Aqueous-deficient Dry Eye Research Articles

Advanced Biomaterials for Lacrimal Tissue Engineering: A Review

The lacrimal gland (LG) is vital for ocular health, producing tears that lubricate and protect the eye. Dysfunction of the LG leads to aqueous-deficient dry eye disease (DED), significantly impacting quality of life. Current treatments mainly address symptoms rather than the underlying LG dysfunction, highlighting the need for regenerative therapies. Tissue engineering offers a promising solution, with biomaterials playing crucial roles in scaffolding and supporting cell growth for LG regeneration. This review focuses on recent advances in biomaterials used for tissue engineering of the lacrimal gland. We discuss both natural and synthetic biomaterials that mimic the extracellular matrix and provide structural support for cell proliferation and differentiation. Natural biomaterials, such as Matrigel, decellularized extracellular matrices, chitosan, silk fibroin hydrogels, and human amniotic membrane are evaluated for their biocompatibility and ability to support lacrimal gland cells. Synthetic biomaterials, like polyethersulfone, polyesters, and biodegradable polymers (PLLA and PLGA), are assessed for their mechanical properties and potential to create scaffolds that replicate the complex architecture of the LG. We also explore the integration of growth factors and stem cells with these biomaterials to enhance tissue regeneration. Challenges such as achieving proper vascularization, innervation, and long-term functionality of engineered tissues are discussed. Advances in 3D bioprinting and scaffold fabrication techniques are highlighted as promising avenues to overcome current limitations.

Investigation of traditional Chinese medicine constitution in individuals afflicted by dry eye disease: A retrospective study.

The aim of this study is to explore the traditional Chinese medicine (TCM) constitution among individuals suffering from dry eye disease. Following the diagnostic criteria outlined in TFO DEWS II, a total of 114 patients with dry eye were included in this study. Based on the classification criteria for dry eye, the patients were categorized into 3 distinct dry eye subtypes. Each participant underwent a thorough clinical assessment for dry eye, and their TCM pattern manifestations were assessed using the "Traditional Chinese Medicine Questionnaire for Dry Eye." The Nine Constitutions Assessment Method was utilized for TCM pattern differentiation and classification. Spearman's correlation analysis was employed to investigate the associations between TCM constitution and dry eye subtypes, clinical indicators, and the relationships between TCM syndromes and dry eye subtypes. Among the 114 patients, the Qi-Stagnation constitution was the most common, with variations in constitution distribution among different dry eye subtypes. Significant correlations were observed between the Blood-Stasis, Yin-Deficiency, Qi-Deficiency, and Yang-Deficiency constitutions and 2, 4, 1, and 4 dry eye indicators, respectively. Spearman's analysis revealed that 5 out of 50 TCM syndromes were associated with mixed dry eye, 5 with evaporative dry eye, and 3 with aqueous tear deficiency dry eye. Further analysis, using lasso regression and binary unconditional logistic regression identified dizziness, lumbago, and weakness as influencing factors for both mixed-type and evaporative-type dry eye. In this study, we extensively examined the TCM constitution in individuals with dry eye, offering valuable insights and guiding future TCM-related research in the context of dry eye. Additionally, we established correlations between TCM syndrome patterns and dry eye indicators.

Anterior Segment Optical Coherence Tomography Imaging of the Lacrimal Gland in Patients With Chronic Ocular Graft-Vs-Host Disease.

The purpose of this study was to explore the image characteristics of the palpebral lobe of the lacrimal gland in patients with chronic ocular graft-vs-host disease (coGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) using anterior segment optical coherence tomography (AS-OCT). This comparative cross-sectional study included 32 patients with coGVHD, 21 patients with severe aqueous tear deficiency dry eye, and 20 healthy control subjects. All subjects underwent an AS-OCT examination on the palpebral lobe of the lacrimal gland. The main outcomes are the number of visible gland lobules, ducts, and blood vessels and the proportions of mille crêpe-like structures in the AS-OCT images. Compared with the other 2 groups, patients with coGVHD had significantly more blood vessels and slightly less visible lobules and ducts (all P <0.05) in the palpebral lacrimal gland. Mille crêpe-like structures were observed only in the coGVHD group. Number of blood vessels was positively correlated with time after allo-HSCT (β: 0.14, 95% confidence interval [CI], 0.01-0.26). Mille crêpe-like structure was positively correlated with coGVHD severity (odds ratio: 9.07, 95% CI, 1.75-16.38) and time after allo-HSCT (odds ratio: 0.13, 95% CI, 0.03-0.23). We reported the AS-OCT characteristics of the palpebral lacrimal gland in coGVHD and found an increased number of blood vessels and mille crêpe-like structures. AS-OCT has the potential in the disease monitoring of coGVHD.

Aqueous-Deficient Dry Eye Increases Lipid Layer Thickness Measured by Dynamic Tear Interferometry.

To investigate the impact of aqueous deficiency on lipid layer thickness (LLT) measurement in dry eye disease before and after treatment of aqueous-deficient dry eye (ADDE) using dynamic tear interferometry. This prospective comparative study included 230 eyes from 230 patients with ADDE. The treatment group with punctal plug insertion was compared with the control group. The average LLT (LLTave) was measured with a LipiView II tear interferometer at baseline and after 1 month. Correlation analyses were performed with the indices of the dynamics of the tear film lipid layer (TFLL). Baseline LLTave values were 116.1 ± 26.7 and 112.3 ± 27.6 nm in the treatment group (n = 121) and the control group (n = 109), respectively. At 1 month, LLTave significantly decreased in the treatment group (difference -41.8 [95% confidence interval (CI) -47.2 to -36.3], P = 0.003). The values of tear meniscus height (TMH) at baseline and 1-month follow-up were negatively correlated with LLTave (both P < 0.001). Spreading time of TFLL to equilibrium and the deviation of TFLL were positively correlated with LLTave (all P < 0.001) and negatively correlated with TMH (P < 0.001 and 0.009). In multivariate analysis (adjusted R2 = 0.411, P < 0.001), LLTave was associated with TMH (B = -1.068; P < 0.001), adjusting for age, sex, and meibomian gland expressibility. In ADDE, the TFLL was measured to be thicker than the normal range of 60 to 99 nm and became thinner with treatment. LLT was affected by not only meibum secretion but also aqueous status due to changes in the dynamics of TFLL.

Confocal Microscopy of the Cornea in Aqueous-Deficient Dry Eye Disease-A Literature Review.

In vivo confocal microscopy (IVCM) is a vital tool in studying dry eye disease (DED), providing insights into morphological changes at ocular surface unit levels. This review presents the main differences in corneal structure between aqueous-deficient dry eye disease (AD-DED) and normal eyes. A comprehensive search of PubMed, Web of Science, Embase, and MEDLINE databases from January 2000 to December 2023 was conducted. The study selection process, as well as data selection and examination, were independently performed by two members of the review team. The review reveals a consistent decrease in corneal surface epithelial cell density in AD-DED cases compared to a control group, but conflicting data on basal epithelial cell density. Notably, the abnormal hyperreflectivity of keratocytes in patients with Sjogren's syndrome was recorded, and there was a significant keratocyte density in AD-DED subjects compared to evaporative DED and control groups. Studies also found a decrease in sub-basal nerve density, increased tortuosity, and the fragmentation of nerve fibers. Dendritic cell density and dendritic cell dendrites increase in AD-DED patients compared to healthy subjects. IVCM is a powerful tool for enhancing our understanding of the pathophysiological mechanisms underlying DED. However, the review underscores the urgent need to standardize the terminology, analysis, and units used for accurate interpretation, a crucial step in advancing our knowledge of DED.

THE RELATIONSHIP BETWEEN RISKS OF OBSTRUCTIVE SLEEP APNEA AND DRY EYE DISEASE

Introduction: Dry Eye Disease (DED) may lead to decreased visual function, chronic tissue changes, eyelid, conjunctival, and corneal abnormality. The prevalence of DED in Asia ranges from 21.6%–37.6%. Several studies pointed out the relationship between DED and Obstructive Sleep Apnea (OSA). In patients with OSA, oxidative stress, hypoxia, and ocular surface inflammation increase, leading to a decrease in the functions of meibomian glands, goblet cells, corneal sensitivity, and tear production as a response to the stimulations from the lacrimal glands. The loss of conjunctival goblet cells and meibomian glands are implications of damage to the tear film quality, which results in DED. Method: This is a population-based cross-sectional study. Data were obtained from the database of Biomarker Smarthealth Research in Mendalanwangi, Sidorahayu, and Cepokomulyo Villages, which are located in Malang Regency, having risks of OSA (based on the STOP-BANG questionnaire), above ≥40 years old, and DED Examination with Tear Break-Up Time (TBUT), MGD (Meibominan Gland Dysfunction), Tear Meniscus (TM) involving a total of 518 respondents. The available data were then processed according to the variables and went through DED examinations. This study employed the purposive sampling method. Result: In this study, moderate risk of OSA suggests a significant influence on the occurrence of DED with an odds ratio (OR) 1.66 (p&lt;0.05). In addition, moderate risk of OSA predisposes ADDE (Aqueous Deficiency Dry Eye)-type and Mix-type DED with OR 2.85 and 1.23 (p&lt;0.05). High risk of OSA correlates with the occurrence of ADDE-type DED with OR 2.37 (p&lt;0.05). The age group &gt;60 years old shows a correlation with Mix-type DED with OR 2.09 (p&lt;0.05). Women have a higher predisposition to ADDE-type with OR 2.58 (p&lt;0.05). Conclusion: Moderate risk of OSA influences the occurrence of DED, both ADDE-type and Mix type; whereas high risk of OSA only correlates with ADDE-type. Older age plays a role in the occurrence of Mix-type DED and women have a higher tendency to present with ADDE- type.

Dry eye disease – the problem of modern days

Dry eye syndrome is a common ophthalmic condition caused by a deficiency in the tear film, leading to discomfort and damage to the ocular surface. Dry eye syndrome is divided into three main categories: ADDE (aqueous deficient dry eye), EDE (evaporative dry eye), and a mixed form. Diagnosis involves assessing clinical symptoms, laboratory tests, and patient history. Treatment depends on the cause and severity of symptoms, including artificial tears, anti-inflammatory medications, autologous serum eye drops, and innovative lipid microemulsion eye drops. These modern drops stabilize the tear film, protect the ocular surface, and support regenerative processes, providing patients with relief and improved quality of life.

Association between dry eye disease subtypes and rheumatoid arthritis

Aim of the workTo evaluate the association of dry eye disease (DED) subtypes (aqueous deficient dry eye, ADDE and evaporative dry eye, EDE) and the presence of rheumatoid arthritis (RA) in patients. Patients and methods260 volunteer DED participants were recruited for an observational cross-sectional study based on the Tear Film Ocular Society Dry Eye Workshop II criteria, which included tear film osmolarity, fluorescence break-up time, and ocular surface damage assessment. Participants were recruited using QR linked to designated mobile forms to obtain symptomatology status, demographics, and RA diagnosis by their medical doctor. Tear meniscus and lipid layer were also evaluated to differentiate between ADDE, EDE, or mixed dry eye in addition to the DED diagnostic criteria. Participants with mixed dry eye were excluded from the analysis to avoid bias. ResultsAfter initial recruitment, 149 eligible participants with an ADDE or EDE diagnosis were included in the final analysis, where 12,1% have an RA diagnosis. The ADDE group had a higher likelihood of having RA (OR = 4.69, 95 %CI = 1.46–15.01) than the EDE group. Additionally, the number of participants with RA in the ADDE group was statistically higher than those in the EDE group (all p = 0.006). Furthermore, a correlation was obtained between RA and a diagnosis of ADDE (p = 0.005). ConclusionThere was a significant association between ADDE and the presence of RA in patients and the association was more likely compared to those with EDE. This finding underscores the need for specific diagnostic and management strategies for RA patients presenting with DED.

Interleukin-1β activates matrix metalloproteinase-2 to alter lacrimal gland myoepithelial cell structure and function.

The aim of the present study is to investigate the role of c-Jun N-terminal kinase (JNK) and matrix metalloproteinase-2 (MMP-2) in mediating the effects of interleukin-1β (IL-1β) on the function of lacrimal gland myoepithelial cells (MECs). MECs isolated from an α-smooth muscle actin-green fluorescent protein (SMA-GFP) transgenic mouse were treated with IL-1β alone or in the presence of SP600125, a JNK inhibitor, or ARP100, an MMP-2 inhibitor. The GFP intensity and the cell size/area were measured, and on day 7, the SMA, calponin, and pro-MMP-2 protein levels and the MEC contraction were assessed. At baseline, the control and treated cells showed no differences in GFP intensity or cell size. Starting on day 2 and continuing on days 4 and 7, the GFP intensity and cell size were significantly lower in the IL-1β-treated samples, and these effects were alleviated following inhibition of either JNK or MMP-2. Compared with the control, the levels of SMA and calponin were lower in the IL-1β-treated samples, and both the JNK and MMP-2 inhibitors reversed this trend. The pro-MMP-2 protein level was elevated in the IL-1β-treated samples, and this effect was abolished by the JNK inhibitor. Finally, oxytocin-induced MEC contraction was diminished in the IL-1β-treated samples, and both the JNK and MMP-2 inhibitors reversed this effect. Our data suggest that IL-1β uses the JNK/MMP-2 pathways to alter MEC functions, which might account for the diminished tears associated with aqueous-deficient dry eye disease.

Dexamethasone Intracanalicular Insert for Clinically Significant Aqueous-Deficient Dry Eye: A Randomized Controlled Trial

PurposeTo evaluate a commercially available dexamethasone intracanalicular insert to treat dry eye. DesignSingle-center, double-masked, randomized controlled trial. ParticipantsPatients with clinically significant aqueous-deficient dry eye [combined ocular surface staining score ≥3 (0-12), corneal fluorescein staining ≥2 (0-6), and Schirmer’s wetting <10 mm at 5 minutes in both eyes] with symptoms (dryness, eye discomfort, or visual fatigue, ≥30 [0-100]) despite treatment with at least one prescription drop and deemed candidate for topical steroid. MethodsSeventy-five adult patients were enrolled. A 1:1 randomization sequence was used to determine which eye of each patient would receive the treatment (dexamethasone 0.4 mg intracanalicular insert with 30-day elution time) or the sham (collagen plug). The fellow eye received the opposite treatment. Patients were masked to treatment assignment. Follow-up visits (at weeks 2, 4, and 6) were performed by a masked investigator. Main Outcome MeasuresDry eye parameters and patient symptoms were used for efficacy and intraocular pressure (IOP) was used for safety assessment. ResultsThe severity of dry eye was comparable between the treatment arms (fellow eyes) at baseline. Eyes that received the dexamethasone insert had significantly less corneal staining at week 4 (mean difference [MD] −0.55, 95% confidence interval [CI] = −0.91, −0.19) and conjunctival staining at week 4 (MD −0.68, 95% CI = −1.05, −0.30) and week 6 (MD −0.34, 95% CI = −0.65, −0.02). Schirmer’s wetting was comparable between the two treatment arms. Although the patients reported less dryness in eyes that received the insert at week 4 (MD −5.5, 95% CI = −11.4, 0.4), there were no statistically significant differences in any patient-reported symptoms. At week 4, dexamethasone-treated eyes were more likely to experience an IOP increase (by 5-10 mm Hg) (9 eyes vs. 1 eye; relative risk [RR] = 9.00, 95% CI = 1.14, 71.0; due to sparse events, the CI was very wide). All cases of increased IOP were managed with short-term topical beta blockers and subsided. ConclusionsDexamethasone intracanalicular insert may be considered a dropless dual treatment for clinically significant aqueous-deficient dry eye when topical steroid treatment is deemed appropriate.

A Rat Dry Eye Model with Lacrimal Gland Dysfunction Induced by Scopolamine.

Aqueous-deficient dry eye (ADDE) is a type of dry eye disease that can result in the reduction of tear secretion quantity and quality. Prolonged abnormal tear production can lead to a disturbance in the ocular surface environment, including corneal damage and inflammation. In severe cases, ADDE can cause vision loss or even blindness. Currently, dry eye treatment is limited to eye drops or physical therapy, which can only alleviate eye discomfort symptoms and cannot fundamentally cure dry eye syndrome. To restore the function of the lacrimal gland in dry eye, we have created an animal model of lacrimal gland dysfunction in rats induced by scopolamine. Through the comprehensive evaluation of the lacrimal gland, corneas, conjunctivas, and other factors, we aim to provide a full understanding of the pathological changes of ADDE. Compared with the current dry eye mouse model, this ADDE animal model includes a functional evaluation of the lacrimal gland, providing a better platform for studying lacrimal gland dysfunction in ADDE.

Enhancement of lacrimal gland cell function by decellularized lacrimal gland derived hydrogel

Sustainable treatment of aqueous deficient dry eye (ADDE) represents an unmet medical need and therefore requires new curative and regenerative approaches based on appropriate in vitro models. Tissue specific hydrogels retain the individual biochemical composition of the extracellular matrix and thus promote the inherent cell´s physiological function. Hence, we created a decellularized lacrimal gland (LG) hydrogel (dLG-HG) meeting the requirements for a bioink as the basis of a LG model with potential for in vitro ADDE studies. Varying hydrolysis durations were compared to obtain dLG-HG with best possible physical and ultrastructural properties while preserving the original biochemical composition. A particular focus was placed on dLG-HG´s impact on viability and functionality of LG associated cell types with relevance for a future in vitro model in comparison to the unspecific single component hydrogel collagen type-I (Col) and the common cell culture substrate Matrigel. Proliferation of LG epithelial cells (EpC), LG mesenchymal stem cells, and endothelial cells cultured on dLG-HG was enhanced compared to culture on Matrigel. Most importantly with respect to a functional in vitro model, the secretion capacity of EpC cultured on dLG-HG was higher than that of EpC cultured on Col or Matrigel. In addition to these promising cell related properties, a rapid matrix metalloproteinase-dependent biodegradation was observed, which on the one hand suggests a lively cell–matrix interaction, but on the other hand limits the cultivation period. Concluding, dLG-HG possesses decisive properties for the tissue engineering of a LG in vitro model such as cytocompatibility and promotion of secretion, making it superior to unspecific cell culture substrates. However, deceleration of biodegradation should be addressed in future experiments.

Immediate and Delayed Effects of Punctal Plug Insertion on Tear Meniscus Height in Severe Aqueous-Deficient Dry Eye.

The aim of this study was to assess the immediate and delayed effects of tear punctal occlusion with punctal plugs on tear meniscus height (TMH) in severe aqueous-deficient dry eye (ADDE) disease. Consecutive patients with severe ADDE related to Sjögren syndrome or ocular graft-versus-host disease underwent inferior and superior occlusion with punctal plugs. TMH was measured using the LacryDiag ocular surface analyzer platform before, 10 minutes, and at least 1 month after punctal occlusion. The corneal fluorescein staining (CFS) score was graded with the Oxford scale (from 0 to 5). Ocular symptoms were graded with a visual analog scale (from 1 to 10). We included 24 eyes of 24 patients (mean age 61 ± 9 years; mean follow-up 7 ± 5 months). The mean TMH was 0.19 ± 0.06 mm at baseline and increased significantly to 0.41 ± 0.13 mm (P < 0.001) and 0.46 ± 0.17 mm (P < 0.001) at 10 minutes after punctal plug insertion and at the end of follow-up, respectively. The median CFS score decreased from 3 ± 1 before plug insertion to 1 ± 2 at the end of follow-up (P < 0.001). Many patients (67%; n = 16) reported subjective improvement of symptoms. TMH was negatively correlated with the CFS score and visual analog scale score assessing symptoms. Upper and lower punctal occlusion increased TMH in patients with severe ADDE as soon as 10 minutes after plug insertion. TMH remained stable over time, which led to the relief of symptoms and reduced corneal staining.

A Comprehensive Study on Tear Meniscus Height Inter-Eye Differences in Aqueous Deficient Dry Eye Diagnosis

(1) Background: Dry eye disease (DED) is a chronic ocular surface condition that requires precise diagnostic tools. The present study aimed to investigate the diagnostic potential of the absolute inter-eye difference (|OD-OS|) in tear meniscus height (TMH) for the detection of the presence of aqueous deficient dry eye (ADDE). (2) Methods: A sample of 260 participants with dry eye complaints underwent ocular surface examinations thorough diagnostic assessments based on the Tear Film and Ocular Surface Society guidelines (TFOS DEWS II). Participants were subsequently categorized as No ADDE and ADDE based on TMH. Statistical analyses to determine the optimal TMH|OD-OS| cut-off value in a randomly selected study group (200 participants) were performed, while a separate validation analysis of the cut-off value obtained in a random cross-validation group (60 participants) was also performed. (3) Results: The significant diagnostic capability of TMH|OD-OS| (area under the curve = 0.719 ± 0.036, p &lt; 0.001) was found. The identified cut-off value of 0.033 mm demonstrated reliable specificity (77.6%) and moderate sensitivity (59.1%). Cross-validation confirmed the cut-off value’s association with the TFOS DEWS II diagnostic criterion (Cramer’s V = 0.354, p = 0.006). (4) Conclusions: The present study provides evidence for the diagnostic potential of TMH|OD-OS| in identifying ADDE. The identified cut-off value enhances the specificity and offers moderate sensitivity, providing an objective tool for clinical decision making.

Treatment Options for Dry Eye Disease at Svjetlost Eye Clinic Sarajevo - a Review

Background: Dry eye disease (DED) is a chronic condition that significantly impacts global health by causing discomfort and vision disturbances. It arises from the loss of tear film homeostasis, driven by inflammation, hyperosmolarity, and ocular surface damage. These elements create a cycle that exacerbates the condition, leading to severe symptoms that can impede daily activities. The Tear Film &amp; Ocular Surface Society Dry Eye Workshop II (TFOS DEWS II) has classified DED into aqueous-deficient dry eye (ADDE) and evaporative dry eye (EDE), with the latter being more common and primarily caused by Meibomian gland dysfunction (MGD). Objective: The aim of this article is to provide a comprehensive overview of the treatment options for dry eye syndrome available at Eye Clinic Svjetlost and their frequency. By exploring the various therapeutic approaches, including medical treatments and advanced procedures such as LipiFlow, it seeks to inform readers about the diverse strategies to manage and alleviate dry eye symptoms. Methods: This review examines treatment strategies for DED, particularly those used at Eye Clinic Svjetlost in Sarajevo, based on a five-year analysis of patient records. Results and Discussion: Key treatments include artificial tears, punctum plugs, cyclosporine, and LipiFlow. Artificial tears, especially lipid-based formulations, are fundamental in managing DED. Punctum plugs offer a non-invasive option to retain natural tears. Cyclosporine, an immunomodulator, reduces inflammation and enhances tear production. LipiFlow, targeting MGD, provides significant and lasting relief.Additionally, lifestyle modifications, environmental adjustments, and nutritional supplements, particularly omega-3 fatty acids, play crucial roles in alleviating symptoms. Conclusion: The effectiveness of these treatments highlights the importance of personalized care tailored to individual patient needs. This comprehensive analysis underscores the need for ongoing research and innovation to improve treatment efficacy and quality of life for DED patients. It serves as a call to action for healthcare professionals and researchers to continue advancing in this field.

Randomness-restricted Diffusion Model for Ocular Surface Structure Segmentation.

Ocular surface diseases affect a significant portion of the population worldwide. Accurate segmentation and quantification of different ocular surface structures are crucial for the understanding of these diseases and clinical decision-making. However, the automated segmentation of the ocular surface structure is relatively unexplored and faces several challenges. Ocular surface structure boundaries are often inconspicuous and obscured by glare from reflections. In addition, the segmentation of different ocular structures always requires training of multiple individual models. Thus, developing a one-model-fits-all segmentation approach is desirable. In this paper, we introduce a randomness-restricted diffusion model for multiple ocular surface structure segmentation. First, a time-controlled fusion-attention module (TFM) is proposed to dynamically adjust the information flow within the diffusion model, based on the temporal relationships between the network's input and time. TFM enables the network to effectively utilize image features to constrain the randomness of the generation process. We further propose a low-frequency consistency filter and a new loss to alleviate model uncertainty and error accumulation caused by the multi-step denoising process. Extensive experiments have shown that our approach can segment seven different ocular surface structures. Our method performs better than both dedicated ocular surface segmentation methods and general medical image segmentation methods. We further validated the proposed method over two clinical datasets, and the results demonstrated that it is beneficial to clinical applications, such as the meibomian gland dysfunction grading and aqueous deficient dry eye diagnosis.

Novel pathomechanisms of impairment of native tear protein complexes in aqueous deficient dry eye syndrome

Aims/Purpose: Dry eye syndrome (DES) is a common yet deplorable disease of the ocular surface with high global prevalence. The pathomechanisms underlying the impairment of the native tear protein complexes remain unexplored. This study established a quantitative proteomics approach to characterize the novel protein complexes and unravel their functional roles in tears of DES patients.Methods: Tear samples were collected using Schirmer's strips from aqueous‐deficient DES (DRY, n = 16) and healthy (CTRL, n = 16) subjects following comprehensive DES clinical examinations. The native tear protein complex profiles were elucidated employing a customized blue native gel electrophoretic (BN‐PAGE) combined with mass spectrometry (MS)‐based proteomics strategy. In‐silico bioinformatics tools were employed for gene annotation analysis of the complexes.Results: Five major native protein complexes designated as complex I (cI, 800 kDa), II (cII, 400 kDa), III (cIII, 240 kDa), IV (cIV, 140 kDa) and V (cV, 66 kDa) were characterized for the first time in human tears. Interestingly, a cluster of immune‐related proteins identified in cI (e.g., IGHA1) were annotated to complement pathways and was found to be significantly increased in abundance in DRY vs. CTRL (p = 8.2 × 10−3). Likewise, increased abundance of another cluster of proteins annotated to inflammatory response (e.g. S100A9) in DRY (p = 1.7 × 10−2) was associated to cIII. On the contrary, cII was largely composed of lacrimal‐specific proteins (e.g., LYZ), which was found to be decreased in abundance in DRY (p = 2.4 × 10−2). Similarly, decrement of antimicrobial proteins in cIV (e.g., LACRT) was observed in DRY (p = 1.7 × 10−2). The expression of a cluster of carrier proteins involved in protein–protein interactions (e.g., ALB) was annotated in cV, which was increased in DRY (p = 4.4 × 10−3). Noteworthy, 35 new DES markers were identified with this methodological approach.Conclusions: Collectively, a tear‐customized BN‐PAGE‐MS analysis was instrumental to decipher the multifaceted biological functions of novel native protein complexes in human tears. For the first time, the intricate molecular mechanistic changes underlying these protein complexes in DES were unravelled, which could be instrumental for potential development of therapeutic strategies in ameliorating DES.

Eye Pain Caused by Epithelial Damage in the Central Cornea in Aqueous-Deficient Dry Eye.

In this study, the severity of eye pain (EP) and associated objective findings were evaluated in aqueous-deficient dry eye (ADDE) patients using PainVision®, a quantitative pain-measuring device. This study involved 53 eyes of 53 ADDE patients (6 males and 47 females; mean age: 64.4 ± 13.4 [mean ± SD] years). Of those, 18 eyes of 18 patients underwent punctal occlusion, and EP and objective findings in those patients were evaluated before and after treatment. In all patients, the severity of EP as measured by PainVision® was assessed using the Pain Degree (PD). The median PD for the 53 patients was 30.6 µA/µA (interquartile range, 16.9-93.2), and the nasal and central corneal staining score and the upper lid-wiper epitheliopathy score were significantly correlated with PD (R = 0.33, 0.33, and 0.28, respectively) (all: p < 0.05). Using the least squares method, the central corneal staining score most significantly affected PD. In the 18 cases that underwent punctal occlusion, PD was significantly reduced (median PD: 24.8 to 7.1 µA/µA; p < 0.0001). Using the least squares method, the central corneal staining score and tear meniscus radius were significantly more influential as factors contributing to PD before and after treatment, and central corneal epithelial damage was the factor most associated with ADDE-related EP.

Effect of Punctal Occlusion on Blinks in Eyes with Severe Aqueous Deficient Dry Eye.

Punctal occlusion (PO) is considered to improve both tear-film instability and increased friction during blinking and may consequently affect blinks. The purpose of this study was to investigate the effect of PO on blinks. This study involved 16 eyes of 16 severe aqueous deficient dry eye (ADDE) patients (mean age: 65.7 years). In all eyes, tear meniscus radius (TMR), spread grade (SG) of the tear-film lipid layer (i.e., SG 1-5: 1 being the best), fluorescein break-up time (FBUT), corneal epithelial damage score (CED), conjunctival epithelial damage score, corneal filament (CF) grade, lid-wiper epitheliopathy (LWE) grade, and superior limbic keratoconjunctivitis (SLK) grade were evaluated at before and at more than 1-month after PO. Moreover, using a custom-made high-speed blink analyzer, palpebral aperture height, blink rate, upper-eyelid closing-phase amplitude/duration/maximum velocity, and upper-eyelid opening-phase amplitude/duration/maximum velocity were measured at the same time point. After PO, TMR, SG, FBUT, CED, and the CF, LWE, and SLK grades were significantly improved, and upper-eyelid opening/closing-phase amplitude and maximum velocity significantly increased (all p < 0.04). The findings of this study suggest that PO improves ocular surface lubrication and that blink-related parameters can reflect the friction that occurs during blinking in eyes with severe ADDE.

Efficacy and Safety of Quantum Molecular Resonance Electrotherapy in Patients with Aqueous-Deficient, Evaporative and Mixed-Type Dry Eye: A Randomized Interventional Study.

To evaluate the efficacy and safety of Quantum Molecular Resonance (QMR) treatment in patients with severe dry eye disease (DED), as well as its effects on aqueous-deficient (ADDE), evaporative (EDE), and mixed (MDE) dry eye. In this prospective, interventional study, 81 patients were randomly allocated to received four treatment sessions of QMR at 1-week intervals (Rexon-Eye®, Resono Ophthalmic, Trieste, Italy) (QRM group) or tear substitute four times daily, containing 0.15% sodium hyaluronate and 3% trehalose (Thealoz Duo®, Thea Pharma, France) (SH-TH group). Outcome measures included ocular surface disease index (OSDI) questionnaire, tear meniscus height (TMH), tear breakup time (TBUT), non-invasive breakup time (NIBUT), corneal fluorescein staining (CFS), lipid layer thickness (LLT), tear film osmolarity (OSM), and meibomian gland dysfunction (MGD) grade, which were assessed at baseline and 1-month and 3-month follow-up. The QMR group achieved better improvements than the SH-TH group in OSDI and SANDE questionnaires, NIBUT, LLT, and CFS. The mean differences between the groups were as follows: OSDI (- 12.4 ± 0.25 points, P = 0.01), SANDE (10.6 ± 1.7 points, P = 0.01), NIBUT (2 ± 0.25s, P = 0.01), LLT (18.7 ± 0.7nm, P = 0.01), and CFS (1.2 ± 0.1 points, P = 0.02). In subgroups analysis, QMR treatment demonstrated a beneficial role to improve DED symptoms and signs in ADDE, EDE, and MDE. QMR is an effective and well-tolerated treatment that seems to improve DED symptoms and signs in patients with severe DED. However, further studies are needed to confirm this. ClinicalTrials.gov identifier NCT06119386.