Intravitreal Injection Research Articles

Common Practice Patterns in the Diagnosis and Management of Acute Retinal Necrosis: A Survey Study of Uveitis Specialists

ABSTRACT Purpose Due to lack of large randomized clinical trials to determine best practices in treating acute retinal necrosis (ARN), there is not a clear consensus amongst ophthalmologists on how to best manage this potentially blinding condition. The aim of this study is to survey common practice patterns and analyze the factors that affect ophthalmologists’ management of ARN. Methods An anonymous survey was distributed to uveitis and retina specialists who are members of the American Uveitis Society (AUS) via email to query practice patterns regarding ARN. The survey included 22 questions with an additional 10 questions based on response. Survey question topics included demographic information, diagnostic testing, antiviral therapy, corticosteroids, and surgical procedures. Results 67 surveys were included for analysis. Most respondents (87%) always or frequently obtain intraocular aqueous fluid for diagnostic PCR testing. The majority of respondents would administer intravitreal antiviral injections to a unilateral immunocompetent ARN patient (67%), but would be even more likely to do so for a bilateral immunosuppressed ARN patient (87%). Respondents tend to treat ARN with systemic rather than local corticosteroids, with the majority (63%) of respondents initiating corticosteroid treatment 48 hours after treatment. Most respondents (79%) never perform a vitrectomy to manage ARN unless the patient has a retinal detachment or tear. The majority (63%) rarely or never perform prophylactic laser barricade, but may consider laser treatment if there is extensive retinal involvement. Conclusion Current practice patterns for diagnosis and management of ARN among AUS members generally align with the suggested practices outlined by the American Academy of Ophthalmology.

Diffusion of nanoparticles in heterogeneous hydrogels as vitreous humour in vitro substitutes

Nanomedicine has the potential to increase the biostability of drugs to treat retinal diseases, improving their performance and decreasing the required number of intravitreal injections. However, accurate pharmacokinetic studies of these nanoparticle-drug conjugates, nanoparticle motion across the vitreous humour and interaction with the retinal cell layers still need to be investigated. Existing nanoparticle tracking techniques require fluorescent labels, which can impact cytotoxicity, nanoparticles’ motion, protein interactions, and cell internalization. In this study, a real-time label-free tracking technology, for single nanoparticles in an optical microscope based on the optical phenomena of caustics, was used to characterise the diffusion of nanoparticles in agar-hyaluronic acid hydrogels, previously validated as vitreous humour substitutes for in vitro models. The results demonstrated that the diffusion of nanoparticles through these hydrogels was heterogeneous, and that nanoparticle size had an important role in nanoparticle distribution across and within in vitro vitreous substitutes. These findings suggest that nanoparticle diameter is a critical parameter for designing novel therapeutics for retinal diseases. Moreover, nanoparticle charge did not affect nanoparticle diffusion or distribution in these synthetic hydrogels. The use of caustics in optical microscopy has been demonstrated to be a reproducible, inexpensive technique for screening novel therapeutics in eye in vitro models.

Особенности отдаленного наблюдения пациентов после оперативного лечения ретинопатии недоношенных

Case study Special features of long-term follow-up in patients after surgical treatment of retinopathy of prematurity E.E. Sidorenko, E.I. SidorenkoI, A.I. Krapivkin, O.A. Kushchuk, D.V. Miguel, E.V. Ermolaeva, V.E. Loskutova, H.T. Le Voino-Yasenetsky Scientific and Practical Center for Specialized Medical Care, Moscow, Russian Federation Pirogov Russian National Research Medical University, Moscow, Russian Federation This article describes a long-term clinical outcomes and functional outcomes of a patient with retinopathy of prematurity stage 4, plus disease, aggressive posterior, who has a history of 2 times treatment with laser retinal coagulation in both eyes, single injection of a vascular endothelial growth factor inhibitor in both eyes and vitrectomy in left eye. As a result of regular dynamic monitoring of the patient in the long-term postoperative period, application of modern and highly informative research methods, exudative macular degeneration was detecet – retinal detachment and vision loss was prevented timely. Key words: retinopathy of prematurity, laser coagulation of the retina, intravitreal injection of vascular endothelial growth factor inhibitor, vitreoretinal surgery, optical coherent tomography, assessment of cognitive functions using the WPPSI-IV method

Incidence and outcomes of post-operative endophthalmitis following elective phacoemulsification cataract surgery, between 2015 and 2022.

Cataract surgery remains the commonest ophthalmic surgical procedure in the UK. Post-operative endophthalmitis (POE) is a sight-threatening complication. This study presents the incidence and outcomes of POE within Moorfields Eye Hospital NHS Foundation Trust (MEH) in London, UK. We conducted a retrospective, tertiary-centre study of the incidence and outcomes of POE following elective phacoemulsification cataract surgery between 2015 and 2022. We report a rate of 18 out of 154 826 (0.012%) cases of POE within seven weeks of cataract surgery. The age range was 43-87 years (mean age 67.1 years), and the male-to-female ratio was 1:1. Two cases were associated with intraoperative vitreous loss, one with anterior capsular tear extending to posterior capsular tear and the other with posterior capsular tear and dropped fragment. Two cases had a concomitant intravitreal injection, one of Triamcinolone Acetonide and the other of Dexamethasone implant (Ozurdex®), to manage chronic uveitic macular oedema. The majority of samples (89.9%) resulted in Gram-positive species. A final best corrected visual acuity (BCVA) of Snellen 6/36 or better was achieved in 12/18 (66.67%). The time from cataract surgery to suspicion of POE ranged from 3 to 44 days (mean 15.8 days). Eight cases (44.4%) required pars plana vitrectomy (PPV). We demonstrate an incidence of POE of 0.012% following phacoemulsification at MEH from January 2015 to December 2022. Such results are a testament to high-quality surgery, training supervision and post-operative care whilst adhering to local and international standards.

Formulation development of thermoresponsive quercetin nanoemulgels and in vitro investigation of their inhibitory activity on vascular endothelial growth factor-A inducing neovascularization from the retinal pigment epithelial cells

Quercetin is one of natural flavonoids. It has ability to hinder neovascularization in cancers by reducing activities of the vascular endothelial growth factor-A (VEGF-A). Regarding this particular activity, quercetin thus has a potential for managing the vasoproliferative retinopathies. Unfortunately, its hydrophobicity resulted in poor ocular bioavailability. A suitable intravitreal formulation should be developed to overcome this problem. This study was conducted to optimize formulations of thermoresponsive quercetin nanoemulgels (T-QNE-Gs) for intravitreal injection and to examine their in vitro for their inhibitory activity on VEGF-A inducing neovascularization from the retinal pigment endothelial cells. T-QNE-Gs were prepared by incorporation of gels consisting of various ratios of Pluronic F127 (F127) to Pluronic F68 (F68), with a fixed concentration of hydroxypropyl methylcellulose, into a quercetin nanoemulsion concentrate. The optimum formulation of T-QNE-Gs was 2F127–1F68 containing F127 and F68 at a 2:1 ratio. After sterilization, S–2F127–1F68 was obtained. The S–2F127–1F68 could flow properly at a room temperature (27 ± 1 °C) and became gel at a temperature of the posterior eye segment (35 ± 1 °C). It effectively inhibited migration and tube formation of the human umbilical vein endothelial cells and suppressed the VEGF-A gene expression and VEGF-A protein levels in the arising retinal pigment epithelial cells under a hypoxic condition. Therefore, S–2F127–1F68 had a potential for treatment of the vassoproliferative retinopathies and can be used for further investigation in animal models.

Endophthalmitis following intravitreal injections administered by junior medical officers in rural Western Australia.

Patients in rural Australia have limited access to intravitreal treatments due to a maldistribution of the ophthalmology workforce. To improve access, a novel outreach service model was implemented whereby junior medical staff administered intravitreal injections under a supervising ophthalmology consultant. This model involves outreach visits in hospitals, mobile clinics and a remote hub with intravitreal injections administered by junior doctors overseen by an ophthalmologist. The article explores the safety of this approach with respect to the rate of post-injection endophthalmitis. A retrospective audit was conducted by the Lions Outback Vision outreach ophthalmology service from 2017 to mid-2023. The number of injections, locations, diagnoses, intravitreal agents used, designation of administering doctor and cases of endophthalmitis were reviewed. A 12 632 intravitreal injections were administered across 32 locations throughout rural Western Australia in the 6.5-year period. Three cases of endophthalmitis occurred representing a rate of 0.0237%. The rate of endophthalmitis in the outreach service is comparable to other centres. The outreach model with supervising ophthalmology consultant support in person or via telehealth and administration of injections by junior medical staff has improved access for underserved or marginalised populations.

Hyperglycemia-independent neonatal streptozotocin-induced retinopathy (NSIR) in rats.

Introduction: Chemicals, such as MNU (N-methyl-N-nitrosourea) and NaIO3 (sodium iodate), are widely used to induce retinal degeneration in rodents. Streptozotocin (STZ) is an analog of N-acetyl glucosamine in which an MNU moiety is linked to a hexose and has a special toxic effect on insulin-producing pancreatic β-cells. It is commonly used to induce hyperglycemia to model diabetes. While intracerebroventricular injection of STZ can produce Alzheimer's disease independent of hyperglycemia, most retinal studies using STZ focus on the effects of hyperglycemia on the retina, but whether STZ has any impact on retinal cells independent of hyperglycemia is unknown. We aimed to investigate the role of cytotoxicity of STZ in rat retina. Methods: Intravitreal or subcutaneous injection of STZ was performed on newborn rats. Electroretinogram (ERG) and H&E staining investigated retinal function and morphological changes. Retinal cell types, cell death, proliferation, inflammation, and angiogenesis were studied by immunostaining. RNA sequencing was performed to examine the transcriptome changes of retinal cells after intravitreal injection of STZ. Results: Intravitreal (5μg or 10μg) or subcutaneous (30mg/kg) injection of STZ at the early stage of newborn rats couldn't induce hyperglycemia but caused NSIR (Neonatal STZ-induced retinopathy), including reduced ERG amplitudes, retinal rosettes and apoptosis, cell cycle arrest, microglial activation, and delayed retinal angiogenesis. STZ did not affect the early-born retinal cell types but significantly reduced the late-born ones. Short-term and long-term hyperglycemia had no significant effects on the NSIR phenotypes. RNA sequencing revealed that STZ induces oxidative stress and activates the p53 pathway of retinal cells. Locally or systemically, STZ injection after P8 couldn't induce SINR when all retinal progenitors exit the cell cycle. Conclusion: NSIR in rats is independent of hyperglycemia but due to STZ's direct cytotoxic effects on retinal progenitor cells. NSIR is a typical reaction to STZ-induced retinal oxidative stress and DNA damage. This significant finding suggests that NSIR may be a valuable model for studying retinal progenitor DNA damage-related diseases, potentially leading to new insights and treatments.

Curcumin and Baicalin Co-Loaded Nanoliposomes for Synergistic Treatment of Non-Small Cell Lung Cancer.

Currently, the treatment of patients with advanced non-small cell lung cancer (NSCLC) mainly relies on traditional chemotherapeutic drugs; however, most of them have limited therapeutic effects and high toxicity. Some natural products with good therapeutic efficacy and low toxicity and side effects are limited in clinical application due to their low solubility and bioavailability. In this study, a nanoliposome drug-carrying system (Lip-Cur/Ba) was developed for the co-delivery of curcumin (Cur) and baicalin (Ba) using the thin-film hydration method. In vitro experiments demonstrated that Lip-Cur/Ba had a strong killing effect on A549 cells, and the inhibitory effect of Lip-Cur/Ba on A549 cells was enhanced by 67.8% and 51.9% relative to that of the single-carrier system, which could reduce the use of a single-drug dose (Lip-Cur and Lip-Ba), delay the release rate of the drug and improve the bioavailability. In vivo experiments demonstrated the antitumor activity of Lip-Cur/Ba by intravitreal injection in BALB/c mice, and there were no obvious toxic side effects. This study provides a new idea for curcumin and baicalin to be used in the co-treatment of NSCLC by constructing a new vector.

Wide-Field Optical Coherence Tomography in Patients with Diabetic Macular Edema.

Background: The goal of the study was to analyze variations in central, perifoveal, and peripheral retinal thickness (RT) and choroidal thickness (CT) in patients with diabetic macular edema (DME) measured with ultra-wide-field optical coherence tomography (UWF-OCT). Additionally, correlations between RT and CT in the central, perifoveal, and peripheral sectors and the presence of selected systemic factors were evaluated. Methods: A total of 74 consecutive adult diabetic patients with DME and 75 healthy controls were included. Study participants were divided into three groups: DME patients without panretinal photocoagulation (PRP; 84 eyes), DME patients after PRP (56 eyes), and healthy controls (125 eyes). RT and CT were analyzed in three zones: a central circle of 3 mm diameter (central), a ring contained between a centered 9 mm circle and the central 3 mm circle (perifoveal), and a second, more peripheral ring between centered 18 mm and 9 mm circles (peripheral). Additionally, DME subgroups were analyzed according to the correlation of RT and CT with age, axial length, best corrected visual acuity (BCVA), diabetes duration, insulin therapy duration, body mass index (BMI), glycosylated hemoglobin (HbA1c) values, intravitreal injection (IVI) count, and the advancement of retinopathy assessed by the simplified diabetic retinopathy severity scale (DRSS). Results: The increase in RT in the far peripheral sectors in DME patients was not significant. The increases in central and perifoveal RT and lower values of CT in PRP-naive DME patients were strongly associated with poorer BCVA. Patients with DME after PRP presented with BCVA improvements significantly related to the number of IVIs. The amount of DME and RT in peripheral sectors were both independent of systemic factors such as BMI, duration of diabetes, duration of insulin intake, retinopathy severity, and HbA1c levels. Conclusions: Peripheral retinal sectors in DME patients are less affected in terms of increase in their thickness compared to central ones. Functional and morphological associations of DME with UWF-OCT testing refer to central and perifoveal sectors.

Safety and Efficacy of Multiple Escalating Doses of RC28-E for Neovascular Age-Related Macular Degeneration: A Phase 1b Trial.

To assess the safety and efficacy of repeated intravitreal injections of RC28-E, a novel bispecific antibody that simultaneously binds vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in patients with neovascular age-related macular degeneration (AMD). This was a prospective, multicenter, open-label clinical trial; 37 patients with choroidal neovascularization secondary to AMD and best-corrected visual acuity (BCVA) letter scores between 73 and 34 were enrolled. Treatment regimens consisted of a 3-month loading phase and a pro re nata (PRN) maintenance phase. This study included three treatment groups: the 0.5, 1.0, and 2.0mg RC28-E groups, with escalating doses ranging from 0.5 to 2.0mg. Patients were evaluated monthly for 48weeks. Safety was assessed based on ocular and systemic adverse events (AEs), pharmacokinetic characteristics, and the presence of anti-RC28-E antibodies. Efficacy was assessed using the mean change in BCVA and central subfield thickness (CST) from baseline to week 48. Most AEs were mild or moderate. The most common AE was a minor injection-related subconjunctival hemorrhage (16.2%). The AEs did not increase with dose or repeated injections. At week 48, mean improvements in BCVA from baseline in the 0.5, 1.0, and 2.0mg groups were 6.1 ± 8.3, 9.9 ± 10.7, and 7.6 ± 9.38 letters, respectively; mean reductions in CST in the three groups were 112.1 ± 160.5, 175.1 ± 212.4, and 128.7 ± 145.8μm, respectively. The serum RC28-E concentrations in 95% of the patients were below the quantification limit of the assay. No significant change from baseline was observed in the mean plasma concentrations of VEGF or FGF over the 48weeks of treatment. Pre-treatment antibodies to RC28-E were detected in 1 of the 37 patients. Antibodies to RC28-E were detected in two patients after dosing with RC28-E for 48weeks. RC28-E was well tolerated and exhibited an overall favorable safety profile with evidence of improvements in BCVA and anatomical parameters.

Bilateral cystoid macular edema as the presenting feature of chronic myeloid leukemia.

Ophthalmic disease may rarely be a presenting feature of chronic myeloid leukemia (CML). We report a case of a 53-year-old man with type 1 diabetes mellitus who presented with a rapid onset of bilateral blurred vision. He was noted to have bilateral macular edema and was initially treated for presumed diabetic macular edema (DME) with intravitreal alifbercept injections. One month later, there was complete resolution of his macular edema. Review of his history and imaging revealed features atypical for DME, specifically; the rapid onset of bilateral blurred vision over 2-3 weeks, numerous cotton wool spots within the macula, the absence of any exudates, the symmetrical macular edema with a "vaulted ceiling" appearance (more typical of cystoid macular edema) and the dramatic response to a single intravitreal aflibercept injection. One week after his intravitreal injection, the patient was diagnosed with CML following marked leucocytosis on a routine blood test by his general practitioner. Although uncommon, sudden onset bilateral edema in the absence of other chronic diabetic changes should prompt consideration of an underlying haematological cause. This case highlights the importance of considering CML as a differential diagnosis in patients presenting with sudden onset, bilateral cystoid macular oedema. Vigilance is especially important in patients with co-existing diabetic retinopathy as the clinical features of leukemic retinopathy can overlap. Furthermore, the diagnosis of CML in a patient with diabetes mellitus should prompt extra observation for accelerated worsening of diabetic retinopathy.

Summary of the Therapeutic Options for Patients with Dry and Neovascular AMD.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness worldwide and a severe medical and social problem. The steadily increasing number of patients is related to the aging of the population. So far, many factors affecting the development of AMD have been identified, which can be divided into non-modifiable, including genetic factors, age, and sex, and modifiable or environmental factors, such as smoking, poor diet, and hypertension. Early stages of age-related macular degeneration are characterized by fundus drusen and abnormalities in the retinal pigment epithelium. In late stages, geographic atrophy and choroidal neovascularization (CNV) are observed. The treatment of AMD, especially its advanced forms, is very challenging. Intensive research has made it possible to treat advanced stages of the dry form of AMD with pegcetacoplan and avacincaptad pegol, new drugs approved for use in the US. Pegcetacoplan targets the C3 and avacincaptad pegol targets the C5, the pivotal proteins of the complement cascade. The drugs are administered by intravitreal injection. The gold standard for neovascular AMD (nAMD) consists of intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) drugs such as bevacizumab, ranibizumab, aflibercept, brolucizumab, and faricimab. Treatment can be administered according to the fixed, pro-re-nata, and treat-and-extend regimens. The latter seems to have the best effect on improving visual acuity (VA) and the maximum therapeutic benefit. The search continues for the best ways to deliver intravitreal drugs. Current methods include sustained-release implants and hydrogel platforms for drug release, while the most promising future pathways for treating dry and nAMD are stem cell and gene therapy.

CHOROIDAL NEOVASCULARIZATION AS A LATE COMPLICATION OF SYPHILITIC CHORIORETINITIS MANAGED WITH INTRAVITREAL AFLIBERCEPT.

To report a rare case of choroidal neovascular membrane (CNV) developed three years after acquired syphilitic chorioretinitis successfully treated with intravitreal aflibercept. Case report. A 44-year-old woman with bilateral decreased vision and a history of syphilitic chorioretinitis 3 years prior to presentation. Her best-corrected visual acuity was <20/400 in the right eye and 20/70 in the left eye. There was no evidence of anterior chamber or vitreous inflammation. Fundoscopy revealed a fibrovascular macular lesion associated with hemorrhages in both eyes. Optical coherence tomography (OCT) and OCT angiography confirmed the diagnosis of bilateral CNV. After ruling out other systemic diseases, the diagnosis of CNV as a late complication of syphilitic chorioretinitis was established. Although treatment was not recommended in the right eye, the left eye was treated with 3 monthly intravitreal injections of aflibercept as a solo therapy. Three weeks after the last injection, the visual acuity improved to 20/25 and remained stable at the 6-month follow-up with no evidence of CNV reactivation. Choroidal neovascular membranes can occur as a late complication of syphilitic chorioretinitis. Solo treatment with intravitreal injections of the anti-vascular endothelial growth factor aflibercept effectively controlled CNV activity and improved visual acuity.

Best Vitelliform Macular Dystrophy Presenting with Choroidal Neovascular Membrane in an Adolescent: A Case Report and a Review of the Literature

Abstract An 11-year-old boy presented to the retina outpatient clinic with a -5-year history of poor vision in the left eye. The best corrected visual acuity at presentation was 6/5 and 6/36, respectively, in the right and left eyes. Ocular examination revealed normal anterior segments in both eyes. Binocular indirect ophthalmoscopy of the right eye revealed a pink disc with a cup disc ratio (CDR) of 0.3, normal vessels while the macula had a yellowish lesion with a scrambled egg appearance and surrounding dome-shaped subretinal fluid with a flat retina and no treatable peripheral retinal lesions. The left eye had a pink disc with CDR O.3, normal vessels with a hyperpigmented lesion at the macula surrounded by a small cuff of subretinal fluid with a flat retina and no treatable peripheral retinal lesions. Optical coherence tomography scan revealed subretinal fluid in both eyes with an active choroidal neovascular membrane in the left eye. He was advised on the need for left intravitreal anti-vascular endothelial growth factor injections.

Human umbilical cord mesenchymal stem cells derived-exosomes on VEGF-A in hypoxic-induced mice retinal astrocytes and mice model of retinopathy of prematurity.

To observe the effect of human umbilical cord mesenchymal stem cells (hUCMSCs) secretions on the relevant factors in mouse retinal astrocytes, and to investigate the effect of hUCMSCs on the expression of vascular endothelial growth factor-A (VEGF-A) and to observe the therapeutic effect on the mouse model of retinopathy of prematurity (ROP). Cultured hUCMSCs and extracted exosomes from them and then retinal astrocytes were divided into control group and hypoxia group. MTT assay, flow cytometry, reverse transcription-polymerase chain reaction (RT-PCR) and Western blot were used to detect related indicators. Possible mechanisms by which hUCMSCs exosomes affect VEGF-A expression in hypoxia-induced mouse retinal astrocytes were explored. At last, the efficacy of exosomes of UCMSCs in a mouse ROP model was explored. Graphpad6 was used to comprehensively process data information. The secretion was successfully extracted from the culture supernatant of hUCMSCs by gradient ultracentrifugation. Reactive oxygen species (ROS) and hypoxia inducible factor-1α (HIF-1α) of mice retinal astrocytes under different hypoxia time and the expression level of VEGF-A protein and VEGF-A mRNA increased, and the ROP cell model was established after 6h of hypoxia. The secretions of medium and high concentrations of hUCMSCs can reduce ROS and HIF-1α, the expression levels of VEGF-A protein and VEGF-A mRNA are statistically significant and concentration dependent. Compared with the ROP cell model group, the expression of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signal pathway related factors in the hUCMSCs exocrine group is significantly decreased. The intravitreal injection of the secretions of medium and high concentrations of hUCMSCs can reduce VEGF-A and HIF-1α in ROP model tissues. HE staining shows that the number of retinal neovascularization in ROP mice decreases with the increase of the dose of hUCMSCs secretion. In a hypoxia induced mouse retinal astrocyte model, hUCMSCs exosomes are found to effectively reduce the expression of HIF-1α and VEGF-A, which are positively correlated with the concentration of hUCMSCs exosomes. HUCMSCs exosomes can effectively reduce the number of retinal neovascularization and the expression of HIF-1α and VEGF-A proteins in ROP mice, and are positively correlated with drug dosage. Besides, they can reduce the related factors on the PI3K/AKT/mTOR signaling pathway.

SHORT-TERM REACTIVATION OF RETINOPATHY OF PREMATURITY AFTER PRIMARY RANIBIZUMAB TREATMENT.

Investigate risk factors for short-term reactivation of retinopathy of prematurity (ROP) after intravitreal ranibizumab (IVR) therapy and determine safety and efficacy of repeat injections. Retrospective chart review study of patients screened for ROP as inpatients between 2013 and 2023 who received IVR within the UCLA health care system. Primary outcomes were rates and timing of short-term ROP reactivation, defined as repeat worsening of ROP to stage 2 or 3 before 52 weeks postmenstrual age, as well as risk factors for reactivation. Other outcomes included adverse events and rates of reactivation after a second intravitreal injection. Eighty-two eyes of 43 patients received primary IVR 0.25 mg/0.025 cc for type 1 ROP. Thirteen patients (22 eyes) (30.2% of patients, 26.8% of eyes) developed short-term reactivation an average of 7.2 weeks ± 1.7 weeks after treatment. Increased reactivation risk was associated with zone I disease (odds ratio 6.23, 95% CI, 1.35-28.7, P = 0.019), lower postmenstrual age at first injection (odds ratio 1.64, 95% CI, 1.19-2.26; P = 0.003), and lower gestational age at birth (odds ratio 1.80, 95% CI, 1.04-3.13, P = 0.037). Of the 13 patients that received repeat injections, five required laser treatment for a second reactivation (11.6% of patients receiving IVR). No eyes developed retinal vascular occlusion, endophthalmitis, or cataract. Repeat injections may be required after primary IVR for aggressive ROP. Repeat IVR treatment for ROP is effective and poses few ophthalmic adverse events, although additional reactivation remains a risk.

ROS-responsive charge reversal mesoporous silica nanoparticles as promising drug delivery system for neovascular retinal diseases

Intravitreal injection of biodegradable implant drug carriers shows promise in reducing the injection frequency for neovascular retinal diseases. However, current intravitreal ocular devices have limitations in adjusting drug release rates for individual patients, thereby affecting treatment effectiveness. Accordingly, we developed mesoporous silica nanoparticles (MSNs) featuring a surface that reverse its charge in response to reactive oxygen species (ROS) for efficient delivery of humanin peptide (HN) to retinal epithelial cells (ARPE-19). The MSN core, designed with a pore size of 2.8 nm, ensures a high HN loading capacity 64.4% (w/w). We fine-tuned the external surface of the MSNs by incorporating 20% Acetyl-L-arginine (Ar) to create a partial positive charge, while 80% conjugated thioketal (TK) methoxy polyethylene glycol (mPEG) act as ROS gatekeeper. Ex vivo experiments using bovine eyes revealed the immobilization of Ar-MSNs-TK-PEG (mean zeta potential: 2 mV) in the negatively charged vitreous. However, oxidative stress reversed the surface charge to −25 mV by mPEG loss, facilitating the diffusion of the nanoparticles impeded with HN. In vitro studies showed that ARPE-19 cells effectively internalize HN-loaded Ar-MSNs-TK, subsequently releasing the peptide, which offered protection against oxidative stress-induced apoptosis, as evidenced by reduced TUNEL and caspase3 activation. The inhibition of retinal neovascularization was further validated in an in vivo oxygen-induced retinopathy (OIR) mouse model.

Multifunctional Nanotherapeutics with Long-Acting Release against Macular Degeneration by Minimally Invasive Administration.

Neovascular age-related macular degeneration (AMD), a leading cause of blindness, requires frequent intravitreal injection of antivascular endothelial growth factor (anti-VEGF), which could generate a succession of complications with poor patient compliance. The current VEGF-targeting therapies often fail in half of patients due to the complex pathologic microenvironment of excessive reactive oxygen species (ROS) production, and increased levels of inflammation are accompanied by choroidal neovascularization (CNV). We herein reported multifunctional nanotherapeutics featuring superior antioxidant and anti-inflammation properties that aim to reverse the pathological condition, alongside its strong targeted antiangiogenesis to CNV and its ability to provide long-term sustained bioactive delivery via the minimally invasive subconjunctival injection, so as to achieve satisfactory wet AMD treatment effects. Concretely, the nanomedicine was designed by coencapsulation of astaxanthin (AST), a red pigmented carotenoid known for its antioxidative, anti-inflammatory and antiapoptotic properties, and axitinib (AXI), a small molecule tyrosine kinase inhibitor that selectively targets the vascular epidermal growth factor receptor for antiangiogenesis, into the Food and Drug Administration (FDA) approved poly(lactic-co-glycolic acid) (PLGA), which forms the nanodrug of PLGA@AST/AXI. Our results demonstrated that a single-dose subconjunctival administration of PLGA@AST/AXI showed a rational synergistic effect by targeting various prevailing risk factors associated with wet AMD, ensuring persistent drug release profiles, maintaining good ocular biocompatibility, and causing no obvious mechanical damage. Such attributes are vital and hold significant potential in treating ocular posterior segment diseases. Moreover, this nanotherapeutic strategy represents a versatile and broad-spectrum nanoplatform, offering a promising alternative for the complex pathological progression of other neovascular diseases.

The effect of intravitreal antiangiogenic diabetic macular edema treatment on the corneal endothelium cell count

BACKGROUND: Antiangiogenic treatment of diabetic macular edema is a first-line therapy in modern ophthalmology. Novel antiangiogenic drugs are increasingly being developed to improve treatment results and solve certain issues. However, owing to the advent of new drugs, more questions arise about their effect on the patient’s retina and other structures of the eye, such as the cornea. AIM: The study aimed to investigate the effect of intravitreal administration of the anti-VEGF drug brolucizumab on the corneal endothelium in patients with diabetic macular edema. METHODS: 106 patients (106 eyes) were included in the prospective study: 31 men and 75 women. The main group consisted of 56 patients (56 eyes) were included in the prospective study: 14 men and 42 women with different stages of diabetic retinopathy with diabetic macular edema, the average age of patients was 62.2±8.4 years. The average number of endothelial cells per 1 mm2 in these patients before the loading dose of brolucizumab was 2378.9±393.3 cl/mm2. The control group included 50 patients (50 eyes) without diabetes who did not receive intravitreal injections or any other surgical interventions on the examined eye for 1 year. All patients underwent endothelial microscopy using the Tomey EM-4000 endothelial microscope (REN 2017/6294), estimated: CD (the number of endothelial cells per 1 mm2); CCT (the central thickness of the cornea, microns); CV (the coefficient of variation, %); 6A (the proportion of hexagonal cells, %). All study participants received intravitreal injections of brolucizumab in a volume of 0.05 ml (5 injections with an interval of 6 weeks). RESULTS: In the main group before intravitreal injections, the indices of the central corneal thickness and the number of endothelial cells per 1 mm2 were 549.7±30.1 microns and 2378.9±393.3 cells/mm2, respectively. After a course of antiangiogenic diabetic macular edema therapy, the central thickness of the cornea was 548.2±30.6 microns, and the number of endothelial cells per 1 mm2 was 2382.3±424.9 cells/mm2. The indicators CV (coefficient of variability, %) and 6A (proportion of hexagonal cells, %) before the start of intravitreal injections were 36.9±5% and 46.8±6.3%, respectively, after the introduction of the loading dose drugs, the average values were 37.9±4.3% and 45.8±6.3%. Changes in all indicators were not static significant. CONCLUSION: The use of brolucizumab as therapy in patients with diabetic macular edema did not cause a negative effect on the cornea, there were no statistically significant changes in the central thickness of the cornea, the number of endothelial cells per 1 mm2, the coefficient of variation and the proportion of hexagonal cells.

Development of a novel SupraChoroidal-to-Optic-NervE (SCONE) drug delivery system

Purpose Targeted drug delivery to the optic nerve head may be useful in the preclinical study and later clinical management of optic neuropathies, however, there are no FDA-approved drug delivery systems to achieve this. The purpose of this work was to develop an optic nerve head drug delivery technique. Methods Different strategies to approach the optic nerve head were investigated, including standard intravitreal and retroorbital injections. A novel SupraChoroidal-to-Optic-NervE (SCONE) delivery was optimized by creating a sclerotomy and introducing a catheter into the suprachoroidal space. Under direct visualization, the catheter was guided to the optic nerve head. India ink was injected. The suprachoroidal approach was performed in New Zealand White rabbit eyes in vivo (25 animals total). Parameters, including microneedle size and design, catheter design, and catheter tip angle, were optimized ex vivo and in vivo. Results Out of the candidate optic nerve head approaches, intravitreal, retroorbital, and suprachoroidal approaches were able to localize India ink to within 2 mm of the optic nerve. The suprachoroidal approach was further investigated, and after optimization, was able to deposit India ink directly within the optic nerve head in up to 80% of attempts. In eyes with successful SCONE delivery, latency and amplitude of visual evoked potentials was not different than the naïve untreated eye. Conclusions SCONE delivery can be used for targeted drug delivery to the optic nerve head of rabbits without measurable toxicity measured anatomically or functionally. Successful development of this system may yield novel opportunities to study optic nerve head-specific drug delivery in animal models, and paradigm-shifting management strategies for treating optic neuropathies. Translational Relevance Here we demonstrate data on a new method for targeted delivery to the optic nerve head, addressing a significant unmet need in therapeutics for optic neuropathies.