scholarly journals Inhibition of Neovascularization and Inflammation in a Mouse Model of Corneal Alkali Burns Using Cationic Liposomal Tacrolimus

2021 ◽  
Vol 9 ◽  
Author(s):  
Xueqi Lin ◽  
Xuewen Yu ◽  
Xiang Chen ◽  
Siting Sheng ◽  
Jingwen Wang ◽  
...  
Keyword(s):  
Retention Time ◽  
Ocular Surface ◽  
Corneal Neovascularization ◽  
Free Drug ◽  
Endothelial Cell Migration ◽  
Cell Counting ◽  
Sodium Fluorescein ◽  
Eye Drops ◽  
Corneal Epithelial ◽  
Biological Compatibility

Eye drops account for more than 90% of commercialized ophthalmic drugs. However, eye drops have certain shortcomings, such as short precorneal retention time and weak corneal penetration. The requirement of frequent instillation of eye drops also causes poor patient compliance, which may lead to further aggravation of the disease. We aimed to develop a cationic liposome formulation to increase the bioavailability of the therapeutic agent and solve the aforementioned problems. In the present study, we prepared cationic liposomal tacrolimus (FK506) with a surface potential of approximately +30 mV, which could bind to the negatively charged mucin layer of the ocular surface. Our results showed that the content of FK506 in the cornea was increased by 93.77, 120.30, 14.24, and 20.36 times at 5, 30, 60, and 90 min, respectively, in the FK506 liposome group (0.2 mg/ml) compared with the free drug group (0.2 mg/ml). Moreover, FITC-labeled FK506 liposomes significantly prolonged the ocular surface retention time to 50 min after a single dose. In addition, the results of the Cell Counting Kit-8 assay, live and dead cell assay, sodium fluorescein staining, and hematoxylin and eosin staining all indicated that FK506 liposomes had good biological compatibility in both human corneal epithelial cells and mouse eyeballs. Compared with the free drug at the same concentration, FK506 liposomes effectively inhibited vascular endothelial growth factor-induced green fluorescent protein-transduced human umbilical vein endothelial cell migration and tube formation in vitro. In a mouse corneal neovascularization model induced by alkali burns, FK506 liposomes (0.2 mg/ml) enhanced corneal epithelial recovery, inhibited corneal neovascularization, and reduced corneal inflammation, and its therapeutic effect was better than those of the commercial FK506 eye drops (1 mg/ml) and the free drug (0.2 mg/ml). Collectively, these results indicate that cationic FK506 liposomes could increase the efficacy of FK506 in the corneal neovascularization model. Therefore, cationic FK506 liposomes can be considered as a promising ocular drug delivery system.

scholarly journals Autologous Blood Products: When, Where, and How?

2021 ◽  
Vol 8 (1) ◽  
pp. 1-9
Author(s):  
Alfonso L Sabater ◽  
Keyword(s):  
Ocular Surface ◽  
Keratoconjunctivitis Sicca ◽  
Therapeutic Option ◽  
Autologous Blood ◽  
Stevens Johnson Syndrome ◽  
Eye Drops ◽  
Corneal Epithelial ◽  
Johnson Syndrome ◽  
Ocular Surface Diseases ◽  
Persistent Epithelial Defects

Autologous blood eye drops have become an interesting, well-known, and widely used therapeutic option for many ocular surface diseases since their introduction into the ophthalmologic field forty-six years ago. The foundation for their use in the treatment of pathologies such as severe keratoconjunctivitis sicca, persistent epithelial defects, ocular chemical burns, recurrent epithelial erosions, Stevens-Johnson syndrome, ocular graft versus host disease, and, lately, in many other ocular surface conditions, relies on the fact that they contain proteins, vitamins, cytokines, and growth factors that participate in the signaling pathways of corneal epithelial healing in similar amounts to those found in normal, healthy tear films

scholarly journals TLR4-Dependent DUOX2 Activation Triggered Oxidative Stress and Promoted HMGB1 Release in Dry Eye

2022 ◽  
Vol 8 ◽  
Author(s):  
Bowen Wang ◽  
Hao Zeng ◽  
Xin Zuo ◽  
Xue Yang ◽  
Xiaoran Wang ◽  
...  
Keyword(s):  
Cell Death ◽  
Western Blot ◽  
Dry Eye ◽  
Ocular Surface ◽  
Cell Counting ◽  
Corneal Epithelial Cell ◽  
Rna Seq ◽  
Corneal Epithelial ◽  
Surface Inflammation ◽  
Ocular Surface Inflammation

Dry eye disease (DED) is one of the most common ocular surface diseases worldwide. DED has been characterized by excessive accumulation of reactive oxygen species (ROS), following significant corneal epithelial cell death and ocular surface inflammation. However, the key regulatory factor remains unclear. In this study, we tended to explore whether DUOX2 contributed to DED development and the underlying mechanism. Human corneal epithelial (HCE) cells were treated with hyperosmolarity, C57BL/6 mice were injected of subcutaneous scopolamine to imitate DED. Expression of mRNA was investigated by RNA sequencing (RNA-seq) and quantitative real-time PCR (qPCR). Protein changes and distribution of DUOX2, high mobility group box 1 (HMGB1), Toll-like receptor 4 (TLR4), and 4-hydroxynonenal (4-HNE) were evaluated by western blot assays and immunofluorescence. Cell death was assessed by Cell Counting Kit-8 (CCK8), lactate dehydrogenase (LDH) release, and propidium iodide (PI) staining. Cellular ROS levels and mitochondrial membrane potential (MMP) were analyzed by flow cytometry. RNA-seq and western blot assay indicated a significant increase of DUOX2 dependent of TLR4 activation in DED both in vitro and in vivo. Immunofluorescence revealed significant translocation of HMGB1 within corneal epithelial cells under hyperosmolar stress. Interestingly, after ablated DUOX2 expression by siRNA, we found a remarkable decrease of ROS level and recovered MMP in HCE cells. Moreover, knockdown of DUOX2 greatly inhibited HMGB1 release, protected cell viability and abolished inflammatory activation. Taken together, our data here suggest that upregulation of DUOX2 plays a crucial role in ROS production, thereafter, induce HMGB1 release and cell death, which triggers ocular surface inflammation in DED.

scholarly journals Why Chain Length of Hyaluronan in Eye Drops Matters

Diagnostics ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 511 ◽  
Author(s):  
Wolfgang G.K. Müller-Lierheim
Keyword(s):  
Molecular Weight ◽  
Epithelial Cells ◽  
Chain Length ◽  
Ocular Surface ◽  
Clinical Performance ◽  
Average Molecular Weight ◽  
Tear Film ◽  
Eye Drops ◽  
Zero Shear Viscosity ◽  
Corneal Epithelial

The chain length of hyaluronan (HA) determines its physical as well as its physiological properties. Results of clinical research on HA eye drops are not comparable without this parameter. In this article methods for the assessment of the average molecular weight of HA in eye drops and a terminology for molecular weight ranges are proposed. The classification of HA eye drops according to their zero shear viscosity and viscosity at 1000 s−1 shear rate is presented. Based on the gradient of mucin MUC5AC concentration within the mucoaqueous layer of the tear film a hypothesis on the consequences of this gradient on the rheological properties of the tear film is provided. The mucoadhesive properties of HA and their dependence on chain length are explained. The ability of HA to bind to receptors on the ocular epithelial cells, and in particular the potential consequences of the interaction between HA and the receptor HARE, responsible for HA endocytosis by corneal epithelial cells is discussed. The physiological function of HA in the framework of ocular surface homeostasis and wound healing are outlined, and the influence of the chain length of HA on the clinical performance of HA eye drops is illustrated. The use of very high molecular weight HA (hylan A) eye drops as drug vehicle for the next generation of ophthalmic drugs with minimized side effects is proposed and its advantages elucidated. Consequences of the diagnosis and treatment of ocular surface disease are discussed.

Gene therapy in the anterior eye segment

2021 ◽  
Vol 21 ◽  
Author(s):  
Cynthia Amador ◽  
Ruchi Shah ◽  
Sean Ghiam ◽  
Andrei A. Kramerov ◽  
Alexander V. Ljubimov
Keyword(s):  
Gene Therapy ◽  
Ocular Surface ◽  
Viral Vectors ◽  
Anterior Segment ◽  
Corneal Neovascularization ◽  
Corneal Epithelial ◽  
Comprehensive Information ◽  
Epithelial Wound Healing ◽  
Anterior Eye Segment

: This review provides comprehensive information about the advances in gene therapy in the anterior segment of the eye including cornea, conjunctiva, lacrimal gland, and trabecular meshwork. We discuss gene delivery systems including viral and non-viral vectors as well as gene editing techniques, mainly CRISPR-Cas9, and epigenetic treatments including antisense and siRNA therapeutics. We also provide a detailed analysis of various anterior segment diseases where gene therapy has been tested with corresponding outcomes. Disease conditions include corneal and conjunctival fibrosis and scarring, corneal epithelial wound healing, corneal graft survival, corneal neovascularization, genetic corneal dystrophies, herpetic keratitis, glaucoma, dry eye disease, and other ocular surface diseases. Although most of the analyzed results on the use and validity of gene therapy at the ocular surface have been obtained in vitro or using animal models, we also discuss the available human studies. Gene therapy approaches are currently considered very promising as emerging future treatments of various diseases, and this field is rapidly expanding.

scholarly journals The Effect of Rebamipide on Ocular Surface Disorders Induced by Latanoprost and Timolol in Glaucoma Patients

2015 ◽  
Vol 2015 ◽  
pp. 1-5 ◽  
Author(s):  
Naoto Tokuda ◽  
Yasushi Kitaoka ◽  
Akiko Matsuzawa ◽  
Junsuke Miyamoto ◽  
Shinsuke Sakae ◽  
...  
Keyword(s):  
Intraocular Pressure ◽  
Ocular Surface ◽  
Barrier Function ◽  
Epithelial Barrier ◽  
Control Group ◽  
Eye Drops ◽  
Drug Induced ◽  
Epithelial Barrier Function ◽  
Corneal Epithelial ◽  
Significant Difference

Purpose. To examine the efficacy of ophthalmic rebamipide suspensions on ocular surface disorders induced by antiglaucoma eye drops.Patients and Methods. Forty eyes of 40 patients receiving latanoprost (0.005%) and timolol (0.5%) were included in this randomized prospective study. The patients were randomly divided into two groups (n= 20): the rebamipide-treated group and control group. Changes in intraocular pressure, tear film break-up time (TBUT), and corneal epithelial barrier function were evaluated at baseline, 4 weeks, and 8 weeks after rebamipide administration. Furthermore, superficial punctate keratopathy severity was evaluated by scoring the lesion area and density.Results. There was no significant difference in intraocular pressure before and after rebamipide treatment. However, corneal epithelial barrier function improved significantly 4 and 8 weeks after rebamipide treatment. TBUT was partially, but significantly, increased (P= 0.02) 8 weeks after rebamipide treatment, whereas no significant change was observed at 4 weeks. Additionally, a significant decrease in area and density of keratopathy was observed 8 weeks after rebamipide treatment but not at 4 weeks. The control group showed no significant difference compared to baseline.Conclusions. Our data suggests that rebamipide treatment may reduce the occurrence of drug-induced ocular surface disorder.

scholarly journals β-blocker eye drops affect ocular surface through β2 adrenoceptor of corneal limbal stem cells

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xingyue Yuan ◽  
Xiubin Ma ◽  
Lingling Yang ◽  
Qingjun Zhou ◽  
Ya Li
Keyword(s):  
Wound Healing ◽  
Ocular Surface ◽  
Eye Drops ◽  
Limbal Stem Cells ◽  
Corneal Wound Healing ◽  
Corneal Epithelial ◽  
Epithelial Wound Healing ◽  
Corneal Wound ◽  
Specific Antagonist ◽  
Β Blocker

Abstract Background Topical application of β-blocker eye drops induces damage to the ocular surface in clinical. However, the mechanism involved remains incompletely understood. The purpose of this study was to investigate the influence and mechanism of β-blocker eye drops on corneal epithelial wound healing. Methods Corneal epithelial wound healing models were constructed by epithelial scraping including in the limbal region and unceasingly received eye drops containing 5 mg/mL β-blocker levobunolol, β1-adrenoceptor (β1AR)-specific antagonist atenolol or β2-adrenoceptor (β2AR)-specific antagonist ICI 118, 551. For the migration assay, the murine corneal epithelial stem/progenitor cells (TKE2) were wounded and subsequently incubated with levobunolol, atenolol, or ICI 118, 551. The proliferation and colony formation abilities of TKE2 cells treated with levobunolol, atenolol, or ICI 118, 551 were investigated by CCK-8 kit and crystal violet staining. The differentiation marker Cytokeratin 3 (CK3), the stem cell markers-Cytokeratin 14 (CK14) and Cytokeratin 19 (CK19), and corneal epithelium regeneration-related signaling including in Ki67 and the phosphorylated epithelial growth factor receptor (pEGFR) and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) were assessed by immunofluorescence staining. Results Levobunolol and ICI 118, 551 impaired corneal wound healing, decreased the expressions of CK3, CK14, and CK19 after limbal region scraping in vivo and reduced the migration and proliferation of TKE2 in vitro, whereas atenolol had no significant effect. Moreover, levobunolol and ICI 118, 551 inhibited corneal wound healing by mediating the expression of Ki67, and the phosphorylation of EGFR and ERK1/2 in the limbal and regenerated corneal epithelium. Conclusion β-blocker eye drops impaired corneal wound healing by inhibiting the β2AR of limbal stem cells, which decreased corneal epithelial regeneration-related signaling. Therefore, a selective β1AR antagonist might be a good choice for glaucoma treatment to avoid ocular surface damage.

Comparison of Ocular Surface Cytological Appearance in Glaucoma Patient Treated with Timolol Maleat 0,5% Latanoprost 0,005% and Timolol-Latanoprost Fixed Combination Preservative Free Eye Drop

2019 ◽  
Vol 44 (2) ◽  
pp. 82
Author(s):  
Maretha Amrayni ◽  
Elsa Gustianty ◽  
Susi Heryati ◽  
Andika Prahasta ◽  
Maula Rifada ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cell Density ◽  
Goblet Cell ◽  
Ocular Surface ◽  
Fixed Combination ◽  
Cell Contact ◽  
Corneal Epithelial ◽  
Preservative Free ◽  
Goblet Cell Density ◽  
Epithelial Metaplasia

Introduction : The longterm use of topical antiglaucoma might cause ocular surface instability due to active substance or preservative used. Impression cytology examination may reveal superficial epithelial cells on conjunctiva and cornea, including goblet cells. Goblet cell density decrease is the most important parameter on evaluation of ocular surface disorder. Objective : This study was to understand ocular surface remodeling due to active substance of topical antiglaucoma with impression cytology examination among the patient prior and 3 months after therapy. Methods : This was a randomized controlled trial study with single blind masking. A total of 45 eyes from 31 patients were used as subject and distributed onto three groups treatment, which were timolol maleat 0.5%, latanoprost 0.005%, and latanoprost-timolol maleat fixed combination. All topical antiglaucoma in this study were preservative free. Result : There were differences between 3 groups in goblet cells density after 3 months therapy (p=0,030). Goblet cell density in timolol group was lower than latanoprost (p=0,041) and fixed combination (p=0,045). There was no significantly difference between 3 groups in conjunctival epithelial metaplasia degree (p=0,706) and cell to cell contact degree in corneal epithelial cells (p=0.66) after 3 months therapy. Conjunctival epithelial metaplasia degree were increased among group of timolol (p=0,008) and fixed combination (p=0,046). Conclusion : Timolol maleat 0,5% caused lower goblet cell density after 3 months therapy compare with latanoprost and fixed combination. There was no significantly difference in conjunctival epithelial metaplasia and cell to cell contact degree in corneal epithelial cells among these glaucoma treatment groups.

scholarly journals The role of KPI-121 0.25% in the treatment of dry eye disease: penetrating the mucus barrier to treat periodic flares

2021 ◽  
Vol 13 ◽  
pp. 251584142110127
Author(s):  
Preeya K. Gupta ◽  
Nandini Venkateswaran
Keyword(s):  
Drug Delivery ◽  
Dry Eye ◽  
Ocular Surface ◽  
Dry Eye Disease ◽  
Eye Disease ◽  
Eye Drops ◽  
Short Term ◽  
Short Term Treatment ◽  
Loteprednol Etabonate ◽  
Mucus Barrier

The tear film, which includes mucins that adhere to foreign particles, rapidly clears allergens and pathogens from the ocular surface, protecting the underlying tissues. However, the tear film’s ability to efficiently remove foreign particles during blinking can also pose challenges for topical drug delivery, as traditional eye drops (solutions and suspensions) are cleared from the ocular surface before the drug can penetrate into the conjunctival and corneal epithelium. In the past 15 years, there has been an increase in the development of nanoparticles with specialized coatings that have reduced affinity to mucins and are small enough in size to pass through the mucus barrier. These mucus-penetrating particles (MPPs) have been shown to efficiently penetrate the mucus barrier and reach the ocular surface tissues. Dry eye disease (DED) is a common inflammatory ocular surface disorder that often presents with periodic flares (exacerbations). However, currently approved immunomodulatory treatments for DED are intended for long-term use. Thus, there is a need for effective short-term treatments that can address intermittent flares of DED. Loteprednol etabonate, an ocular corticosteroid, was engineered to break down rapidly after administration to the ocular surface tissues and thereby reduce risks associated with other topical steroids. KPI-121 is an ophthalmic suspension that uses the MPP technology to deliver loteprednol etabonate more efficiently to the ocular tissues, achieving in animal models a 3.6-fold greater penetration of loteprednol etabonate to the cornea than traditional loteprednol etabonate ophthalmic suspensions. In clinical trials, short-term treatment with KPI-121 0.25% significantly reduced signs and symptoms of DED compared with its vehicle (placebo). Recently approved KPI-121 0.25%, with its novel drug delivery design and ease of use, has the potential to effectively treat periodic flares of DED experienced by many patients.

scholarly journals Effectiveness of 0.66% Povidone-Iodine Eye Drops on Ocular Surface Flora before Cataract Surgery: A Nationwide Microbiological Study

2021 ◽  
Vol 10 (10) ◽  
pp. 2198
Author(s):  
Rosario Musumeci ◽  
Pasquale Troiano ◽  
Marianna Martinelli ◽  
Matteo Piovella ◽  
Claudio Carbonara ◽  
...  
Keyword(s):  
Cataract Surgery ◽  
Ocular Surface ◽  
Povidone Iodine ◽  
Bacterial Species ◽  
Bacterial Flora ◽  
Bacterial Load ◽  
Controlled Study ◽  
Eye Drops ◽  
Microbiological Analysis ◽  
Contralateral Eye

A multicenter, nonrandomized, prospective, controlled study was conducted to evaluate, as perioperative prophylactic treatment, the anti-infective effectiveness of 0.66% povidone-iodine eye drops (IODIM®) against the bacterial flora of the conjunctival surface of patients who undergo cataract surgery. Eye drops containing 0.66% povidone-iodine were applied to the eye undergoing cataract surgery; the untreated contralateral eye was used as control. One hundred and twenty patients set to receive unilateral cataract surgery were enrolled in 5 Italian Ophthalmology Centers and pretreated for three days with 0.66% povidone-iodine eye drops. The contralateral eye, used as control, was left untreated. Conjunctival swabs of both eyes were collected at the baseline visit and after three days of treatment, just before the cataract surgery. A qualitative and quantitative microbiological analysis of bacterial presence was evaluated by means of bacterial culture, followed by identification. Methicillin resistance determination was also performed on staphylococci isolates. Bacterial load before and after treatment of the eye candidate for cataract surgery was evaluated and compared to the untreated eye. A reduction or no regrowth on the culture media of the bacterial load was observed in 100% of the study subjects. A great heterogenicity of bacterial species was found. The 0.66% povidone-iodine eye drops, used for three days prior to cataract surgery, were effective in reducing the conjunctival bacterial load. The 0.66% povidone-iodine eye drops (IODIM®) might represent a valid perioperative prophylactic antiseptic adjuvant treatment to protect the ocular surface from microbial contamination in preparation of the surgical procedure.

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