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AbstractPurposeMethodsResultsConclusionBufalin (BU) is a bioactive ingredient extracted from the skin and parotid venom glands of Bufo raddei, which can effectively inhibit angiogenesis. The aim of this study was to investigate whether BU could affect corneal neovascularization (CoNV).A rat CoNV model (right eye) was constructed by administration of NaOH, and the left eye served as a control. Corneal damage scores of rats were detected. Hematoxylin & eosin, TUNEL, and Masson staining examined pathological changes, apoptosis, and fibrosis of corneal tissues. Immunohistochemistry and western blotting assessed the expression of proteins.BU intervention resulted in a significant reduction in corneal inflammatory cells, repair of corneal epithelial hyperplasia, significant reduction in stromal edema, and reduction in vascular proliferation. BU can inhibit corneal neovascularization.This study demonstrated that BU inhibits CoNV, fibrosis, and inflammation by modulating the STAT3 signaling pathway, elucidating the intrinsic mechanism of its protective effect. BU has great potential in the treatment of CoNV caused by corneal alkali burns. [ABSTRACT FROM AUTHOR]

Corneal neovascularization (CNV) is a major cause of blindness worldwide. However, the recent drug treatment is limited by repeated administration and low drug bioavailability. In this work, SU6668 (an inhibitor of receptor tyrosine kinases) and indocyanine green (ICG) are loaded onto poly(lactic- co -glycolic acid) (PLGA) nanoparticles, and then coated with anti-VEGFR2 single chain antibody (AbVr2 scFv) genetically engineered cell membrane vesicles. The nanomedicine is delivered via eye drops, and the hyperthermia induced by laser irradiation could block the blood vessels. Meanwhile, the photothermal effect can also cause the degradation of nanomaterials and release chemotherapeutic drugs in the blocked area, thereby continuously inhibit the neovascularization. Furthermore, SU6668 could inhibit the expression of heat shock protein 70 (HSP70), promoting the cell death induced by photothermal effect. In conclusion, the combination of photothermal and chemotherapy drugs provides a novel, effective and safe approach for the treatment of CNV. [Display omitted] [ABSTRACT FROM AUTHOR]

Lymphangiogenesis plays a pivotal role in the pathogenesis of various vascular disorders, including ocular vascular diseases and cancers. Deregulation of N6‐methyladenosine (m6A) modification has been identified as a key contributor to human diseases. However, the specific involvement of m6A modification in lymphatic remodeling remains poorly understood. In this study, we demonstrate that inflammatory stimulation and corneal sutures induce elevated levels of methyltransferase‐like 3 (METTL3)‐mediated m6A modification. METTL3 knockdown inhibits lymphatic endothelial viability, proliferation, migration, and tube formation in vitro. METTL3 knockdown attenuates corneal sutures‐induced lymphangiogenesis and intratumoral lymphangiogenesis initiated by subcutaneous grafts, consequently restraining corneal neovascularization, tumor growth, and tumor neovascularization in vivo. Mechanistically, METTL3 knockdown upregulates prostaglandin–endoperoxide synthase 2 expression through an m6A–YTHDF2‐dependent pathway, enhancing the synthesis of cyclopentenone prostaglandins (CyPGs). Aberrant CyPG production in lymphatic endothelial cells impairs mitochondrial oxidative phosphorylation, contributing to pathological lymphangiogenesis. Moreover, selective inhibition of METTL3 with STM2457 reduces m6A levels in lymphatic endothelial cells, effectively suppressing pathological lymphangiogenesis. This study provides compelling evidence that lymphatic‐specific METTL3 plays a critical role in vascular patterning through prostaglandin metabolism reprogramming. Thus, METTL3 emerges as a promising target for treating lymphangiogenesis‐related diseases. [ABSTRACT FROM AUTHOR]

Purpose: to evaluate in experiment the dynamics and intensity of vascular sprouting in the donor cornea during keratoplasty against the background of pre-existing neoangiogenesis when using a conditioned medium of mesenchymal stem cells.Materials and methods. The object of the study was 15 rabbits (10 recipient rabbits, 5 donor rabbits) of the gray Chinchilla breed weighing 2.5–3.2 kg. The experiments were carried out in two stages. At the first stage, 10 animals were simulated with a unilateral thermal burn of the peripheral zone of the cornea with limbal involvement. Penetrating keratoplasty was performed using standard technology on the 15th day of the experiment. At the second stage, the recipient rabbits were divided into experimental and control groups. 5 rabbits, 5 eyes, in the control group and 5 rabbits, 5 eyes, in the main group. In the main group, instillations of paracrine factors of mesenchymal stem cells were used as postoperative treatment from the 1st to the 30th knocks four times. In the control group, treatment was carried out by instillation of antibiotics (Oftaquix) and keratoprotectors (Korneregel) three times for 30 days. Research methods included biomicroscopy, photographic recording of the anterior segment of the eye, examination using a Pentacam AXL device, and histological examination. The observation periods were 1st, 3rd, 7th, 14th, 30th day.Results. The results of postoperative treatment at the second stage of the experiment, as well as the results of histology, showed a pronounced antiangiogenic effect of the conditioned medium of mesenchymal stem cells. This was confirmed by the absence of pronounced vascularization of the donor cornea, the attenuation of the inflammatory reaction and the formation of a scar on the 30th day of drug instillation. In the control group, graft disease developed from the seventh day.Conclusion. The results obtained during the work seem promising. The use of the conditioned medium of mesenchymal stem cells demonstrated a sufficiently pronounced effectiveness compared with standard drug therapy in the postoperative period after high-risk end-to-end keratoplasty in experimental animals performed on a model of post-burn corneal neovascularization.

Abstract Background Warburg-Cinotti syndrome is a rare syndrome caused by de novo or inherited variants in discoding domain receptor tyrosine kinase 2 (DDR2). Only six cases have been reported worldwide and our knowledge of this disease remained sparse especially from an ophthalmological perspective, since previous literature mostly focused on systemic malformations or genetics. Case presentation A seven-year-old boy developed a gelatinous vascularized conjunctiva-like mass secondary to trauma. The mass enlarged and gradually invaded the cornea. With each surgical intervention, the mass recurred and grew even larger rapidly. The patient ended up with the mass covering the entire cornea along with symblepharon formation. Whole exome sequencing revealed a hemizygous variant in the DDR2 gene, which is consistent with Warburg-Cinotti syndrome. Conclusions Considering Warburg-Cinotti syndrome, we should be vigilant of patients exhibiting progressive conjunctival invasion of the cornea, even those without systemic manifestations or a positive family history.

Guojuan Pu,1,2 Zhen Liang,1,2 Jieran Shi,2 Yuan Tao,1,2 Ping Lu,1,2 Huiling Qing,1,2 Junjie Zhang1,2 1Henan Eye Hospital, Henan Eye Institute, Henan Provincial People’s Hospital, Zhengzhou, 450003, People’s Republic of China; 2People’s Hospital of Zhengzhou University, Zhengzhou, 450003, People’s Republic of ChinaCorrespondence: Junjie Zhang, Henan Eye Hospital, Henan Eye Institute, Henan Provincial People’s Hospital, and People’s Hospital of Zhengzhou University, Number 7 Weiwu Road, Zhengzhou, 450003, People’s Republic of China, Email zhangjunjie@zzu.edu.cnBackground: Corneal neovascularization (CNV) is a common eye disease that leads to blindness. New treatment strategies are urgently needed due to the limitations of current treatment methods.Methods: We report the synthesis of peptide Nap-FFEEPCAIWF (Comp.3) via chemical conjugation of Nap-FFEE (Comp.2) to antiangiogenic peptide PCAIWF (Comp.1). Comp.3 self-assembled into a hydrogel (gel of 3) composed of nanofibers, which enhanced the antiangiogenic function of the epitope.Results: We developed a novel peptide with an amphiphilic framework, Comp.3, which could self-assemble into a supramolecular hydrogel with a well-ordered nanofiber structure. The nanofibers exhibited good biocompatibility with corneal epithelial cells, presenting a promising strategy to enhance the efficacy of free peptide–based drugs in the treatment of ocular vascular diseases, such as CNV and other angiogenesis-related diseases.Conclusion: Nap-FFEEPCAIWF nanofibers provide an alternative approach to enhancing the therapeutic efficiency of free peptide–based drugs against ocular vascular diseases. Keywords: antiangiogenic peptide, self-assembled, hydrogel, nanofiber, corneal neovascularization

Abstract Sirolimus (SR) is a macrolide with antifungal and antitumor immunosuppressant properties, classified as a selective inhibitor of mammalian target of rapamycin (mTOR). In this study, an ionic in situ gel of SR (SR-SUS-ISG) was formulated using gellan gum, exhibiting stability regardless of temperature and pH variations, causing minimal irritation. Harnessing the physiological conditions of the eye, SR-SUS-ISG underwent gelation upon contact with ions, increasing drug viscosity and prolonging retention on the ocular surface. Concurrently, SR-SUS-ISG displayed favorable shear dilution properties, reducing viscosity at ambient temperature, enhancing fluidity, and facilitating convenient packaging and transport. Biocompatibility assessments on both human corneal epithelial cells and rabbit eyes demonstrated that SR-SUS-ISG could well be tolerated. Pharmacokinetic investigations in rabbit ocular aqueous humor revealed sustained release, improved corneal penetration, and enhanced bioavailability. Additionally, in a rat corneal alkali burn model, SR-SUS-ISG exhibited inhibitory effects on corneal neovascularization, associated with decreased levels of the inflammatory factors VEGF and MMPs. These findings suggested that SR-SUS-ISG held promise as an effective ocular drug delivery system. Graphical Abstract

Background: Corneal neovascularization (CNV) is a sight-threatening condition that necessitates epigenetic control. The role of lysine-specific demethylase 1 (LSD1) in CNV remains unclear, despite its established significance in tumor angiogenesis regulation. Methods: An alkali burn-induced CNV mouse model was used in vivo. The effects of LSD1 inhibitor tranylcypromine hydrochloride (TCP) were examined through slit lamp, histological staining, and immunofluorescence. The expression of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) levels were assessed in corneal tissues. Oxidative stress and ferrous ion expression during CNV were determined using 4-HNE, GPX4, and FerroOrange staining. In vitro, a hypoxia-reoxygenation (H/R) model was established using human umbilical vein endothelial cells (HUVECs) to study LSD1 or hypoxia-inducible factor (HIF-1α) knockdown and lentiviral overexpression of HIF-1α. The effects on HUVECs migration, invasion, and angiogenesis were evaluated through cell scratching assay, transwell migration assay and tube formation assay. The role of ferroptosis was investigated using ROS staining, FerroOrange staining, and key ferroptosis proteins. Further, The JAK2/STAT3 pathway's involvement in CNV regulation was explored through in vivo experiments with subconjunctival injection of AG490. Results: The results showed a substantial correlation between corneal damage and LSD1 levels. In addition, HIF-1α expression was also elevated after alkali burns, and subconjunctival injection of TCP reduced corneal inflammation and neovascularization. Corneal alkali burns increased ROS levels and reduced antioxidative stress indicators, accompanied by elevated ferrous ion levels, which were reversed by TCP injection. In vitro, TCP or siRNAs inhibited H/R-induced ferroptosis and angiogenesis in HUVECs by affecting specific protein expressions and MDA, SOD, and GSH levels. HIF-1α levels, associated with ROS production, ferroptosis, and angiogenesis, increased during H/R, but were reversed by TCP or siRNA administration. HIF-1α overexpression counteracted the effects of LSD1 inhibition. Additionally, AG490 injection effectively reduced HIF-1α and VEGFA expression in the CNV model. Discussion: These findings suggest that LSD1 inhibition via the HIF-1α-driven pathway prevents angiogenesis, oxidative stress, and ferroptosis in corneal alkali burn-induced CNV, highlighting LSD1 as a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Dexamethasone (DEX) has been demonstrated to inhibit the inflammatory corneal neovascularization (CNV). However, the therapeutic efficacy of DEX is limited by the poor bioavailability of conventional eye drops and the increased risk of hormonal glaucoma and cataract associated with prolonged and frequent usage. To address these limitations, we have developed a novel DEX-loaded, reactive oxygen species (ROS)-responsive, controlled-release nanogel, termed DEX@INHANGs. This advanced nanogel system is constructed by the formation of supramolecular host-guest complexes by cyclodextrin (CD) and adamantane (ADA) as a cross-linking force. The introduction of the ROS-responsive material, thioketal (TK), ensures the controlled release of DEX in response to oxidative stress, a characteristic of CNV. Furthermore, the nanogel's prolonged retention on the corneal surface for over 8 h is achieved through covalent binding of the integrin β1 fusion protein, which enhances its bioavailability. Cytotoxicity assays demonstrated that DEX@INHANGs was not notably toxic to human corneal epithelial cells (HCECs). Furthermore, DEX@INHANGs has been demonstrated to effectively inhibit angiogenesis in vitro. In a rabbit model with chemically burned eyes, the once-daily topical application of DEX@INHANGs was observed to effectively suppress CNV. These results collectively indicate that the nanomedicine formulation of DEX@INHANGs may offer a promising treatment option for CNV, offering significant advantages such as reduced dosing frequency and enhanced patient compliance. [Display omitted] • The nanogel achieves stable adhesion to the cornea for >8 h by binding to the integrin β1 fusion protein. • Once-daily topical application of DEX@INHANGs effectively inhibited CNV in a rabbit model with chemically burned eyes. • The nanomedicine formulation of DEX@INHANGs holds promise as a potential treatment option for CNV. [ABSTRACT FROM AUTHOR]

Background: Warburg-Cinotti syndrome is a rare syndrome caused by de novo or inherited variants in discoding domain receptor tyrosine kinase 2 (DDR2). Only six cases have been reported worldwide and our knowledge of this disease remained sparse especially from an ophthalmological perspective, since previous literature mostly focused on systemic malformations or genetics. Case presentation: A seven-year-old boy developed a gelatinous vascularized conjunctiva-like mass secondary to trauma. The mass enlarged and gradually invaded the cornea. With each surgical intervention, the mass recurred and grew even larger rapidly. The patient ended up with the mass covering the entire cornea along with symblepharon formation. Whole exome sequencing revealed a hemizygous variant in the DDR2 gene, which is consistent with Warburg-Cinotti syndrome. Conclusions: Considering Warburg-Cinotti syndrome, we should be vigilant of patients exhibiting progressive conjunctival invasion of the cornea, even those without systemic manifestations or a positive family history. [ABSTRACT FROM AUTHOR]

Objective: Unusual or unexpected effect of treatment Background: Acute corneal hydrops, a rare complication of keratoconus, is characterized by sudden onset of corneal stroma edema. It typically manifests as an acute decrease in visual acuity, accompanied by pain and photophobia. Prompt recognition and interventions are critical for effective resolution of hydrops and prevention of corneal vascularization. Herein, we present a case of a patient with keratoconus who developed corneal hydrops, successfully managed using full-thickness compression sutures and intracameral air injection. Case Report: A woman in her early 30s, with a history of keratoconus, presented with symptoms of acute hydrops in her left eye. On presentation, best corrected visual acuity was hand motion. Slit-lamp examination revealed marked corneal edema with multiple stromal clefts. The decision was made to perform full-thickness compression sutures combined with intracameral air injection to expedite edema resolution and prevent neovascularization. Three full-thickness sutures were placed across Descemet membrane breaks, and an air bubble was left, filling 50% of the anterior chamber. At 3-month follow-up, a clear, compact cornea was noted, with no evidence of vascularization. The patient was scheduled for penetrating keratoplasty for visual rehabilitation. Conclusions: The combination of full-thickness compression sutures and intracameral air seems to be an effective and safe method for preventing corneal angiogenesis following hydrops. As corneal scaring is often an inevitable complication of acute corneal hydrops, keratoplasty is necessary for improving visual acuity. Hence, the prevention of corneal vascularization should be the major aim in the management of corneal hydrops to ensure successful keratoplasty. [ABSTRACT FROM AUTHOR]

Sirolimus (SR) is a macrolide with antifungal and antitumor immunosuppressant properties, classified as a selective inhibitor of mammalian target of rapamycin (mTOR). In this study, an ionic in situ gel of SR (SR-SUS-ISG) was formulated using gellan gum, exhibiting stability regardless of temperature and pH variations, causing minimal irritation. Harnessing the physiological conditions of the eye, SR-SUS-ISG underwent gelation upon contact with ions, increasing drug viscosity and prolonging retention on the ocular surface. Concurrently, SR-SUS-ISG displayed favorable shear dilution properties, reducing viscosity at ambient temperature, enhancing fluidity, and facilitating convenient packaging and transport. Biocompatibility assessments on both human corneal epithelial cells and rabbit eyes demonstrated that SR-SUS-ISG could well be tolerated. Pharmacokinetic investigations in rabbit ocular aqueous humor revealed sustained release, improved corneal penetration, and enhanced bioavailability. Additionally, in a rat corneal alkali burn model, SR-SUS-ISG exhibited inhibitory effects on corneal neovascularization, associated with decreased levels of the inflammatory factors VEGF and MMPs. These findings suggested that SR-SUS-ISG held promise as an effective ocular drug delivery system. [ABSTRACT FROM AUTHOR]

Corneal neovascularization is a significant cause of vision loss, often resulting in corneal clouding and chronic inflammation. Shark cartilage is widely recognized as a significant natural source of anti-angiogenic compounds. Our previous studies have shown that a polypeptide from white-spotted catshark (Chiloscyllium plagiosum Bonnet) has the potential to inhibit the angiogenesis of breast tumors. This study applied this peptide (SAIF) to a corneal alkali injury model to assess its effect on corneal neovascularization. Results revealed that SAIF inhibits endothelial cell proliferation, migration, and tube formation. SAIF inhibited VEGF-induced angiogenesis in the matrigel plug. Using the corneal alkali injury model, SAIF significantly inhibited corneal vascular neovascularization in mice. We found that SAIF not only significantly inhibited the upregulation of pro-angiogenic factors such as VEGF, bFGF, and PDGF expression induced by alkali injury, but also promoted the expression of anti-angiogenesis factor PEDF. Moreover, we also analyzed the MMPs and TIMPs involved in extracellular matrix (ECM) remodeling, angiogenesis, and lymphangiogenesis. We found that SAIF treatment inhibited the expression of pro-angiogenic factors like MMP1, MMP2, MMP3, MMP9, MMP13, and MMP14, and promoted the expression of anti-angiogenesis factors such as MMP7, TIMP1, TIMP2, and TIMP3. In conclusion, SAIF acts as an anti-angiogenic factor to inhibit the proliferation, migration, and tube formation of endothelial cells, inhibit pro-angiogenic factors, promote anti-angiogenic factors, and regulate the expression of MMPs, ultimately inhibiting corneal neovascularization. [ABSTRACT FROM AUTHOR]

Purpose: To study the demographic, clinical, and microbiological profile of Demodex‑related blepharokeratoconjunctivitis (BKC) at a tertiary eye care hospital. Methods: This retrospective observational study was conducted from January 2016 to September 2022. It included 83 patients with microbiologically proven Demodex BKC who presented to the cornea department of our tertiary care eye center. The clinical, microbiological, and demographic data of the 83 cases were analyzed. Results: Of the 83 cases, 57 (68.67%) were younger than 40 years, and 25 (30.12%) were below 20. Most patients presented with a good visual acuity of 20/40 or better (93 eyes; 84.55%). The disease was unilateral in 55 patients and bilateral in 28. Cylindrical dandruff was the predominant presentation noted in 61 eyes (54.95%), followed by corneal scarring in 47 eyes (42.34%) and corneal vascularization in 40 eyes (36.04%). On light microscopy, 87.95% of the positive samples were identified as Demodex folliculorum, 7.23% as Demodex brevis, and 6.02% remained unidentified. Tea tree oil and lid scrubs eradicated the disease in most patients clinically (75/83, 90.36%). Conclusion: The spectrum of BKC includes both lid signs and corneal involvement. It can be a cause of recurrent BKC and detection of the mite by microscopic evaluation of the lashes can confirm the diagnosis. In most cases, the tea tree oil can effectively manage this condition. However, low doses of topical steroids are needed to control the inflammation in patients with corneal involvement. [ABSTRACT FROM AUTHOR]

PurposeMethodsResultsConclusionTo report two cases of bilateral blepharokeratoconjunctivitis associated with hidradenitis suppurativa (HS).Case report and literature review. The clinical courses of two patients with HS, including ocular presentation and medical management, are described.Two female patients aged 18 and 23-years-old with severe HS presented with bilateral blepharokeratoconjunctivitis. Shared slit lamp findings included bilateral corneal neovascularization and inferior corneal thinning. Systemic immunosuppression was needed in the first case, which resulted in improvement in the patient’s ophthalmic and dermatological findings.We report two cases of bilateral blepharokeratoconjunctivitis in two patients with severe HS. To our knowledge, this association has not previously been described in the literature. Clinicians should be aware of this association given its potentially visually devastating manifestations and the need for early therapeutic interventions. [ABSTRACT FROM AUTHOR]

Background/Objectives: Aniridia-associated keratopathy (AAK) is a potentially vision-threatening pathology in congenital aniridia, for which both the underlying etiopathogenesis and effective treatment remain unclear. Methods:This prospective study was conducted to assess and compare the short-term outcome after superficial keratectomy (SK) alone or in a combination with an amniotic membrane transplantation (AMT). Here, 76 eyes were enrolled in 76 patients with grade 4 AAK. In all eyes, in order to assess preoperatively the efficiency of the limbal epithelial stem cells (LESC), the presence of corneal epithelial cells in confocal microscopy was established. The analyses included: best corrected visual acuity (BCVA), the stage of AAK and the number of corneal quadrants involved in corneal neovascularization (CNV). Results: Six months after surgery, the mean BCVA was 0.05 and ranged from 0.002 up to 0.1 in both groups. Improvement in BCVA occurred in 94.29% patients when *SK alone* was performed, and in 92.68% when in combination with AMT. There were no statistically significant differences in the effect of therapy depending on the type of surgery, regarding BCVA, stage of AAK and the number of quadrants with CNV. Conclusions: SK alone is an effective procedure in short outcomes limited to six months for advanced AAK in association with LESC partial efficiency. [ABSTRACT FROM AUTHOR]

Abstract Lymphangiogenesis plays a pivotal role in the pathogenesis of various vascular disorders, including ocular vascular diseases and cancers. Deregulation of N6‐methyladenosine (m6A) modification has been identified as a key contributor to human diseases. However, the specific involvement of m6A modification in lymphatic remodeling remains poorly understood. In this study, we demonstrate that inflammatory stimulation and corneal sutures induce elevated levels of methyltransferase‐like 3 (METTL3)‐mediated m6A modification. METTL3 knockdown inhibits lymphatic endothelial viability, proliferation, migration, and tube formation in vitro. METTL3 knockdown attenuates corneal sutures‐induced lymphangiogenesis and intratumoral lymphangiogenesis initiated by subcutaneous grafts, consequently restraining corneal neovascularization, tumor growth, and tumor neovascularization in vivo. Mechanistically, METTL3 knockdown upregulates prostaglandin–endoperoxide synthase 2 expression through an m6A–YTHDF2‐dependent pathway, enhancing the synthesis of cyclopentenone prostaglandins (CyPGs). Aberrant CyPG production in lymphatic endothelial cells impairs mitochondrial oxidative phosphorylation, contributing to pathological lymphangiogenesis. Moreover, selective inhibition of METTL3 with STM2457 reduces m6A levels in lymphatic endothelial cells, effectively suppressing pathological lymphangiogenesis. This study provides compelling evidence that lymphatic‐specific METTL3 plays a critical role in vascular patterning through prostaglandin metabolism reprogramming. Thus, METTL3 emerges as a promising target for treating lymphangiogenesis‐related diseases.

Abstract Corneal neovascularization (CNV) is one of the common blinding factors worldwide, leading to reduced vision or even blindness. However, current treatments such as surgical intervention and anti-VEGF agent therapy still have some shortcomings or evoke some adverse effects. Recently, SU6668, an inhibitor targeting angiogenic tyrosine kinases, has demonstrated growth inhibition of neovascularization. But the hydrophobicity and low ocular bioavailability limit its application in cornea. Hereby, we proposed the preparation of SU6668 pure nanoparticles (NanoSU6668; size ~135 nm) using a super-stable pure-nanomedicine formulation technology (SPFT), which possessed uniform particle size and excellent aqueous dispersion at 1 mg/mL. Furthermore, mesenchymal stem cell membrane vesicle (MSCm) was coated on the surface of NanoSU6668, and then conjugated with TAT cell penetrating peptide, preparing multifunctional TAT-MSCm@NanoSU6668 (T-MNS). The T-MNS at a concentration of 200 µg/mL was treated for CNV via eye drops, and accumulated in blood vessels with a high targeting performance, resulting in elimination of blood vessels and recovery of cornea transparency after 4 days of treatment. Meanwhile, drug safety test confirmed that T-MNS did not cause any damage to cornea, retina and other eye tissues. In conclusion, the T-MNS eye drop had the potential to treat CNV effectively and safely in a low dosing frequency, which broke new ground for CNV theranostics.

Purpose: To study the demographic, clinical, and microbiological profile of Demodex-related blepharokeratoconjunctivitis (BKC) at a tertiary eye care hospital. Methods: This retrospective observational study was conducted from January 2016 to September 2022. It included 83 patients with microbiologically proven Demodex BKC who presented to the cornea department of our tertiary care eye center. The clinical, microbiological, and demographic data of the 83 cases were analyzed. Results: Of the 83 cases, 57 (68.67%) were younger than 40 years, and 25 (30.12%) were below 20. Most patients presented with a good visual acuity of 20/40 or better (93 eyes; 84.55%). The disease was unilateral in 55 patients and bilateral in 28. Cylindrical dandruff was the predominant presentation noted in 61 eyes (54.95%), followed by corneal scarring in 47 eyes (42.34%) and corneal vascularization in 40 eyes (36.04%). On light microscopy, 87.95% of the positive samples were identified as Demodex folliculorum, 7.23% as Demodex brevis, and 6.02% remained unidentified. Tea tree oil and lid scrubs eradicated the disease in most patients clinically (75/83, 90.36%). Conclusion: The spectrum of BKC includes both lid signs and corneal involvement. It can be a cause of recurrent BKC and detection of the mite by microscopic evaluation of the lashes can confirm the diagnosis. In most cases, the tea tree oil can effectively manage this condition. However, low doses of topical steroids are needed to control the inflammation in patients with corneal involvement.

Abstract Background Corneal neovascularization (CoNV) threatens vision by disrupting corneal avascularity, however, current treatments, including pharmacotherapy and surgery, are hindered by limitations in efficacy and adverse effects. Minocycline, known for its anti-inflammatory properties, could suppress CoNV but faces challenges in effective delivery due to the cornea's unique structure. Therefore, in this study a novel drug delivery system using minocycline-loaded nano-hydroxyapatite/poly (lactic-co-glycolic acid) (nHAP/PLGA) nanoparticles was developed to improve treatment outcomes for CoNV. Results Ultra-small nHAP was synthesized using high gravity technology, then encapsulated in PLGA by a double emulsion method to form nHAP/PLGA microspheres, attenuating the acidic by-products of PLGA degradation. The MINO@PLGA nanocomplex, featuring sustained release and permeation properties, demonstrated an efficient delivery system for minocycline that significantly inhibited the CoNV area in an alkali-burn model without exhibiting apparent cytotoxicity. On day 14, the in vivo microscope examination and ex vivo CD31 staining corroborated the inhibition of neovascularization, with the significantly smaller CoNV area (29.40% ± 6.55%) in the MINO@PLGA Tid group (three times daily) than that of the control group (86.81% ± 15.71%), the MINO group (72.42% ± 30.15%), and the PLGA group (86.87% ± 14.94%) (p

Corneal neovascularization (CoNV) is a sight-threatening condition affecting an estimated 1.4 million people per year, and the incidence is expected to rise. It is a complication of corneal pathological diseases such as infective keratitis, chemical burn, corneal limbal stem cell deficiency, mechanical trauma, and immunological rejection after keratoplasties. CoNV occurs due to a disequilibrium in proangiogenic and antiangiogenic mediators, involving a complex system of molecular interactions. Treatment of CoNV is challenging, and no therapy thus far has been curative. Anti-inflammatory agents such as corticosteroids are the mainstay of treatment due to their accessibility and well-studied safety profile. However, they have limited effectiveness and are unable to regress more mature neovascularization. With the advent of advanced imaging modalities and an expanding understanding of its pathogenesis, contemporary treatments targeting a wide array of molecular mechanisms and surgical options are gaining traction. This review aims to summarize evidence regarding conventional and emerging therapeutic options for CoNV. [ABSTRACT FROM AUTHOR]

To determine the safety and feasibility of human autologous adipose tissue-derived adult mesenchymal stem cells (ASCs) for ocular surface regeneration in patients with bilateral limbal stem-cell deficiency (LSCD). A phase IIa clinical trial was designed (, NCT01808378) with 8 patients, 3 of whom had aniridia, 2 meibomian glands diseases, 2 multiple surgeries and 1 chronic chemical injury. The therapeutic protocol was as follows: 6-mm of central corneal epithelium was removed, 400,000 ASCs were injected into each limboconjunctival quadrant, 400,000 ASCs were suspended over the cornea for 20 min, and finally the cornea was covered with an amniotic membrane patch. No adverse events were detected after a mean of 86,5 months of follow-up. One year after surgery, 6 of the 8 transplants were scored as successful, five patients had improved uncorrected visual acuity (mean of 12 letters), two patients presented epithelial defects (also present at baseline) and the mean percentage of corneal neovascularization was of 28.75% (36.98%, at baseline). Re-examination 24 months after treatment disclosed preserved efficacy in 4 patients. At the last visit (after a mean of 86,5 months of follow up) epithelial defects were absent in all patients although improvement in all of the variables was only maintained in patient 3 (meibomian glands agenesia). ASCs are a feasible and conservative therapy for treating bilateral LSCD. The therapeutic effect differs between etiologies and diminishes over time. [ABSTRACT FROM AUTHOR]

Background: Corneal neovascularization (CoNV) threatens vision by disrupting corneal avascularity, however, current treatments, including pharmacotherapy and surgery, are hindered by limitations in efficacy and adverse effects. Minocycline, known for its anti-inflammatory properties, could suppress CoNV but faces challenges in effective delivery due to the cornea's unique structure. Therefore, in this study a novel drug delivery system using minocycline-loaded nano-hydroxyapatite/poly (lactic-co-glycolic acid) (nHAP/PLGA) nanoparticles was developed to improve treatment outcomes for CoNV. Results: Ultra-small nHAP was synthesized using high gravity technology, then encapsulated in PLGA by a double emulsion method to form nHAP/PLGA microspheres, attenuating the acidic by-products of PLGA degradation. The MINO@PLGA nanocomplex, featuring sustained release and permeation properties, demonstrated an efficient delivery system for minocycline that significantly inhibited the CoNV area in an alkali-burn model without exhibiting apparent cytotoxicity. On day 14, the in vivo microscope examination and ex vivo CD31 staining corroborated the inhibition of neovascularization, with the significantly smaller CoNV area (29.40% ± 6.55%) in the MINO@PLGA Tid group (three times daily) than that of the control group (86.81% ± 15.71%), the MINO group (72.42% ± 30.15%), and the PLGA group (86.87% ± 14.94%) (p < 0.05). Fluorescein sodium staining show MINO@PLGA treatments, administered once daily (Qd) and three times daily (Tid) demonstrated rapid corneal epithelial healing while the Alkali injury group and the DEX group showed longer healing times (p < 0.05). Additionally, compared to the control group, treatments with dexamethasone, MINO, and MINO@PLGA were associated with an increased expression of TGF-β as evidenced by immunofluorescence, while the levels of pro-inflammatory cytokines IL-1β and TNF-α demonstrated a significant decrease following alkali burn. Safety evaluations, including assessments of renal and hepatic biomarkers, along with H&E staining of major organs, revealed no significant cytotoxicity of the MINO@PLGA nanocomplex in vivo. Conclusions: The novel MINO@PLGA nanocomplex, comprising minocycline-loaded nHAP/PLGA microspheres, has shown a substantial capacity for preventing CoNV. This study confirms the complex's ability to downregulate inflammatory pathways, significantly reducing CoNV with minimal cytotoxicity and high biosafety in vivo. Given these findings, MINO@PLGA stands as a highly promising candidate for ocular conditions characterized by CoNV. [ABSTRACT FROM AUTHOR]

Summary: Background: Corneal neovascularization (CNV) is a vision-threatening disease and an increasing public health concern. It was found that administering an Akt inhibitor in the second phase of retinopathy significantly decreased retinal neovascularization. Methods: This study investigated the effect of an Akt inhibitor on the angiogenesis of human umbilical vein endothelial cells (HUVECs) and its impacts on the degree of CNV and corneal opacity in a rat keratoplasty model. Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2′-deoxyuridine (EdU) assays, tube formation assays, cell scratch experiments, and a fully allogeneic corneal transplant model were performed. Results: It was found that an Akt inhibitor inhibited the proliferation, angiogenesis, and migration of HUVECs induced by vascular endothelial growth factor (VEGF). The results showed that both CNV and corneal opacity were decreased in rats after Akt inhibitor administration. Conclusion: The research illustrates the vital role of Akt inhibitors in mediating CNV. The analysis shows that the Akt inhibitor may provide a novel and feasible therapeutic approach to prevent CNV, but its mechanism needs further investigation. [ABSTRACT FROM AUTHOR]

Purpose: To present the clinical outcome of mitomycin intravascular chemoembolization (MICE) as a prophylactic treatment in a patient with HSV-induced corneal neovascularization (NV) before penetrating keratoplasty (PKP). Observations: A 53-year-old male patient presented with a medical history of recurrent herpes simplex virus (HSV) corneal infection. The patient reported worsening visual acuity despite maintenance treatment with systemic antivirals and topical corticosteroids. After the appearance of corneal NV, subconjunctival triamcinolone and bevacizumab injections were given with limited and temporary improvement. Due to worsening corneal NV, MICE was subsequently performed, resulting in the elimination of corneal NV from the visual axis, which allowed for successful PKP 4 months later. Cataract surgery was performed 6 months after PKP. Conclusions and importance: This report describes the potential efficacy of MICE as a prophylactic treatment for corneal NV prior to PKP.

The cornea is a transparent outer layer of the anterior eye segment, innervated by a high density of neural tissue. In the process of corneal innervation, trigeminal ganglion originated corneal nerves traverse different types of corneal cell in the epithelial and stromal layers. Corneal stromal cells, epithelial cells, immune cells, and other cells interact closely to maintain corneal microenvironmental homeostasis. In addition, corneal nerves is associated with the occurrence and development of many ocular surface diseases. Corneal nerves release various active peptides that regulate corneal sensation, maintain epithelial integrity and proliferation, improve wound healing, and manage local inflammation and immune response. This article reviews the advances in the corneal nerve regulation of the ocular surface microenvironment, providing some new ideas for the further study and treatment of corneal nerve-associated diseases.

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.

Corneal neovascularization is a significant cause of vision loss, often resulting in corneal clouding and chronic inflammation. Shark cartilage is widely recognized as a significant natural source of anti-angiogenic compounds. Our previous studies have shown that a polypeptide from white-spotted catshark (Chiloscyllium plagiosum Bonnet) has the potential to inhibit the angiogenesis of breast tumors. This study applied this peptide (SAIF) to a corneal alkali injury model to assess its effect on corneal neovascularization. Results revealed that SAIF inhibits endothelial cell proliferation, migration, and tube formation. SAIF inhibited VEGF-induced angiogenesis in the matrigel plug. Using the corneal alkali injury model, SAIF significantly inhibited corneal vascular neovascularization in mice. We found that SAIF not only significantly inhibited the upregulation of pro-angiogenic factors such as VEGF, bFGF, and PDGF expression induced by alkali injury, but also promoted the expression of anti-angiogenesis factor PEDF. Moreover, we also analyzed the MMPs and TIMPs involved in extracellular matrix (ECM) remodeling, angiogenesis, and lymphangiogenesis. We found that SAIF treatment inhibited the expression of pro-angiogenic factors like MMP1, MMP2, MMP3, MMP9, MMP13, and MMP14, and promoted the expression of anti-angiogenesis factors such as MMP7, TIMP1, TIMP2, and TIMP3. In conclusion, SAIF acts as an anti-angiogenic factor to inhibit the proliferation, migration, and tube formation of endothelial cells, inhibit pro-angiogenic factors, promote anti-angiogenic factors, and regulate the expression of MMPs, ultimately inhibiting corneal neovascularization.

Abstract Purpose: To evaluate the pro-angiogenic effect of topical erythropoietin on cornea in chemical burn-injured rabbit eyes. Methods: The corneal alkali-burn injury was induced in 10 eyes of 10 rabbits using filter paper saturated with 1.0 mol sodium hydroxide. The eyes were categorized into the treatment group (n = 5) that received topical erythropoietin (3000 IU/mL) every 8 hr for one month versus the control group (n = 5) that received normal saline every 8 hr for one month. All eyes were treated with topical ciprofloxacin every 8 hr until corneal re-epithelialization was complete. Corneal epithelial defects, stromal opacity, and neovascularization were evaluated after the injury. At the conclusion of the study, the rabbits were euthanized and their corneas were submitted to histopathological examination. Results: Baseline characteristics including the rabbits' weight and the severity of corneal injury were comparable in two groups. Time to complete corneal re-epithelialization was 37 days in the treatment group and 45 days in the control group (P = 0.83). There was no significant difference between the groups in the rate of epithelial healing or corneal opacification. Clinical and microscopic corneal neovascularization was observed in one eye (20%) in the treatment group and two eyes (40%) in the control group (P = 0.49). Conclusion: Recombinant human erythropoietin administered topically did not induce vessel formation in rabbit corneas after chemical burn.

AIM: To investigate the effectiveness and safety of subconjunctival injection of conbercept in the treatment of corneal neovascularization (CNV). METHODS: The data on 10 consecutively recruited patients with CNV who received a subconjunctival conbercept (1 mg) once, and measured the area, length, and diameter of neovascularization before and after (1d, 1, 2wk, and 1mo) treatment as well as the occurrence of systemic and ocular complications after treatment were analyzed. RESULTS: There was a statistically significant reduction in the area of CNV one day after treatment (mean±SD: 38.46±11.36 mm2), compared with before treatment (42.46±12.80 mm2, P

Background: To overcome the drawbacks of traditional therapy for corneal neovascularization (CNV), we evaluated the efficacy of polyethylene glycol (PEG)-conjugated Ala-Pro-Arg-Pro-Gly (APRPG) peptide modified dexamethasone (Dex), a novel nano-prodrug (Dex-PEG-APRPG, DPA). Methods: Characterization of DPA nano-prodrug were measured with transmission electron microscopy (TEM) and dynamic light scattering (DLS) analyses. Cytotoxicity and effects on cell migration and tube formation of DPA were evaluated in vitro. A murine CNV model was established by cornea alkali burn. The injured corneas were given eye drops of DPA (0.2 mM), Dex solution (0.2 mM), Dexp (2 mM), or normal saline three times a day. After two weeks, eyes were obtained for the analysis of histopathology, immunostaining, and mRNA expression. Results: DPA with an average diameter of 30 nm, presented little cytotoxicity and had good ocular biocompatibility. More importantly, DPA showed specific targeting to vascular endothelial cells with efficient inhibition on cell migration and tube formation. In a mouse CNV model, clinical, histological, and immunohistochemical examination results revealed DPA had a much stronger angiogenesis suppression than Dex, resembling a clinical drug with an order of magnitude higher concentration. This was ascribed to the significant downregulations in the expression of pro-angiogenic and pro-inflammatory factors in the corneas. In vivo imaging results also demonstrated that APRPG could prolong ocular retention time. Conclusions: This study suggests that DPA nano-prodrug occupies advantages of specific targeting ability and improved bioavailability over conventional therapy, and holds great potential for safe and efficient CNV therapy.

Corneal neovascularization (CNV) is a heavy attribute of blinding disease changes. Existing medications need numerous infusions and have a limited absorption. Investigating novel drugs with safety, efficacy, and convenience is crucial. In this study, we developed a bone morphogenetic protein 4 (BMP4)-loaded poloxamer-oxidized sodium alginate (F127-OSA) thermosensitive hydrogel. The 14 % F127-OSA hydrogel transformed from sol to gel at 31–32 °C, which might extend the application period on the ocular surface. The hydrogel's porous structure and uniform dispersion made it possible for drugs to release gradually. We used a suture-induced rat CNV model to investigate the mechanism of CNV inhibition by hydrogel. We discovered that F127-OSA hydrogel loaded with BMP4 could significantly reduce the length and area of CNV, relieve corneal edema, and stop aberrant epithelial cell proliferation. The hydrogel's efficacy was superior to that of the common solvent group. Additionally, BMP4 thermosensitive hydrogel repaired ultrastructure, including microvilli, intercellular junctions, and damaged apical junctional complexes (AJCs), suggesting a potential mechanism by which the hydrogel prevented CNV formation. In conclusion, our investigation demonstrates that F127-OSA thermosensitive hydrogel loaded with BMP4 can repair corneal epithelial AJCs and is a promising novel medication for the treatment of CNV.

Purpose: To describe a case of chronic ocular surface disease associated with Stevens-Johnson Syndrome (SJS) in which the addition of nightly topical ophthalmic preservative free vitamin A ointment to the daily use of a customized ocular surface prosthetic device (PROSE) appears to mitigate disease progression. Observations: A 51-year-old female with SJS secondary to lamotrigine use presented for follow up evaluation. Ocular history was significant for acute SJS twenty-four years prior with chronic ocular surface sequelae predominantly affecting the left eye. The condition had been stabilized without progression by utilizing long term PROSE daytime wear along with nightly application of topical ophthalmic vitamin A ointment. The patient reported non-compliance with vitamin A ointment use for the prior three months. The ocular surface examination of the left eye was notable for significantly progressed inferior keratinization and neovascularization which had been unchanged over the course of the three prior annual exams. After restarting nightly topical ophthalmic vitamin A ointment and continuing regular PROSE use, there was no further ocular surface disease progression in the ensuing 4 years of follow up. Conclusion and Importance: The use of nightly topical ophthalmic vitamin A ointment may be a viable adjuvant therapy alongside daily PROSE use for progressive chronic SJS ocular surface disease.

Osthole (OST), a natural coumarin compound, has shown a significant inhibitory effect on corneal neovascularization (CNV). But, its effect on treating CNV is restricted by its water insolubility. To overcome this limitation, an OST-loaded microemulsion (OST-ME) was created to improve the drug's therapeutic effect on CNV after topical administration. The OST-ME formulation comprised Capryol-90 (CP-90), Cremophor® EL (EL-35), Transcutol-P (TSP) and water, and sodium hyaluronate (SH) was also included to increase viscosity. The OST-ME had a droplet size of 16.18 ± 0.02 nm and a low polydispersity index (0.09 ± 0.00). In vitro drug release from OST-ME fitted well to the Higuchi release kinetics model. Cytotoxicity assays demonstrated that OST-ME was not notably toxic to human corneal epithelial cells (HCECs), and the formulation had no irritation to rabbit eyes. Ocular pharmacokinetics studies showed that the areas under the concentration–time curves (AUC0-t) in the cornea and conjunctiva were 19.74 and 63.96 μg/g*min after the administration of OST-ME, both of which were 28.2- and 102.34-fold higher than those after the administration of OST suspension (OST-Susp). Moreover, OST-ME (0.1%) presented a similar therapeutic effect to commercially available dexamethasone eye drops (0.025%) on CNV in mouse models. In conclusion, the optimized OST-ME exhibited good tolerance and enhanced 28.2- and 102.34-fold bioavailability in the cornea and conjunctiva tissues compared with suspensions in rabbit eyes. The OST-ME is a potential ocular drug delivery for anti-CNV. [ABSTRACT FROM AUTHOR]

Corneal neovascularization (CNV) is a global threat to human health. Traditional anti-angiogenesis agent may have therapy effect, while the inflammation in disease area remains unsolved. Herein, we reported two binding-induced fibrillogenesis (BIF) peptides as peptidic network antibodies for high-efficient and long-lasting anti-angiogenesis with reduced inflammatory response. BIF peptides could self-assemble into nanoparticles and further perform BIF behavior through binding Ca2+. In vitro, the migration of integrin α v β 3 highly expressed endothelial cells was inhibited by BIF peptides. In vivo, one BIF peptide (0.012 mg/Kg) exhibited higher anti-angiogenesis effect than monoclonal antibody bevacizumab (0.96 mg/Kg) in a CNV rabbit model on day 14, despite that the dose of BIF was only 1.3% of bevacizumab. Meanwhile, the inflammatory response, such as PI3 kinase/Akt pathway in CNV was successfully inhibited as well. The peptidic network antibody could block integrin α v β 3 via a long-term retention mode, which led to long-term therapeutic effect. The study provides BIF peptides as promising therapeutic agents for both anti-angiogenesis and reduced inflammatory response. Schematic drawing of PA-F(G)H nanoparticles binding to integrin α v β 3 on the surface of ECs to form PA-F(G)H nanofibers, trapping integrin α v β 3 for the inhibition of neovascularization and inflammation in a CNV rabbit model. [Display omitted] [ABSTRACT FROM AUTHOR]

AIM: To evaluate the efficacy of transplantation of human umbilical cord mesenchymal stem cells(hUCMSCs)in the treatment of corneal alkali burn in rabbits, and study the infiltration of polymorphonuclear neutrophils(PMNs)and the changes of vascular endothelial growth factor(VEGF)expression.METHODS: Corneal alkali burn models were established in right eyes of 75 healthy Japanese white rabbits, which were divided into three groups(group A, B and C), with 25 rabbits in each group. Group A was treated with amniotic membrane combined with hUCMSCs on the day after corneal alkali burn. Group B was treated with amniotic membrane only. Group C did not give any treatment after corneal alkali burn. At 3, 7, 14, 21 and 28d after corneal alkali burn, the corneal recovery was observed by slit lamp and photographed, the growth of corneal neovascularization(CNV)was scored, and corneal tissue was separated to make pathological sections. PMNs infiltration was observed by hematoxylin-eosin(HE)staining, and the expression of VEGF was determined by immunohistochemical staining.RESULTS: The growth of CNV in group A was much slower than that in group B at 14d after alkali burn. The CNV growth score around lesions of group A was significantly lower than that of group B(P

Ya-Chun Chu,1,2,&ast; Hsu-Wei Fang,2,3,&ast; Yu-Yi Wu,1 Yu-Jun Tang,1 Erh-Hsuan Hsieh,1 YiZhou She,4 Che-Yi Chang,1 I-Chan Lin,5,6 Yin-Ju Chen,1,7– 9 Guei-Sheung Liu,1,10– 12 Ching-Li Tseng1,8,9,13 1Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei City, Taiwan; 2Department of Chemical Engineering and Biotechnology, National Taipei University of Technology, Taipei City, Taiwan; 3Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli County, Taiwan; 4School of Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei City, Taiwan; 5Department of Ophthalmology, Wan Fang Hospital, Taipei Medical University, Taipei City, Taiwan; 6Department of Ophthalmology, School of Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan; 7Department of Radiation Oncology, Taipei Medical University Hospital, Taipei City, Taiwan; 8International Ph.D. Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei City, Taiwan; 9Center for Precision Medicine and Translational Cancer Research, Taipei Medical University Hospital, Taipei City, Taiwan; 10Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC, Australia; 11Ophthalmology, Department of Surgery, University of Melbourne, East Melbourne, VIC, Australia; 12Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia; 13Research Center of Biomedical Device, College of Biomedical Engineering, Taipei Medical University, Taipei City, Taiwan&ast;These authors contributed equally to this workCorrespondence: Ching-Li Tseng, Tel +886 2 2736 1661 (ext. 5214), Email chingli@tmu.edu.twBackground: Corneal neovascularization (NV) is a process of abnormal vessel growth into the transparent cornea from the limbus and can disturb the light passing through the cornea, resulting in vision loss or even blindness. The use of nanomedicine as an effective therapeutic formulation in ophthalmology has led to higher drug bioavailability and a slow drug release rate. In this research, we designed and explored the feasibility of a new nanomedicine, gp91 ds-tat (gp91) peptide-encapsulated gelatin nanoparticles (GNP-gp91), for inhibiting corneal angiogenesis.Methods: GNP-gp91 were prepared by a two-step desolvation method. The characterization and cytocompatibility of GNP-gp91 were analyzed. The inhibition effect of GNP-gp91 on HUVEC cell migration and tube formation was observed by an inverted microscope. The drug retention test in mouse cornea was observed by in vivo imaging system, fluorescence microscope, and DAPI/TAMRA staining. Finally, the therapeutic efficacy and evaluation of neovascularization-related factors were conducted through the in vivo corneal NV mice model via topical delivery.Results: The prepared GNP-gp91 had a nano-scale diameter (550.6 nm) with positive charge (21.7 mV) slow-release behavior (25%, 240hr). In vitro test revealed that GNP-gp91 enhanced the inhibition of cell migration and tube formation capacity via higher internalization of HUVEC. Topical administration (eyedrops) of the GNP-gp91 significantly prolongs the retention time (46%, 20 min) in the mouse cornea. In chemically burned corneal neovascularization models, corneal vessel area with a significant reduction in GNP-gp91 group (7.89%) was revealed when compared with PBS (33.99%) and gp91 (19.67%) treated groups via every two days dosing. Moreover, GNP-gp91 significantly reduced the concentration of Nox2, VEGF and MMP9 in NV’s cornea.Conclusion: The nanomedicine, GNP-gp91, was successfully synthesized for ophthalmological application. These data suggest that GNP-gp91 contained eyedrops that not only have a longer retention time on the cornea but also can treat mice corneal NV effectively delivered in a low dosing frequency, GNP-gp91 eyedrops provides an alternative strategy for clinical ocular disease treatment in the culture.Graphical Abstract: Keywords: gp91 peptide, gelatin, nanoparticles, ocular retention, control release, corneal neovascularization, eye drops

Corneal neovascularization is a severe eye disease that is often associated with an inflammatory cycle and increased oxidative stress. Excessive reactive oxygen species can cause harmful changes in the corneal epithelium and lead to vicious inflammatory cycles, resulting in an increase in corneal neovascularization. Unfortunately, many drugs used in clinic are water-insoluble and have low bioavailability on the ocular surface, which limits their effectiveness. Therefore, it's crucial to design a new drug delivery system. In this study, we designed an oxide-responsive nanoparticle system called MPA, which was consisted of the large pore sized-mesoporous silica nanoparticles (MSNs) core and the polydopamine (PDA) surface shell via the linkage with disulfide bond. Finally, the nanoparticles are endowed with the enhanced loading efficiency and the controllable release of fenofibrate (Feno) in response to the abundant ROS level in the inflammatory environment. In an in vivo study using mice, treatment with MPA@ Feno resulted in minimal corneal neovascularization area and length and significantly reduced expression of pro-angiogenic factors and oxidative stress factors. Therefore, MPA solves the problem of poor drug solubility, clearing oxygen species in the pathological environment, which will improve its therapeutic effect in corneal neovascularization.

Corneal neovascularization (CNV) badly damages the corneal transparency, resulting in visual disturbance and blindness. The frequent administration of glucocorticoid eye drops in clinical increases the possibility of side effects and reduces patient compliance. Considering CNV is often accompanied by an increase in ROS production, a ROS-responsive monomer 2-(methylthio)ethyl methacrylate was introduced into the matrix as a "gating switch". The prepared dexamethasone contact lenses (MCLs@Dex) showed a significant H 2 O 2 -responsive release for 168 h. To avoid corneal hypoxia and neovascularization caused by long-term wearing, high‑oxygen-permeability fluorosiloxane materials were incorporated. The oxygen permeability of MCLs@Dex was 4 times that of commercially available hydrogel contact lenses and had ultra-low protein adsorption, which meets the requirements of long-term wearing. In vivo pharmacokinetic studies showed that MCLs@Dex increased the mean residence time by 19.7 times and bioavailability by 2.29 times compared with eye drops, validating the ROS response and sustained release properties. More importantly, MCLs@Dex had satisfactory effects on reducing inflammation and decreasing the related cytokines and oxidative stress levels, and demonstrated significant inhibition of neovascularization, with a suppression rate of 76.53% on the 14th day. This responsive drug delivery system provides a promising new method for the safe and effective treatment of ocular surface diseases. A long-term corneal contact lens with inflammation-responsive molecular-gated drug release, which can self-adaptively release dexamethasone in the high ROS environment, and play a role in enhancing efficacy and reducing toxicity. [Display omitted] • Molecular-gated contact lens for the treatment of corneal neovascularization • Responsive release of dexamethasone at the site of inflammation • High oxygen permeability and good biocompatibility for 7-day continuous wear [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to compare the efficacy of topical bevacizumab and motesanib in an experimental corneal neovascularization model, and find the most effective motesanib dose. Materials and methods: In experiments, 42 Wistar Albino rats were randomly divided into six groups (n = 7). Corneal cauterization was applied to all groups except the group 1. Group 1 did not receive any treatment. Topical dimethylsulfoxide was applied to sham group three times a day(tid). Topical bevacizumab drops (5 mg/ml) were applied to Group 3 tid. Topical motesanib drops with a dose of 2.5, 5, and 7.5 mg/ml were respectively applied in Groups 4, 5, and 6 tid. On the 8th day, corneal photographs of all rats were taken under general anesthesia, and the percentage of corneal neovascular area was calculated. VEGF-A mRNA, VEGFR-2 mRNA, miRNA-21, miRNA-27a, miRNA-31, miRNA-126, miRNA-184, and miRNA-204 were evaluated by the qRT-PCR method in corneas taken after decapitation. Results: The percentage of corneal neovascularization areas and VEGF-A mRNA expression levels were decreased in all treatment groups compared to group 2 (p < 0.05). VEGFR-2 mRNA levels were found to be statistically significantly decreased in groups 4 and 6 compared to group 2 (p < 0.05). Statistically significant changes were detected in the expression levels of only miRNA-126 among all miRNAs. Conclusion: Motesanib with a dose of 7.5 mg/ml statistically significantly suppressed the VEGFR-2 mRNA level compared with other treatment doses and may be more effective than bevacizumab. Further, miRNA-126 can be used as a proangiogenic marker. [ABSTRACT FROM AUTHOR]

Background: Corneal neovascularization (CNV) is a pathological condition that can disrupt corneal transparency, thus harming visual acuity. However, there is no effective drug to treat CNV. Sunitinib (STB), a small-molecule multiple receptor tyrosine kinase inhibitor, was shown to have an effect on CNV. The purpose of this study was to develop an STB microemulsion (STB-ME) eye drop to inhibit CNV by topical application. Methods: We successfully prepared an STB-ME by the phase inversion emulsification method, and the physicochemical properties of STB-MEs were investigated. The short-term storage stability, cytotoxicity to human corneal epithelial cells, drug release, ocular irritation, ocular pharmacokinetics and the inhibitory effect on CNV were evaluated in vitro and in vivo. Results: The optimal formulation of STB-ME is composed of oleic acid, CRH 40, Transcutol P, water and sodium hyaluronate (SH). It is a uniform spherical particle with a mean droplet size of 18.74 ± 0.09 nm and a polydispersity index of 0.196 ± 0.004. In the in vitro drug release results, STB-ME showed sustained release and was best fitted by a Korsmeyer-Peppas model (R2 = 0.9960). The results of the ocular pharmacokinetics in rabbits showed that the formulation containing SH increased the bioavailability in the cornea (2.47-fold) and conjunctiva (2.14-fold). STB-ME (0.05% and 0.1%), administered topically, suppressed alkali burn-induced CNV in mice more effectively than saline, and high-dose (0.1%) STB-ME had similar efficacy to dexamethasone (0.025%). Conclusion: This study provides a promising formulation of STB-ME for the inhibition of CNV by topical administration, which has the excellent characteristics of effectiveness, sustained release and high ocular bioavailability. [ABSTRACT FROM AUTHOR]