Effectiveness of cyclosporine nanoemulsion eye drops in patients with mild-to-moderate dry eyes: objective and subjective evaluation.

BACKGROUND: To compare and evaluate objective and subjective clinical parameters between 0.05% cyclosporine nanoemulsion (CsN) and 0.15% hyaluronic acid (HA) administration in patients with mild-to-moderate dry eyes. METHODS: In this prospective, randomized, double-masked, single-center, and placebo-controlled parallel study, patients with mild-to-moderate dry eyes were randomly allocated to be treated with 0.05% CsN or 0.15% HA twice daily. Patients were followed-up at 4, 8, and 12 weeks. Objective and subjective parameters were evaluated during each visit. RESULTS: A total of 35 patients were enrolled in this study. Compared with baseline, tear film break-up time and fluorescein staining scores at 4, 8, and 12 weeks significantly improved in the CsN group. However, the Schirmer I test showed no statistically significant change until week 12. Using the Symptom Assessment in Dry Eye (SANDE) score, both groups gradually showed significant improvement compared with baseline values. However, the Dry Eye-Related Quality-of-life Score Questionnaire (DEQS) showed no statistically significant change during the treatment period. CONCLUSIONS: Both 0.05% CsN and 0.15% HA administration twice a day effectively improved the objective signs and subjective symptoms of patients with mild-to-moderate dry eyes. However, patients treated with 0.05% CsN experienced greater and faster improvement.

Exploring novel pharmacological trends: Natural compounds in dry eye disease management.

Dry eye disease (DED) is an ocular condition characterized by altered tear film homeostasis, resulting in symptoms like tear film instability, hyperosmolarity, inflammation, and neurosensory abnormalities. It affects visual acuity and quality of life and is influenced by age, gender, and environmental factors. The first line of treatment consists of dynamically developing artificial tears, gels, and eyelid sprays, which can be supplemented with natural ingredients for enhanced efficacy. Other therapeutic steps include auto-logous serum tears, anti-inflammatory and immunosuppressive eyedrops, or oral tablets. Management also targets Meibomian gland dysfunction and the ocular surface micro-biome. This article explores various therapeutic approaches, including natural compounds and complementary strategies. Natural compounds, such as vitamins, and herbal substances (e.g., trehalose), offer promising benefits in enhancing tear film stability and ocular surface protection. Apitherapeutic products like manuka honey and propolis exhibit antibacterial and anti-inflammatory properties. Additionally, human tissue-derived solutions, such as auto-logous serum tears and amniotic membrane extracts, hold the potential for ocular surface regeneration. Other strategies, including polyherbal eye drops, liposomal eyelid sprays, and microbiome-supporting solutions offer alternative therapeutic avenues. Moreover, patient education, lifestyle modifications, and interdisciplinary collaboration play crucial roles in DED management, emphasizing the importance of holistic care approaches.

Tolerability of Diquas LX on tear film and meibomian glands findings in a real clinical scenario.

Long-acting diquafosol ophthalmic solution (DQS-LX) has significant advantages regarding patient adherence owing to the reduced frequency of required eye drops; however, some patients prefer conventional diquafosol ophthalmic solution (DQS) over DQS-LX. Herein, to clarify the characteristics of patients according to their preference for ophthalmic solutions, dry eye (DE) and meibomian gland (MG) findings were retrospectively investigated. This study enrolled 341 patients with DE (mean age, 62.1 ± 11.7 years) treated at the Itoh Clinic between November 8, 2022, and July 31, 2023, who switched from DQS to DQS-LX. Patients were divided into two groups: those who continued DQS-LX administration (DQS-LX group) and those who wished to revert to conventional DQS (DQS group). Data regarding subjective symptoms assessed using the Standard Patient Evaluation of Eye Dryness (SPEED) questionnaire, tear film breakup time (BUT), tear meniscus height (TMH), corneal and conjunctival fluorescein staining (CFS), conjunctival hyperemia/papilla, meiboscore, plugging, vascularity, meibum grade, and Schirmer's score at the time of DQS-LX switch were evaluated. Of the 341 patients, 31 (9.1%) wished to revert to conventional DQS. In total, 16 eyes of 16 patients in the DQS group and 32 eyes of 32 patients in the DQS-LX group-for whom complete data were available-were included in the analysis. The DQS-LX group had higher SPEED scores, lower TMHs (P < 0.001, respectively), shorter FBUTs, greater CFS findings, larger meibum grades, lower Schirmer scores, and more pluggings compared with the DQS group (P = 0.005, 0.001, 0.001, 0.046, 0.003, respectively). Meiboscores and vascularity did not differ significantly between the two groups (P = 0.73 and 0.39, respectively). In conclusion, patients with low tear film volume and DE complicated by moderate or severe meibomian gland dysfunction (MGD) preferred DQS-LX, while those with allergic findings preferred conventional DQS.

Effect of laughter exercise versus 0.1% sodium hyaluronic acid on ocular surface discomfort in dry eye disease: non-inferiority randomised controlled trial.

OBJECTIVE: To assess efficacy and safety of laughter exercise in patients with symptomatic dry eye disease. DESIGN: Non-inferiority randomised controlled trial. SETTING: Recruitment was from clinics and community and the trial took place at Zhongshan Ophthalmic Center, Sun Yat-sen University, the largest ophthalmic centre in China, between 18 June 2020 to 8 January 2021. PARTICIPANTS: People with symptomatic dry eye disease aged 18-45 years with ocular surface disease index scores ranging from 18 to 80 and tear film break-up time of eight seconds or less. INTERVENTIONS: Participants were randomised 1:1 to receive laughter exercise or artificial tears (0.1% sodium hyaluronic acid eyedrop, control group) four times daily for eight weeks. The laughter exercise group viewed an instructional video and participants were requested to vocalise the phrases "Hee hee hee, hah hah hah, cheese cheese cheese, cheek cheek cheek, hah hah hah hah hah hah" 30 times per five minute session. Investigators assessing study outcomes were masked to group assignment but participants were unmasked for practical reasons. MAIN OUTCOME MEASURES: The primary outcome was the mean change in the ocular surface disease index (0-100, higher scores indicating worse ocular surface discomfort) from baseline to eight weeks in the per protocol population. The non-inferiority margin was 6 points of this index score. Main secondary outcomes included the proportion of patients with a decrease from baseline in ocular surface disease index score of at least 10 points and changes in dry eye disease signs, for example, non-invasive tear break up time at eight weeks. RESULTS: 299 participants (mean age 28.9 years; 74% female) were randomly assigned to receive laughter exercise (n=149) or 0.1% sodium hyaluronic acid (n=150). 283 (95%) completed the trial. The mean change in ocular surface disease index score at eight weeks was -10.5 points (95% confidence interval (CI) -13.1 to -7.82) in the laughter exercise group and -8.83 (-11.7 to -6.02) in the control group. The upper boundary of the CI for difference in change between groups was lower than the non-inferiority margin (mean difference -1.45 points (95% CI -5.08 to 2.19); P=0.43), supporting non-inferiority. Among secondary outcomes, the laughter exercise was better in improving non-invasive tear break up time (mean difference 2.30 seconds (95% CI 1.30 to 3.30), P<0.001); other secondary outcomes showed no significant difference. No adverse events were noted in either study group. CONCLUSIONS: The laughter exercise was non-inferior to 0.1% sodium hyaluronic acid in relieving subjective symptoms in patients with dry eye disease with limited corneal staining over eight weeks intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT04421300.

Sodium hyaluronate and pranoprofen improve visual function and reduce inflammation in patients with dry eye.

OBJECTIVE: The aim of this study was to investigate the clinical use of sodium hyaluronate (SH) combined with pranoprofen in treating patients with dry eye. METHODS: A total of 117 patients with dry eye who were treated in the Traditional Chinese Medicine Hospital of Kunshan from March 2020 and May 2022 were included. According to the therapy approaches, they were treated with SH (SH group), pranoprofen (pranoprofen group), and SH combined with pranoprofen (joint group) (n = 39). RESULTS: The effective rates of dry eye were 79.49%, 74.36% and 94.87% in the SH group, the pranoprofen group and the joint group, respectively (p < 0.05). After treatment, the tear BUT and SIT in the joint group were all prominently increased than those in the other two groups (p < 0.05). The corneal fluorescein staining and dry eye symptom scores in the joint group after treatment were dramatically lower than those in the other two groups (p < 0.001). After treatment, the visual contrast sensitivity (12 c/d, 18 c/d and 24 c/d) in the joint group was markedly higher than those in the other two groups (p < 0.001). The CPR, TNF-α, IFN-γ and IL-1ß levels in the joint group were notably decreased than those in other two groups (p < 0.001). After treatment, the VRQOL quality-of-life scores in the joint group were significantly higher than those in the other two groups (p < 0.05). CONCLUSION: SH combined with pranoprofen showed clear therapeutic benefit in treating dry eye, and the curative effect was more favorable than with either medication alone.

Allogeneic serum-based eye drops may give better results than autologous drops in Sjögren's syndrome dry eye.

PURPOSE: Sjögren's syndrome (SS) may cause severe dry eye symptoms. One of the therapeutic option known for almost 40 years are autologous serum eye drops (ASEDs). Due to the presence of many pro-inflammatory factors in the autologous serum of SS patients, the use of allogeneic serum is often considered a better option. In our facility almost one-fifth of the patients using allogeneic serum-based eye drops (alloSEDs) suffered from autoimmune diseases, including SS. The study aim was to compare the effectiveness of both ASEDs and alloSEDs in SS patients. METHODS: From the group of SS patients using alloSEDs, five female SS patients aged 39-73 years were selected. They had the longest history of the use of the product. The analysis was based on OSDI forms and internal questionnaires which compared the effects of ASEDs and alloSEDs application. The patients used alloSEDs for a period of 5-28 months. All had previously used ASEDs for at least 2 years. RESULTS: For all five patients the mean OSDI after application of ASEDs and before introducing alloSEDs was 68.71, while the mean OSDI after the use of alloSEDs was 30.49. CONCLUSION: In SS the treatment results are better with alloSEDs than with ASEDs. Almost all SS patients who applied both autologous and allogeneic drops reported better effects with the latter as also confirmed by the study cases.

M2 macrophage-derived extracellular vesicles ameliorate Benzalkonium Chloride-induced dry eye.

Dry eye disease (DED) is a common ocular condition affecting a significant portion of the global population, yet effective treatment options remain elusive. This study investigates the therapeutic potential of M2 macrophage-derived extracellular vesicles (M2-EVs) in a mouse model of DED. The DED model was established using 0.2% benzalkonium chloride (BAC) eye drops, applied twice daily for a week. Post induction, the mice were categorized into 5 groups: PBS, Sodium Hyaluronate (HA, 0.1%), Fluoromethalone (FM, 0.1%), M0-EVs, and M2-EVs. The efficacy of M2-EVs was assessed through tear production, corneal fluorescein staining and HE staining. RNA sequencing (RNA-seq) was employed to investigate the mechanisms underlying the therapeutic effects of M2-EVs in DED. Notably, the M2-EVs treated group exhibited the highest tear secretion, indicating improved tear film stability and reduced corneal surface damage. Histological analysis revealed better corneal structure organization in the M2-EVs group, suggesting enhanced ocular surface repair and corneal preservation. Furthermore, M2-EVs treatment significantly decreased pro-inflammatory cytokine levels and showed unique enrichment of genes related to retinal development. These findings suggest that M2-EVs could serve as a promising noninvasive therapeutic approach for human DED, targeting ocular surface inflammation.

Diquafosol Improves Corneal Wound Healing by Inducing NGF Expression in an Experimental Dry Eye Model.

Dry eye disease (DED) is caused by inflammation and damage to the corneal surface due to tear film instability and hyperosmolarity. Various eye drops are used to treat this condition. Each eye drop has different properties and mechanisms of action, so the appropriate drug should be used according to clinical phenotypes. This study aims to compare the therapeutic mechanisms of cyclosporine A (CsA) and diquafosol tetrasodium (DQS). An experimental in vivo/in vitro model of DED using hyperosmolarity showed decreased cell viability, inhibited wound healing, and corneal damage compared to controls. Treatment with cyclosporine or diquafosol restored cell viability and wound healing and reduced corneal damage by hyperosmolarity. The expression of the inflammation-related genes il-1ß, il-1α, and il-6 was reduced by cyclosporine and diquafosol, and the expression of Tnf-α, c1q, and il-17a was reduced by cyclosporine. Increased apoptosis in the DED model was confirmed by increased Bax and decreased Bcl-2 and Bcl-xl expression, but treatment with cyclosporine or diquafosol resulted in decreased apoptosis. Diquafosol increased NGF expression and translocation into the extracellular space. DED has different damage patterns depending on the progression of the lesion. Thus, depending on the type of lesion, eye drops should be selected according to the therapeutic target, focusing on repairing cellular damage when cellular repair is needed or reducing inflammation when inflammation is high and cellular damage is severe.

Improvement in signs and symptoms of severe dry eye disease after dual therapy with high-potency steroids and 0.05% cyclosporine.

OBJECTIVE: To evaluate the effectiveness and safety of combining 0.05% cyclosporine A (CsA) with high-potency steroids for treating severe dry eye disease (DED). MATERIALS AND METHODS: This retrospective comparative case series included 93 patients treated with 0.05% CsA for severe DED. Among them, we included data from 54 eyes of 27 patients who received high-potency steroids in the study group and from 132 eyes of 66 patients who did not receive high-potency steroids in the control group. Data on demographic characteristics, comorbidities, medications and intraocular pressure (IOP) were recorded. The primary outcomes were changes in symptom and sign scores. The ocular surface disease index was used as the symptom score, whereas tear break-up time, Schirmer I test without anaesthesia, ocular surface staining scores and presence of meibomian gland dysfunction were considered as sign scores. Repeated one-way ANOVA and generalized linear mixed models were used to evaluate differences. RESULTS: In the control group, symptom scores decreased from 1 to 2 months and from 2 to 3 months after treatment (p = .002 and .049). In the high-potency steroid group, symptom scores improved during these intervals (p = .003 and .005). The sign score in the control group remained unchanged (all p > .05), while the high-potency steroid group exhibited progressive improvement in sign scores (all p < .05). The high-potency steroid group had more favourable symptom (p = .035) and sign (p < .001) scores than did the control group. However, multiple systemic diseases were associated with poor symptom (p = .025) and sign (p = .014) scores. The risks for glaucoma and cataract formation were similar between the two groups (all p > .05). CONCLUSIONS: Dual therapy combining high-potency steroids and 0.05% CsA significantly improved the signs and symptoms of severe DED compared with 0.05% CsA monotherapy, without severe complications.

High-potency steroid plus CsA is more effective than CsA monotherapy in alleviating the signs and symptoms of DED.Dual therapy has acceptable safety particularly in terms of IOP and cataract risk.Dual therapy is a viable option for patients with severe DED without contraindications.

Nanomedicines for Dry Eye Syndrome: Targeting Oxidative Stress with Modern Nanomaterial Strategies.

Dry eye syndrome (DES) is a dynamic, chronic disease of the ocular surface and ocular appendages caused by inflammation. The most common symptoms include redness, itching, and blurred vision, resulting from dysfunction of the meibomian glands and impaired tear-film production. Factors contributing to the development of DES include environmental elements, such as UV radiation, and internal elements, such as hormonal imbalances. These factors increase oxidative stress, which exacerbates inflammation on the surface of the eye and accelerates the development of DES. In recent years, the incidence of DES has risen, leading to a greater need to develop effective treatments. Current treatments for dry eye are limited and primarily focus on alleviating individual symptoms, such as reducing inflammation of the ocular surface. However, it is crucial to understand the pathomechanism of the disease and tailor treatment to address the underlying causes to achieve the best possible therapeutic outcomes. Therefore, in this review, we analyzed the impact of oxidative stress on the development of DES to gain a better understanding of its pathomechanism and examined recently developed nanosystems that allow drugs to be delivered directly to the disease site.

Recombinant human nerve growth factor (cenegermin) for moderate-to-severe dry eye: phase II, randomized, vehicle-controlled, dose-ranging trial.

BACKGROUND: Dry eye disease (DED) includes neurosensory abnormalities as part of its multifactorial etiology. Nerve growth factor is important for maintaining corneal nerve integrity and wound healing. Cenegermin (recombinant human nerve growth factor) is a topical biologic that promotes corneal healing in patients with neurotrophic keratitis. The purpose of this study was to evaluate efficacy and safety of cenegermin in moderate-to-severe DED and identify an optimal dosing strategy. METHODS: This was a phase II, multicenter, randomized, double-masked, vehicle-controlled, dose-ranging clinical trial in patients with moderate-to-severe DED, including Sjögren's DED (NCT03982368). Patients received 1 drop of cenegermin 3 times daily (t.i.d.; 20 mcg/mL), cenegermin 2 times daily (b.i.d.; 20 mcg/mL) and vehicle once daily, or vehicle t.i.d. for 4 weeks. Follow-up continued for 12 additional weeks. The primary endpoint was change in Schirmer I score from baseline to week 4. Other key endpoints included rate of responders (Schirmer I test > 10 mm/5 min) after treatment and change in Symptoms Assessment iN Dry Eye (SANDE) scores from baseline to end of follow-up. A 1-sided test (α = 0.025) was used to evaluate statistical significance. RESULTS: At week 4, mean changes in Schirmer I scores were not statistically significantly different in either cenegermin group versus vehicle (cenegermin vs vehicle [treatment difference; 95% CI]: t.i.d., 2.60 mm and b.i.d., 3.99 mm vs 1.68 mm [t.i.d.: 0.93; -1.47 to 3.32, P = 0.078; b.i.d.: 2.31; -0.08 to 4.70, P = 0.066]). More patients responded to treatment with cenegermin t.i.d. and b.i.d. versus vehicle (t.i.d.: 25.9% [21/81, P = 0.028]; b.i.d.: 29.3% [24/82, P = 0.007] vs 11.9% [10/84]), with statistical significance (set at P < 0.025) observed in the b.i.d. group. Only cenegermin t.i.d. yielded statistically significant (P < 0.025) reductions in SANDE scores versus vehicle, which were sustained up to the end of follow-up (P value range, 0.002-0.008). Eye pain, primarily mild and transient, was the most frequently observed treatment-emergent adverse event with cenegermin. Similar results were observed in patients with Sjögren's DED. CONCLUSIONS: Cenegermin was well tolerated and although this study did not meet its primary endpoint, significant improvement in patient-reported symptoms of dry eye was observed through follow-up. Larger studies evaluating cenegermin in patients with DED are warranted. TRIAL REGISTRATION: NCT03982368; registered May 23, 2019.

Multifunctional Cerium Oxide Nanozyme for Synergistic Dry Eye Disease Therapy.

Dry eye disease (DED) is a chronic multifactorial ocular surface disease mainly caused by the instability of tear film, characterized by a series of ocular discomforts and even visual disorders. Oxidative stress has been recognized as an upstream factor in DED development. Diquafosol sodium (DQS) is an agonist of the P2Y2 receptor to restore the integrity/stability of the tear film. With the ability to alternate between Ce3+ and Ce4+, cerium oxide nanozymes could scavenge overexpressed reactive oxygen species (ROS). Hence, a DQS-loaded cerium oxide nanozyme was designed to boost the synergistic treatment of DED. Cerium oxide with branched polyethylenimine-graft-poly(ethylene glycol) as nucleating agent and dispersant was fabricated followed with DQS immobilization via a dynamic phenylborate ester bond, obtaining the DQS-loaded cerium oxide nanozyme (defined as Ce@PBD). Because of the ability to mimic the cascade processes of superoxide dismutase and catalase, Ce@PBD could scavenge excessive accumulated ROS, showing strong antioxidant and anti-inflammatory properties. Meanwhile, the P2Y2 receptors in the conjunctival cells could be stimulated by DQS in Ce@PBD, which can relieve the incompleteness and instability of the tear film. The animal experiments demonstrated that Ce@PBD significantly restored the defect of the corneal epithelium and increased the number of goblet cells, with the promotion of tear secretion, which was the best among commercial DQS ophthalmic solutions.

The evolution of cyclosporine treatments for treatment of ocular surface diseases.

PURPOSE OF REVIEW: Cyclosporine is a versatile immunomodulatory drug commonly employed in modern medicine. Although cyclosporine was initially used to prevent solid organ transplant rejection, its indications have extended to treat many inflammatory or autoimmune diseases. Cyclosporin is available for use in oral, intravenous, and topical forms, including eye drops to treat corneal and ocular surface conditions. It is naturally advantageous to administer cyclosporin directly into the eye, avoiding potential and dose limiting systemic adverse effects. However, the transition from systemic to topical administration has been a challenging one. This report reviews the evolution of ophthalmic cyclosporine treatment and explores its clinical impacts and future research directions. RECENT FINDINGS: Latest advancements in formulations - from oil-based solutions to nanomicelle and gel systems and waterless formulations - have improved the therapeutic efficacy and tolerability of topically applied cyclosporine, demonstrating greater effectiveness in treating ocular surface parameters compared to oil-based solution. SUMMARY: Cyclosporine continues to be a safe and effective immunomodulatory drug in the field of ophthalmology to treat various chronic inflammatory ocular surface diseases and dry eye. Currently, there are several commercially available topical preparations available for ophthalmic use each with unique formulation and clinical outcomes.

SPARC overexpression in allogeneic adipose-derived mesenchymal stem cells in dog dry eye model induced by benzalkonium chloride.

BACKGROUND: Nowadays, companion and working dogs hold significant social and economic importance. Dry eye, also known as dry keratoconjunctivitis (KCS), a common disease in ophthalmology, can readily impact a dog's working capacity and lead to economic losses. Although there are several medications available for this disease, all of them only improve the symptoms on the surface of the eye, and they are irritating and not easy to use for long periods of time. Adipose-derived mesenchymal stem cells (ADMSC) are promising candidates for tissue regeneration and disease treatment. However, long-term in vitro passaging leads to stemness loss of ADMSC. Here, we aimed to use ADMSC overexpressing Secreted Protein Acidic and Rich in Cysteine (SPARC) to treat 0.25% benzalkonium chloride-treated dogs with dry eye to verify its efficacy. For in vitro validation, we induced corneal epithelial cell (HCECs) damage using 1 µg/mL benzalkonium chloride. METHODS: Fifteen male crossbred dogs were randomly divided into five groups: normal, dry eye self-healing control, cyclosporine-treated, ADMSC-CMV-treated and ADMSC-OESPARC-treated. HCECs were divided into four groups: normal control group, untreated model group, ADMSC-CMV supernatant culture group and ADMSC-OESRARC supernatant culture group. RESULTS: SPARC-modified ADMSC had the most significant effect on canine ocular surface inflammation, corneal injury, and tear recovery, and the addition of ADMSC-OESPARC cell supernatant also had a salvage effect on HCECs cellular damage, such as cell viability and cell proliferation ability. Moreover, analysis of the co-transcriptome sequencing data showed that SPARC could promote corneal epithelial cell repair by enhancing the in vitro viability, migration and proliferation and immunosuppression of ADMSC. CONCLUSION: The in vitro cell test and in vivo model totally suggest that the combination of SPARC and ADMSC has a promising future in novel dry eye therapy.

Mechanistic elucidation of QiJu-DiHuang Wan in management of age-related dry eye through metabolomics and network pharmacology.

BACKGROUND: QiJu-DiHuang Wan (QJDHW), a frequently employed Chinese herbal formula, is used to treat blurred vision. Even so, it is unclear how it works in treating age-related dry eyes. OBJECTIVE: The aim of this research is to explore the potential mechanisms of QJDHW in treating dry eye using UHPLC-QE-MS, metabolomics, and network pharmacology. METHODS: Six male SD rats were segregated into control and QJDHW groups. Following intervention, The primary active ingredients in QJDHW-containing serum were identified using UHPLC-QE-MS. Metabolomics and network pharmacology were utilized to investigate potential targets and pathways involved following QJDHW use. Primary lacrimal epithelial cells were used for validation. RESULTS: A total of 425 active ingredients of QJDHW were identified, along with 210 active ingredients in QJDHW-containing serum. A comparison of QJDHW-containing serum and control serum samples revealed 40 metabolic differentiators. A total of 24 metabolites were found in QJDHW and QJDHW-containing serum. Network pharmacology identified 3,144 targets for dry eye disease, and 102 metabolite action targets were found for QJDHW-entering components. KEGG Enrichment Analysis revealed significance of HIF-1, apoptosis, cell cycle and PI3K-Akt, among others. HIF-1 and PI3K-Akt were chosen for verification in the oxidative damage model of lacrimal epithelial cells. CONCLUSION: The main active ingredients of QJDHW and its containing serum were elucidated by UHPLC-QE-MS demonstrating that QJDHW treats age-associated dry eye by inhibiting HIF1α/NF-κB through ROS inhibition and PI3K/p-AKT activation.

Rosmarinic acid-grafted gelatin nanogels for efficient diquafosol delivery in dry eye disease therapy.

Dry eye disease (DED) is a prevalent ocular disorder characterized by unstable tear film condition with loss of aqueous or mucin, excessive oxidative stress, and inflammation, leading to discomfort and potential damage to the ocular surface. Current DED therapies have shown restricted therapeutic effects such as frequent dosing and temporary relief with potential unwanted side effects, urgently necessitating the development of innovative efficient therapeutic approaches. Herein, we developed rosmarinic acid (RosA) conjugated gelatin nanogels loading diquafosol sodium (DQS), DRGNG, for simultaneous ROS-scavenging and mucin-secreting DED treatment. Mechanically, DRGNG suppressed the ROS production, reduced inflammatory factors, and prompted mucin secretion in vitro and in vivo. The whole transcriptome RNA sequencing in vitro further provided a detailed analysis of the upregulation of anti-oxidant, anti-inflammatory, and mucin-promotion pathways. Therapeutically, both in evaporative DED and aqueous deficient DED models, the dual-functional DRGNG could prolong the retention time at the ocular surface, efficiently suppress the oxidative stress response, reverse ocular surface morphology, and recover tear film homeostasis, thus alleviating the DED when the dosage is halved compared to the commercial Diquas®. Our findings contribute to developing innovative therapies for DED and offer insights into the broader applications of nanogels in ocular drug delivery and oxidative stress-related conditions.

The efficacy of vitamin D supplementation in dry eye disease: A systematic review and meta-analysis.

PURPOSE: Vitamin D (VD) is a vitamin with anti-inflammatory and immunomodulatory effects. Several studies have shown that VD deficiency is associated with the incidence and severity of dry eye disease (DED) in humans. This meta-analysis compared signs and symptoms in patients with DED before and after VD supplementation. METHODS: Ten databases (PubMed, Cochrane, Web of science, Ovid, Embase, Scopus, CNKI, CSTJ, Wanfang, Sinomed) and four clinical trials registry websites (ISRCTN, CT, ICTRP, ICH GCP) were searched for studies on the efficacy of VD supplement in patients with DED that were published up to 2023 January. A total of 8 studies with 439 cases were included. Two reviewers independently assessed the quality of the literature and extracted data to calculate standard mean differences (SMD) for the Schirmer's test (SH test), tear film break-up time (TBUT), corneal fluorescein staining scores (CFSS, Oxford Scale, 0-5), lid hyperemia, ocular surface disease index (OSDI), and visual analogue pain scale (VAS). RESULTS: The analysis showed that VD supplementation improved tear production (SMD 1.43, 95% CI 0.81, 2.05, p = 0.000) and tear film stability (SMD 1.19, 95% CI 0.83, 1.55, p = 0.000) and reduced lid hyperemia (SMD -0.71, 95% CI -1.09, -0.32, p = 0.000) and OSDI (SMD -1.10, 95% CI -1.45, -0.74, p = 0.000), which is effective in alleviating the signs and symptoms of DED. CONCLUSIONS: VD supplementation could be an adjuvant treatment to alleviate the signs and symptoms of dry eye in the future. However, further studies regarding its most appropriate administration and dosage need to be conducted.

Multifunctional cerium oxide nanozymes with high ocular surface retention for dry eye disease treatment achieved by restoring redox balance.

Dry eye disease (DED) is a kind of multifactorial ocular surface disease that displays ocular discomfort, visual disturbance, and tear film instability. Oxidative stress is a fundamental pathogenesis in DED. An imbalance between the reactive oxygen species (ROS) level and protective enzyme action will lead to oxidative stress, cell dysfunction, tear hyperosmolarity, and inflammation. Herein, a multifunctional cerium oxide nanozyme with high ocular surface retention property was designed to neutralize over-accumulated ROS and restore redox balance. Cerium oxide nanozymes were fabricated via branched polyethylenimine-graft-poly (ethylene glycol) nucleation and dispersion, followed by phenylboronic acid (PBA) functionalization (defined as Ce@PB). Due to the dynamic chemical bonding formation between the PBA segment and the cis-diol groups in the mucin layer of the tear film, Ce@PB nanozymes possess good adhesive capability to the ocular surface, thus extending the drug's retention time. On the other hand, Ce@PB nanozymes could mimic the cascade processes of superoxide dismutase and catalase to maintain intracellular redox balance. In vitro and in vivo studies suggest that such multifunctional nanozymes possess good biocompatibility and hemocompatibility. More importantly, Ce@PB nanozymes treatment in the animal model could repair corneal epithelial defect, increase the number of goblet cells and promote tear secretion, thus achieving an effective treatment for DED. STATEMENT OF SIGNIFICANCE.

ROS-responsive celastrol-nanomedicine alleviates inflammation for dry eye disease.

Dry eye disease (DED) is a major global eye disease leading to severe eye discomfort and even vision impairment. The incidence of DED has been gradually increasing with the high frequency of use of electronic devices. It has been demonstrated that celastrol (Cel) has excellent therapeutic efficacy in ocular disorders. However, the poor water solubility and short half-life of Cel limit its further therapeutic applications. In this work, a reactive oxygen species (ROS) sensitive polymeric micelle was fabricated for Cel delivery. The micelles improve the solubility of Cel, and the resulting Cel loaded micelles exhibit an enhanced intervention effect for DED. Thein vitroresults demonstrated that Cel-nanomedicine had a marked ROS responsive release behavior. The results ofin vitroandin vivoexperiments demonstrated that Cel has excellent biological activities to alleviate inflammation in DED by inhibiting TLR4 signaling activation and reducing pro-inflammatory cytokine expression. Therefore, the Cel nanomedicine can effectively eliminate ocular inflammation, promote corneal epithelial repair, and restore the number of goblet cells and tear secretion, providing a new option for the treatment of DED.