Single Subconjunctival Injection Research Articles

Combination Nanomedicine Strategy for Preventing High-Risk Corneal Transplantation Rejection.

High-risk (HR) corneal transplantation presents a formidable challenge, with over 50% of grafts experiencing rejection despite intensive postoperative care involving frequent topical eyedrop administration up to every 2 h, gradually tapering over 6-12 months, and ongoing maintenance dosing. While clinical evidence underscores the potential benefits of inhibiting postoperative angiogenesis, effective antiangiogenesis therapy remains elusive in this context. Here, we engineered controlled-release nanomedicine formulations comprising immunosuppressants (nanoparticles) and antiangiogenesis drugs (nanowafer) and demonstrated that these formulations can prevent HR corneal transplantation rejection for at least 6 months in a clinically relevant rat model. Unlike untreated corneal grafts, which universally faced rejection within 2 weeks postsurgery, a single subconjunctival injection of the long-acting immunosuppressant nanoparticle alone effectively averted graft rejection for 6 months, achieving a graft survival rate of ∼70%. Notably, the combination of an immunosuppressant nanoparticle and an anti-VEGF nanowafer yielded significantly better efficacy with a graft survival rate of >85%. The significantly enhanced efficacy demonstrated that a combination nanomedicine strategy incorporating immunosuppressants and antiangiogenesis drugs can greatly enhance the ocular drug delivery and benefit the outcome of HR corneal transplantation with increased survival rate, ensuring patient compliance and mitigating dosing frequency and toxicity concerns.

Subconjunctival injection of rapamycin-loaded polymeric microparticles for effective suppression of noninfectious uveitis in rats

Noninfective uveitis is a major cause of vision impairment, and corticosteroid medication is a mainstay clinical strategy that causes severe side effects. Rapamycin (RAPA), a potent immunomodulator, is a promising treatment for noninfective uveitis. However, because high and frequent dosages are required, it is a great challenge to implement its clinical translation for noninfective uveitis therapy owing to its serious toxicity. In the present study, we engineered an injectable microparticulate drug delivery system based on biodegradable block polymers (i.e., polycaprolactone-poly (ethylene glycol)-polycaprolactone, PCEC) for efficient ocular delivery of RAPA via a subconjunctival injection route and investigated its therapeutic efficacy in an experimental autoimmune uveitis (EAU) rat model. RAPA-PCEC microparticles were fabricated using the emulsion-evaporation method and thoroughly characterized using scanning electron microscopy, fourier transform infrared spectroscopy, X-ray diffraction, and differential scanning calorimetry. The formed microparticles exhibited slow in vitro degradation over 28 days, and provided both in vitro and in vivo sustained release of RAPA over 4 weeks. Additionally, a single subconjunctival injection of PCEC microparticles resulted in high ocular tolerance. More importantly, subconjunctival injection of RAPA-PCEC microparticles significantly attenuated the clinical signs of EAU in a dose-dependent manner by reducing inflammatory cell infiltration (i.e., CD45+ cells and Th17 cells) and inhibiting microglial activation. Overall, this injectable microparticulate system may be promising vehicle for intraocular delivery of RAPA for the treatment of noninfective uveitis.

Dexamethasone sodium phosphate loaded nanoparticles for prevention of nitrogen mustard induced corneal injury

Nitrogen mustard (NM) is a potent vesicating chemical warfare agent that is primarily absorbed through skin, inhalation, or ocular surface. Ocular exposure of NM can cause acute to chronic keratopathy which can eventually lead to blindness. There is a current lack of effective countermeasures against ocular exposure of NM despite their imperative need. Herein, we aim to explore the sustained effect of Dexamethasone sodium phosphate (DSP)-loaded polymeric nanoparticles (PLGA-DSP-NP) following a single subconjunctival injection in the management and prevention of corneal injury progression upon exposure to NM. DSP is an FDA approved corticosteroid with proven anti-inflammatory properties. We formulated PLGA-DSP-NP with zinc chelation ion bridging method using PLGA polymer, with particles of approximately 250 nm and a drug loading of 6.5 wt%. Under in vitro sink conditions, PLGA-DSP-NP exhibited a sustained drug release for two weeks. Notably, in NM injured cornea, a single subconjunctival (SCT) injection of PLGA-DSP-NP outperformed DSP eyedrops (0.1%), DSP solution, placebo NP, and saline, significantly mitigating corneal neovascularization, ulceration, and opacity for the two weeks study period. Through PLGA-DSP-NP injection, sustained DSP release hindered inflammatory cytokine recruitment, angiogenic factors, and endothelial cell proliferation in the cornea. This strategy presents a promising localized corticosteroid delivery system to effectively combat NM-induced corneal injury, offering insights into managing vesicant exposure.

Subconjunctival injection of human umbilical cord mesenchymal stem cells alleviates experimental allergic conjunctivitis via regulating T cell response

BackgroundT helper 2 (Th2) cells are thought to play critical roles in allergic conjunctivitis (AC). They release inflammatory cytokines to promote an allergic response in AC. Due to individual heterogeneity and long-term chronic management, current therapies do not always effectively control AC. Mesenchymal stem cells (MSCs) have been shown to be effective in treating allergy-related disorders, but it is unclear how exactly the Th2-mediated allergic response is attenuated. This study aims to elucidate the therapeutic effect and mechanism of the human umbilical cord MSCs (hUCMSCs) in a mouse model of experimental AC (EAC).MethodsA mouse EAC model was established by inoculating short ragweed (SRW) pollen. After the SRW pollen challenge, the mice received a single subconjunctival or tail vein injection of 2 × 106 hUCMSCs, or subconjunctival injection of hUCMSCs conditioned medium (hUCMSC-CM), and dexamethasone eye drops was used as positive control; subsequent scratching behavior and clinical symptoms were assessed. Immunostaining and flow cytometry were carried out to show allergic reactions and the activation of CD4 + T cell subsets in the conjunctiva and cervical lymph nodes (CLNs). Gene expression was determined by RNA-seq and further verified by qRT-PCR and Western blot. Co-culture assays were performed to explore the regulatory role of hUCMSCs in the differentiation of CD4 + naive T cells (Th0) into Th2 cells.ResultsSubconjunctival administration of hUCMSCs resulted in fewer instances of scratching and lower inflammation scores in EAC mice compared to the tail vein delivery, hUCMSC-CM and control groups. Subconjunctival administration of hUCMSCs reduced the number of activated mast cells and infiltrated eosinophils in the conjunctiva, as well as decreased the number of Th2 cells in CLNs. After pretreatment with EAC mouse serum in vitro to mimic the in vivo milieu, hUCMSCs were able to inhibit the differentiation of Th0 into Th2 cells. Further evidence demonstrated that repression of Th2 cell differentiation by hUCMSCs is mediated by CRISPLD2 through downregulation of STAT6 phosphorylation. Additionally, hUMCSCs were able to promote the differentiation of Th0 cells into regulatory T cells in CLNs of EAC mice.ConclusionsSubconjunctival injection of hUCMSCs suppressed the Th2-allergic response and alleviated clinical symptoms. This study provides not only a potential therapeutic target for the treatment of AC but also other T cell-mediated diseases.

Successful treatment of equine corneal neovascularisation by subconjunctival aflibercept

AbstractA 10‐year‐old Westphalian horse was presented for examination following a 4‐week history of ocular trauma and mycotic ulcerative keratitis of the right eye, complicated with uveitis and corneal neovascularisation. The right eye was treated for corneal neovascularisation with a 0.1 mL (4 mg) subconjunctival injection of aflibercept. A single subconjunctival injection of aflibercept was sufficient for complete regression of corneal neovascularisation. This is the first reported case of corneal neovascularisation in a horse successfully treated with subconjunctival aflibercept.

Local Adenoviral Delivery of Vascular Endothelial Growth Factor C Induces Lymphangiogenesis in the Conjunctiva in Rabbits

Introduction: The purpose of this study was to determine if conjunctival lymphangiogenesis can be induced using adenoviral delivery of vascular endothelial growth factor C (VEGF-C). Methods: Seventeen New Zealand white rabbits received a subconjunctival injection containing 3.5 × 107 plaque-forming units of an adenoviral vector containing the gene-encoding VEGF-C (Ad-VEGF-C). The contralateral eye was used for control experiment (the same volume of either saline or an empty vector). After 2 weeks, the animals were examined with trypan blue conjunctival lymphangiography, and the eyes were harvested for histology and immunohistochemistry (podoplanin and CD31). Results: Trypan blue conjunctival lymphangiography revealed significantly more extensive conjunctival vessel network in the Ad-VEGF-C group compared with control: 1.35 ± 0.67 versus 0.28 ± 0.17 vessel length/analysed area (p = <0.0001). This finding was confirmed with immunohistochemistry, where a significant increase in the number of lymphatic vessels was found compared to control; 34 ± 9 per mm2 versus 13 ± 8 per mm2 (p = 0.0019). Furthermore, there was a significant increase in lymphatic cross-sectional area; 32,500 ± 7,900 µm2 per mm2 versus 17,600 ± 9,700 µm2 per mm2 (p = 0.0149). Quantification of blood vessels revealed no significant difference in blood vessel density between Ad-VEGF-C and control; 19 ± 9 per mm2 versus 14 ± 8 per mm2 (p = 0.1971). There was no significant difference in total blood vessel area; 13,200 ± 7,600 µm2 per mm2 versus 7,100 ± 3,000 µm2 per mm2 (p = 0.0715). Eyes treated with an adenoviral vector (VEGF-C or empty vector) responded with a reactive cellular response, predominantly lymphocytes, towards the vector. Conclusion: The study demonstrates the feasibility of inducing conjunctival lymphangiogenesis with a single subconjunctival injection of Ad-VEGF-C. Future studies will explore how this can be used with a therapeutic purpose.

Использование аутологичной кондиционированной плазмы (ACP) в лечении перфоративной язвы роговицы (клинический случай)

Purpose. To evaluate the effectiveness of a combined approach in the treatment of perforated corneal ulcers using autologous conditioned plasma (ACP). Material and methods. In the Republican Clinical Ophthalmological Hospital, 3 patients with a corneal ulcer were treated using ACP. Two patients with corneal ulcer without perforation, one patient with corneal ulcer with perforation. Two patients with a corneal ulcer without perforation, in addition to the standard conservative treatment, received a single application of ACP in the area of the corneal ulcer in several layers, a single subconjunctival injection of ACP. In both cases, the ulcerative process was stopped successfully. A technique for a combined approach to the closure of perforated corneal ulcers has been developed, including primary suturing of the corneal defect in the ulcer area in order to reduce the risk of fluid perfusion; restoration of the anterior chamber with sterile air; multilayer applications of autologous conditioned plasma into the ulcer area and, as it is filled with ACP, the coverage area is expanded to the entire cornea. On average, the coating consists of 5–7 layers with 20–30 sec. polymerization. It is important to remove excess autoplasma with a tupfer and prevent excesses from entering the conjunctival fornix, which minimizes the risk of displacement of the ACP film. Surgery is performed against the background of active antibacterial, antiinflammatory and keratoprotective therapy. Additionally, a soft contact lens was applied at the end of the operation. Results. During surgery, the closure of the perforation of the cornea with an ACP composite was achieved, a stable anterior chamber of the eyeball was noted, and there was no external filtration of the cornea. These results remained stable over the entire follow-up period of 1 month. Conclusions. A positive preliminary clinical result was demonstrated using a combined approach in the treatment of corneal ulcer complicated by perforation using autologous conditioned plasma. Application of ACP to the cornea contributed to the creation of a durable composite to block the perforation. After expanding the number of patients treated by this technique, we assume that this technique can be considered as an alternative for urgent treatment of perforated corneal ulcers without penetrating keratoplasty. Keywords: corneal ulcer with perforation, autologous conditioned plasma, platelet-rich plasma

Fibrin glue as a novel therapy for contracted socket in comparison to mitomycin-c and triamcinolone acetonide at Dr. Soetomo General Academic Hospital, Surabaya, Indonesia

Background: Contracted socket is still a major problem for patients with anophthalmia. The main factor for this condition is inflammation and fibrosis, which result in conjunctival shortening. Myofibroblasts that express α-SMA are the primary mediators of anophthalmic socket contraction. Methods: One healthy eye of a New Zealand white rabbit were randomly selected for evisceration and divided into four treatment groups, each with five rabbits. Each rabbit in the group received a single subconjunctival injection of a different agent. Group, I was the control group that received no injection, Group II received MMC 0.4 mg/ml, Group III received TCA 40 mg/ml, and Group 4 received fibrin glue. After 14 days, the animals were euthanized, and conjunctival samples were submitted for histopathological analysis. A monoclonal α-SMA antibody was applied, and pathologists provided the IRS score for each sample. The differences in α-SMA expression were statistically analyzed with a significant level of p &lt;0.05 Result: All groups displayed a statistically significant decrease in α-SMA expression compared to the control group (p&lt;0.05) as sorting as MMC group with p=0.007, TCA group with p=0.007, and fibrin glue with p= 0.009. MMC was the most effective at reducing α-SMA (p=0.004). Surprisingly, there were no statistically significant differences between MMC, TCA, and fibrin glue when they were evaluated independently. Conclusion: A single subconjunctival injection of fibrin glue may be used as a novel treatment to prevent socket contracture in actively healing sockets.

An injectable thermosensitive hydrogel for dual delivery of diclofenac and Avastin® to effectively suppress inflammatory corneal neovascularization

Corneal neovascularization (CNV) is a sequela of anterior segment inflammation, which could lead to vision impairment and even blindness. In the present study, the dual delivery of anti-inflammatory agent (i.e., diclofenac; DIC) and anti-VEGF antibody (i.e., Avastin®; Ava) by the thermosensitive hydrogel (Poly(dl-lactide)-poly(ethylene glycol)-poly(dl-lactide); PDLLA-PEG-PDLLA) is expected to effectively inhibit CNV via their synergistic effects. The optimal DIC micelles were formulated and then mixed with Ava and PDLLA-PEG-PDLLA aqueous solution to generate various DIC@Ava-loaded hydrogels. The co-encapsulation of DIC micelles and Ava did not influence the gelling behavior of the system, and the resulting DIC@Ava-loaded hydrogel provided sustained drug release of both DIC and Ava without compromising their pharmacological activity over 19 days. As indicated by in vitro cytotoxicity and in vivo ocular biocompatibility test, the proposed PDLLA-PEG-PDLLA hydrogel caused minimal cytotoxicity against all tested cell lines at a polymeric concentration ranging from 0.05 mg/mL to 0.8 mg/mL and demonstrated good ocular biocompatibility after a single subconjunctival injection. Using the rabbit CNV model, we documented the superior anti-angiogenic effects of the DIC@Ava-loaded hydrogel over Ava alone medication (treatment with Ava solution and Ava-loaded hydrogel) due to synergistic effects of anti-VEGF and anti-inflammatory action. Overall, the proposed DIC@Ava-loaded hydrogel might be a powerful strategy to reduce CNV.

Pharmacokinetics of Sirolimus in a Novel Liposome Delivery System in Selected Ocular Tissues and Plasma Following a Single Subconjunctival Injection in Dutch Belted Rabbits.

Purpose: To determine the pharmacokinetics of a proprietary liposomal sirolimus (LS) formulation in ocular tissues and plasma following a single subconjunctival (SCJ) injection in Dutch belted rabbits (DBR). Analytical methods for detection of LS in plasma, aqueous humor (AH), vitreous humor (VH), retina, combined retina/choroid/retinal pigment epithelium, sclera, and iris/ciliary body were developed to examine samples. Methods: Thirty male DBR were subconjunctivally injected in both eyes with 0.1 mL of LS of 1,000 μg/mL. At selected times post-injection, ocular tissues and whole blood samples were obtained. Sirolimus concentrations were measured using liquid chromatography/tandem mass spectrometry. Results: No LS was detected in serum or AH at any time. All other examined ocular tissues had quantifiable amounts of LS at all times. LS levels were highest in sclera and lowest in VH, suggesting LS followed the supraciliary and suprachoroidal spaces to reach the posterior segment. Vitreous peak of sirolimus levels occurred at 2 h, and the sclera adjacent to the injection peaked at both 2 and 96 h. LS levels in remaining ocular tissues peaked at 6 h and decreased with time, persisting at presumed therapeutic levels on day 22. Conclusions: LS can quickly diffuse into posterior intraocular tissues after SCJ injection without reaching quantifiable levels in AH or serum in DBR. Peak levels occurred in posterior intraocular tissues at 6 h and persisted in all tissues after 3 weeks. SCJ LS in DBR is safe, has a stable pharmacokinetic profile, and should be considered for further study in human trials for autoimmune ophthalmopathies.

Preoperative Intralesional Bevacizumab Injection in Primary Pterygium in Tunisian Patients: A Randomized Controlled Prospective Study.

To assess the efficacy and safety of a single preoperative intralesional bevacizumab injection as an adjuvant treatment before primary pterygium surgery. We conducted a randomized controlled interventional study from January 2019 to December 2020. The study included a total of 60 patients (60 eyes) with primary pterygium. We defined two groups of 30 patients each. Group A received an intralesional injection of bevacizumab (Avastin), 1 month before surgery (lesion excision and conjunctival autograft). Group B (control) had only the surgical treatment. Patients were followed up 7 days (D7), 1 month (M1), 3 months (M3), and 6 months (M6) postoperatively. Pre-, per-, and postoperatively, photographs of the lesions were taken, as well as a histopathological examination. The main outcome measures were the change in functional discomfort following intralesional bevacizumab injection and pterygium recurrence. Recurrence was defined as fibrovascular tissue growth invading the cornea. Therapeutic success was defined as the absence of pterygium recurrence in M6. The mean age of the 60 patients was 54.17 ± 10.53. After bevacizumab injection, the preoperative functional discomfort score decreased significantly (P = 0.048). There was a significant improvement in grade and color intensity (P = 0.001). We noted no local nor systemic complications after intralesional injection of bevacizumab. After pterygium excision, the success rate was statistically higher in Group A (P = 0.047). There was no significant difference in either final best-corrected spectral visual acuity or astigmatism between the two groups. We noted a statistically significant association between recurrence and color intensity (P = 0.046), vascular density (P = 0.049), and the degree of elastic tissue degeneration (P = 0.040). A single preoperative subconjunctival injection of bevacizumab 1 month before surgery decreases the vascularity of newly formed blood vessels and hence may reduce the recurrence rate.

Ion-Complex Microcrystal Formulation Provides Sustained Delivery of a Multimodal Kinase Inhibitor from the Subconjunctival Space for Protection of Retinal Ganglion Cells.

Glaucoma is the leading cause of irreversible blindness worldwide. Elevated intraocular pressure (IOP) is one of the major risk factors for glaucoma onset and progression, and available pharmaceutical interventions are exclusively targeted at IOP lowering. However, degeneration of retinal ganglion cells (RGCs) may continue to progress despite extensive lowering of IOP. A complementary strategy to IOP reduction is the use of neuroprotective agents that interrupt the process of cell death by mechanisms independent of IOP. Here, we describe an ion complexation approach for formulating microcrystals containing ~50% loading of a protein kinase inhibitor, sunitinib, to enhance survival of RGCs with subconjunctival injection. A single subconjunctival injection of sunitinib-pamoate complex (SPC) microcrystals provided 20 weeks of sustained retina drug levels, leading to neuroprotection in a rat model of optic nerve injury. Furthermore, subconjunctival injection of SPC microcrystals also led to therapeutic effects in a rat model of corneal neovascularization. Importantly, therapeutically relevant retina drug concentrations were achieved with subconjunctival injection of SPC microcrystals in pigs. For a chronic disease such as glaucoma, a formulation that provides sustained therapeutic effects to complement IOP lowering therapies could provide improved disease management and promote patient quality of life.

COMPARISON OF RECURRENCE INCIDENCE AFTER PTERYGIUM EXCISION BY USING PEROPRATIVE SUBCONJUNCTIVAL BEVACIZUMAB INJECTION VERSUS CONJUNCTIVAL AUTO GRAFT

Background: A pterygium is a fleshy, wing-shaped growth from the conjunctiva, crossing over the limbus onto the cornea. The tissue is fibrovascular and can occur over the nasal or temporal cornea. It can be a bilateral process and asymmetric with one eye affected by a larger pterygium than the other. Objectives: To compare between Subconjunctival injection of bevacizumab (Avastin) and conjunctival autograft in the treatment of primary pterygium. Patients and Methods: This study was performed on 40eyes of 40 patients with primary pterygia of variable durations. The eyes were randomly classified into two equal groups: group A patients to be treated by Subconjunctival Bevacizumab (avastin) 0.2 ml (5 mg) for Primary Pterygium Excision, group B patients treated by conjunctival auto graft. Best corrected visual acuity, occurrence of recurrence, IOP and postoperative complications were compared. Patients were evaluated preoperatively then 1 day, 1 week, 1 month, 3 months after surgery. Eye photography was done before surgery and during the follow up period. This study was conducted at Department of Ophthalmology Al-Azhar University Hospital and Kobry El Kobba Military Hospital, from August 2018 to July 2020. Results: When the two groups were compared together, we found no statistically significant differences among them in multiple compared items, but the recurrence rate in group A (bevacizumab group) occurred in (10%), while in group B conjunctival auto graft no recurrence occurred and this was statistically insignificant difference among the 2 groups. There were no statistically significant differences regarding improvement in visual acuity, intraocular pressure change and postoperative complications among the two groups. Conclusion: A single preoperative subconjunctival injection of bevacizumab had decreased the recurrence rate befor primary pterygium excision, but did not give a more desirable recurrence rate. On the other hand conjunctival autograft was more effective than bevacizumab in reducing the recurrence rate of primary pterygium after surgical excision.

Regenerative and Antioxidant Properties of Autologous Platelet-Rich Plasma Can Reserve the Aging Process of the Cornea in the Rat Model.

Aging is a natural progressive decline in the biological function of cells. Age-related changes in the cornea can affect its ability to refract light or repair itself. Platelet-rich plasma (PRP) has a promising role in regenerative medicine and evidenced its efficacy in multiple fields, but in corneal aging has not yet been elucidated. The present work was performed to estimate the regenerative antioxidant effect of PRP on corneal aging in rats. Rats were assigned into two main groups: (GI) adult group and (GII) aged group. The adult group was divided into GIa (adult rats), GIb (adult-saline treated), and GIc (adult-PRP treated). The aged group was divided into GIIa (aged rats) and GIIb (aged, PRP treated). PRP was administered by a single subconjunctival injection. After 10 days, histological, ultrastructural, immunohistochemical, and morphometrical investigations were carried out. Examination of the corneal sections of the aged group revealed corneal epithelial thinning, shedding of the surface epithelium with loss of desmosomal junction, and irregularity in Bowman's membrane. Disorganized widely spaced collagen bundles and neovascularization were detected in corneal stroma associated with thickening in Descemet's membrane. Ultrastructural examination revealed shrunken hyperchromatic nuclei, swollen mitochondria, and scanty cytoplasm with a strong nuclear reaction for caspase-3 immunostaining. Moreover, antioxidant/free radicals' imbalance was detected by the increase of malondialdehyde (MDA) level with a decrease of glutathione peroxidase (GPx) and superoxide dismutase (SOD) levels. In contrast, GIIb (aged, PRP treated) section examination revealed a restoration of the thickness of the corneal epithelial layer and Descemet's membrane with an amendment of collagen fiber regularity that is associated with weak nuclear reaction to caspase-3 and recovery of the balance in the redox state. These findings proved the effectiveness of PRP as a promising regenerative treatment for the age-associated changes in the cornea.

In vivo biocompatibility and efficacy of dexamethasone-loaded PLGA-PEG-PLGA thermogel in an alkali-burn induced corneal neovascularization disease model

Challenges of ophthalmic drug delivery arise not only from the limited solubility of hydrophobic therapeutics, but also the restricted permeability and fast clearance of drugs due to the complex anatomy and physiology of eyes. Excellent biocompatibility of a thermosensitive polymer, PLGA-PEG-PLGA (1800–1500–1800, LA:GA ratio = 3:1), as an ophthalmic delivery system was demonstrated in our previous work. In this study, delivery of dexamethasone using this thermogel via a single subconjunctival injection for prolonged treatment was evaluated with corneal neovascularization using an alkali-burn diseased model in rat. Solubility of dexamethasone in the polymeric solution was increased by 5.2-fold and the resulting drug-loaded solution formed in situ rigid gel at body temperature. Prolonged in vitro release of dexamethasone from the gel structure was noted. Dexamethasone gel formulation was demonstrated to be more effective in reducing the burn stimulus and neovascularization in the rat diseased model. The findings suggest the PLGA-PEG-PLGA in situ gelling system can be applied for ophthalmic drug delivery to achieve sustained drug release and improved efficacy.

Single subconjunctival injection formulation using sol-gel mesoporous silica as a controlled release system for drop-free post-cataract surgery care.

To develop a mesoporous silica drug delivery system and target drop-free care after cataract surgery with a single subconjunctival injection. Laboratory. Experimental animal study. Ketorolac was infiltration-loaded into sol-gel mesoporous silica particles encapsulated with poly(allylamine hydrochloride) and poly(sodium 4-styrenesulfonate) using a layer-by-layer adsorption technique (SG-Ket-LBL). The formulation was subjected to an in vitro and in vivo drug release study in addition to ocular toxicology evaluation. Thermogravimetric analysis revealed that the drug loading efficiency was 4.4% for the SG-Ket-LBL particles. The in vivo safety study demonstrated that the formulation was well tolerated after subconjunctival injection and aqueous humor pharmacokinetics showed sustained therapeutic drug release for the targeted time window of 6 to 8 weeks. Findings indicated that sol-gel mesoporous silica could be used as a drug carrier for subconjunctival administration. The tested formulation, SG-Ket-LBL, provided therapeutic ketorolac for 6 to 8 weeks, which might be used for a single subconjunctival injection to replace nonsteroidal anti-inflammatory drug eyedrops after cataract surgery.

Subconjunctival Aflibercept for the Treatment of Formed Corneal Neovascularization.

To evaluate the effect of a single subconjunctival aflibercept injection on formed corneal neovascularization. A prospective clinical trial, conducted at a single tertiary medical center. Included were consecutive patients with corneal pathologies complicated by corneal neovascularization, who were candidates for anti-vascular endothelial growth factor treatment at the discretion of a cornea specialist. A single subconjunctival injection of 0.08 mL of Aflibercept (Eylea 25 mg/mL) was administered near the limbus in proximity to the areas of maximal pathological neovascularization. Follow-up visits were scheduled on days 7, 30, 60, and 90 following injection. Best-corrected visual acuity (BCVA), intraocular pressure, slitlamp examination, digital cornea photography, specular microscopy, and anterior-segment optical coherence tomography were documented at each visit. The images were graded by a masked observer for density, extent, and centricity of corneal vascularization. Six eyes of six patients were analyzed. No clinically significant ocular or systemic adverse events were documented. No change was noted in extent, density, or centricity of corneal blood vessels at seven, 30, and 90 days after injection (P>0.1 for all time point comparisons, Friedman test). Best-corrected visual acuity fluctuated insignificantly in 5/6 patients during follow-up time, and objective but not subjective improvement of BCVA was noted in one patient with no concurrent change of neovascularization. The recruitment has therefore halted prematurely. A single subconjunctival aflibercept injection seems to be well tolerated. However, it is ineffective for regressing formed corneal neovascularization.

SUBCONJUCTIVAL INJECTION OF BEVACIZUMAB IN CORNEAL NEOVASCULARIZATION

Purpose: The aim of this work was to assess the outcome of subconjunctival bevacizumab(Avastin) injection in patients with corneal neovascularization (NV). Methods: Twenty eyes oftwenty patients (13 male and 7 female) with corneal neovascularization resulted from variableocular surface disorders were included in this prospective, non-controlled study. All eyesreceived a single subconjunctival injection of 2.5 mg (0.1 ml) bevacizumab using 1 ml syringe27 Guage needle. Morphological changes in the major and minor vessels were studied by slitlamp biomicroscopy and corneal photography pre-injection and one week, 2 months and 6months post injection. Results: Obvious recession of minor vessels of Corneal NV was noticedin most eyes at first week post-injection. The extent of corneal neovascularization of the majorvessels was significantly decreased 1weeks post-injection. This decrease continued noticeablyfor 6 months. Conclusions: Bevacizumab can be safely and effectively used in corneal NVtreatment. It can be considered in the treatment of both minor and major vessel NV resultedfrom long standing chronic inflammation (trachoma), long-standing corneal ischemia (followingcontact lens wear) and other different causes. Bevacizumab was well tolerated over themonitoring period in this research. Further controlled and long term studies are required to fullyevaluate the long term effects of this recent treatment.

Investigations Into Bioenergetic Neuroprotection of Cone Photoreceptors: Relevance to Retinitis Pigmentosa.

Recent studies suggest cone degeneration in retinitis pigmentosa (RP) may result from intracellular energy depletion. We tested the hypothesis that cones die when depleted of energy by examining the effect of two bioenergetic, nutraceutical agents on cone survival. The study had three specific aims: firstly, we, studied the neuroprotective efficacies of glucose and creatine in an in vitro model of RP. Next, we utilized a well-characterized mouse model of RP to examine whether surviving cones, devoid of their inner segments, continue to express genes vital for glucose, and creatine utilization. Finally, we analyzed the neuroprotective properties of glucose and creatine on cone photoreceptors in a mouse model of RP. Two different bioenergy-based therapies were tested in rd1 mice: repeated local delivery of glucose and systemic creatine. Optomotor responses were tested and cone density was quantified on retinal wholemounts. The results showed that glucose supplementation increased survival of cones in culture subjected to mitochondrial stress or oxidative insult. Despite losing their inner segments, surviving cones in the rd1 retina continued to express the various glycolytic enzymes. Following a single subconjunctival injection, the mean vitreous glucose concentration was significantly elevated at 1 and 8 h, but not at 16 h after injection; however, daily subconjunctival injection of glucose neither enhanced spatial visual performance nor slowed cone cell degeneration in rd1 mice relative to isotonic saline. Creatine dose-dependently increased survival of cones in culture subjected to mitochondrial dysfunction, but not to oxidative stress. Despite the loss of their mitochondrial-rich inner segments, cone somas and axonal terminals in the rd1 retina were strongly positive for both the mitochondrial and cytosolic forms of creatine kinase at each time point examined. Creatine-fed rd1 mice displayed enhanced optomotor responses compared to mice fed normal chow. Moreover, cone density was significantly greater in creatine-treated mice compared to controls. The overall results of this study provide tentative support for the hypothesis that creatine supplementation may delay secondary degeneration of cones in individuals with RP.

Intravitreal ranibizumab for persistent diabetic vitreous haemorrhage: a randomised, double-masked, placebo-controlled feasibility study.

To determine the feasibility of a definitive study of intravitreal ranibizumab to promote the clearance of persistent diabetic vitreous haemorrhage and thereby avoid vitrectomy. This randomised, double-masked, placebo-controlled feasibility study recruited24 participants with persistent diabetic vitreous haemorrhage listed for pars plana vitrectomy.Participants were randomised to a single 0.5-mg intravitreal ranibizumab injection or a single subconjunctival saline injection.The primary outcome measure was thenumber of participants requiring pars plana vitrectomy at week 7. Eight of 12 participants (66.7%) in the ranibizumab group required vitrectomy at week 7 versus 12 of 12 (100%) in the placebo group (absolute risk reduction 33.3%, 95% confidence interval 2.1-70.7%;p=0.09). One additional eye in the ranibizumab group required vitrectomy by 12months. Mean visual acuity letter score at 12months was 72.7±12.3 in the ranibizumab group and 75.1±10.1 in the placebo group. Safety was similar across groups. Intravitreal ranibizumab may reduce the likelihood of proceeding to vitrectomy in patients with persistent, dense diabetic vitreous haemorrhage. Further studies appear feasible and justified.