Search Results (69)

The therapeutic potential of exosomes (Exos), a subpopulation of extracellular vesicles (EVs) secreted by various cell types, has been broadly emphasized. Exos are endosome-derived membrane-bound vesicles 50–150 nm in size. Exos can be general or cell type-specific. Their contents enable them to function as multi-signaling and vectorized vehicles. Exos are important for maintaining cellular homeostasis. They are released into extracellular spaces, leading to uptake by neighboring or distant cells and delivering their contents to modulate cell signaling. Exos influence tissue responses to injury, infection, and disease by fusion with the target cells and transferring their cargo, including cytokines, growth and angiogenic factors, signaling molecules, lipids, DNA, mRNAs, and non-coding RNAs. They are implicated in various physiological and pathological conditions, including ocular surface events, such as corneal scarring, wound healing, and inflammation. Their biocompatibility, stability, low immunogenicity, and easy detectability in bodily fluids (blood, tears, saliva, and urine) make them promising tools for diagnosing and treating ocular diseases. The potential to engineer specific Exo cargos makes them outstanding therapeutic delivery vehicles. The objective of this review is to provide novel insights into the functions of Exo cargos and their applications as biomarkers and therapeutics, or targets in the cornea. Full article

The ocular surface is susceptible to a wide spectrum of inflammatory, degenerative, and neurotrophic diseases that can impair vision. The complex pathophysiology and limited therapeutic options associated with these conditions continue to pose significant clinical challenges. Nerve Growth Factor (NGF), a neurotrophin initially recognized for its role in neuronal survival and differentiation, has emerged as a key regulator of ocular surface homeostasis and repair. Beyond its neurotrophic functions, NGF is suggested to influence epithelial proliferation, immune responses, tear secretion, and angiogenesis. Experimental and clinical studies have implicated NGF in both the pathogenesis and potential treatment of various ocular surface diseases, including allergic conjunctivitis, neurotrophic keratopathy (NK), immune-mediated and herpetic keratitis, and dry eye disease (DED), as well as post-surgical corneal wound healing. Notably, recombinant human NGF (rhNGF, cenegermin) has been approved as the first topical biologic therapy for NK. Despite encouraging clinical outcomes, challenges such as high treatment costs, limited long-term data, and potential proangiogenic effects remain. This review consolidates current evidence on the role of NGF in ocular surface health and disease, highlighting its biological mechanisms, clinical applications, and future therapeutic potential. Full article

The cornea, a highly innervated and avascular ocular tissue, relies on intricate neuro-immune interactions to maintain homeostasis. Among key neuromediators, substance P (SP)—a neuropeptide belonging to the tachykinin family—plays a dual role in corneal physiology and pathology. This review synthesizes current knowledge on SP’s involvement in corneal innervation, epithelial homeostasis, immune regulation, neovascularization, and wound healing, while highlighting its dichotomous effects in both promoting tissue repair and exacerbating inflammation. SP, primarily signaling through the neurokinin-1 receptor (NK1R), influences corneal epithelial proliferation, barrier function, and wound healing by modulating cytokines, chemokines, and growth factors. However, its overexpression is linked to pain sensitization, inflammatory keratitis, and corneal neovascularization, driven by interactions with immune cells (e.g., mast cells, neutrophils) and pro-angiogenic factors (e.g., VEGF). Clinical studies demonstrate altered SP levels in dry eye disease, neurotrophic keratitis, and post-refractive surgery, correlating with nerve damage and ocular surface dysfunction. Emerging therapies targeting SP pathways- such as NK1R antagonists (e.g., fosaprepitant) and SP-IGF-1 combinations-show promise for treating neurotrophic ulcers but face challenges due to SP’s context-dependent actions. Future research should clarify the roles of NK2R/NK3R receptors and optimize SP-based interventions to balance its reparative and inflammatory effects. Understanding SP’s multifaceted mechanisms could advance the development of therapies for corneal diseases, particularly those involving sensory neuropathy and immune dysregulation. Full article

Background/Objectives: The management of ocular tumors often necessitates surgery, either alone or in combination with radiotherapy, chemotherapy, or other modalities. While crucial for tumor control, these treatments can significantly impact the ocular surface, leading to both acute and chronic complications. This review examines iatrogenic ocular surface diseases resulting from oncologic interventions, emphasizing their pathophysiology, diagnostic challenges, and management strategies. Methods: A literature review was conducted to identify studies on iatrogenic ocular surface complications associated with ocular tumor treatments. Results: Ocular surface complications include direct damage from surgical manipulation, leading to corneal opacities and persistent epithelial defects, as well as dry eye disease secondary to postoperative chemosis. These disruptions may progress to more severe conditions such as keratopathy, corneal ulcers, limbal stem cell deficiency, and stromal scarring, further impairing visual function. Structural alterations contribute to eyelid malpositions—including ectropion, entropion, round eye, and lagophthalmos—which exacerbate exposure-related damage and ocular surface instability. In cases of uveal melanomas, the exposure of episcleral brachytherapy plaques can induce chronic conjunctival irritation, promoting adhesion formation and symblepharon. Surgical interventions disrupt ocular surface homeostasis, while radiotherapy and chemotherapy exacerbate these effects through cytotoxic and inflammatory mechanisms. Conclusions: Preventing and managing iatrogenic ocular surface complications require a multidisciplinary approach involving early diagnosis, personalized treatment strategies, and targeted postoperative care. Comprehensive pre- and postoperative planning is essential to optimize both visual function and long-term ocular surface integrity, ultimately ensuring a balance between oncologic control with functional and aesthetic preservation. Full article

Recent research has highlighted the critical role of microbiota in organ transplant outcomes, particularly in the gut. However, the impact of ocular surface microbiota (OSM) on corneal transplantation remains largely unexplored. This piece examines the potential connection between OSM imbalances and corneal graftoutcomes, suggesting that microbial shifts could influence immune responses and transplant success. The OSM, though characterized by low microbial density, plays a critical role in local immune modulation and ocular surface homeostasis. Dysbiosis in this microbiota may compromise the immune privilege of the cornea, potentially increasing the risk of graft rejection. Looking at gut microbiota studies, where dysbiosis has been linked to graft failure, it is reasonable to hypothesize that similar mechanisms might be at play on the ocular surface. Disruptions in cornea’s immune tolerance pathways, such as anterior chamber-associated immune deviation (ACAID), may lead to pro-inflammatory responses that threaten graft survival. In addition, ocular surface diseases such as dry eye disease, microbial keratitis, and allergic conjunctivitis, already associated with OSM dysbiosis, may further exacerbate post-transplant complications. Despite the lack of direct studies linking OSM to corneal transplant outcomes, this opinion piece highlights the necessity for future research. Standardizing microbiota analysis methodologies and exploring therapeutic interventions, such as ocular probiotics, could open new roads for improving corneal transplant success and patient prognosis. Full article

Neurotrophic keratopathy (NK) is a rare degenerative disease caused by impairment of the trigeminal nerve, leading to corneal anesthesia, epithelial breakdown, and progressive vision loss. Conventional treatments primarily focus on symptom management and the prevention of complications, but they do not address the underlying nerve dysfunction. Corneal neurotization (NT) has emerged as a promising surgical intervention aimed at restoring corneal sensation and improving ocular surface homeostasis. This review evaluates the outcomes of corneal neurotization in patients with NK and compares the effectiveness of direct (DNT) and indirect (INT) techniques. Studies have reported significant improvements in corneal sensitivity, with success rates ranging from 60.7% to 100% (mean: 90%). Most patients experienced recovery of corneal sensation, as measured by the Cochet–Bonnet aesthesiometer, with no significant differences in outcomes between DNT and INT. Indirect neurotization using a sural nerve graft was the most commonly employed technique (63% of cases), while the use of acellular allografts demonstrated comparable efficacy and simplified the procedure. Postoperative corneal sensitivity increased significantly, from a preoperative average of 2.717 mm to 36.01 mm, with reinnervation typically occurring within 4–6 months and peaking at 12 months. In vivo confocal microscopy confirmed the presence of nerve regeneration. Neurotization was found to be safe, with minimal donor-site complications, which generally resolved within one year. Although the procedure improves corneal sensation and tear film stability, visual acuity outcomes remain variable due to pre-existing corneal damage. Early intervention is, therefore, recommended to prevent irreversible scarring. However, the number of patients undergoing the procedure remains limited, making it difficult to draw definitive conclusions. Most available studies consist of small case series. Further research with larger sample sizes is needed to refine surgical techniques and optimize patient selection, thereby improving outcomes in the management of NK. Full article

The tear film, consisting of the aqueous and lipid layers, maintains the homeostasis of the ocular surface; therefore, when disturbed, it can cause dry eye, which affects millions of people worldwide. Understanding the dynamics of the tear film layers is essential for developing efficient drug delivery systems for dry eye disease. Quantum dots (QDs) offer the potential for real-time monitoring of tear film and evaluating its dynamics. Hydrophilic silicon QDs (Si-QDs) have already been optimised to image the aqueous layer of the tear film. This study was conducted to optimise hydrophobic Si-QDs to image the lipid layer of the tear film. Si-QDs were synthesised in solution and characterised by transmission electron microscope and spectrofluorophotometry. The fluorescence emission of Si-QDs was monitored in vitro when mixed with artificial tears. The cytotoxicity was assessed in cultured human corneal epithelial cells using an MTT assay following 24 h of exposure. Si-QDs were 2.65 ± 0.35 nm in size and were non-toxic at <16 µg/mL. Si-QDs emitted stable green fluorescence for 20 min but demonstrated aggregation at higher concentrations. These findings highlight the potential of hydrophobic Si-QDs as a biomarker for the real-time imaging of the tear film lipid layer. However, further research on surface functionalisation and preclinical evaluations are recommended for enhanced solubility and biocompatibility in the ocular surface. Full article

Keratoconus (KC) is a progressive ocular disorder marked by structural and functional alterations of the cornea, leading to significant visual impairment. Recent studies indicate that these corneal changes are linked to molecular and cellular mechanisms that disrupt and degrade the extracellular matrix. This degradation is influenced by proteinases that contribute to a loss of homeostasis and an imbalance in the antioxidant/oxidative state within the cornea, fostering oxidative stress, inflammation, and apoptosis. Although these biological processes have been identified primarily through molecular biology research, omics technologies have significantly advanced our understanding of the physiological and pathological phenomena associated with KC. Omics studies encompassing genomics, transcriptomics, proteomics, epigenomics, and metabolomics, have emerged as critical tools in elucidating the complex biological landscape of various diseases, including ocular conditions. The integrative application of these studies has demonstrated their potential in personalizing medicine across diverse fields such as oncology, neurology, and ophthalmology. This review aims to describe findings from omics research applied to keratoconus, highlighting the genomic, transcriptomic, proteomic, epigenomic, and metabolomic aspects derived from ocular and other biological samples. Notably, the molecular insights gained from these studies hold promise for identifying biomarkers of keratoconus, which could enhance diagnostic accuracy and therapeutic strategies. The exploration of these biomarkers may facilitate improved management and treatment options for patients, contributing to personalized care in keratoconus management. Full article

Background/Objectives: A novel ophthalmic formulation, XanterDES, containing 0.2% xanthan gum and 0.025% desonide sodium phosphate (DES), was developed to alleviate ocular surface discomfort and irritation. This study aimed to evaluate its pharmacodynamic properties and to characterize its rheological behavior and mucoadhesive characteristics, compared to another formulation containing 0.2% hyaluronic acid and 0.001% hydrocortisone (HYD). Methods: A rabbit (New Zealand White) model of LPS-induced uveitis was used to test different concentrations of DES on ocular markers of inflammation. The efficacy of XanterDES and HYD on induced dry eye was evaluated by assessing tear volume and corneal damage in C57BL/6 mice exposed to a controlled environmental chamber. The rheological and mucoadhesive properties of XanterDES and HYD were assessed using a HAAKE RheoStress RS600 rheometer and a TA-XT2 texture analyzer, respectively. Results: In the uveitis model, unlike DES 0.25%, a low concentration of 0.025% DES showed a significant inhibitory activity localized to the eye surface and effectively reduced corneal edema. In the dry eye model, XanterDES demonstrated superior efficacy compared to HYD, effectively preventing both tear volume reduction and corneal damage. XanterDES also demonstrated pseudoplastic and enhanced mucoadhesive properties compared to HYD. Conclusions: The ancillary anti-inflammatory effects of a low dose of DES combined with the biophysical properties of xanthan gum are supportive of a favorable therapeutic profile, promoting the maintenance or restoration of ocular surface homeostasis while minimizing the risk of adverse effects typically associated with standard-dose corticosteroids. The comparison with another low-dose corticosteroid highlights the superiority of XanterDES in pharmacodynamic and biophysical performance. Full article

Allergic conjunctivitis (AC) is the most common allergic eye disorder. Antiallergic eyedrops are the first line of pharmacological treatment. However, the application of antiallergic eyedrops can potentially alter tear homeostasis and affect the ocular surface, which may result in iatrogenic diseases such as dye eye disease (DED). Long-term treatment of AC with eyedrops containing preservatives and other components may increase the risk of DED and ocular surface damage. Here, we examined 20 clinical trials published during the past ten years with antihistamine ophthalmic formulations in the treatment of AC, to evaluate the extent of evidence about their safety and tolerability. Remarkably, we find that most trials lack an evaluation of the critical ocular surface parameters, such as tear film break-up time, tear volume, corneal and conjunctival damage, and inflammation, to properly assess the state of the ocular surface state after prolonged treatment. There is a need to increase awareness of the use of specific formulations that do not increase the risk of iatrogenic DED. Full article

Purpose: To evaluate how Video Display Terminal (VDT) use, Contact Lens (CL) wear, and eyedrop use affect ocular surface parameters in participants with ocular discomfort and how these factors may vary across different age groups. Methods: The current cross-sectional study initially involved a total of 252 participants who completed a self-administered survey to collect information about ocular discomfort and lifestyle factors. This online survey was composed of an Ocular Surface Disease Index (OSDI) questionnaire and three extra questions regarding lifestyle factors (VDT use, CL wear, and eyedrop use). Only 185 symptomatic participants, those with OSDI values > 12, were scheduled to undergo a comprehensive ocular examination that included tear film osmolarity, Fluorescein Break-Up Time (FBUT), Maximum Blink Interval (MBI), and corneal staining. Results: Differences in ocular parameters and lifestyle factors across age groups (<40 years, 40–60 years, >60 years) were analyzed, along with their correlations and regression. Significant age group differences were found in OSDI, osmolarity, FBUT, and MBI (One-way ANOVA, all p ≤ 0.029). Correlations were observed between CL wear and osmolarity and MBI (Pearson’s correlation, both p ≤ 0.049). Multiple regression confirmed age associations with OSDI, osmolarity, FBUT, and MBI (Multiple linear regression, all p ≤ 0.040) and found links between VDT use and osmolarity and MBI (Multiple linear regression, both p ≤ 0.038) and between eyedrop use and OSDI (Multiple linear regression, p = 0.040). Conclusion: Aging is a primary factor affecting ocular homeostasis, with older adults showing lower FBUT and MBI values and higher osmolarity. Prolonged use of VDTs exacerbates this effect, further contributing to ocular discomfort and destabilized tear film. No associations between CL wear and any of the ocular parameters were found. Eyedrop use shows varied effects on ocular comfort across age groups, emphasizing the need for age-specific ocular care. Overall, these findings confirm that aging and extended VDT use play a significant role in ocular surface discomfort. Full article

This review aimed to evidence the predisposing conditions for Salzmann nodular degeneration (SND), where particular attention was paid to its association with ocular and systemic diseases. SND is a rare disease characterized by bluish-white nodules located in the mid-periphery of the cornea, which are otherwise completely clear. SND has been found in association with different systemic and ocular diseases, and it may have unilateral or bilateral presentation. Initial forms are only diagnosed occasionally as they are asymptomatic, whereas, in advanced disease, the visual acuity might be seriously impaired. Although SND is well described, its exact etiopathology is currently still unknown and is frequently misdiagnosed. It is associated with ocular surface inflammatory conditions and previous corneal surgery, and it has been described in different systemic diseases. Diagnosis is clinically based with slit lamp examinations, and instrumental assessments with corneal topography permit one to observe the alterations of the corneal profile, whereas anterior segment–optical coherence tomography (AS-OCT) is used to investigate the stromal depth of the nodules. Therapy might be conservative with the objective of improving the ocular surface homeostasis and surgical outcomes, where the aim is to restore the corneal regularity and visual acuity. Ophthalmologists should pay particular attention when detecting nodules in patients with ocular and non-ocular inflammatory diseases to guarantee the patient a timely diagnosis and a better therapeutic outcome. Additionally, collaboration between specialists who deal with treating patients suffering from disorders potentially associated with SND is recommended. Full article

Diabetic retinopathy (DR) remains the leading cause of blindness in the working-age population. Its progression causes gradual damage to corneal nerves, resulting in decreased corneal sensitivity (CS) and disruption of anterior-eye-surface homeostasis, which is clinically manifested by increased ocular discomfort and dry eye disease (DED). This study included 52 DR patients and 52 sex- and age-matched controls. Ocular Surface Disease Index (OSDI) survey, tear film-related parameters, CS, and in vivo corneal confocal microscopy (IVCM) of the subbasal plexus were performed. Furthermore, all patients underwent tear sampling for neurotrophin and cytokine analysis. OSDI scores were greater in DR patients than in controls (p = 0.00020). No differences in the Schirmer test score, noninvasive tear film-break-up time (NIBUT), tear meniscus or interferometry values, bulbar redness, severity of blepharitis or meibomian gland loss were found. In the DR group, both the CS (p < 0.001), and the scotopic pupil diameter (p = 0.00008) decreased. IVCM revealed reduced corneal nerve parameters in DR patients. The stage of DR was positively correlated with the OSDI (Rs = +0.51, 95% CI: + 0.35–+0.64, p < 0.001) and negatively correlated with IVCM corneal nerve parameters and scotopic pupillometry (Rs = −0.26, 95% CI: −0.44–−0.06, p = 0.0097). We found negative correlations between the OSDI and IVCM corneal innervation parameters. The DR group showed lower tear film-brain-derived neurotrophic factor (BDNF) levels (p = 0.0001) and no differences in nerve growth factor (NGF)-β, neurotrophin (NT)-4, vascular endothelial growth factor (VEGF), interleukin (IL)-1β, IL-4, IL-5, IL-6, or IL-12 concentrations. Tumor necrosis factor (TNF)-α, IL-2, IL-8, IL-10, granulocyte macrophage colony-stimulating factor (GM-CSF), and interferon (IFN)-γ levels were decreased among patients with DR. Corneal innervation defects have a direct impact on patients’ subjective feelings. The evolution of DR appears to be associated with corneal nerve alterations, emphasizing the importance of IVCM. Full article

Wilson disease is a genetic disorder of the liver characterized by excess accumulation of copper, which is found ubiquitously on earth and normally enters the human body in small amounts via the food chain. Many interesting disease details were published on the mechanistic steps, such as the generation of reactive oxygen species (ROS) and cuproptosis causing a copper dependent cell death. In the liver of patients with Wilson disease, also, increased iron deposits were found that may lead to iron-related ferroptosis responsible for phospholipid peroxidation within membranes of subcellular organelles. All topics are covered in this review article, in addition to the diagnostic and therapeutic issues of Wilson disease. Excess Cu²⁺ primarily leads to the generation of reactive oxygen species (ROS), as evidenced by early experimental studies exemplified with the detection of hydroxyl radical formation using the electron spin resonance (ESR) spin-trapping method. The generation of ROS products follows the principles of the Haber–Weiss reaction and the subsequent Fenton reaction leading to copper-related cuproptosis, and is thereby closely connected with ROS. Copper accumulation in the liver is due to impaired biliary excretion of copper caused by the inheritable malfunctioning or missing ATP7B protein. As a result, disturbed cellular homeostasis of copper prevails within the liver. Released from the liver cells due to limited storage capacity, the toxic copper enters the circulation and arrives at other organs, causing local accumulation and cell injury. This explains why copper injures not only the liver, but also the brain, kidneys, eyes, heart, muscles, and bones, explaining the multifaceted clinical features of Wilson disease. Among these are depression, psychosis, dysarthria, ataxia, writing problems, dysphagia, renal tubular dysfunction, Kayser–Fleischer corneal rings, cardiomyopathy, cardiac arrhythmias, rhabdomyolysis, osteoporosis, osteomalacia, arthritis, and arthralgia. In addition, Coombs-negative hemolytic anemia is a key feature of Wilson disease with undetectable serum haptoglobin. The modified Leipzig Scoring System helps diagnose Wilson disease. Patients with Wilson disease are well-treated first-line with copper chelators like D-penicillamine that facilitate the removal of circulating copper bound to albumin and increase in urinary copper excretion. Early chelation therapy improves prognosis. Liver transplantation is an option viewed as ultima ratio in end-stage liver disease with untreatable complications or acute liver failure. Liver transplantation finally may thus be a life-saving approach and curative treatment of the disease by replacing the hepatic gene mutation. In conclusion, Wilson disease is a multifaceted genetic disease representing a molecular and clinical challenge. Full article

Corneal ulcers, characterized by severe inflammation of the cornea, can lead to serious, debilitating complications and may be vision-threatening for horses. In this study, we aimed to investigate the role of endoplasmic reticulum (ER) stress in corneal stem progenitor cell (CSSC) dysfunction and explore the potential of equine adipose-derived stromal stem cell (ASC)-derived extracellular vesicles (EVs) to improve corneal wound healing. We showed that CSSCs expressed high levels of CD44, CD45, and CD90 surface markers, indicating their stemness. Supplementation of the ER-stress-inducer tunicamycin to CSSCs resulted in reduced proliferative and migratory potential, accumulation of endoplasmic reticulum (ER)-stressed cells in the G0/G1 phase of the cell cycle, increased expression of proinflammatory genes, induced oxidative stress and sustained ER stress, and unfolded protein response (UPR). Importantly, treatment with EVs increased the proliferative activity and number of cells in the G2/Mitosis phase, enhanced migratory ability, suppressed the overexpression of proinflammatory cytokines, and upregulated the anti-inflammatory miRNA-146a-5p, compared to control and/or ER-stressed cells. Additionally, EVs lowered the expression of ER-stress master regulators and effectors (PERK, IRE1, ATF6, and XBP1), increased the number of mitochondria, and reduced the expression of Fis-1 and Parkin, thereby promoting metabolic homeostasis and protecting against apoptosis in equine CSSCs. Our findings demonstrate that MSCs-derived EVs represent an innovative and promising therapeutic strategy for the transfer of bioactive mediators which regulate various cellular and molecular signaling pathways. Full article