Polyethylene Glycol-Based Synthetic Hydrogel Sealant for Filtration Bleb Leaks: An In Vivo and Histologic Study.

Purpose: To evaluate the efficacy of polyethylene glycol (PEG)-based synthetic sealant for closing bleb leaks after glaucoma filtration surgery. Methods: Tube shunt surgery that included implantation of a 22-gauge indwelling catheter and intraoperative mitomycin C was performed in the left eyes of 11 New Zealand white rabbits. Seven days postoperatively, all filtration blebs were perforated with an 18-gauge needle to create a bleb hole. In six rabbits, the holes were covered with the sealant and irradiated with blue-green light for 60 seconds; in the five control rabbits, the holes were untreated. For 3 weeks after the tube shunt surgery, the eyes were checked for bleb leaks, and the intraocular pressure (IOP) was measured in both eyes. Finally, the operated eyes were enucleated for histologic examination. Results: The bleb leaks stopped in the eyes in which sealant was used and persisted in the other eyes. The sealant preserved the bleb function; the IOPs in these eyes were significantly (P < 0.05) lower than the right eyes that did not undergo surgery. Hematoxylin and eosin staining showed that the holes were closed and covered with conjunctival epithelial cells in the eyes in which sealant was applied; the holes were open in the control eyes. Immunohistochemical staining showed that the bleb holes in which the sealant was applied had fewer inflammatory cells. Conclusions: The PEG sealant has the potential to seal bleb leaks effectively. Translational Relevance: Application of the PEG sealant can be used as adjunct therapy for bleb leaks in glaucoma surgery.

Patching retinal breaks with polyethylene glycol-based synthetic hydrogel sealant for retinal detachment in rabbits.

The purpose of this study was to evaluate absorbable polyethylene glycol (PEG)-based synthetic hydrogel as a sealant for retinal breaks in rhegmatogenous retinal detachment (RD). A three-port, 25-gauge vitrectomy was performed on nine Dutch pigmented rabbit eyes. Subsequently, RD was induced by creating a retinal break. The retina was then reattached by fluid-air exchange. In six of nine eyes (RD-PEG group), PEG sealant was applied to completely cover the retinal breaks, and then photopolymerized with light; thereafter, intravitreous air was replaced with balanced salt solution (BSS). In the remaining three eyes (RD group), PEG sealant was not applied, but the intravitreous air was replaced with BSS. Ophthalmological examinations and intraocular pressure measurements were conducted preoperatively, and at 1 and 7 days, and 1, 3, and 6 months postoperatively. Histological examinations of the eyes were performed after 6 postoperative months. At surgery, retinal reattachment with PEG sealant was achieved in all eyes in the RD-PEG group. Fundoscopic and optical coherence tomographic examinations revealed that the retina remained attached in all the eyes of the RD-PEG group throughout the 6-month observation period. Histological examination revealed no signs of damage in the retinal layers at the edges of the retinal breaks that were in contact with the sealant. In the RD group, the retinas detached in all eyes within 7 days postoperatively. The PEG sealant closed the retinal breaks and maintained retinal reattachment. Intraocular tamponade was not necessary.

Polyethylene Glycol-Based Synthetic Hydrogel Sealant for Closing Vitrectomy Wounds: An In Vivo and Histological Study.

PURPOSE: We conducted an in vivo study using Dutch pigmented rabbit eyes to test the usefulness of polyethylene glycol (PEG) sealant for the closure of sutureless sclerotomies in microincisional vitrectomy surgery (MIVS). METHODS: Three-port, 23-gauge vitrectomy was performed on rabbit eyes. After air leakage was confirmed by the application of 0.625% povidone-iodine at the sclerotomy site, PEG sealant was subconjunctivally injected using a 27-gauge needle through conjunctival incisions to cover the sclerotomy wounds, following which it was polymerized by the application of xenon light for 60 seconds. Ophthalmological examinations and intraocular pressure measurements were conducted the day before and 1, 3, 5, and 7 days after surgery. The eyes were enucleated for histological evaluation 7 days after surgery. RESULTS: PEG sealant was rapidly polymerized by the application of xenon light after subconjunctival injection, and it firmly sealed the sclerotomies without air leakage, as confirmed by povidone-iodine dropping, in all cases. Conjunctival and scleral wounds closed with PEG sealant were successfully attached and remained intact till the end of the follow-up period. There was no sign of postoperative hypotony or infection in any eye, and no adverse effects of PEG sealant were found. In histological examination, linear scar formation and eosinophilic staining of collagen fibers were observed at the sclerotomy sites, while the sclerotomy tunnels appeared tightly closed. CONCLUSIONS: PEG sealant can be useful for the closure of sutureless 23-gauge vitrectomy incisions in rabbits. TRANSLATIONAL RELEVANCE: The PEG sealant may become an effective option for closing vitrectomy incisions including pediatric cases.

In Vivo and In Vitro Feasibility Studies of Intraocular Use of Polyethylene Glycol-Based Synthetic Sealant to Close Retinal Breaks in Porcine and Rabbit Eyes.

PURPOSE: Absorbable polyethylene glycol-based synthetic sealant (PEG sealant) polymerizes under xenon illumination and forms a clear, flexible, and firmly adherent hydrogel. The intraocular biocompatibility of PEG sealant and efficacy for closing retinal breaks were evaluated. METHODS: In an in vitro study, retinal detachment with a tear was created in porcine eyecups after vitreous gel removal. Polyethylene glycol-based synthetic sealant was applied to cover the tear and polymerized with a 40-second application of xenon light. Retinal adhesion strength was tested by forcefully squirting balanced salt solution (BSS) onto the retinal tear. Polyethylene glycol-based synthetic sealant was soaked in the BSS, incubated at 37°C, and the pH measured periodically over 72 hours. In an in vivo study, PEG sealant was injected into the vitreous cavity of the left eyes of rabbits. Ophthalmologic examinations were performed and bilateral ERGs were recorded simultaneously before and 28 days after injection. The eyes were enucleated for histological evaluation. RESULTS: Adhesion of PEG sealant to the retina was good in BSS. A forceful squirt of BSS onto the retinal tear covered with PEG sealant did not detach the retina; the retinal tear without PEG sealant detached immediately. The pH of the BSS containing PEG sealant was between 7.2 and 8.2. No inflammatory reaction was observed in the eyes throughout 28 days of follow-up. The ERGs recorded before and after injection showed typical patterns. Histological examinations did not reveal any abnormality or inflammation. CONCLUSIONS: Polyethylene glycol-based synthetic sealant appeared to effectively seal retinal breaks and was not toxic to the eye.

Multifocal electroretinograms in Stargardt's disease/fundus flavimaculatus.

PURPOSE: To determine whether the characteristics of multifocal electroretinograms (mfERGs) were correlated with the ophthalmic appearance of the fundus in patients with Stargardt's disease/fundus flavimaculatus (SFF). METHODS: Full-field ERGs, mfERGs, and general ophthalmic examinations were performed on 49 eyes with SFF. RESULTS: The SFF patients were divided into four subtypes according to the classification of Noble and Carr [Arch Ophthalmol 1979;97:1281-1285]. The patients with type 1 SFF had severely reduced mfERGs in the macular area and reduced and delayed responses in the mid-periphery. The type 2 SFF patients had reduced but recordable mfERGs from the center of the macula with more depressed responses in the paramacular area, and the type 3 SFF patients had reduced and delayed mfERGs both in the macula and periphery. The patients with type 4 SFF had normal mfERGs in the macular area and delayed responses in all outer zones. CONCLUSIONS: These mfERG findings indicate that each subtype of SFF has unique characteristics corresponding to the abnormal retinal functions.

Influence of subretinal fluid in advanced stage retinopathy of prematurity on proangiogenic response and cell proliferation.

PURPOSE: The clinical phenotype of advanced stage retinopathy of prematurity (ROP, stages 4 and 5) cannot be replicated in an animal model. To dissect the molecular events that can lead up to advanced ROP, we examined subretinal fluid (SRF) and surgically dissected retrolental membranes from patients with advanced ROP to evaluate its influences on cell proliferation, angiogenic properties, and macrophage polarity. METHODS: We compared our findings to SRF collected from patients with uncomplicated rhegmatogenous retinal detachment (RD) without proliferative vitreoretinopathy and surgically dissected epiretinal membrane from eyes with macular pucker. All subretinal fluid samples were equalized for protein. The angiogenic potential of SRF from ROP eyes was measured using a combination of capillary cord formation in a fibrin clot assay, and its proliferative effect was tested with a DNA synthesis of human retinal microvascular endothelial cells. Findings were compared with SRF collected from participants with uncomplicated rhegmatogenous RD without proliferative vitreoretinopathy. The ability of SRF to induce nitric oxide production was measured in vitro using murine J774A.1 macrophages. Cytokine profiles of SRF from ROP and RD eyes were measured using a multienzyme-linked immunosorbent assay (ELISA). Fluorescent immunohistochemistry of retrolental membranes from ROP was performed to detect the presence of leukocytes and the composition of tissue macrophages using markers for M1 and M2 differentiation. RESULTS: The cytokine composition in SRF revealed that in ROP, not only were several proangiogenic factors were preferentially elevated but also the profile of proinflammatory factors was also increased compared to the RD eyes. SRF from ROP eyes supported cell proliferation and endothelial cord formation while SRF from RD eyes had inhibitory effects. SRF from eyes with ROP but not RD robustly induced nitric oxide production in macrophages. Furthermore, fluorescent immunostaining revealed a preponderance of M1 over M2 macrophages in retrolental fibrous membranes from ROP eyes. The cytokine profile and biologic properties of SRF in ROP promote a proangiogenic environment, which supports the maintenance and proliferation of fibrous membranes associated with advanced stages of ROP. In contrast, SRF from RD eyes exhibits a suppressive environment for endothelial cell proliferation and angiogenesis. CONCLUSIONS: Our investigation demonstrates that the microenvironment in advanced ROP eyes is proangiogenic and proinflammatory. These findings suggest that management of advanced ROP should not be limited to the surgical removal of the fibrovascular membranes and antiangiogenic therapy but also directed to anti-inflammatory therapy and to promote M2 activation over M1 activity.

The efficacy of mizoribine for the treatment of rheumatoid arthritis and its correlation with renal function.

OBJECTIVES: To evaluate the correlation between the efficacy of mizoribine (MZR) and the factors that might effect MZR concentration: renal function and dosage and administration of MZR in patients with rheumatoid arthritis (RA). METHODS: The efficacy of MZR treatment was prospectively evaluated in 97 RA regardless of dosage, at the 14 participated institutions. The Disease Activity Score 28-CRP3 was used to assess RA activity. The renal function was evaluated based on the serum creatinine and serum cystatin-C (Cys-C). The patients were followed up for 24 weeks. RESULTS: The patients with a mean age 66.2 years included 18 male. The renal function assessment showed increased creatinine in 16.4% of patients and increased Cys-C in 54.5%, suggesting the higher sensitivity of Cys-C to detect impaired renal function than creatinine. In patients with good or moderate response according to the European League against Rheumatism classification criteria, the Cys-C was significantly higher compared with those with no response. MZR treatment was significantly more effective in patients with an arithmetic product of the single MZR dose used and Cys-C of 179 or more. CONCLUSIONS: The efficacy of MZR may increase in proportion to its single dose, or increased Cys-C level in patients with impaired renal function.

Quantitative fundus autofluorescence and optical coherence tomography in best vitelliform macular dystrophy.

PURPOSE: Quantitative fundus autofluorescence (qAF), spectral domain optical coherence tomography (SD-OCT) segmentation, and multimodal imaging were performed to elucidate the pathogenesis of Best vitelliform macular dystrophy (BVMD) and to identify abnormalities in lesion versus nonlesion fundus areas. METHODS: Sixteen patients with a clinical diagnosis of BVMD were studied. Autofluorescence images (30°, 488-nm excitation) were acquired with a confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference to account for variable laser power and detector sensitivity. The grey levels (GLs) of each image were calibrated to the reference, zero GL, magnification, and normative optical media density, to yield qAF. Horizontal SD-OCT scans were obtained and retinal layers manually segmented. Additionally, color and near-infrared reflectance (NIR-R) images were registered to AF images. All patients were screened for mutations in BEST1. In three additional BVMD patients, in vivo spectrofluorometric measurements were obtained within the vitelliform lesion. RESULTS: Mean nonlesion qAF was within normal limits for age. Maximum qAF within the lesion was markedly increased compared with controls. By SD-OCT segmentation, outer segment equivalent thickness was increased and outer nuclear layer thickness decreased in the lesion. Changes were also present in a transition zone beyond the lesion border. In subclinical patients, no abnormalities in retinal layer thickness were identified. Fluorescence spectra recorded from the vitelliform lesion were consistent with those of retinal pigment epithelial cell lipofuscin. CONCLUSIONS: Based on qAF, mutations in BEST1 do not cause increased lipofuscin levels in nonlesion fundus areas.

Stargardt-Fundus flavimaculatus: recent advancements and treatment.

Stargardt disease is the most common form of autosomal recessive macular dystrophy. Mutation in the ABCA4 gene (ABCR protein) is responsible for disease manifestation in more than 95% of Stargardt patients. ABCA4 codes for a member of the ATP binding cassette transmembrane protein involved in the transport of all-trans retinal. Dysfunction in this protein causes accumulation of lipofuscin, which is toxic to the RPE and photoreceptors. Presenting symptoms, fundus appearance, and progression of the disease are widely variable in this disease. Different imaging modalities have been utilized to study the presentation and evolution of fundus changes. Although there is ongoing research to better understand the disease process and ways to alternate its path, currently there is no treatment for Startgardt patients.

Portable optical coherence tomography in management of vitreoretinal diseases: current developments, indications, and implications.

The advent of optical coherence tomography (OCT) technology has greatly enhanced our understanding of vitreoretinal diseases; it has become a routine diagnostic imaging method for the evaluation of vitreoretinal abnormalities and injuries in adult and pediatric patients. The use of OCT has recently been extended beyond the offices and clinics to perioperative and intraoperative settings. The new development in high-resolution and high-speed spectral domain OCT, along with the improvement in portability, has made the device more valuable than ever before. Our article summarizes the current development of the portable OCT devices in clinical, perioperative, and intraoperative settings in the management of vitreoretinal diseases.

Vogt-Koyanagi-Harada syndrome: review of clinical features.

Vogt-Koyanagi-Harada syndrome is a bilateral, chronic, diffuse granulomatous panuveitis associated with poliosis, vitiligo, and central nervous system and auditory signs. Increasing reports have been published to describe the clinical features of Vogt-Koyanagi-Harada syndrome. These manifestations are variable. This article presents a review of the clinical features.

Effect of aging on macular features of X-linked retinoschisis assessed with optical coherence tomography.

PURPOSE: X-linked retinoschisis (XLRS) is one of the most common causes of macular degeneration in young men. The purpose of this study was to use optical coherence tomography combined with ophthalmoscopy to study the effects of aging on the morphologic changes associated with XLRS. METHODS: Twenty-five eyes of 17 men with XLRS ranging in age from 3 years to 68 years were studied using ophthalmoscopy and optical coherence tomography. Optical coherence tomography was used to measure macular thickness and to evaluate XLRS-related structural changes. Correlation analyses between the findings and patients' age and visual acuity were performed. RESULTS: Mean visual acuity was 20/100 (range, 20/40 to 20/400). There were no correlations between visual acuity and age or macular thickness. However, there was a significant decrease in macular thickness with age (P < 0.01). Eyes with posterior vitreous detachment had significantly decreased central foveal thickness (P < 0.001). Various retinal morphologic changes could be identified by optical coherence tomography, including epiretinal membranes, intraretinal cysts, tissue pillars bridging the schisis cavities, and tissue hyperreflectivity in collapsed XLRS. These findings were significantly correlated with age. CONCLUSION: Optical coherence tomography revealed various retinal morphologic changes associated with XLRS. These changes were correlated with age but not with visual acuity. Younger patients showed cystic retinal elevation, whereas older patients showed collapsed retinoschisis with retinal thinning.

Endophthalmitis in the era of small gauge transconjunctival sutureless vitrectomy--meta analysis and review of literature.

PURPOSE: The goal of this study was to review, evaluate, and perform a meta-analysis on the current literature that reports rates of postoperative endophthalmitis after small gauge transconjunctival sutureless vitrectomy (TSV) and compare it to 20-gauge pars plana vitrectomy (20G PPV). METHODS: We performed an extensive review of the current literature. We included only large comparative institutional reviews. Meta-analysis of these reviews was performed. RESULTS: We found six large retrospective comparative cases series on the 25-gauge (25G) TSV as compared to 20G PPV. The test for homogeneity for the meta-analysis indicates that the studies are not homogeneous and therefore the evidence is tentative. CONCLUSION: We cannot conclude that 25G TSV has a higher rate of postoperative endophthalmitis compared to the 20G PPV. Future retrospective or prospective trials need to take into consideration multiple factors.

Prospects for treatment of pediatric vitreoretinal diseases with vascular endothelial growth factor inhibition.

While angiogenesis inhibitors are already widely used to treat retinal disease in adults, only limited reports are currently available for the use of anti-VEGF in pediatric vitreoretinal diseases such as retinopathy of prematurity, Coats' disease, familial exudative vitreoretinopathy and retinopathy of incontinentia pigmenti. The limited trials of anti-VEGF therapy for pediatric vitreoretinal diseases are promising, although more extensive controlled trials will be needed to confirm their safety and efficacy. This paper will examine the current evidence for use of anti-VEGF therapy in a number of pediatric vitreoretinal disorders and describe a case of anti-VEGF therapy in retinopathy of incontinentia pigmenti.

Growth factors outside the PDGF family drive experimental PVR.

PURPOSE: Proliferative vitreoretinopathy (PVR) is a recurring and problematic disease for which there is no pharmacologic treatment. Platelet-derived growth factor (PDGF) in the vitreous is associated with experimental and clinical PVR. Furthermore, PDGF receptors (PDGFRs) are present and activated in epiretinal membranes of patient donors, and they are essential for experimental PVR. These observations suggest that PVR arises at least in part from PDGF/PDGFR-driven events. The goal of this study was to determine whether PDGFs were a potential therapeutic target for PVR. METHODS: Experimental PVR was induced in rabbits by injecting fibroblasts. Vitreous specimens were collected from experimental rabbits or from patients undergoing vitrectomy to repair retinal detachment. A neutralizing PDGF antibody and a PDGF Trap were tested for their ability to prevent experimental PVR. Activation of PDGFR was monitored by antiphosphotyrosine Western blot analysis of immunoprecipitated PDGFRs. Contraction of collagen gels was monitored in vitro. RESULTS: Neutralizing vitreal PDGFs did not effectively attenuate PVR, even though the reagents used potently blocked PDGF-dependent activation of the PDGF alpha receptor (PDGFRalpha). Vitreal growth factors outside the PDGF family modestly activated PDGFRalpha and appeared to do so without engaging the ligand-binding domain of PDGFRalpha. This indirect route to activate PDGFRalpha had profound functional consequences. It promoted the contraction of collagen gels and appeared sufficient to drive experimental PVR. CONCLUSIONS: Although PDGF appears to be a poor therapeutic target, PDGFRalpha is particularly attractive because it can be activated by a much larger spectrum of vitreal growth factors than previously appreciated.

Evaluation of macular abnormalities in Stargardt's disease using optical coherence tomography and scanning laser ophthalmoscope microperimetry.

BACKGROUND: The purpose of this study is to evaluate the diagnostic value of optical coherence tomography (Stratus OCT) and scanning laser ophthalmoscope (SLO) microperimetry in patients with Stargardt's disease (STGD), and the correlation between macular morphology and visual function in these patients. METHODS: Twenty-two patients with STGD (mean age 44 years, range 11 to 71 years) and 20 age-matched healthy control subjects were included in the study. OCT imaging was performed using six radial line scans manually centered on the fovea. SLO microperimetry was used to assess central scotoma and fixation behavior in patients with STGD. RESULTS: Mean best corrected Snellen visual acuity (BCVA) was 20/80, range 20/25 to 20/300 (log MAR 0.6, range 0.1 to 1.2) in the STGD group and 20/20 (log MAR 0.0) in the control group. Foveal thickness was significantly reduced in patients with STGD (119.0 +/- 19.6 microm) compared to controls (210.7 +/- 19.6 microm, P < 0.0001). A significant correlation between foveal thickness and BCVA was observed within the STGD group (R(2) = 0.62, P < 0.0001). Photoreceptor loss in the macular area and a corresponding central scotoma were observed in all STGD patients. CONCLUSIONS: OCT findings, particularly reduced foveomacular thickness and photoreceptor loss in the macular area may be useful in the diagnosis of STGD. Furthermore, a strong correlation between foveal thickness and visual function was observed in our patients. Assessment of central visual function using SLO microperimetry provides additional useful information, important in the management of STGD.

Retinal blood flow and nerve fiber layer measurements in early-stage open-angle glaucoma.

PURPOSE: To evaluate the relationship between retinal circulatory abnormalities and retinal nerve fiber layer (RNFL) thinning in early-stage open-angle glaucoma (OAG) to help elucidate the mechanisms underlying the development of glaucomatous optic neuropathy. DESIGN: Prospective cross-sectional. METHODS: Twelve patients with early OAG and a known maximum untreated intraocular pressure less than 22 mm Hg (age, 61.4 +/- 9.7 years; Humphrey visual field mean deviation -2.7 +/- 2.1) and eight age-matched healthy control subjects (age, 58.5 +/- 8.3 years) were included in the study. Blood column diameter, centerline blood speed, and retinal blood flow were measured in the major inferior temporal retinal artery using a Canon laser Doppler blood flow instrument (CLBF 100; Canon, Tokyo, Japan). Peripapillary RNFL thickness was measured using a Stratus optical coherence tomography instrument. RESULTS: On average, there were significant reductions in retinal blood speed (P = .009) and flow (P = .010) in OAG patients compared to controls. The RNFL was significantly thinner in the OAG patients compared to controls (P = .002). There were significant inverse correlations between retinal blood flow and average RNFL thickness and RNFL thickness in the inferior quadrant within the glaucoma group (Rsq = 0.50, P = .01; Rsq = 0.62, P = .003). CONCLUSION: The results showed that a thinner RNFL was associated with a higher retinal blood flow in patients with early-stage OAG. The mechanisms underlying this phenomenon remain to be elucidated.

Plasmin is the major protease responsible for processing PDGF-C in the vitreous of patients with proliferative vitreoretinopathy.

PURPOSE: Proliferative vitreoretinopathy (PVR) is the primary cause of failure of retinal reattachment surgery. Growth factors such as platelet-derived growth factor (PDGF) are strongly associated with PVR. Of the five PDGF family members, PDGF-C predominates in the vitreous of experimental and clinical PVR. PDGF-C is secreted as a latent protein that requires proteolytic processing for activation. Although tissue plasminogen activator (tPA) is primarily responsible for processing PDGF-C in cultured cells, it constitutes a minority of the processing activity in the vitreous of experimental animals and in patients with PVR. Identifying the major PDGF-C processing protease was the purpose of this study. METHODS: The presence of serum proteins in the vitreous was detected by Coomassie blue staining and Western blotting. PDGF-C processing activity was detected in an in vitro processing assay using either native or recombinant PDGF-C as the substrate. Plasmin activity was blocked using alpha(2)-plasmin inhibitor. Phosphorylation of the PDGF receptor (PDGFR) was monitored by antiphosphotyrosine Western blotting. Vitreous specimens were collected from experimental rabbits or from patients undergoing vitrectomy to repair retinal detachment or for other reasons. RESULTS: A number of prominent serum proteins (albumin and IgG) were detected in the vitreous of all patients undergoing retinal surgery. The level of these proteins markedly increased in the vitreous of rabbits as they developed PVR. These observations suggested that serum-borne proteases are also likely to be present in the vitreous. Indeed, plasmin (a protease capable of processing PDGF-C) was present in the vitreous from PVR rabbits and retinal surgery patients. Plasmin was dramatically more effective than tPA in processing PDGF-C in an in vitro assay. Blocking plasmin activity eliminated most of the processing activity in the vitreous of patients and rabbits with PVR. CONCLUSIONS: Plasmin was the major PDGF-C processing protease in the vitreous of PVR rabbits and patients undergoing retinal surgery. Blocking plasmin prevented the generation of active PDGF-C, which is the major PDGF isoform relevant for PVR. These observations are the first report of an in vivo protease responsible for processing PDGF-C. In addition, plasmin was identified as a novel therapeutic target for patients with PVR.