and reducing intraocular pressure is the only clinically proven way to slow the disease. Although current medical, laser, and surgical treatments mainly change aqueous humor dynamics, they do not counteract the cellular and extracellular abnormalities of the conventional outflow pathway. Growing evidence shows that loss and dysfunction of trabecular meshwork cells impair aqueous humor drainage, supporting regenerative approaches that rebuild the outflow system rather than bypass it. In this narrative review, we present novel stem cell-based strategies to regenerate the trabecular meshwork and Schlemm’s canal, particularly trabecular meshwork (TM) stem cells, mesenchymal stem cells, pluripotent stem cell-derived TM-like cells, and neural crest-derived progenitors. We review recent evidence suggesting that transplanted cells may restore outflow not just through engraftment and cellular replacement, but also through paracrine signaling, stimulation of endogenous cell proliferation, extracellular matrix modification, and rejuvenation of the trabecular microenvironment. This review discusses advances in lineage specification, cell targeting and delivery, single-cell and transcriptomic characterization, mechanobiology, and bioengineered models of the human aqueous out-flow pathway. New approaches, such as magnetically guided cell delivery and the identification of cells that promote trabecular tissue regeneration and repopulation, show how rapidly this field has developed. We cover key translational barriers, including cell identity, manufacturing standardization, long-term engraftment, tumorigenicity, immune responses, off-target localization, and limited clinical efficacy data. Reconstructing the aqueous outflow pathway using stem cells remains a preclinical endeavor. However, it may shift the focus from chronic pressure control to biologically restoring outflow function in glaucoma.

Dry eye disease is a multifactorial disorder which is heterogeneous in nature, caused by interactions among ocular surface abnormalities, systemic diseases, environmental factors and host susceptibility. The inherited variation related to the pathophysiology of dry eye disease is not very well characterized, but known mechanisms include inflammation, tear film instability, neurosensory dysfunction and lacrimal and meibomian gland changes. Studies exploring the contribution of genetics suggest that dry eye disease (DED) and specific ocular surface endophenotypes are heritable. Candidate-gene and human leukocyte antigen association studies have reinforced contributions from pathways associated with innate and adaptive immunity, inflammatory regulation and neural function, and glandular homeostasis, but many associations require replication in larger, more diverse populations. Genome-wide association studies and biobank-based assessments have recently begun to shed light on the polygenic architecture of Dry Eye Disease (DED) and its genetic overlap with other related conditions worldwide. This paper evaluates critically the current evidence on DED heritability, candidate susceptibility genes, HLA associations, genome-wide signals, polygenic risk models and genetic pleiotropy. It will cover how transcriptomic, epigenomic, and single-cell approaches can link inherited susceptibility loci to disease-relevant cell states and molecular pathways across the ocular surface unit, including the cornea, conjunctiva, lacrimal gland, and meibomian glands. The study would stress phenotypic heterogeneity, ancestry-related limitations, and inconsistent diagnostic definitions. In the end, we will evaluate opportunities and existing constraints in the incorporation of genomic information with clinical endophenotypes and environmental exposures to support risk stratification, biomarker discovery, identification of therapeutic targets, and the development of future ocular surface precision medicine.

Ocular surface malignancies include ocular surface squamous neoplasia (OSSN), con-junctival melanoma, and conjunctival lymphoma. These rare disorders may threaten vi-sion and, in some cases, life. Early identification may be difficult because malignant le-sions can resemble benign ocular surface conditions. Artificial intelligence (AI), including machine learning and deep learning, has emerged as a potential aid to detection, classi-fication, and referral. This structured narrative review, organized with reference to SANRA principles, synthesizes PubMed/MEDLINE literature on AI applications in ocular surface oncology available through 29 August 2026. We examine slit-lamp photography, anterior segment optical coherence tomography, in vivo confocal microscopy, ultrasound biomicroscopy, and smartphone imaging. Deep-learning models have shown promising performance in selected binary OSSN tasks, whereas multiclass studies report lower sen-sitivity for rare malignancies such as conjunctival melanoma and lymphoma. Smartphone-based screening has also been evaluated in a prospective referral pathway, although the reference standard and verification process limit interpretation of popula-tion-level sensitivity. Dataset imbalance, image-acquisition variability, limited external and prospective validation, explainability, and workflow integration remain barriers to implementation. Future work should prioritize multicenter datasets, standardized acquisition, calibrated thresholds, and prospective human–AI evaluations. Current evidence supports further evaluation of AI as an adjunct for detection and referral, not as a re-placement for specialist assessment or histopathology.

Imaging the retina is a powerful non-invasive probe of systemic vascular, neurological, metabolic, and renal disease, making it a cornerstone of the new field of systemic oculomics. Advanced retinal imaging techniques like optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) provide detailed imaging of structural and microvascular changes potentially associated with systemic disease. Derived from fundus photography, structural imaging, vascular imaging, and artificial intelligence-based image analysis, retinal biomarkers have been associated with cardiovascular and cerebrovascular disease, neurodegenerative disorders, diabetes, chronic kidney disease, and related clinical outcomes. However, the translational maturity of these biomarkers is variable depending on imaging modality, target disease, intended clinical use, and level of validation. Longitudinally, retinal vascular characteristics have been associated with cardiovascular as well as cerebrovascular outcomes. In addition, optical coherence tomography has provided reproducible measures of neuroaxonal injury in selected neurological conditions. This is especially true for multiple sclerosis. The majority of retinal biomarkers in Alzheimer disease, Parkinson disease, chronic kidney disease, and systemic risk prediction remain experimental because of heterogeneous methodologies, insufficient external validation, and insufficient evidence for incremental clinical utility. Diabetes is the most developed translational model with established retinal screening pathways and validated ocular applications of imaging and artificial intelligence, although these cannot be directly extrapolated to systemic diagnosis or treatment guidance. This narrative review assesses retinal biomarkers for cardiovascular, neurological, metabolic, and renal disease with a focus on analytical validity, clinical validity, incremental value, clinical utility, and implementation. The retina is increasingly accepted as a site for discovery of systemic biomarkers and adjunctive risk assessment, although most applications to systemic disease remain to be standardized, validated independently, and studied prospectively before being suitable for routine clinical use.

The management of glaucoma with drugs is mostly via the topical route, although these treatments have poor ocular bioavailability. Other problems limiting their therapeutic effect include pre-corneal clearance, corneal and ocular surface barriers, and the need for a long-term treatment regimen. Nanoparticle-mediated drug-delivery systems have shown the potential, particularly in preclinical studies, to improve ocular penetration and precorneal retention and to facilitate controlled drug release, with the aim of reducing dosing frequency. In this narrative review, the researchers focus on various nanoparticle-based approaches for sustained intraocular pressure control in glaucoma. The review encompasses carrier-based nanosystems, drug nanocrystals and nanosuspensions, nanoscale permeability or surface modifiers, multiscale nano-enabled formulations, and nanoparticle- or nanocarrier-integrated delivery devices. These approaches are designed to deliver conventional and innovative ocular hypotensive agents. Pharmacokinetics, corneal permeability, drug stability, tolerability, and duration of action of intraocular pressure-lowering drugs are critically reviewed across a predominantly preclinical evidence base; the two small human studies identified (n = 6 and n = 17) support clinical feasibility but do not establish durable clinical effectiveness, long-term safety, adherence benefit, or prevention of glaucoma progression. This review distinguishes improvements in ocular drug disposition from demonstrated IOP-lowering benefit and separates preclinical proof of concept from human evidence by applying an evidence-stratified formulation–performance framework rather than ranking nanocarriers by material class or isolated physicochemical properties. The available evidence is dominated by drugs that lower IOP, which in turn distinguishes prolonged control of IOP from any direct disease-modifying or neuroprotective action, for which glaucoma-specific evidence remains substantially more limited. The review further assesses the obstacles to clinical translation, including long-term safety, manufacturing reproducibility, sterilization, regulatory requirements, and patient and treatment burden. Generally, nanoengineered systems are promising platforms to address pharmacokinetic and treatment-delivery limitations of conventional glaucoma therapy, but comparative clinical effectiveness, long-term safety, adherence benefit, cost-effectiveness, and meaningful effects on glaucoma progression remain insufficiently demonstrated.

This hypothesis originated from the first author’s personal experience in adult neurology, in which selected refractory cranial or postherpetic neuralgias occasionally appeared to improve rapidly after off-label misoprostol. The original records are unavailable; these physician recollections are not efficacy data and serve only as the hypothesis generator. Independent published precedents are limited to small uncontrolled reports in multiple-sclerosis-associated trigeminal neuralgia. A further recollection was that perceived benefit often waned after several weeks at conventional daily exposure, whereas lower or intermittent exposure sometimes appeared to remain useful for longer; this observation is likewise unverifiable and does not define a therapeutic dose. Misoprostol is rapidly converted to misoprostol acid (plasma half-life of 20–40 min). We ask whether a brief, reversible exposure could produce pharmacodynamic persistence, defined here as a reproducible pain-relevant effect that outlasts measurable drug exposure, through EP-receptor trafficking, compartmentalized GPCR signaling, or downstream cellular changes. The model also predicts that the concentration–response relationship may be non-monotonic: increasing or repeated exposure could attenuate or reverse a favorable effect by recruiting opposing EP pathways or adaptive receptor/cellular responses. No direct evidence shows that misoprostol produces such persistence in neural tissue, and PGE2/EP signaling can also be pronociceptive. Receptor-resolved concentration–response and pulse-washout experiments must therefore separately demonstrate receptor signaling, persistent cellular change, altered neuronal excitability, and ultimately blinded analgesic benefit. Neuropathic corneal pain is considered only a secondary mechanistic model. No evidence-based dose can currently be recommended.

Background: Optical coherence tomography (OCT) has been recognised as a non-invasive imaging modality capable of offering high-resolution visualisation of the corneal tissue. Objective: This review evaluates the role of OCT in chronic corneal disease, focusing on how descriptive imaging has progressed to quantitative imaging biomarkers with translational potential. Methods: A comprehensive review of the published literature on OCT imaging in corneal disease was conducted, emphasising structural features, quantitative parameters, and biomarkers. Results: OCT facilitates detailed visualisation of corneal microstructure, including variations in epithelial thickness, stromal reflectivity patterns, corneal thickness distribution, and interface abnormalities. These morphological observations are converted into quantitative measures that function as imaging biomarkers for disease severity, progression, and therapeutic effectiveness. In conditions such as keratoconus, chronic infectious keratitis, and corneal dystrophies, OCT-derived parameters offer valuable information for phenotyping and longitudinal monitoring. Additionally, advances in automated image analysis and artificial intelligence further increase the potential of OCT for biomarker discovery and evidence-based clinical decision-making. Conclusions: The development and validation of robust OCT-based biomarkers have the potential to enable earlier diagnosis, improved disease monitoring, and personalised treatment strategies. Future research that integrates quantitative imaging, computational analysis, and longitudinal clinical data will be essential to fully realise the translational potential of OCT in corneal disease management.

Background: Age-related macular degeneration (AMD) represents a leading cause of irreversible vision loss worldwide, driven by intricate interactions among oxidative stress, low-degree chronic inflammation, and macular pigment depletion in aging retinas. Lutein, a component of the macular pigment, has attracted significant attention in AMD management for its antioxidant and blue-light filtering properties. Its oral supplementation, however, although showing potential in slowing AMD progression, requires daily intake and results in variable macular absorption. Trans-scleral iontophoresis (TSI) is a non-invasive technique using low-intensity electric currents to deliver charged molecules into biological tissues and represents an innovative method to deliver lutein into the retina. Methods: The present narrative review synthesizes and discusses the results of lutein supplementation in AMD patients; the ocular iontophoresis basal principles, efficacy, safety and limitations in treating different ophthalmic pathologies; and the evolving clinical evidence supporting lutein TSI in the AMD management. Results: Ex-vivo studies have shown that lutein TSI may provide efficient, localized, rapid, and sustained retinal supplementation of macular pigment, overcoming oral intake limitations. Recent preliminary clinical studies have demonstrated that this technique is well-tolerated and effective in enhancing macular pigment optical density and improving some visual functions in AMD patients. Conclusions: Ex-vivo and pilot clinical studies highlight the capacity of TSI to deliver lutein inside the retina, overcoming physiological barriers that may limit the efficacy of lutein oral administration. The demonstration of the efficacy of the procedure in preserving/improving visual functions and delaying disease progression in AMD patients requires further long-term randomized controlled clinical studies.

Oculomics uses ocular images, ocular biofluids and functional ocular tests to extract diagnostic information on local or systemic biological states. Most current evidence is cross-sectional: one retinal photograph, OCT scan, OCTA examination or tear sample is compared with a reference population, or converted into a diagnostic or prognostic score. This approach is useful for screening and risk enrichment, but it does not show whether the same patient is changing over time. In this review, dynamic oculomics, or oculomic kinetics, is presented as a diagnostic-monitoring approach based on repeated ocular measurements within the same individual. Its object is the personal trajectory: baseline level, short-term variability, long-term drift, response to stimulus, recovery and modification by treatment. We discuss the biological basis of ocular trajectories, the limits imposed by local ocular regulation and disease, and the technical constraints of fundus photography, structural OCT, OCTA, functional challenge tests, tear analysis, aqueous humour analysis, continuous intraocular pressure monitoring and home-based imaging. We also examine artificial intelligence, validation, governance, health-economic considerations and practical implementation. The available evidence does not support a universal ocular surrogate for systemic disease. More realistic applications include detection of unexpectedly rapid tissue change, individualised risk stratification, treatment-response assessment and recognition of discordance between systemic markers and ocular tissue behaviour.