Seeing through tears: Understanding and managing dry eye disease.

INTRODUCTION: The term Dry eye can be attributed to the Swedish ophthalmologist Henrik S.C. Sjogren. He was the first to refer to the triad of dry eye, dry mouth, and joint pain in his original thesis in 1933 Zur kenntnis der keratoconjuctivitis sicca. Dry eye disease is a “multifactorial disease of the tears and ocular surface that results in discomfort, visual disturbance, and tear film instability resulting in damage to the ocular surface. Dry eye disease is also accompanied by increase in osmolarity of the tear film and inflammation of the ocular surface” [i] The ocular surface (cornea, conjunctiva, accessory lacrimal glands), meibomian glands (specific sebaceous glands of the eyelid margin, which produce the outer lipid film of the tear film), the main lacrimal gland, and the innervation between them form a functional unit. Any or all of these structures may be affected in dry eye disease Recent studies show that dry eye is an inflammatory disease that has many features in common with autoimmune disease Stress to the ocular surface (environmental factors, infection, endogenous stress, antigens, genetic factors) is considered as the main triggering mechanism. Proinflammatory cytokines, chemokines, and matrix metalloproteinases lead to the expansion of autoreactive T helper cells which infiltrate the ocular surface and lacrimal gland which results in damage to the ocular surface.Classification into “dry eye with reduced tear production (aqueous-deficient)” and “dry eye with increased evaporation of the tear film (hyperevaporative)” has proved useful on practical grounds.From different studies it is assumed that around 10% of patients with dry eye have aqueous-deficient disorder AND Hyperevaporative disorders is mostly caused by dysfunction of the meibomian glands..Mixed hyperevaporative/aqueous-deficient accounts for more than 80% of the total cases.[ii] The prevalence of dry eye in the world population ranges from 6 to 34 %. It is more common in those aged over 50, and affects mainly women. Since the introduction of the Schirmer’s test in 1903, other tests have been developed to evaluate dry eye, such as biomicroscopy, the tear film breakup time (BUT), vital dyes (lissamine green and rose bengal), fluorescein, leaf fern test, corneal sensitivity test, conjunctiva impression cytology, optical coherence tomography (OCT), and tear osmolarity measurement. There is no gold standard diagnostic test but it is recommended to combine at least two tests. Strategies for treating Dry Eye Disease have recently been modified and include patient education, tear substitute, corticosteroids, secretagogues, fatty acids, immunomodulators, occlusion of lacrimal puncta surgery and, tarsorrhaphy. Biological therapy and new topical immunomodulators such as tacrolimus, tofacitinib and IL-1 receptor inhibitor are being tested.[iii] [i] Brewitt H, Sistani F. Dry eye disease: the scale of the problem. Survey of ophthalmology. 200 Mar 11;45:S199-202. [ii] Messmer EM. The pathophysiology, diagnosis, and treatment of dry eye disease. Deutsches Ärzteblatt International. 2015 Jan;112(5):71. [iii] Valim V, Trevisani VF, de Sousa JM, Vilela VS, Belfort R. Current approach to dry eye disease. Clinical reviews in allergy & immunology. 2015 Dec;49(3):288-97.

To investigate the regulatory roles of the members of the peroxisome proliferator-activated receptor (PPAR) family in lacrimal gland dysfunction under conditions of desiccating stress or diabetes. Quantitative polymerase chain reaction (qPCR) was used to examine the expression of PPARs in the cornea, conjunctiva, meibomian gland, and lacrimal gland in adult rats. The rats were divided into 3 groups: a control group, dry eye group, and diabetic group. The phenol red threads test, tear film break-up time (BUT) test and fluorescein staining were carried out to evaluate the development of dry eye. Based on bioinformatics research, qPCR was used to examine the expression level of PPARγ, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), sirtuin 1 (Sirt1), myeloid differentiation factor 88 (MyD88) and transforming growth factor-β (TGF-β) in the lacrimal glands. PPARα and PPARβ/δ were mainly expressed in the conjunctiva and the lacrimal gland, respectively. However, PPARγ was expressed in both the conjunctiva and lacrimal gland, at much higher levels than those measured for PPARα and PPARβ/δ. Dry eye rats and diabetic rats both showed decreased tear secretion, shortened BUT, and increased corneal staining. Significant changes in gene expression were observed compared with the control group. In the lacrimal glands of dry eye rats and diabetic rats, expression of PPARγ decreased (P<0.05), expression of Sirt1 also decreased (P<0.01), whereas expression of TNF-α, IL-1β, IL-6, MyD88, and TGF-β increased (P<0.05). Among PPARs, PPARγ might play a dominant role in the regulation of metabolic- and inflammatory-signaling pathways on the ocular surfaces and in lacrimal glands. Down-regulation of PPARγ is highly relevant to lacrimal gland dysfunction under desiccating-stress and diabetic conditions. PPARγ, thus, is a potential therapeutic target in the treatment of environment- or diabetes-induced dry eye diseases.

To evaluate whether specific meibomian gland morphological features can serve as diagnostic indicators of dry eye disease in patients with type 2 diabetes mellitus. This cross-sectional study included patients with type 2 diabetes mellitus and age-matched healthy controls. All participants underwent a comprehensive ocular surface evaluation, including the ocular surface disease index, tear break-up time, Schirmer's I test, corneal staining, eyelid margin scoring, meibum expressibility assessment, meibography scoring, and evaluation of meibomian gland loss area. Meibomian gland morphology was assessed bilaterally. Dry eye severity was determined based on ocular surface disease index scores, tear break-up time, Schirmer's test results, and corneal staining scores. Correlations between meibomian gland features and ocular surface parameters, age, diabetes duration, and hemoglobin A1c levels were analyzed. Receiver operating characteristic analysis was performed to determine the diagnostic value of specific meibomian gland features for dry eye disease. Dry eye disease was diagnosed in 56.6% of patients with diabetes and 22.6% of controls. Compared with controls, patients with diabetes had significantly higher ocular surface disease index scores, greater corneal staining, worse meibum expressibility, increased meibomian gland loss, and lower tear break-up time and Schirmer values (all p<0.05). Meibomian gland dropout, shortening, tortuosity, distortion, overlapping, ghost glands, and lack of extension to the lid margin were significantly more prevalent in patients with diabetes (p<0.05) and showed significant correlations with age, HbA1c levels, and diabetes mellitus duration. Receiver operating characteristic analysis identified meibomian gland dropout, ghost glands, shortening, and lack of extension to the lid margin as the most predictive morphological features for dry eye disease in patients with diabetes. Type 2 diabetes mellitus is associated with distinct meibomian gland morphological alterations that correlate with both dry eye disease severity and systemic diabetic parameters, suggesting potential diagnostic value.

Lacrimal Gland in Sjögren's Syndrome

Ocular surface tissues, primarily consisting of the cornea, meibomian glands, conjunctiva and lacrimal glands, are crucial components of the eyes and are in direct contact with external environment. Various ocular surface abnormalities can lead to ocular surface diseases, and in severe cases, blindness. The intricate diversity of cell types and states, along with the absence of definitive biomarkers for ocular surface tissues, has posed significant challenges to fully understanding corneal stability, disease mechanisms, and therapeutic development. Single-cell RNA sequencing (scRNA-seq) is an advanced analytical technique used to examine the transcriptomes of individual cells. It enables detailed analysis of complex cellular dynamics, the distinction of various cell types, and the discovery of new biomarkers, thus deepening our insight into diverse cellular behaviors. Currently, scRNA-seq is mainly applied to study the developmental processes of ocular surface cells and to explore the pathogenic mechanisms of related diseases, such as dry eye disease, pterygium, keratoconus, Fuchs corneal endothelial dystrophy, ocular graft-versus-host disease, and primary acquired nasolacrimal duct obstruction, which involve the cornea, conjunctiva, and lacrimal gland. This review summarizes the principles and applications of the scRNA-seq technique, including its mechanism, effects, limitations, and applications in ocular surface research, aiming to bridge the gap between incomplete understanding and rapid technological progress of scRNA-seq.

The prevalence of dry eye disease (DED) is rising globally and needs to be urgently addressed by medical professionals because it lowers patients' quality of life. There are as yet no available data in the literature about the prevalence of and risk factors for DED in the Gaza Strip, a gap that the present study seeks to address. A cross-sectional study was carried out between March and August 2022 in Gaza governorates using a proportional stratified sampling technique. Only Gazan individuals ≥ 18 years old and able to follow the instructions were included. The Ocular Surface Disease Index (OSDI) questionnaire, which has previously been translated into Arabic and validated, was applied to evaluate DED symptoms. Subjective clinical tests for DED conducted were tear meniscus height (TMH), meibomian gland dysfunctions (MGDs), Marx line (ML), conjunctival Lissamine green staining (LGS), tear film break-up time test (TBUT), corneal fluorescein staining (CFS) and Schirmer II tear test (STT). DED was defined based on an Arab-OSDI score ≥ 13 and at least one positive clinical sign. A total of 426 participants were assessed from four areas (North Gaza Strip, 82; Gaza City, 147; Mid-Zone Gaza Strip, 62; South Gaza Strip, 135). The prevalence of DED in the present study was 31.5% (95% CI: 27.1, 36.1). Age > 50 years old (odds ratio [OR] = 10.45; 95% CI: 2.95, 37.05; P < 0.001), female gender (OR = 3.24; 95% CI: 1.40, 7.52, P = 0.006), menopause or pregnancy (OR = 2.59; 95% CI: 1.25, 5.35; P = 0.03) and pharmacotherapy (artificial tears; OR = 9.91; 95% CI: 2.77, 35.46; P < 0.001) were each associated with DED symptoms. South Gaza Strip (OR = 0.04; 95% CI: 0.01, 0.12; P < 0.001), unemployed (OR = 11.67; 95% CI: 1.43, 95.44; P = 0.02), non-consumption of caffeine (OR = 0.40; 95% CI: 0.19, 0.88; P = 0.02) and TMH < 0.2 (OR = 1.80; 95% CI: 1.02, 3.19; P = 0.04) were associated with TBUT < 5 s. LGS was associated with those > 50 years old (OR = 2.70; 95% CI: 1.38, 5.28; P = 0.004), previous refractive or ocular surface surgeries (OR = 2.97; 95% CI: 1.34, 6.59; P = 0.008) and CFS ≥ 1 (OR = 1.91; 95% CI: 1.07, 3.44; P = 0.03). Various aspects of DED were linked with different risk factors, suggesting that DED subtypes have different underlying pathophysiologies.

Background Dry eye is among the most prevalent complications following refractive surgery, significantly impacting the training and daily lives of recruits. While recent years we have witnessed some advancements in understanding the occurrence and progression of dry eye, the specific effects of refractive surgery on this condition remain unclear. This study aims to investigate the impact of refractive surgery on dry eye among 300 army recruits. Methods A series of examinations specific to dry eye were conducted on the subjects using the OSDI questionnaire and the ocular surface comprehensive analyzer. The correlation between refractive surgery and dry eye was analyzed in conjunction with dry eye symptoms and related data. Additionally, optical coherence tomography (OCT) was employed to observe fundus changes in dry eye patients, comparing those with low to moderate myopia against patients with high myopia prior to surgery. The morphology of the meibomian glands in the upper eyelid was assessed using the Keratograph 5M ocular surface analyzer, where the area of meibomian gland loss was calculated and scored, facilitating an exploration of the relationship between meibomian gland loss and dry eye. Furthermore, the dry eye detection rates of Non-Invasive Break-Up Time (NIBUT), Lipid Layer Thickness Measurement (LTMH), and basal Schirmer secretion (SIT) were calculated, and the diagnostic differences among these three methods for dry eye were analyzed. Results According to the OSDI questionnaire, 117 (39%) patients opted for SMILE, 60 (20%) for F-LASIK, and 123 (41%) for LASIK. Among the recruits, 78 (26%) were diagnosed with dry eye following refractive surgery. Single factor and multiple logistic regression analyses indicated that LASIK may serve as an independent risk factor for the development of dry eye after refractive surgery. Furthermore, the incidence of leopard-pattern fundus was significantly higher in recruits with high myopia compared to those with low to moderate myopia. Keratograph5M assessments revealed that 52.6% of patients exhibited no meibomian gland loss; 45.5% had meibomian gland loss of less than 1/3; 1.9% experienced meibomian gland loss ranging from 1/3 to 2/3; and no patients had meibomian gland loss exceeding 2/3. These results suggest that there is no direct relationship between dry eye and meibomian gland loss following refractive surgery. Additionally, the dry eye detection rate using non-invasive tear break-up time (NIBUT) was 92.6%, while the detection rate for LTMH dry eye was 91.0%. The basal Schirmer test (SIT) yielded a dry eye detection rate of 78.2%, indicating that non-invasive tear assessment methods have a higher detection rate for dry eye. Conclusions The incidence of dry eye among recruits following excimer laser corneal refractive surgery is significantly higher than that observed with other surgical methods, suggesting that it may represent an independent risk factor for dry eye post-refractive surgery. Consequently, we do not recommend the use of laser in situ keratomileusis for refractive surgery.

Dry eye is among the most prevalent complications following refractive surgery, significantly impacting the training and daily lives of recruits. While recent years we have witnessed some advancements in understanding the occurrence and progression of dry eye, the specific effects of refractive surgery on this condition remain unclear. This study aims to investigate the impact of refractive surgery on dry eye among 300 army recruits. A series of examinations specific to dry eye were conducted on the subjects using the OSDI questionnaire and the ocular surface comprehensive analyzer. The correlation between refractive surgery and dry eye was analyzed in conjunction with dry eye symptoms and related data. Additionally, optical coherence tomography (OCT) was employed to observe fundus changes in dry eye patients, comparing those with low to moderate myopia against patients with high myopia prior to surgery. The morphology of the meibomian glands in the upper eyelid was assessed using the Keratograph 5M ocular surface analyzer, where the area of meibomian gland loss was calculated and scored, facilitating an exploration of the relationship between meibomian gland loss and dry eye. Furthermore, the dry eye detection rates of Non-Invasive Break-Up Time (NIBUT), Lipid Layer Thickness Measurement (LTMH), and basal Schirmer secretion (SIT) were calculated, and the diagnostic differences among these three methods for dry eye were analyzed. According to the OSDI questionnaire, 117 (39%) patients opted for SMILE, 60 (20%) for F-LASIK, and 123 (41%) for LASIK. Among the recruits, 78 (26%) were diagnosed with dry eye following refractive surgery. Single factor and multiple logistic regression analyses indicated that LASIK may serve as an independent risk factor for the development of dry eye after refractive surgery. Furthermore, the incidence of leopard-pattern fundus was significantly higher in recruits with high myopia compared to those with low to moderate myopia. Keratograph5M assessments revealed that 52.6% of patients exhibited no meibomian gland loss; 45.5% had meibomian gland loss of less than 1/3; 1.9% experienced meibomian gland loss ranging from 1/3 to 2/3; and no patients had meibomian gland loss exceeding 2/3. These results suggest that there is no direct relationship between dry eye and meibomian gland loss following refractive surgery. Additionally, the dry eye detection rate using non-invasive tear break-up time (NIBUT) was 92.6%, while the detection rate for LTMH dry eye was 91.0%. The basal Schirmer test (SIT) yielded a dry eye detection rate of 78.2%, indicating that non-invasive tear assessment methods have a higher detection rate for dry eye. The incidence of dry eye among recruits following excimer laser corneal refractive surgery is significantly higher than that observed with other surgical methods, suggesting that it may represent an independent risk factor for dry eye post-refractive surgery. Consequently, we do not recommend the use of laser in situ keratomileusis for refractive surgery.

The lacrimal glands produce tears to support a healthy homeostatic environment on the ocular surface. The lacrimal gland dysfunction characteristic of dry eye disease causes ocular discomfort and visual disturbances and in severe cases can result in a loss of vision. The demand for adequate restoration of lacrimal gland function has been intensified due to advances in stem cell biology, developmental biology, and bioengineering technologies. In addition to conventional therapies, including artificial tears, tear alternatives (such as autologous serum eye drops) and salivary gland transplantation, a regenerative medicine approach has been identified as a novel strategy to restore the function of the lacrimal gland. Recent studies have demonstrated the potential of progenitor cell injection therapy to repair the tissue of the lacrimal glands. A current three-dimensional (3D) tissue engineering technique has been shown to regenerate a secretory gland structure by reproducing reciprocal epithelial-mesenchymal interactions during ontogenesis in vitro and in vivo. A novel direct reprogramming method has suggested a possibility to induce markers in the lacrimal gland developmental process from human pluripotent stem cells. The development of this method is supported by advances in our understanding of gene expression and regulatory networks involved in the development and differentiation of the lacrimal glands. Engineering science has proposed a medical device to stimulate tearing and a bio-hybrid scaffold to reconstruct the 3D lacrimal gland structure. In this review, we will summarize recent bioengineering advances in lacrimal gland regeneration toward the functional restoration of the lacrimal glands as a future dry eye therapy.

Dry eye disease (DED) is a multifactorial disease affecting approximately 5-50% of individuals in various populations. Contributors to DED include, but are not limited to, lacrimal gland hypofunction, meibomian gland dysfunction (MGD), ocular surface inflammation, and corneal nerve dysfunction. Current DED treatments target some facets of the disease, such as ocular surface inflammation, but not all individuals experience adequate symptom relief. As such, this review focuses on alternative and adjunct approaches that are being explored to target underlying contributors to DED. Neuromodulation, stem cell treatments, and oral royal jelly have all been studied in individuals with DED and lacrimal gland hypofunction, with promising results. In individuals with MGD, devices that provide eyelid warming or intense pulsed light therapy may reduce DED symptoms and signs, as may topical Manuka honey. For those with ocular surface inflammation, naturally derived anti-inflammatory agents may be helpful, with the compound trehalose being farthest along in the process of investigation. Nerve growth factor, blood-derived products, corneal neurotization, and to a lesser degree, fatty acids have been studied in individuals with DED and neurotrophic keratitis (i.e. corneal nerve hyposensitivity). Various adjuvant therapies have been investigated in individuals with DED with neuropathic pain (i.e. corneal nerve hypersensitivity) including nerve blocks, neurostimulation, botulinum toxin, and acupuncture, although study numbers and design are generally weaker than for the other DED sub-types. Several alternatives and adjunct DED therapies are being investigated that target various aspects of disease. For many, more robust studies are required to assess their sustainability and applicability.

Dry eye affects a large number of people worldwide.A vicious cycle involving multiple factors tends to be implicated in its pathophysiology.Tear secretion is regulated by the sympathetic and parasympathetic nervous systems.Corneal nerve fibers secrete neurotransmitters and neuropeptides, which together participate in the maintenance of ocular surface homeostasis.Abnormal neuromodulation can cause abnormal tear secretion and a disruption of ocular surface homeostasis, leading to dry eye.The persistent abnormal tear film in dry eye can damage the normal repair system of ocular surface and leave the ocular surface and the lacrimal gland in a chronic inflammatory state.The cornea in dry eye patients is more sensitive to temperature change and mechanical stimulation than in healthy individuals.Symptomatic eye pain may be related to the effect of chronic inflammation on the corneal pain signal pathway.In vivo confocal microscopy and corneal esthesiometry can be used to evaluate the corneal nerve morphology and function in dry eye patients.This may ead to a more comprehensive treatment of dry eyes through the use of nerve related factors to nourish the cornea and the stimulation of neural pathways or related neural receptors to increase tear secretion.This study reviewed the relationship between neurosensory abnormalities and dry eye. Key words: Dry eye; Tear film; Ocular surface; Corneal nerves; Corneal sensitivity; In vivo confocal microscope

BackgroundThe purpose of this investigation was to evaluate the morphology and physiological function of the meibomian glands between type 2 diabetics with dry eye disease (DED) and control subjects. Doing so will help to better reveal the pathologic mechanisms of meibomian gland dysfunction (MGD) and DED in type 2 diabetes mellitus (T2DM).MethodsNinety subjects were divided into the following four groups: DM-DED group: T2DM patients with DED (n = 30); DM control group: DM patients without DED (n = 18); DED group: DED patients without DM (n = 26); and normal control group: normal subjects (n = 16). All participants administered the ocular surface disease index (OSDI) questionnaire, tear meniscus height (TMH), noninvasive Keratograph tear film break-up time (NIKBUT), Schirmer I test (SIT), corneal fluorescein staining (CFS), eyelid margin abnormality examinations, meibum quality and meibomian gland (MG) dropout evaluations. ResultsThe percentage of MG dropout in the upper and lower lids was significantly higher in the DM-DED group than the DED group (P < 0.05 or P < 0.01). However, there was no significant difference in other MG parameters between these two groups. Oppositely, Significant difference was observed in all of MG parameters except MG dropout in the lower lids comparing DM group with normal controls (P < 0.05 or P < 0.01). While the SIT values decreased in the DM-DED group compared to the DED group (P < 0.05), no significant differences were found in the values of other tear parameters. ConclusionsThe higher prevalence and increased severity of MGD was found in patients with both T2DM and DED compared to those only with DED. Trial registrationChinese Clinical Trial Registry ChiCTR1800019939, date of registration December 9, 2018, prospectively registered.

Purpose: To examine the morphological changes in the meibomian glands of eyes of patients with dry eye disease using the non-contact infrared meibography system and to assess their relationship with meibomian dropout, signs, and tear-film function.Methods: Subjects included 264 randomly selected patients (528 eyes) suffering from dry eye disease (95 males, 169 females; age range, 7–85 years; mean male age, 39.83 ± 19.17 years; mean female age, 46.16 ± 17.38 years). Tear-film break-up time (BUT) was measured and tear-film production was evaluated by the Schirmer test I (SIT). Subjective symptoms were also scored. The upper and lower eyelids were turned over, and the meibomian glands were observed using the non-contact meibography system. Partial or complete loss of the meibomian glands (meibomian dropout) was scored for each eyelid from grade 0 (no loss) through grade 3 (lost area was >2/3 of the total meibomian gland area).Results: The average SIT result was 6.71 ± 6.13 mm (range 0–30 mm) and that for BUT was 3.13 ± 2.39 s (range 0–10 s). The average fluorescein staining score was 4.25 ± 4.05 (range 0–12). In addition, the mean meibomian gland photographic score was 4.35 ± 1.39. The correlation between the meibomian gland photographic scores and various ocular surface examinations were evaluated using Kendall’s correlation. SIT and BUT were significantly negatively correlated with the meibomian gland photographic score, whereas corneal fluorescein staining was positively correlated.Conclusions: The results suggest a large proportion of meibomian dropout cases among patients with dry eye disease, indicating that treatment targeted at the meibomian gland will become an important direction for treating dry eye disease. Meibography is recommended as a routine test for dry eye disease.

Dysfunctional Neural Regulation of Lacrimal Gland Secretion and its Role in the Pathogenesis of Dry Eye Syndromes

This thesis explores the development of an evaporative dry eye (EDE) animal model based on Meibomian gland cauterisation, aiming to replicate the tear film alteration caused by Meibomian gland dysfunction (MGD), a major driver of EDE. Dry eye disease (DED), which causes ocular surface inflammation, pain, and discomfort, is a multifactorial condition with significant impact on quality of life. EDE is the most common subtype, linked to MGD, which impairs lipid secretion from Meibomian glands, increasing the tear evaporation rate. The cauterisation method, as suggested by existing literature, faced challenges: technique variability and unclear guidelines on how many glands to cauterise or whether both eyelids should be involved. These inconsistencies can compromise the model’s reliability, indicating the need for further optimisation to ensure reproducibility and consistency in experimental outcomes. This thesis also presents a novel multiplex electrochemiluminescence immunoassay (ECLIA) for detecting key biomarkers in rat tear samples, critical for DED research. Biomarkers such as interleukin-17 (IL-17), matrix metalloproteinase-9 (MMP-9), and intercellular adhesion molecule-1 (ICAM-1) were targeted. The assay was validated with promising results, showing that the detection ranges for these biomarkers met the required parameters, though precision was identified as a limiting factor. Variations were mainly due to human error, such as pipetting inconsistencies and evaporation during incubation. Suggestions for improving precision include standardising operator expertise, minimising reagent variability, and controlling incubation conditions. These improvements would increase reliability and broaden the assay's detection range. Additionally, the thesis investigates the role of oxidative stress and ferroptosis in DED. Ferroptosis, a form of iron-dependent cell death linked to lipid peroxidation, is thought to contribute to DED pathogenesis. In vitro studies with the ferroptosis inhibitor UAMC-3203 suggested potential in reducing oxidative stress. However, clear evidence for ferroptosis in DED models was not found. In vivo tests showed that UAMC-3203 could restore GPX4 gene expression closer to the control group, hinting at potential benefits of ferroptosis inhibition. Finally, the thesis proposes optimising the EDE model with inflammation-triggering agents like LFA-1 and ICAM-1 inhibitors, or toll-like receptor agonists, to enhance chronicity and inflammation. The use of advanced 3D cell culture models for better simulation of the ocular surface is also discussed, highlighting their potential for testing new therapies. Further research is needed to address the multifactorial causes of DED and improve treatments for this widespread condition.