The exposome, defined as the totality of external exposures individuals experience throughout the lifespan and the internal biological responses they trigger, is increasingly recognized as a major, modifiable determinant of health. The eye is uniquely vulnerable to exposome risk factors because it comprises an external interface directly exposed to the environment, a transparent lens highly sensitive to cumulative oxidative injury, and metabolically active retina prone to inflammation and vascular dysregulation. Research linking ocular diseases to air pollution, climate and weather factors, heavy metals, persistent organic pollutants, and emerging threats such as micro-/nanoplastics has expanded rapidly, yet the evidence remains fragmented and lacks systematic integration. In this review, we propose an anatomy-informed ocular exposome atlas along the visual axis to comprehensively evaluate evidence from clinical studies, pathological mechanisms, and intervention strategies across major disease groups-including ocular surface diseases, cataract, refractive errors, glaucoma, and retinal diseases. We further integrate cross-disease mechanistic pathways (oxidative stress, cellular responses, inflammation, immune reactions) and discuss causality. Finally, we identify priority research directions and provide actionable recommendations for prevention and policy.
Ocular toxoplasmosis is a common infectious eye disease caused by the ubiquitous parasite, Toxoplasma gondii, and the leading cause of posterior uveitis in most populations worldwide. For the growing number of individuals living with some form of immunocompromise, T. gondii often represents an aggressive ocular pathogen. To demonstrate how an impaired immune system may impact the course and outcomes of ocular toxoplasmosis, the clinical descriptions of 276 immunocompromised patients, published across 109 reports in the medical literature, were compiled, and relevant epidemiological and immunological studies were summarised. The diverse phenotypes of ocular toxoplasmosis associated with congenital or acquired immunodeficiency or immunosuppression are described; diagnostic methods and their interpretation are outlined; and management approaches that may limit infectious ocular and systemic complications are highlighted. The visual outcome of ocular toxoplasmosis is often poor in immunocompromised individuals. Atypical presentations occur frequently in this patient group, and in over one-half of those whose clinical information has been reported, the diagnosis was initially missed. By synthesising the published literature, this review offers a perspective that may support improved outcomes of ocular toxoplasmosis in people living with systemic immunocompromise.
Retinoblastoma (RB) represents the most common primary intraocular malignancy in childhood and stands as a paradigm for translating molecular oncology into precision clinical management. This review synthesizes the comprehensive evolution in the understanding and treatment of RB. First, we deconstruct the intricate oncogenic circuitry that extends far beyond Knudson's classic "two-hit" RB1 inactivation model, describing non-classical MYCN-driven pathogenesis, multi-layered epigenetic reprogramming (including chromatin, RNA and histone changes), and distinct histological subtypes with defined clinical correlates, such as the favorable-prognosis cavitary RB. Single-cell genomics has elucidated the cellular origin from cone precursor cells and intratumoral heterogeneity. Risk stratification has been refined through well-defined classification systems, from the therapy-guiding International Intraocular Retinoblastoma Classification (IIRC) to the comprehensive American Joint Committee on Cancer Tumor-Node-metastasis (AJCC TNM) staging. Furthermore, the diagnostic paradigm has advanced from conventional anatomical imaging to liquid biopsies, enabling non-invasive molecular staging and monitoring via tumor-derived cell-free DNA analysis. Concurrently, the therapeutic landscape has undergone a radical shift, moving from enucleation and external-beam radiotherapy to an era dominated by local sight-preserving strategies. We provide a critical synthesis of the evidence for intravenous chemotherapy and the transformative role of super-selective intra-arterial chemotherapy (IAC), and describe essential randomized controlled trials, technical innovations, and optimized drug regimens. Finally, we explore emerging targeted molecular therapies and future directions. By integrating cutting-edge molecular insights with robust, high-level clinical evidence, this review offers the framework for achieving patient and eye survival as well as vision preservation in children with Retinoblastoma.
Smartphone-based fundus imaging (SBFI) is an emerging approach with potential relevance for global ophthalmic care, including in low- and middle-income countries and other resource-constrained settings. This scoping review, based on a structured literature search, synthesises current SBFI technology, clinical and teaching applications, implementation challenges and future directions. Analysing 30 hardware solutions (based on three principal technical designs) and 274 scientific publications and other relevant sources, we found that some SBFI devices can provide fields of view and image quality sufficient to support screening or triage for referable diabetic retinopathy, glaucoma-related optic nerve head changes, and selected retinopathy of prematurity applications. Reported sensitivity, specificity and gradability varied by disease, device, protocol, operator, and reference standard; no universal performance threshold could be inferred. After brief training, allied healthcare workers can acquire usable images in selected settings, suggesting that SBFI may support task-shifted screening and referral pathways. Artificial intelligence may further support scalability by assisting image-quality and protocol compliance assessment, frame selection, montage generation and disease classification. However, costs, maintenance requirements, data governance and domain shift remain important implementation considerations. Key challenges include variable image quality and fields of view, heterogeneous reporting, smartphone compatibility, regulatory compliance, photobiological safety verification, data security, and patient privacy. We therefore suggest minimum reporting standards to increase comparability across studies. Large-scale implementation and cost-effectiveness studies are needed to determine whether improved access to ophthalmic imaging can translate into sustainable and equitable eye-care services.
Pigment epithelial detachment (PED) represents a critical structural finding across the spectrum of chorioretinal diseases, occurring in 63-80% of eyes with neovascular age-related macular degeneration and frequently in central serous chorioretinopathy, polypoidal choroidal vasculopathy, and inflammatory conditions. This review provides a comprehensive analysis of current multimodal imaging techniques in the diagnosis and management of PEDs. We examine the role of various imaging modalities including optical coherence tomography (OCT), OCT angiography (OCTA), en face OCT, fluorescein angiography (FA), indocyanine green angiography (ICGA), infrared imaging (IR), and fundus autofluorescence (FAF) in evaluating PEDs. Each imaging modality provides unique insights: OCT reveals characteristic structural changes and quantitative biomarkers (height, volume, prechoroidal cleft); OCTA demonstrates type 1-4 MNV localisation; en face OCT visualises internal architecture; FA shows leakage patterns; ICGA identifies choroidal hyperpermeability; IR assists RPE evaluation; and FAF highlights dysfunction patterns. The integration of these imaging techniques has enhanced our understanding of PED pathophysiology-hydrostatic imbalance, RPE pump failure, Bruch's alterations-and improved classification into drusenoid, serous, fibrovascular, and haemorrhagic subtypes. This review particularly emphasises how advanced OCT/OCTA has advanced our knowledge of PED natural history, treatment response (anti-VEGF/PDT), and complications (RPE tears). We also discuss future directions in AI-driven classification and imaging biomarkers for personalised therapeutic approaches. The synergistic use of multimodal imaging represents a cornerstone in PED management, enabling precise diagnosis, risk stratification, and tailored treatment strategies.
Glaucoma is a multifactorial optic neuropathy in which intraocular pressure is the principal modifiable risk factor but not the whole of the disease. Three recurring observations in the epidemiology and pharmacology of open-angle glaucoma, each of which has several possible explanations, together motivate a mechanistic question: open-angle glaucoma incidence rises steeply across the presbyopic decades, glaucoma risk is increased in myopia, and the intraocular pressure of some normal-tension eyes falls in response to muscarinic agonists. This review develops, and then critically grades, the hypothesis that these observations are connected by the mechanical role that accommodation may play in the regulation of aqueous dynamics. The proposal, termed accommodative aqueous regulation (AAR), is that the cyclic ciliary-muscle engagement delivered to the anterior segment during ordinary accommodation contributes to the regulation of aqueous humour, principally by conditioning conventional (trabecular) outflow, the accommodative outflow mechanism (AOM), and that its progressive loss at presbyopia is one contributory, refractive-state-dependent factor in the outflow deterioration that predisposes susceptible eyes to glaucoma. The claim is deliberately limited. The mechanism is offered as a threshold-lowering modifier acting in susceptible eyes within a multifactorial disease, not as a necessary or sufficient cause, and the mapping of refractive state onto glaucoma subtype, associating emmetropia with high-tension open-angle disease, hyperopia with angle-closure, and high myopia with the normal-tension phenotype, is presented as a probabilistic tendency rather than a rule that any individual eye must obey. Established physiology is separated from hypothesis at every step. The mechanical coupling of the ciliary muscle to a mechanosensitive outflow apparatus is supported; the central claim, that ordinary accommodative cycling conditions outflow across a lifetime and that its loss contributes to glaucoma, remains untested and is graded as such. We conclude by specifying the experiments that would confirm or refute it.
Lactate was once regarded merely as a byproduct of glycolysis, but is now recognized as a multifunctional metabolite that coordinates energy redistribution, intercellular communication, receptor-mediated signaling, and epigenetic regulation. In the retina, these functions are especially consequential because visual processing depends on a highly specialized and energetically demanding tissue, characterized by steep oxygen gradients, a dual vascular supply, and tightly integrated metabolic crosstalk among photoreceptors (PCs), Müller glia, the retinal pigment epithelium, vascular cells, and retinal ganglion cells. In this review, we synthesize current advances in lactate signaling and lactylation in the retina, and examine how their dysregulation contributes to neovascularization, inflammation, and neurodegeneration in disorders including diabetic retinopathy, age-related macular degeneration, autoimmune uveitis and glaucoma. Drawing from these metabolic insights, therapeutic interventions targeting lactate signaling and lactylation are discussed as potential approaches to mitigate retinal abnormalities. Collectively, this review highlights the central importance of lactate signaling and lactylation in retinal physiology and pathology, and provides a conceptual framework for developing metabolic interventions aimed at restoring retinal lactate homeostasis.
CDHR1 is a recently identified cause of autosomal recessive retinal degeneration manifesting as three distinct clinical phenotypes: macular dystrophy, cone-rod dystrophy or retinitis pigmentosa. In this review, we summarise the discovery and characterisation of CDHR1, clinical phenotypes, natural history and therapeutic approaches including gene supplementation and CRISPR gene editing. CDHR1 is a non-classical cadherin that is highly expressed in cone and rod photoreceptors and is essential for the higher-order organisation of the functionally critical outer segments. Promising pre-clinical data show that AAV gene supplementation therapy delivered by subretinal injection can lead to long-term morphological, structural, functional and behavioural improvements in the Cdhr1 knockout mouse model. Notably, CDHR1 supplementation restored full-length photoreceptor outer segments that are usually shortened and disorganised in disease models and prolonged photoreceptor survival - key mechanisms for the functional and behavioural rescue effects that were observed. The disease is likely to be underdiagnosed because CDHR1-associated macular dystrophy - likely to be the most common disease phenotype - is most often caused by a 'silent' nucleotide substitution that has previously been overlooked by genetic testing. Since the macular dystrophy phenotype has phenotypic similarities to advanced dry age-related macular degeneration (AMD), misdiagnoses are common. CDHR1-associated macular dystrophy also shares phenotypic features with a variety of monogenic masquerades such as ABCA4, PRPH2 and GUCY2D-associated macular dystrophies; we present a flowchart to guide the clinical distinction of these disorders which is now critical for patients as their treatments diverge. AAV gene therapy may be beneficial across the CDHR1 disease spectrum - including those with hypomorphic variants associated with macular dystrophy or retinitis pigmentosa. The coding sequence fits into AAV and with the macular dystrophy phenotype, there is a large time window for potential intervention and a large treatable population. Hence clinical trials are anticipated. It is therefore important that patients with CDHR1-associated retinal degeneration are accurately phenotyped and genetically confirmed to support the application of CDHR1 gene therapy.
Age-related macular degeneration (AMD) is a complex disease wherein age, genetics, and environment play a role. How each of these factors contribute to the overall disease initiation and progression remains largely unelucidated. A renewed examination of the existing literature regarding the blood supply to the outer retina may provide novel insights. Hypoxia in the retinal pigment epithelium (RPE) can produce features of AMD, including photoreceptor degeneration. In the macula, the choriocapillaris has unique features making it susceptible to hypoperfusion, producing low-grade ischemia and chronic tissue hypoxia. The choriocapillaris experiences vascular loss and decreased blood flow early in AMD. Genetic risk, when viewed through a new lens, points to vascular insult as central to AMD pathophysiology. Complement-related risk genes are active in the vasculature, from large tributary vessels to small vessels of the choriocapillaris. HtrA serine peptidase 1 (HTRA1) is associated with cerebral small vessel disease and localizes to the choriocapillaris in AMD. Ageing can be interpreted as inevitable atherosclerosis from large to small vessels of the cerebral system. Western diets, smoking, and a rising prevalence of metabolic syndrome in people over age 60 are confirmed to accelerate both atherosclerosis and AMD. A perfusion-based model for complement-related, soft drusen-associated AMD is proposed while also explaining a second phenotype of non-complement related subretinal drusenoid deposit-associated AMD. Common to both phenotypes of AMD is chronic hypoperfusion causing decreased oxygen exchange and waste removal at the neurovascular unit of the choriocapillaris, RPE, and photoreceptors. Understanding AMD as an end-organ vascular disease may move us towards a unifying hypothesis.
Bioadhesive materials have been successfully applied across several ophthalmic fields, yet their translation into vitreoretinal surgery for the repair of retinal breaks and defects remains limited. Conventional strategies, including gas and silicone oil tamponade, continue to dominate retinal stabilization; however, they primarily provide temporary cavity-based support rather than direct interfacial closure of retinal defects and may require postoperative positioning, secondary interventions, or carry tamponade-related complications. Despite advances in biomaterial engineering, broader translation of vitreoretinal bioadhesives remains constrained by posterior-segment-specific barriers, including inadequate wet-surface bonding, residual adherent vitreous at retinal break margins, biomechanical mismatch with the compliant neural retina, unfavorable swelling or degradation behavior, inflammatory or proliferative responses, and challenges in precise intraoperative delivery. Importantly, the required adhesive profile differs by indication: peripheral retinal breaks require focal sealing and resistance to fluid ingress and tractional stress, whereas macular holes, optic disc pit maculopathy, and regenerative retinal repair may require different balances of scaffold support, controlled bioactivity, tissue bridging, fibrosis avoidance, and long-term safety. Hydrogel-based vitreous substitutes can reproduce key viscoelastic properties of the native vitreous but remain largely investigational and primarily provide temporary intraocular support rather than direct focal defect repair. Accordingly, next-generation platforms should be designed not simply for adhesion strength, but for indication-specific function, controlled persistence, intraoperative deliverability, secondary-surgery compatibility, and rigorous preclinical and clinical validation. Rather than serving as tamponade replacements, future bioadhesives may be better conceptualized as precision intraocular platforms that complement volumetric tamponade and retinopexy by adding interface-directed defect sealing, biological modulation, and controlled intraocular delivery. This review critically reappraises vitreoretinal bioadhesive strategies, with primary emphasis on retinal detachment and defect repair, through a problem-driven, retina-centered framework that integrates clinical vitreoretinal evidence with adhesion-engineering principles, providing a barrier-oriented translational perspective for interface-directed retinal repair. Building on this analysis, we outline an innovative perspective on the key functional and translational design principles for next-generation vitreoretinal bioadhesives and propose a mechanism-informed roadmap for scalable clinical translation.
Posterior-segment retinal diseases remain a leading cause of irreversible vision loss worldwide, yet effective treatment continues to be limited by the challenge of achieving sufficient and durable drug exposure within target ocular tissues. Although intravitreal injection has transformed the management of retinal diseases, therapeutic success is determined not only by drug potency but also by transport across retinal interfaces, intraocular distribution, and long-term tissue exposure. Traditionally, these challenges have been attributed primarily to the restrictive nature of the blood-retinal barrier (BRB). In this review, we propose a shift from a barrier-centric view of ocular drug delivery toward a biological gateway framework. We examine how the inner and outer BRB actively regulate therapeutic access through coordinated mechanisms including paracellular restriction, transcellular transport, receptor-mediated trafficking, and disease-associated remodeling. Building upon this biological foundation, we discuss how route-specific delivery strategies-including systemic, intravitreal, suprachoroidal, and subretinal administration-interact with distinct BRB interfaces and influence therapeutic exposure. We further review clinically established and emerging delivery platforms, including sustained-release implants, refillable port-based systems, gene-based therapies, hydrogels, polymeric and lipid-based carriers, biomimetic systems, inorganic and hybrid nanomaterials, and stimulus-responsive platforms. Particular emphasis is placed on how material properties, pharmacokinetic behavior, and biological interactions collectively determine drug localization, retention, and efficacy. Finally, we discuss disease-adaptive delivery systems, cell-specific targeting, quantitative exposure modeling, and translational challenges that influence clinical implementation. By integrating retinal biology, pharmacokinetics, materials science, chemistry, and clinical ophthalmology, this review provides a gateway-centered framework for the rational design of next-generation drug delivery strategies for posterior-segment diseases.
The retina, as an extension of the central nervous system, shares a common embryological origin with the brain. In Alzheimer's disease (AD), studies of human tissue and animal models have revealed that hallmark AD pathologies, including amyloid-β (Aβ) deposits and pathological tau protein tangles, also appear in the retina. These findings, coupled with advances in high-resolution retinal imaging techniques, suggest the potential to detect and characterize AD-related molecular and structural changes in the retina. However, retinal findings across different AD mouse models have significant discrepancies and show limited concordance with human phenotypes, complicating the identification of AD-specific alterations and the selection of optimal models for translational research. Moreover, the temporal sequence and functional significance of retinal abnormalities across the AD continuum, from preclinical stages to mild cognitive impairment and overt dementia, remain poorly defined. Addressing these knowledge gaps is essential to establish the retina as a reliable, non-invasive screening and monitoring approach. This review synthesizes current evidence on the spectrum of retinal alterations in AD, including vascular dysfunction, neuroinflammation, impaired Aβ clearance, and neurodegeneration, as observed in diverse mouse models. We compare these manifestations across species and between different models, highlighting findings along the disease continuum to delineate convergent and divergent pathways. We further discuss how emerging technologies enable the identification of AD-specific retinal alterations, and advocate for a paradigm shift from non-specific morphological assessment (“seeing shapes”) toward molecular-level interrogation (“seeing components”). Interdisciplinary efforts and technological integration are crucial to establish retina as a dynamic mirror of pathology in AD.
Restoring vision through prosthetic devices represents one of the most ambitious frontiers in translational neuroscience. Despite decades of progress, functional outcomes remain highly variable, often falling short of patient expectations, as adapting to restored vision through visual prostheses is a complex process influenced by neural plasticity, perceptual learning, and psychological factors. We propose a five-stage framework that captures the hierarchically dependent yet fragile process of adaptation: Device Activation, Perceptual Calibration, Cognitive Integration, Behavioral Generalization, and Psychosocial Adjustment. Across retinal and cortical prosthesis designs, the earlier stages are frequently achieved, but progression to fluent, real-world use and sustained device acceptance is far less common. The most consistent point of failure lies between Cognitive Integration and Behavioral Generalization: skills acquired in structured training rarely transfer to unconstrained everyday behavior. Technical constraints, insufficient training, and unrealistic expectations frequently stall adaptation at this threshold, leading to frustration, limited daily use, or device abandonment. By examining visual-prosthesis clinical trials, case studies of surgical vision restoration, and evidence from cochlear implants and sensory substitution devices, we identify key determinants of successful adaptation: timely intervention, intuitive device usability, sustained rehabilitation, and long-term psychosocial support. Understanding the mechanisms of adaptation is essential for improving visual prostheses and ultimately enhancing quality of life for individuals with restored sight.
Purpose To develop an international consensus on terminology for adult pathologic myopia based on contemporary imaging, with emphasis on optical coherence tomography (OCT). Methods An international panel of 32 experts in myopia and retinal disease from 13 countries was assembled. The writing group reviewed existing classification systems and the published literature and developed candidate statements organized into six domains: atrophic, mechanical expansion, tractional, neovascular, optic nerve, and retinal detachment. A Delphi process with anonymous voting was used. Consensus was defined a priori as ≥75% agreement (Agree or Strongly Agree). Statements not reaching consensus were revised based on structured feedback and re-voted. Results Forty-four consensus statements were developed that met the predefined threshold for agreement after iterative revision. The mean agreement was 90.6% (median 92.5%). The framework emphasizes structural definitions derived from OCT and multimodal imaging rather than fundus appearance. The nomenclature system organizes manifestations of pathologic myopia into six domains reflecting distinct but often overlapping anatomical and biomechanical processes. Key elements include the central role of choroidal thinning in visual function, recognition of focal chorioretinal loss as a structural endpoint across multiple pathways, and integration of mechanical, tractional, and vascular mechanisms in disease expression. Conclusions This consensus establishes a unified, imaging-based lexicon for adult pathologic myopia grounded in structural anatomy and contemporary imaging. By organizing disease features into six domains and defining entities using OCT, the framework reduces ambiguity, improves reproducibility, and provides a foundation for future classification systems, clinical studies, and therapeutic trials.
Myopia is increasingly recognised as a risk factor strongly linked to visual impairment and sight-threatening ocular disease rather than a simple refractive state. The assumption of causality to these secondary effects underpins myopia control and its long-term public health value. This review considers epidemiologic, longitudinal, mechanistic, interventional, natural-experiment, and genetic evidence to evaluate causality based on Bradford Hill's nine criteria: strength, consistency, specificity, temporality, biological gradient, plausibility, coherence, experiment, and analogy.The graded dose-response relationship between myopia and visual impairment has been demonstrated across multiple populations. Similar patterns are shown for a range of myopia-related ocular diseases. Risks for myopic maculopathy and rhegmatogenous retinal detachment rise steeply with increasing refractive error and axial length, following reproducible log-linear dose-response patterns. Associations with primary open-angle glaucoma are more modest but consistent, supported by longitudinal and genetic causal-inference analyses, though diagnostic overlap in highly myopic eyes complicates interpretation. Cataract relationships are subtype-specific, with the strongest evidence for posterior subcapsular cataract; nuclear cataract associations require caution given lens-induced refractive shifts. The criteria for biological plausibility and the related concept of coherence are strong: axial elongation produces predictable remodelling of sclera, choroid, retina and optic nerve head that can be directly related to clinical phenotypes. Experimental evidence is mostly indirect but also supportive, and analogy with other axial-length-modifying conditions lends further support.Overall, convergent evidence across all of Bradford Hill's criteria supports a causal role of myopia in the major myopia-associated ocular diseases and justifies myopia management as a strategy to limit lifetime axial elongation.
The tumour microenvironment comprising tumour cells, immune infiltrates, stromal components, and the extracellular matrix (ECM) plays a central role in cancer biology, modulating key hallmarks, such as proliferation, immune evasion, and metastasis. The ECM is a dynamic network of collagens, elastin, glycoproteins, and proteoglycans and emerging evidence highlights its role in tumour progression, with loss of matrix organisation altering tumour cell behaviour through both pro- and anti-tumourigenic mechanisms. Uveal melanoma (UM), the most common primary intraocular malignancy in adults, carries a poor prognosis due to its propensity for hepatic metastasis and limited therapeutic options. The uveal tract, comprising the choroid, ciliary body, and iris, relies on highly specialised ECM architectures, and we describe in this review how they support nutrient exchange, lens accommodation, and light regulation while mediating essential biochemical and biomechanical signalling. Understanding this baseline ECM is essential for interpreting the pathological matrix remodelling that occurs in UM. We describe marked compositional differences in ECM between low- and high-metastatic risk primary UM, revealing key mechanisms of tumour progression, including upregulation of structural collagens, fibronectin, laminins, and ECM-remodelling enzymes that activate oncogenic signalling pathways enhancing proliferation, invasion, and metastatic competence. We also explore the hepatic metastatic niche, where stellate cell-driven ECM remodelling promotes a fibrotic, immune-restrictive microenvironment that limits therapeutic efficacy. Finally, we discuss experimental constraints limiting ECM research and highlight advances in decellularised scaffolds, three-dimensional culture systems, and multi-omics technologies to dissect tumour-matrix interactions and uncover ECM-targeted therapeutic vulnerabilities with the potential to improve UM's poor clinical outcomes.
Tear fluid exhibits a unique molecular composition distinct from blood, suggesting the presence of a selective blood-tear barrier (BTB) that regulates molecular exchange between ocular vasculature and the tear film. Although sporadically mentioned in the literature, the structure, functional roles, and mechanisms of disruption of this barrier have not yet been characterized. Based on current evidence, this review proposes a conceptual model in which the BTB comprises three successive compartments: the tear film, the epithelial layer, and the vascular endothelium, with tight junctions playing a central role in maintaining barrier integrity. The BTB appears to play a bidirectional protective role at the ocular surface, shielding the eye from external exposure while preventing the entry of blood-derived factors. This protective function is supported by literature describing interactions with microorganisms, blood-derived factors, drugs, and environmental factors. Similar to other physiological barriers in the body, the BTB is likely susceptible to disruption or breakdown. Potential disruptors include ocular surgery, topical or systemic drugs, contact lens wear, ocular surface diseases, and systemic conditions. Understanding the structure, functional roles, and mechanisms of disruption of the BTB is essential for maintaining ocular surface health and advancing the understanding of ocular surface disease.
Proteins are studied using a wide variety of methods, each with its inherent limitations. Here we analyze the contributions of different methods to our understanding of one of the most extensively studied proteins, arrestin-1, which plays a key role in the regulation of light-evoked signaling of photopigments in the photoreceptor cells in the retina. The data obtained by biochemical and biophysical methods in vitro are consistent with the results of in vivo studies in genetically modified mice and the symptoms seen in human patients. The structures of free arrestin-1 and its complex with rhodopsin provided very detailed information and stimulated structure-function studies. However, while the results of follow-up experiments confirmed some predictions from the crystal structures, they were inconsistent with others. In particular, the arrestin-1 tetramer in solution and in the photoreceptors of living mice was shown to be dramatically different from that revealed by the crystal structures. The prevalent complex (es) of wild type arrestin-1 with rhodopsin also appear to differ from the one in the solved structure of the two interacting mutant proteins. The lessons learned with arrestin-1 likely also apply to other proteins.
Glaucoma is a leading cause of irreversible blindness worldwide, characterized by progressive retinal ganglion cell loss and functional impairment. It is a clinically heterogeneous disease driven by complex, multilayered molecular mechanisms. High-throughput multi-omic technologies are catalyzing a shift toward integrated multi-omic strategies to define glaucoma trajectory and disentangle its pathophysiology. Genomic, transcriptomic, epigenomic, proteomic, metabolomic, lipidomic, microbiome, and phenomic data can help identify biomarkers, molecular endotypes, and pathways that shape glaucoma susceptibility and progression. In this review, we synthesize the current multi-omic landscape in glaucoma, evaluate the strengths and limitations of each modality, and highlight key challenges in integrative approaches. Lastly, we propose conceptual and methodological frameworks for leveraging multi-omics to define the full spectrum of glaucoma, with a focus on optic nerve integrity, mechanistic insights, and precision medicine, while remaining agnostic to evolving omics technologies.
Corneal cross-linking (CXL) has emerged as an important therapeutic strategy for enhancing the biomechanical stability of corneal tissues. Originally introduced to slow or halt the progression of keratoconus (KC), its indications have expanded to include a variety of corneal ectatic and infectious disorders, alongside a growing interest in scleral reinforcement for progressive myopia. Recent advances in cross-linking technologies focused on optimizing reagent formulations, refining delivery strategies, and incorporating functional biomaterials such as nanoparticles, hydrogels, and microneedle-based systems to enhance stromal penetration, achieve controlled release, and reduce procedural invasiveness. Despite these developments, key challenges remain, particularly in achieving consistent treatment depth, maintaining long-term biosafety, and ensuring stable clinical outcomes. This review summarizes the mechanisms of action and classification of contemporary ophthalmic cross-linking methods and agents, evaluating their clinical and experimental outcomes in corneal and scleral cross-linking while weighing their respective strengths and limitations. Furthermore, this review identifies key constraints of current protocols and highlights emerging strategies aimed at improving treatment precision, safety, and reproducibility, thereby providing a conceptual framework for the development of next-generation ophthalmic cross-linking therapies.
