Search Results (38)

Rhegmatogenous retinal detachment (RRD) is a sight-threatening condition involving retinal detachment and the accumulation of fluid in the subretinal space. Proliferative vitreoretinopathy (PVR) is a pathologic complication that develops after RRD surgery, and approximately 5–10% of RRD cases develop post-operative PVR. Prolonged inflammation in the wound healing process, epithelial–mesenchymal transition (EMT), retinal pigment epithelial (RPE) cell migration and proliferation, and epiretinal, intraretinal, and subretinal fibrosis are typical in the formation of PVR. RPE cells undergo EMT and become fibroblast-like cells that migrate to the retina and vitreous, promoting PVR formation. Fibroblasts transform into myofibroblasts, which promote fibrosis by overproducing the extracellular matrix (ECM). RPE cells, fibroblasts, glial cells, macrophages, T lymphocytes, and increased ECM production form contractile epiretinal membranes. Cytokine release, complement activation, RPE cells, glial cells, and endothelial cells are all involved in retinal immune responses. Normally, wounds heal within 4 to 6 weeks, including hemostasis, inflammation, proliferation, and remodeling phases. Properly initiated inflammation, complement activation, and the function of neutrophils and glial cells heal the wound in the first stage. In a retinal wound, glial cells proliferate and fill the injured area. Gliosis tries to protect the neurons and prevent damage, but it becomes harmful when it causes scarring. If healing is complicated, prolonged inflammation leads to pathological fibrosis. Currently, there is no preventive treatment for the formation of PVR, and it is worth studying in the future. Full article

The abnormal growth of irregular new blood vessels into the subretinal or intraretinal space is known as macular neovascularization (MNV). People over 50 are often affected by this disorder, which is typically brought on by age-related macular degeneration. In addition, MNV can be found in people under 50 years of age, who may present primary ophthalmic diseases such as pathological myopia, angioid streaks, traumatic choroidal rupture, or suspected ocular histoplasmosis syndrome. However, it is important to consider a specific set of young individuals who may develop MNV even in the absence of pathological myopia or other identifiable inflammatory, peripapillary, post-traumatic, or degenerative fundus abnormalities. This latter condition is classified as idiopathic MNV. After a literature review focused on young patients affected by one of these two clinical entities, we report the case of a Caucasian young woman suffering for four years from an idiopathic and quiescent MNV that started exuding after childbirth, probably due to the induction with oxytocin, and was treated with intravitreal Aflibercept 2 mg injections. Full article

Photoreceptor degeneration is a major cause of untreatable blindness worldwide and has recently been targeted by emerging technologies, including cell- and gene-based therapies. Cell types of neural lineage have shown promise for replacing either photoreceptors or retinal pigment epithelial cells following delivery to the subretinal space, while cells of bone marrow lineage have been tested for retinal trophic effects following delivery to the vitreous cavity. Here we explore an alternate approach in which cells from the immature neural retinal are delivered to the vitreous cavity with the goal of providing trophic support for degenerating photoreceptors. Rat and human retinal progenitor cells were transplanted to the vitreous of rats with a well-studied photoreceptor dystrophy, resulting in substantial anatomical preservation and functional rescue of vision. This work provides scientific proof-of-principle for a novel therapeutic approach to photoreceptor degeneration that is currently being evaluated in clinical trials. Full article

The mouse model of laser-induced choroidal neovascularization (LI-CNV) has been widely used to study neovascular age-related macular degeneration; however, it still lacks a comprehensive characterization. Here, CNV was induced in the eyes of 12-week-old C57BL/6J male mice by argon laser irradiation. We studied the CNV lesion progression of an LI-CNV mouse cohort by using multimodal imaging (color fundus, optical coherence tomography (OCT), and fluorescence angiography, focal electroretinography features for 14 days, and related cytokines, angiogenic factors, and reactive gliosis for 5 days. CNV lesions involving the rupture of the Bruch’s membrane were confirmed using funduscopy and OCT after laser photocoagulation. During the initial stage, from the CNV induction until day 7, CNV lesions presented leakage observed by using fluorescence angiography and a typical hyperreflective area with cell infiltration, subretinal leakage, and degeneration of photoreceptors observed through OCT. This correlated with decreased retinal responses to light. Moreover, inflammatory and angiogenic markers were reduced to basal levels in the first 5 days of CNV progression. In contrast, reactive gliosis and the VEGF expression in retinal sections were sustained, with infiltration of endothelial cells in the subretinal space. In the second stage, between days 7 and 14 post-induction, we observed stabilization of the CNV lesions, a hyperfluorescent area corresponding to the formation of fibrosis, and a partial rescue of retinal function. These findings suggest that the LI-CNV lesion development goes through an acute phase during the first seven days following induction, and then the CNV lesion stabilizes. According to these results, this model is suitable for screening anti-inflammatory and anti-angiogenic drugs in the early stages of LI-CNV. At the same time, it is more convenient for screening anti-fibrotic compounds in the later stages. Full article

Background: Although anti-vascular endothelial growth factor (anti-VEGF) therapy is the first choice of treatment for eyes with neovascular age-related macular degeneration (AMD), it sometimes results in retinal pigment epithelium (RPE) tears. This study presents the detailed clinical characteristics of RPE tears to help predict their occurrence before anti-VEGF therapy initiation. Methods: This study retrospectively analyzed neovascular age-related macular degeneration (nAMD) patients who visited the Kyushu University Hospital and started anti-VEGF therapy between April 2013 and June 2020. Using medical records, we collected the clinical data of patients with RPE tears, including age, sex, best-corrected visual acuity (BCVA), number of anti-VEGF drug injections and the type and size of pigment epithelial detachment (PED). Results: RPE tears occurred in 16 (1.50%) eyes of 16 patients in all 1068 nAMD eyes of 987 patients. The mean age of these patients with RPE tear was 81.7 ± 8.7 years. Fifteen eyes had typical AMD and one eye had polypoidal choroidal vasculopathy. The mean number of anti-VEGF drug injections before RPE tears was 5.0 ± 5.1. All patients experienced PED before the RPE tear (hemorrhagic, 4 eyes; serous vascular, 2 eyes; fibrovascular, 10 eyes). The average PED height and area were 615.7 ± 175.3 μm and 21.0 ± 7.2 mm², respectively. The sub-RPE cleft was observed in 10 eyes. The logMAR BCVA immediately after the RPE tear (0.73 ± 0.40) at 6 months (0.86 ± 0.51) and 12 months (0.84 ± 0.43) after the RPE tear were significantly worse than that before the RPE tear (0.58 ± 0.31; p < 0.05). The BCVA of patients with RPE tears that spread to the fovea was poorer than that of patients without RPE tears. Conclusions: In patients with nAMD, RPE tears tended to occur in typical AMD eyes with high or large PEDs, and sub-RPE clefts. The visual prognosis depended on whether the RPE tear included the fovea. Full article

Deposition of calcium-containing minerals such as hydroxyapatite and whitlockite in the subretinal pigment epithelial (sub-RPE) space of the retina is linked to the development of and progression to the end-stage of age-related macular degeneration (AMD). AMD is the most common eye disease causing blindness amongst the elderly in developed countries; early diagnosis is desirable, particularly to begin treatment where available. Calcification in the sub-RPE space is also directly linked to other diseases such as Pseudoxanthoma elasticum (PXE). We found that these mineral deposits could be imaged by fluorescence using tetracycline antibiotics as specific stains. Binding of tetracyclines to the minerals was accompanied by increases in fluorescence intensity and fluorescence lifetime. The lifetimes for tetracyclines differed substantially from the known background lifetime of the existing natural retinal fluorophores, suggesting that calcification could be visualized by lifetime imaging. However, the excitation wavelengths used to excite these lifetime changes were generally shorter than those approved for retinal imaging. Here, we show that tetracycline-stained drusen in post mortem human retinas may be imaged by fluorescence lifetime contrast using multiphoton (infrared) excitation. For this pilot study, ten eyes from six anonymous deceased donors (3 female, 3 male, mean age 83.7 years, range 79–97 years) were obtained with informed consent from the Maryland State Anatomy Board with ethical oversight and approval by the Institutional Review Board. Full article

Retinal detachment (RD) is a neurodegenerative blinding disease caused by plethora of clinical conditions. RD is characterized by the physical separation of retina from the underlying retinal pigment epithelium (RPE), eventually leading to photoreceptor cell death, inflammation, and vision loss. Albeit the activation of complement plays a critical role in the pathogenesis of RD, the retinal cellular source for complement production remains elusive. Here, using C3 tdTomato reporter mice we show that retinal injury upregulates C3 expression, specifically in Müller cells. Activation of the complement cascade results in the generation of proinflammatory cleaved products, C3a and C5a, that bind C3aR and C5aR1, respectively. Our flow cytometry data show that retinal injury significantly upregulated C3aR and C5aR1 in microglia and resulted in the infiltration of peripheral immune cells. Loss of C3, C5, C3aR or C5aR1 reduced photoreceptor cell death and infiltration of microglia and peripheral immune cells into the sub-retinal space. These results indicate that C3/C3aR and C5/C5aR1 play a crucial role in eliciting photoreceptor degeneration and inflammatory responses in RD. Full article

Interphotoreceptor retinoid-binding protein (IRBP) is an abundant glycoprotein in the subretinal space bound by the photoreceptor (PR) outer segments and the processes of the retinal pigmented epithelium (RPE). IRBP binds retinoids, including 11-cis-retinal and all-trans-retinol. In this study, visual function for demanding visual tasks was assessed in IRBP knock-out (KO) mice. Surprisingly, IRBP KO mice showed no differences in scotopic critical flicker frequency (CFF) compared to wildtype (WT). However, they did have lower photopic CFF than WT. IRBP KO mice had reduced scotopic and photopic acuity and contrast sensitivity compared to WT. IRBP KO mice had a significant reduction in outer nuclear layer (ONL) thickness, PR outer and inner segment, and full retinal thickness (FRT) compared to WT. There were fewer cones in IRBP KO mice. Overall, these results confirm substantial loss of rods and significant loss of cones within 30 days. Absence of IRBP resulted in cone circuit damage, reducing photopic flicker, contrast sensitivity, and spatial frequency sensitivity. The c-wave was reduced and accelerated in response to bright steps of light. This result also suggests altered retinal pigment epithelium activity. There appears to be a compensatory mechanism such as higher synaptic gain between PRs and bipolar cells since the loss of the b-wave did not linearly follow the loss of rods, or the a-wave. Scotopic CFF is normal despite thinning of ONL and reduced scotopic electroretinogram (ERG) in IRBP KO mice, suggesting either a redundancy or plasticity in circuits detecting (encoding) scotopic flicker at threshold even with substantial rod loss. Full article

The prevalent cause of retinal detachment is a full-thickness retinal break and the ingress of fluid into the subretinal space. To prevent progression of the detachment, laser photocoagulation (LPC) lesions are placed around the break in clinical practice to seal the tissue. Unlike the usual application under indirect ophthalmoscopy, we developed a semi-automatic treatment planning software based on a sequence of optical coherence tomography (OCT) scans to perform navigated LPC treatment. The depth information allows demarcation of the border where the neurosensory retina is still attached to the retinal pigment epithelium (RPE), which is critical for prevention of detachment progression. To evaluate the method, artificially provoked retinal breaks were treated in seven ex-vivo porcine eyes. Treatment outcome was assessed by fundus photography and OCT imaging. The automatically applied lesions surrounding each detachment (4.4–39.6 mm²) could be identified as highly scattering coagulation regions in color fundus photography and OCT. Between the planned and applied pattern, a mean offset of 68 µm (SD ± 16.5 µm) and a mean lesion spacing error of 5 µm (SD ± 10 µm) was achieved. The results demonstrate the potential of navigated OCT-guided laser retinopexy to improve overall treatment accuracy, efficiency, and safety. Full article

The complement system is crucial for immune surveillance, providing the body’s first line of defence against pathogens. However, an imbalance in its regulators can lead to inappropriate overactivation, resulting in diseases such as age-related macular degeneration (AMD), a leading cause of irreversible blindness globally affecting around 200 million people. Complement activation in AMD is believed to begin in the choriocapillaris, but it also plays a critical role in the subretinal and retinal pigment epithelium (RPE) spaces. Bruch’s membrane (BrM) acts as a barrier between the retina/RPE and choroid, hindering complement protein diffusion. This impediment increases with age and AMD, leading to compartmentalisation of complement activation. In this review, we comprehensively examine the structure and function of BrM, including its age-related changes visible through in vivo imaging, and the consequences of complement dysfunction on AMD pathogenesis. We also explore the potential and limitations of various delivery routes (systemic, intravitreal, subretinal, and suprachoroidal) for safe and effective delivery of conventional and gene therapy-based complement inhibitors to treat AMD. Further research is needed to understand the diffusion of complement proteins across BrM and optimise therapeutic delivery to the retina. Full article

Wnt/β-catenin signaling is essential for embryonic eye development in both the anterior eye and retina. WNT2B, a ligand and activator of the Wnt/β-catenin pathway, assists in the development of the lens and peripheral regions of the eye. In humans WNT2B mutations are associated with coloboma and WNT2B may also assist in retinal progenitor cell differentiation in chicken, yet the potential role of WNT2B in retinal neuronal development is understudied. This study explored the effects of WNT2B on retinal neuronal and vascular formation using systemic Wnt2b knockout (KO) mice generated by crossing Wnt2b^flox/flox (fl/fl) mice with CMV-cre mice. Wnt2b KO eyes exhibited relatively normal anterior segments and retinal vasculature. Ectopic formation of rod photoreceptor cells in the subretinal space was observed in Wnt2b KO mice as early as one week postnatally and persisted through nine-month-old mice. Other retinal neuronal layers showed normal organization in both thickness and lamination, without detectable signs of retinal thinning. The presence of abnormal photoreceptor genesis was also observed in heterozygous Wnt2b mice, and occasionally in wild type mice with decreased Wnt2b expression levels. Expression of Wnt2b was found to be enriched in the retinal pigment epithelium compared with whole retina. Together these findings suggest that WNT2B is potentially involved in rod photoreceptor genesis during eye development; however, potential influence by a yet unknown genetic factor is also possible. Full article

An ultrathin nano photodiode array fabricated in a flexible substrate can be an ideal therapeutic replacement for degenerated photoreceptor cells damaged by Age-related Macula Degeneration (AMD) and Retinitis Pigmentosa (RP), such as retinal infections. Silicon-based photodiode arrays have been attempted as artificial retinas. Considering the difficulties caused by hard silicon subretinal implants, researchers have diverted their attention towards organic photovoltaic cells-based subretinal implants. Indium-Tin Oxide (ITO) has been a favorite choice as an anode electrode. A mix of poly(3-hexylthiophene) and [6,6]-phenyl C61-butyric acid methyleste (P3HT: PCBM) has been utilized as an active layer in such nanomaterial-based subretinal implants. Though encouraging results have been obtained during the trial of such retinal implants, the need to replace ITO with a suitable transparent conductive electrode will be a suitable substitute. Further, conjugated polymers have been used as active layers in such photodiodes and have shown delamination in the retinal space over time despite their biocompatibility. This research attempted to fabricate and characterize Bulk Hetero Junction (BHJ) based Nano Photo Diode (NPD) utilizing Graphene–polyethylene terephthalate (G–PET)/semiconducting Single-Wall Carbon Nano Tubes (s-SWCNT): fullerene (C₆₀) blend/aluminium (Al) structure to determine the issues in the development of subretinal prosthesis. An effective design approach adopted in this analysis has resulted in developing an NPD with an Efficiency of 10.1% in a non-ITO-driven NPD structure. Additionally, the results show that the efficiency can be further improved by increasing active layer thickness. Full article

Choroidal neovascularization (CNV) is a pathological angiogenesis of the choroidal plexus of the retina and is a key feature in the wet form of age-related macular degeneration. Mononuclear phagocytic cells (MPCs) are known to accumulate in the subretinal space, generating a chronic inflammatory state that promotes the growth of the choroidal neovasculature. However, how the MPCs are recruited and activated to promote CNV pathology is not fully understood. Using genetic and pharmacological tools in a mouse model of laser-induced CNV, we demonstrate a role for the p75 neurotrophin receptor (p75^NTR) in the recruitment of MPCs, in glial activation, and in vascular alterations. After laser injury, expression of p75^NTR is increased in activated Muller glial cells near the CNV area in the retina and the retinal pigmented epithelium (RPE)-choroid. In p75^NTR knockout mice (p75^NTR KO) with CNV, there is significantly reduced recruitment of MPCs, reduced glial activation, reduced CNV area, and the retinal function is preserved, as compared to wild type mice with CNV. Notably, a single intravitreal injection of a pharmacological p75^NTR antagonist in wild type mice with CNV phenocopied the results of the p75^NTR KO mice. Our results demonstrate that p75^NTR is etiological in the development of CNV. Full article

In dry age-related macular degeneration (AMD), inflammation plays a key role in disease pathogenesis. Innate immune cells such as microglia and neutrophils infiltrate the sub-retinal space (SRS) to induce chronic inflammation and AMD progression. But a major gap in our understanding is how these cells interact with each other in AMD. Here, we report a novel concept of how dynamic interactions between microglia and neutrophils contribute to AMD pathology. Using well-characterized genetically engineered mouse models as tools, we show that in the diseased state, retinal pigmented epithelial (RPE) cells trigger pro-inflammatory (M1) transition in microglia with diminished expression of the homeostatic marker, CX3CR1. Activated microglia localize to the SRS and regulate local neutrophil function, triggering their activation and thereby inducing early RPE changes. Ligand receptor (LR)-loop analysis and cell culture studies revealed that M1 microglia also induce the expression of neutrophil adhesion mediators (integrin β1/α4) through their interaction with CD14 on microglia. Furthermore, microglia-induced neutrophil activation and subsequent neutrophil-mediated RPE alterations were mitigated by inhibiting Akt2 in microglia. These results suggest that the Akt2 pathway in microglia drives M1 microglia-mediated neutrophil activation, thereby triggering early RPE degeneration and is a novel therapeutic target for early AMD, a stage without treatment options. Full article

Age-related macular degeneration (AMD) is a global leading cause of visual impairment in older populations. ‘Wet’ AMD, the most common subtype of this disease, occurs when pathological angiogenesis infiltrates the subretinal space (choroidal neovascularization), causing hemorrhage and retinal damage. Gold standard anti-vascular endothelial growth factor (VEGF) treatment is an effective therapy, but the long-term prevention of visual decline has not been as successful. This warrants the need to elucidate potential VEGF-independent pathways. We generated blood out-growth endothelial cells (BOECs) from wet AMD and normal control subjects, then induced angiogenic sprouting of BOECs using a fibrin gel bead assay. To deconvolute endothelial heterogeneity, we performed single-cell transcriptomic analysis on the sprouting BOECs, revealing a spectrum of cell states. Our wet AMD BOECs share common pathways with choroidal neovascularization such as extracellular matrix remodeling that promoted proangiogenic phenotype, and our ‘activated’ BOEC subpopulation demonstrated proinflammatory hallmarks, resembling the tip-like cells in vivo. We uncovered new molecular insights that pathological angiogenesis in wet AMD BOECs could also be driven by interleukin signaling and amino acid metabolism. A web-based visualization of the sprouting BOEC single-cell transcriptome has been created to facilitate further discovery research. Full article