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Integrated Approaches, Molecular Mechanism and Therapies in Ocular Surface Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (20 December 2025) | Viewed by 13609

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Special Issue Editors

Prof. Dr. Caterina Gagliano

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Guest Editor

Department of Medicine and Surgery, University of Enna “Kore”, Piazza dell'Università, 94100 Enna (EN), Italy
Interests: glaucoma; clinical ophthalmology; retinal diseases; inflammation; immunology of infectious diseases; OCT; macular degeneration; eye diseases; corneal diseases; ocular surface; dry eye diseases; retinal degeneration; inherited retinal disorders; rare ophthalmic diseases

Dr. Marco Zeppieri

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Guest Editor

Department of Ophthalmology, University Hospital of Udine, 33100 Udine, Italy
Interests: clinical ophthalmology; glaucoma; tonometry; ocular hypertension; visual field testing; OCT; pachymetry; refractive errors; cornea; dry eye disorders; stem cells; corneal wound lesions; ocular surface; lid diagnostics and treatments
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Mario Damiano Toro

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Guest Editor

1. Eye Clinic, Public Health Department, University of Naples Federico II, 80131 Naples, Italy
2. Department of General and Pediatric Ophthalmology, Medical University of Lublin, 20-079 Lublin, Poland
Interests: cataract surgery; ocular trauma management; vitreoretinal surgery; experimental ocular surgery; 3D surgery; secondary IOL implantation; pole-to-pole surgery

Special Issue Information

Dear Colleagues,

We are pleased to host a Special Issue entitled “Integrated Approaches, Molecular Mechanism and Therapies in Ocular Surface Diseases”. This Special Issue seeks to investigate the novel applications of blood-derived products in the treatment and management of ocular surface diseases. We welcome submissions from top scholars, clinicians, and healthcare professionals who are pioneers in their fields. This issue will cover a wide range of topics, including the molecular and cellular mechanisms, clinical applications, and outcomes of using autologous serum, platelet-rich plasma, umbilical cord derivatives, and other novel blood-based therapies to treat conditions such as dry eye syndrome, corneal ulcers, and persistent epithelial defects.

Our goal is to create a complete collection of original research articles, reviews, and case studies that demonstrate the efficacy and safety of these treatments, as well as their integration into established therapy procedures. This special issue aims to expand our understanding and application of blood component therapy in ophthalmology by bringing together varied perspectives and discoveries. In addition, our goal is to explore the molecular processes by which these medicines are derived from blood exercise and their effects on illnesses of the ocular surface. This Special Issue will enhance our comprehension of how these medicines might be optimized for clinical use by examining the fundamental biological processes and their therapeutic consequences.

We welcome papers that shed light on patient selection, treatment methods, and long-term outcomes, as well as those that investigate the molecular mechanisms underlying the healing benefits of these therapies. This is a great opportunity to contribute to a growing field of study with important clinical consequences, and we look forward to receiving your valuable submissions.

Prof. Dr. Caterina Gagliano
Dr. Marco Zeppieri
Prof. Dr. Mario Damiano Toro
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

ocular surface diseases
dry eye
corneal ulcers
persistent epithelial defects
blood-derived products
blood-based therapies

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Published Papers (7 papers)

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Editorial

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5 pages, 352 KB

Open AccessEditorial

Special Issue “Integrated Approaches, Molecular Mechanisms and Therapies in Ocular Surface Diseases”

by Marco Zeppieri, Mario Damiano Toro and Caterina Gagliano

Int. J. Mol. Sci. 2026, 27(11), 5106; https://doi.org/10.3390/ijms27115106 - 4 Jun 2026

Viewed by 147

Abstract

The ocular surface is a highly specialized and dynamic complex system, characterized by close interconnections among epithelial integrity, immunological privilege, and tear film homeostasis, all of which are essential for proper visual function [...] Full article

(This article belongs to the Special Issue Integrated Approaches, Molecular Mechanism and Therapies in Ocular Surface Diseases)

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Research

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22 pages, 8668 KB

Open AccessArticle

Therapeutic Efficacy of Rapamycin in an Experimental Mouse Model of Corneal Alkali Burn

by Basanta Bhujel, Hun Lee, Ho Seok Chung and Jae Yong Kim

Int. J. Mol. Sci. 2026, 27(8), 3688; https://doi.org/10.3390/ijms27083688 - 21 Apr 2026

Viewed by 672

Abstract

Corneal alkali burn induces severe inflammation and tissue damage, leading to loss of corneal transparency and vision impairment. In this study, we evaluated the therapeutic potential of rapamycin (RAPA) compared with cyclosporine A (CsA) in a mouse model of corneal alkali burn, focusing on nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)–mediated inflammatory signaling and its impact on corneal wound healing and repair. Notably, RAPA robustly suppressed NF-κB activation, reduced infiltration of F4/80 macrophages and MPO neutrophils, and downregulated pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6. RAPA also markedly inhibited corneal neovascularization, as evidenced by decreased VEGF expression, reduced CD31 vessel formation, and suppression of Ang-2. RAPA substantially inhibited pathological fibrotic remodeling by reducing TGF-β1 expression, attenuating myofibroblast activation (α-SMA), decreasing collagen III deposition, and modulating matrix remodeling through suppression of MMP-9. Crucially, RAPA preserved epithelial barrier integrity by maintaining occludin expression, supported proper epithelial differentiation through sustained expression of CK12, and enhanced mucin layer stability by increasing MUC1 expression. It also restored tear production, reduced apoptotic cell death (TUNEL), and decreased dysregulated epithelial proliferation (Ki67). In conclusion, RAPA showed superior efficacy compared with CsA, primarily by enhancing corneal wound healing and facilitating structural and functional outcomes in the burned cornea. These findings underscore RAPA as a promising therapeutic candidate for ocular surface repair and vision restoration in extensive corneal injury. Full article

(This article belongs to the Special Issue Integrated Approaches, Molecular Mechanism and Therapies in Ocular Surface Diseases)

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13 pages, 3113 KB

Open AccessArticle

Meesmann Corneal Dystrophy with Epithelial Basement Membrane Abnormalities: Clinical and Genetic Analysis of Two Families with Novel and Known Mutations in KRT3 and KRT12

by Víctor Charoenrook, Raquel Larena, Álvaro Ferragut-Alegre, Alix De Faria, Rebeca Valero, Mònica Martí-Orpinell, Gemma Julio and Rafael I. Barraquer

Int. J. Mol. Sci. 2026, 27(3), 1326; https://doi.org/10.3390/ijms27031326 - 29 Jan 2026

Viewed by 547

Abstract

This study describes the clinical and genetic features of Meesmann epithelial corneal dystrophy (MECD) in two unrelated families and reports new genotype–phenotype associations. Ten patients from a Lebanese family (n = 4) (Family 1) and a Spanish family (n = 6) (Family 2) underwent ophthalmologic evaluation, in vivo confocal microscopy (IVCM), anterior segment optical coherence tomography (AS-OCT) with epithelial thickness mapping (ET-map), and targeted next-generation sequencing (NGS) using a custom-designed 133-gene panel associated with anterior segment dystrophies. In Family 1, a novel homozygous KRT12 c.1181T>C (p.Leu394Pro) variant was identified in the symptomatic proband and his clinically asymptomatic brother, while both parents, who were first cousins, were heterozygous for this nucleotide variant. The proband also carried the heterozygous KRT3 c.250C>T (p.Arg84Trp) variant, which has been previously reported but, to our knowledge, has not been described in co-occurrence until now. In addition, the proband showed a complex phenotype with signs of MECD and epithelial basal membrane alterations consistent with epithelial basement membrane dystrophy (EBMD). In Family 2, four affected members carried the KRT3 c.1492G>A (p.Glu498Lys) variant in heterozygosity, which has been previously described. The elderly members affected showed typical signs of MECD and EBMD. To our knowledge, these concomitant alterations have not been previously described with genetical confirmation. In conclusion, this study provides the first evidence that the co-occurrence of variants in two Meesmann corneal dystrophy-associated genes (KRT3 and KRT12) can jointly account for the disease phenotype. We also highlight the association of MECD with EBMD in both families. Characterization using IVCM and AS-OCT ET-Map provides a deeper understanding of the morphological changes and phenotypic variability in MECD, confirming the utility of this multimodal imaging approach for diagnosis and management. Full article

(This article belongs to the Special Issue Integrated Approaches, Molecular Mechanism and Therapies in Ocular Surface Diseases)

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14 pages, 4882 KB

Open AccessArticle

Allogeneic Umbilical Cord Blood Serum Eyedrops for the Treatment of Severe Dry Eye Disease Patients

by Marco Zeppieri, Giuseppe Gagliano, Matteo Capobianco, Caterina Gagliano, Francesco Cappellani, Giuseppa Tancredi, Alessandro Avitabile, Ludovica Cannizzaro and Fabiana D’Esposito

Int. J. Mol. Sci. 2025, 26(21), 10782; https://doi.org/10.3390/ijms262110782 - 6 Nov 2025

Cited by 1 | Viewed by 1402

Abstract

Human allogeneic umbilical cord blood serum stands out as a potent adjunct to conventional therapies for ocular surface disorders related to severe Dry Eye Disease. By expediting ocular surface regeneration and fostering epithelial integrity, umbilical cord blood serum not only enhances subjective patient experiences but also improves objective clinical indicators. This makes it particularly useful in patients with corneal ulcers through ocular surface regeneration and anti-inflammatory activity. This retrospective, interventional, non-randomized clinical study aims to explore the efficacy of allogenic umbilical cord blood serum in patients who had previously received other treatments unsuccessfully. This study was a retrospective, non-comparative, interventional clinical study involving 55 patients (35 females and 20 males) aged 18–82 years with severe Dry Eye Disease who were unresponsive to standard treatments. The study was conducted at Eye Center “G.B. Morgagni-DSV”, Catania, Italy. Patients were categorized based on the etiology of severe Dry Eye Disease into four groups: group I consisted of 26 patients with filamentary keratitis and corneal ulcers associated with rheumatologic diseases such as Sjogren’s syndrome and systemic sclerosis; group II comprised 15 patients with graft-versus-host disease; group III consisted of 10 patients with corneal neurotrophic ulcers; group IV included four patients with Steven–Johnson syndrome. Outcomes evaluated before and after treatment were OSDI (Ocular Surface Disease Index) and SANDE (Symptom Assessment in Dry Eye) Questionnaires, VAS (Visual Analog Scale), Slit-Lamp Examination, Esthesiometry, Lissamine Green Staining, NIBUT (Non-Invasive Break-Up Time) and BUT, Fluorescein Staining with Photography and Oxford Classification, Schirmer Test, Best-Corrected Visual Acuity (BCVA), Meibography. We observed a significant improvement in SANDE, VAS and OSDI questionnaires, Schirmer Test, BUT, BCVA, and Oxford classification after treatment with allogeneic cord blood serum eyedrops. Clinical variables, such as corneal inflammation, conjunctivalization, corneal neovascularization, or pain, were also considered individually. Nevertheless, pain and inflammation reduced markedly over time until completely healed in all cases. Our study highlights the remarkable efficacy of allogeneic cord blood serum eyedrops in patients with severe Dry Eye Disease who have shown absent or inadequate response to usual treatments for dry eye. This underscores the need for further comprehensive investigations in this field. Full article

(This article belongs to the Special Issue Integrated Approaches, Molecular Mechanism and Therapies in Ocular Surface Diseases)

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21 pages, 3294 KB

Open AccessArticle

Characterization of Corneal Defects in ATG7-Deficient Mice

by Thomas Volatier, Andreas Mourier, Johanna Mann, Berbang Meshko, Karina Hadrian, Claus Cursiefen and Maria Notara

Int. J. Mol. Sci. 2025, 26(20), 9989; https://doi.org/10.3390/ijms26209989 - 14 Oct 2025

Viewed by 3188

Abstract

Regulated proteolysis via autophagy is essential for cellular homeostasis, yet the specific role of autophagy-related gene 7 (ATG7) in corneal epithelial maintenance remains unclear. Using a conditional knockout mouse model (Atg7^f/f K14Cre^+/−), we investigated the impact of ATG7 deficiency on corneal epithelial autophagy, morphology, and vascular dynamics. Loss of ATG7 disrupted autophagosome formation, evidenced by increased LC3B expression but reduced LC3B-positive puncta and absence of autophagosomes ultrastructurally. Although gross corneal morphology was preserved, ATG7 deficiency led to thickened epithelium and increased peripheral lymphatic vessel sprouting, indicating a pro-inflammatory and pro-lymphangiogenic microenvironment. Proteomic analysis revealed upregulation of RAB8, TM9S3, and RETR3, suggesting activation of compensatory pathways such as exophagy, reticulophagy, and Golgiphagy. Inflammatory and angiogenic components were downregulated, suggesting a moderate loss of inhibitory capacity based on the lymphatic phenotypes observed. At the same time, while these two compensatory changes occur, other proteins that positively regulate lysosome formation are reduced, resulting in a phenotype linked to deficient autophagy. These findings demonstrate that ATG7-mediated autophagy maintains corneal epithelial homeostasis and immune privilege, with implications for understanding corneal inflammation and lymphangiogenesis in ocular surface diseases. Full article

(This article belongs to the Special Issue Integrated Approaches, Molecular Mechanism and Therapies in Ocular Surface Diseases)

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22 pages, 6428 KB

Open AccessArticle

Rebamipide Enhances Pathogen Defense and Mitigates Inflammation in a Particulate Matter-Induced Ocular Surface Inflammation Rat Model

by Basanta Bhujel, Se-Heon Oh, Woojune Hur, Seorin Lee, Hun Lee, Ho-Seok Chung and Jae Yong Kim

Int. J. Mol. Sci. 2025, 26(8), 3922; https://doi.org/10.3390/ijms26083922 - 21 Apr 2025

Cited by 2 | Viewed by 2739

Abstract

Particulate matter (PM) exposure is known to induce significant ocular surface inflammation, necessitating effective therapeutic interventions. This study compared the efficacy of 2% rebamipide (REB) with 0.1% hyaluronic acid (HA) eye drops in investigating the anti-inflammatory and pathogen-clearance effects in a PM-induced ocular surface inflammation model using Sprague–Dawley (SD) rats. Parameters including clinical signs, histological changes, mucin secretions, inflammatory cytokines, mast cell degranulation, dysregulated cell proliferation, and cellular apoptosis were evaluated. 2% REB alleviated ocular surface inflammation by downregulating the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) inflammatory pathway and upregulating epidermal growth factor receptor (EGFR) signaling, thereby enhancing mucin secretion and promoting pathogen clearance. Histopathological analysis, western blot, and immunohistochemical staining revealed a marked reduction in inflammatory markers including MMP-9, IL-1β, TNF-α, IL-17, and CD-4, decreased mast cell degranulation, increased goblet cell density, and enhanced expression of mucins, including MUC5AC and MUC16, in the 2% REB-treated group compared to the 0.1% HA-treated and PM-exposed groups. Moreover, 2% REB demonstrated decreased apoptosis (TUNEL) and reduced uncontrolled cell proliferation (Ki67), indicating improved cellular integrity. In conclusion, 2% REB is a promising treatment option for PM-induced ocular surface inflammation in a rat model compared with 0.1% HA, offering the benefits of reducing inflammation, clearing pathogens, and protecting overall ocular health. Full article

(This article belongs to the Special Issue Integrated Approaches, Molecular Mechanism and Therapies in Ocular Surface Diseases)

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Review

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23 pages, 16541 KB

Open AccessReview

Adhesion Mechanism, Applications, and Challenges of Ocular Tissue Adhesives

by Zuquan Hu, Xinyuan He, Lijing Teng, Xiangyu Zeng, Simian Zhu, Yu Dong, Zhu Zeng, Qiang Zheng and Xiaomin Sun

Int. J. Mol. Sci. 2025, 26(2), 486; https://doi.org/10.3390/ijms26020486 - 8 Jan 2025

Cited by 6 | Viewed by 3936

Abstract

Corneal injury is prevalent in ophthalmology, with mild cases impacting vision and severe cases potentially resulting in permanent blindness. In clinical practice, standard treatments for corneal injury involve transplantation surgery combined with pharmacological therapy. However, surgical sutures exhibit several limitations, which can be overcome using tissue adhesives. With recent advances in biomedical materials, the use of ophthalmic tissue adhesives has expanded beyond wound closure, including tissue filling and drug delivery. Furthermore, the use of tissue adhesives has demonstrated promising outcomes in drug delivery, ophthalmic disease diagnosis, and biological scaffolds. This study briefly introduces common adhesion mechanisms and their applications in ophthalmology, aiming to increase interest in tissue adhesives and clinical ophthalmic treatment. Full article

(This article belongs to the Special Issue Integrated Approaches, Molecular Mechanism and Therapies in Ocular Surface Diseases)

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