In Vitro Physicochemical and Pharmacokinetic Properties of Bevacizumab Dissolved in Silicone Oils Compared to Hydrogel-Substitutes and Porcine Vitreous Bodies.

Anti-VEGF agents, e.g., bevacizumab, are used in retinal surgery, while their interaction with silicone oils and novel hydrogels remains unclear. This study examines the in vitro pharmacokinetics of bevacizumab in silicone oil-filled eyes compared to various hydrogel replacements and the porcine vitreous body as well as its impact on the interface tension of silicone oils. An in vitro model filled with light or heavy silicone oil, porcine vitreous bodies, or hydrogels (alginate and polyethylene glycol (PEG)-based) was equilibrated with a balanced salt solution. Monitoring of bevacizumab in the aqueous phase was conducted for up to 24 h, and its effect on interfacial tension was studied. Significant differences in bevacizumab partitioning were observed across endotamponades after 24 h. In silicone oils, bevacizumab was found exclusively in the aqueous phase, while in the other endotamponades, it accumulated in the gel phase (96.1% in porcine vitreous body, 83.5% in alginate, and 27.6% in PEG-based hydrogel). Bevacizumab significantly reduced interfacial tension (40 to 8 mN/m), possibly enhancing silicone oil emulsification. The type of endotamponade heavily influenced the bevacizumab concentration in the aqueous. The vitreous body and replacement hydrogels likely serve as a drug reservoir, highlighting the need for in vivo studies to explore these interactions prior to clinical application.

Bubble-graft coverage after Descemet Membrane Endothelial Keratoplasty depending on gaze angle.

PURPOSE: In Descemet Membrane Endothelial Keratoplasty (DMEK) a gas bubble is usually used to attach the graft to the host cornea. In this study, we observed the bubble size and bubble-graft coverage at different gaze angles following DMEK. METHODS: This observational prospective study analyzed 465 images of patients who underwent an uneventful DMEK. Intraoperatively, the anterior chamber was filled up to 90% of its volume with a 20% Sulfur Hexafluoride (SF6) gas-air mixture. Postoperatively, the bubble was photographed daily in different gaze angles ranging from a supine position (0°) to an upright position (90°) and a slightly inclined position (105°). The primary outcomes were bubble-graft coverage and bubble diameters depending on the gaze angle and time after DMEK. RESULTS: The highest bubble-graft coverage was achieved at a 0° gaze angle at all times of measurement. In the first 48 h after DMEK, the mean bubble-graft coverage was over 85% at a gaze angle between 0° and 45°. Starting 72 h after DMEK, the graft coverage declined at all gaze angles. The graft coverage at a 0° gaze angle was 88.61 ± 10.90% after 96 postoperative hours, while the graft coverage was below 85% at all other gaze angles. CONCLUSION: Our clinical results provide novel insight into variation in bubble-graft coverage as a function of gaze angle and may be used to aid in patient counselling for appropriate body positioning following DMEK to prevent early graft detachment. Maintaining supine positioning seems to be most advantageous starting 48 h after DMEK.

Higher phosphate concentrations as in aqueous humor of diabetic patients increase intraocular lens calcification.

BACKGROUND: Clinical evidence suggests an association between phosphate concentrations in aqueous humor and the risk of intraocular lens (IOL) calcification. To test this hypothesis the influence of different phosphate concentrations on IOL calcification was evaluated in an in vitro electrophoresis model. METHODS: 20 IOLs of two hydrophilic IOL models (CT Spheris 204, Zeiss; Lentis L-313, Oculentis) and one hydrophobic control IOL model (Clareon CNA0T0, Alcon) were exposed to physiologic and elevated phosphate concentrations, similar to diabetic aqueous humor. IOL calcification was analyzed by alizarin red staining, von Kossa staining, scanning electron microscopy, energy dispersive x-ray spectroscopy and transmission electron microscopy with electron diffraction. RESULTS: Higher phosphate concentrations were associated with IOL calcification. Analyses of IOL surfaces and cross-sections documented calcification in no CT Spheris and 4 Lentis IOLs following exposure to 10 mM Na2HPO4, compared with 7 and 11 positive analyses following exposure to 14 mM Na2HPO4, respectively. Furthermore, a clear association between IOL calcification and the duration of electrophoresis was demonstrated, confirming increased phosphate concentrations and duration of exposure as risk factors of IOL calcification. CONCLUSIONS: Findings suggest that higher phosphate concentrations in aqueous humor, as seen in diabetic patients, contribute to an increased IOL calcification risk, potentially explaining clinical observations showing an increased risk of IOL calcification in patients with diabetes.

Viscoelastic, Optical, and Surgical Properties of Vitreous Body Replacement Hydrogels After Aging Compared to Porcine Vitreous Bodies And Silicone Oils.

Purpose: First- (monomers), second- (pre-gelated), and third- (in situ gelating after injection) generation hydrogels were previously introduced to replace the vitreous body after vitrectomy surgery. In this study, we evaluated the surgical, optical, and viscoelastic properties of vitreous body replacement hydrogels before and after an accelerated aging protocol previously applied to intraocular implants. Methods: Measurements of injection force, removal speed using a clinically established vitrectomy setup, as well as evaluation of forward light scattering and viscoelastic properties before and after an accelerated aging protocol were conducted. Results were compared to porcine and human vitreous bodies, as well as currently clinically applied lighter- and heavier-than-water silicone oils. Results: Removal speed of all tested hydrogels is substantially lower than the removal speed of porcine vitreous body (0.2 g/min vs. 2.7 g/min for the best performing hydrogel and porcine vitreous body, respectively). Forward light scattering in second-generation vitreous body replacement hydrogels was higher after the aging process than the straylight of the average 70-year-old vitreous body (9.4 vs. 5.5 deg2/sr, respectively). The viscoelastic properties of all hydrogels did not change in a clinically meaningful manner; however, trends toward greater stiffness and greater elasticity after aging were apparent. Conclusions: This study demonstrates surgical weaknesses of the hydrogels that need to be addressed before clinical use, especially low removal speed. Pre-linked hydrogels (second-generation) showed inferior performance regarding surgical properties compared to in situ gelating hydrogels (third-generation). Translational Relevance: This study highlights possible pitfalls regarding surgical and optical properties when applying vitreous replacement hydrogels clinically.

Early intraocular lens explantations: 10-year database analysis.

BACKGROUND: The aim of this study was to analyze the causes and characteristics of IOL explantation within the first year after primary implantation. METHODS: In this retrospective, cross sectional database study, a database consisting of over 2500 IOL explants sent from 199 national and international doctors over the past 10 years was analyzed. All IOLs explanted within the first year after implantation were included in this analysis. Explants with insufficient information as well as phakic and Add-on IOLs were excluded. Main outcome measures were the reason for explantation, the time between implantation and explantation, as well as IOLs' and patients' characteristics. Additionally, the explanted IOLs were microscopically and histologically analyzed, as required. RESULTS: Of all explanted IOLs from the database, 1.9% (n = 50) were explanted within the first year after implantation. The most frequent reasons for early IOL explantation were IOL dislocation (32%), visual intolerance (26%), opacification (20%), and intraoperative complications (16%). The time between implantation and explantation was the shortest in cases with intraoperative complications (1.5 ± 3.1 days), followed by IOL dislocation (90.9 ± 103.9 days), visual intolerance (98.3 ± 86.5 days), opacifications (253.5 ± 124.0 days) and other indications (249.7 ± 124.0 days). Calcification of hydrophilic IOLs was the main type of opacification (80%). Notably, seven IOLs required immediate intraoperative exchange due to an intraoperative crack in the optic or a torn off haptic. CONCLUSION: Indications for early IOL explantation were IOL dislocation, visual intolerance, opacification, and intraoperative complications. Especially intraoperative damages to the IOL and early calcification show a potential for improvement of affected IOLs and implantation systems.

Evaluation of Parameters and Nozzle Tip Damage after Clinical Use of Three Hydrophilic Intraocular Lens Injector Models.

Purpose: To assess the nozzle tip damage and the parameters of three different hydrophilic intraocular lens (IOL) injector models. Methods: After routine cataract surgeries at the University Eye Hospital Heidelberg, all the used IOL injectors were collected from the operating room and sent to our laboratory. Nozzle tip damage was assessed under a microscope and graded as follows: no damage (grade 0), slight scratches (1), deep scratches (2), extensions (3), cracks (4), and bursts (5). Each damage grade was assigned a score from 0 to 5, and the total damage score for each injector system was calculated and compared. Nozzle tip parameters (diameters and areas), plunger tip parameters, and tip angles were also measured in each model. Results: The damage scores were (median, Q3-Q1): 1 (1-1) for Accuject, 1 (1-1) for Bluemixs, and 1 (1-1) for RayOne. There was no statistically significant difference in the damage scores between the study groups (P > 0.05). The outer cross-sectional vertical and horizontal diameters were 1.69 and 1.69 mm for Accuject, 1.69 and 1.69 mm for Bluemixs, and 1.70 and 1.71 mm for RayOne. Plunger tip areas were 0.78 mm2 for Accjuect, 0.74 mm2 for Bluemixs, and 0.43 mm2 for RayOne. Plunger tip area/inner cross-sectional area of the nozzle tip (%) was 31.2% for RayOne, 66.7% for Accuject, and 63.8% for Bluemixs. The tip angles for three injector models were 56° (Accuject), 56° (Bluemixs), and 44° (RayOne). Conclusions: All the injector models showed mild to moderate damage to the nozzle tip after IOL implantation, even with smaller diameter tips. RayOne resulted in the lowest ratio between plunger tip area and inner cross-sectional area of the nozzle tip and a better distribution of damage categories than the other two groups. All three injector models had relatively small tip parameters. If smaller incisions are required in certain patients, smaller tip parameters should be considered.

Forward Light Scattering of the Vitreous Gel After Enzymatic Aging: An In Vitro Model to Study Vitreous Opacification.

Purpose: Symptomatic vitreous opacifications, so-called floaters, are difficult to objectively assess majorly limiting the possibility of in vitro studies. Forward light scattering was found previously to be increased in eyes with symptomatic floaters. Using an objective setup to measure forward light scattering, we studied the effects of enzymatically digesting the components of the vitreous body on straylight to develop an in vitro model of vitreous opacifications. Methods: Fifty-seven porcine vitreous bodies were digested using hyaluronidase, collagenase, trypsin, and bromelain, as well as using a combination of hyaluronidase + collagenase and hyaluronidase + bromelain. A modified C-Quant setup was used to objectively assess forward light scattering. Results: Depletion of hyaluronic acid majorly increased vitreous straylight (mean increase 34.4 deg2/sr; P = 0.01), whereas primarily digesting the vitreous gel with collagenase or trypsin did not significantly affect straylight. When collagenase or bromelain is applied in hyaluronic acid depleted vitreous gels, the increase in forward light scattering is reversed partially. Conclusions: The age-related loss of hyaluronic acid primarily drives the increase in vitreous gel straylight induced by conglomerates of collagen. This process can be reversed partially by digesting collagen. This in vitro model allows the objective quantification and statistical comparison of straylight burden caused by vitreous opacities and, thus, can serve as a first testing ground for pharmacological therapies, as demonstrated with bromelain.

Quantification of Straylight Induced by Silicone Oil Adherent to Intraocular Lenses of Different Materials.

PURPOSE: A complication of using silicone oil as an intraocular endotamponade is its adhesion to intraocular lenses (IOLs). Forward light scattering is a measure to quantify the optical disturbance caused by adherent oil droplets. We tested the straylight caused by silicone oil adhesion to different IOLs and examined whether an approved cleaning solution, F4H5, reverses the induced straylight. DESIGN: An experimental study. METHODS: Two hydrophobic acrylic IOL models and 1 hydrophilic model with a hydrophobic surface (n = 8 per model: 24 lenses) had straylight measured before contact with silicone oils, providing a baseline for subsequent testing: 12 lenses with lighter-than-water silicone oil (Siluron 2000) and 12 with heavier-than-water oil (Densiron 68). The final measurement was performed after cleansing with F4H5 when we used scanning electron and light microscopy to detect surface changes. RESULTS: Straylight was majorly increased in IOLs with adherent silicone oil (baseline vs adherent oil median 3.1 [2.1, 3.9] and 39.7 [22.7, 87.8] deg2/sr, respectively; P < .001). No difference was seen between heavier- and lighter-than-water silicone oils. Between IOL types, induced straylight varied significantly, with 1 hydrophobic model reaching the highest average straylight. F4H5 significantly reduced straylight values in all IOL types (median 9.4 [5.4, 13.8] deg2/sr). The microscopy revealed surface changes on the IOLs even after cleaning. CONCLUSIONS: Silicone oil adhesion to IOLs can induce amounts of straylight known to cause severe optical disturbance. F4H5 cleansing solution reversed straylight values to only slightly increased values. We found no difference in straylight formation between the lighter- and heavier-than-water silicone oils.

Forward Light Scattering of First to Third Generation Vitreous Body Replacement Hydrogels after Surgical Application Compared to Conventional Silicone Oils and Vitreous Body.

To treat certain vitreoretinal diseases, the vitreous body, a hydrogel composed of mostly collagen and hyaluronic acid, must be removed. After vitrectomy surgery, the vitreous cavity is filled with an endotamponade. Previously, pre-clinical hydrogel-based vitreous body substitutes either made from uncrosslinked monomers (1st generation), preformed crosslinked polymers (2nd generation), or in situ gelating polymers (3rd generation) have been developed. Forward light scattering is a measure of Stray light induced by optical media, when increased, causing visual disturbance and glare. During pinhole surgery, the hydrogels are injected into the vitreous cavity through a small 23G-cannula. The aim of this study was to assess if and to what extent forward light scattering is induced by vitreous body replacement hydrogels and if Stray light differs between different generations of vitreous body hydrogel replacements due to the different gelation mechanisms and fragmentation during injection. A modified C-Quant setup was used to objectively determine forward light scattering. In this study, we found that the 1st and 3rd generation vitreous body replacements show very low stray light levels even after injection (2.8 +/- 0.4 deg2/sr and 0.2 +/- 0.2 deg2/sr, respectively) as gel fragmentation and generation of interfaces is circumvented. The 2nd generation preformed hydrogels showed a permanent increase in stray light after injection that will most likely lead to symptoms such as glare when used in patients (11.9 +/- 0.9 deg2/sr). Stray light of the 2nd generation hydrogels was 3- and 2-fold increased compared to juvenile and aged vitreous bodies, respectively. In conclusion, this significant downside in the forward light scattering of the 2nd generation hydrogels should be kept in mind when developing vitreous body replacement strategies, as any source of stray light should be minimized in patients with retinal comorbidities.

Influence of Subclinical Corneal Edema on Contrast Sensitivity in Fuchs Endothelial Corneal Dystrophy.

PURPOSE: The aim of this study was to compare visual function, with a focus on contrast sensitivity, between patients with Fuchs endothelial corneal dystrophy (FECD) with and without subclinical corneal edema. METHODS: In this cross-sectional, observational, single-center study, 46 pseudophakic eyes of 31 patients with FECD were divided into 2 groups depending on the presence of subclinical corneal edema. All eyes presented with a Krachmer grade of 5 and no clinical corneal edema. The criteria for subclinical corneal edema were loss of regular isopachs, displacement of the thinnest point, and focal posterior surface depression in Scheimpflug tomography. If more than 1 criterion was present, subclinical corneal edema was diagnosed. The corrected distance visual acuity, contrast sensitivity (Pelli-Robson chart and CSV-1000 test with optional glare), and straylight were measured. The differences between both groups were analyzed using clustered Wilcoxon rank-sum tests. RESULTS: The corrected distance visual acuity and the contrast sensitivity, measured with a Pelli-Robson chart, were significantly inferior in eyes with subclinical corneal edema compared with eyes without subclinical edema ( P < 0.05). At all spatial frequencies, eyes with subclinical edema demonstrated lower contrast sensitivity with a statistically significantly reduction in total contrast sensitivity when tested with ( P = 0.005) and without ( P = 0.002) glare. The straylight did not significantly differ between both groups ( P > 0.05). CONCLUSIONS: The corrected distance visual acuity and contrast sensitivity were significantly reduced in FECD eyes with subclinical corneal edema compared with those with no subclinical edema. This decrease in visual quality may be considered when evaluating the need for surgical intervention at earlier stages of FECD.

Impact of Lens Opacity on Optical Coherence Tomography Angiography Metrics.

PURPOSE: To evaluate the impact of lens opacity on the reliability of optical coherence tomography angiography metrics and to find a vessel caliber threshold that is reproducible in cataract patients. METHODS: A prospective cohort study of 31 patients, examining one eye per patient, by applying 3 × 3 mm macular optical coherence tomography angiography before (18.94 ± 12.22 days) and 3 months (111 ± 23.45 days) after uncomplicated cataract surgery. We extracted superficial (SVC) and deep vascular plexuses (DVC) for further analysis and evaluated changes in image contrast, vessel metrics (perfusion density, flow deficit and vessel-diameter index) and foveal avascular area (FAZ). RESULTS: After surgery, the blood flow signal in smaller capillaries was enhanced as image contrast improved. Signal strength correlated to average lens density defined by objective measurement in Scheimpflug images (Pearson's r: -.40, p: .027) and to flow deficit (r= -.70, p < .001). Perfusion density correlated to the signal strength index (r = .70, p < .001). Vessel metrics and FAZ area, except for FAZ area in DVC, were significantly different after cataract surgery, but the mean change was approximately 3-6%. A stepwise approach in extracting vessels according to their pixel caliber showed a threshold of > 6 pixels caliber (∼20-30 µm) was comparable before and after lens removal. CONCLUSION: In patients with cataract, OCTA vessel metrics should be interpreted with caution. In addition to signal strength, contrast and pixel properties can serve as supplementary quality metrics to improve the interpretation of OCTA metrics. Vessels with ∼20-30 µm in caliber seem to be reproducible.

Late central graft detachment due to double endothelial layer after repeat Descemet membrane endothelial keratoplasty.

Purpose: To report late central graft detachment after repeat Descemet membrane endothelial keratoplasty (DMEK) without visual reduction. Observations: A 71-year-old patient with Fuchs' endothelial corneal dystrophy received a DMEK in his left eye. At 11 month post-operatively, a subtotal graft detachment was noted. Due to increasing corneal edema with vision loss, the first DMEK was removed and a repeat-DMEK was performed. At four months post repeat-DMEK, the graft was fully adherent to the posterior stroma. There was no significant corneal edema, and the best corrected visual acuity was 20/25. At 16-months after repeat-DMEK, a central graft detachment was noted, but there was no concurrent corneal edema or any loss of visual acuity. The mean density of the central endothelial cells was measured at 842 cells/mm2. Given the lack of corneal edema, visual reduction or subjective visual complaint, the graft detachment was followed-up for up to 20-months post repeat-DMEK with no further intervention, where the central cornea remained clear. Conclusions and Importance: To our knowledge, this is the first report of a central repeat-DMEK graft detachment that occurred 16 months after surgery despite initial attachment. Interestingly, there was no concurrent corneal edema or vision reduction. We describe a potential mechanism for clear central cornea in the presence of a central graft detachment after repeat-DMEK.

Functional and Morphological Responses to Fluocinolone Acetonide 0.19 mg in Noninfectious Uveitic Macular Edema Evaluated as the Area-Under-the-Curve.

Purpose: This study investigated the impact of baseline clinical and optical coherence tomography (OCT) factors on the response to a 0.19-mg fluocinolone acetonide (FAc) implant in patients with noninfectious uveitic macular edema evaluated by the area under the curve over 24 months. Methods: A retrospective study was conducted of eyes of patients with noninfectious uveitic macular edema undergoing FAc treatment, with follow-up from baseline to 24 months. The area under the curve (AUC) of best-corrected visual acuity (BCVA) and the central macular thickness (CMT) were calculated using the trapezoidal rule. Clinical and OCT data at the time of FAc administration were collected, and associations with AUC of BCVA and CMT changes were investigated. Results: Twenty-three patients were enrolled. BCVA and CMT significantly improved after FAc implantation (P < 0.05). AUCBCVA and AUCCMT were 0.41 ± 0.33 logarithm of minimal angle of resolution/6 months and 320.15 ± 321.64 µm/6 months, respectively. Better baseline BCVA (coefficient [coef.] = 0.83, P < 0.001) and macular thickness reduction after FAc administration (coef. = -0.0001, P < 0.05) were associated with better BCVA after FAc treatment. In contrast, baseline OCT biomarkers such as ellipsoid zone reflectivity and choroidal vascularity index, sex, or disease duration before FAc injection showed no correlation with AUCBCVA and AUCCMT (P > 0.05). The younger the patient at the time of FAc injection, the greater the reduction in CMT (coef. = 1.76, P < 0.05). Conclusions: Among all clinical and morphological baseline factors, Baseline BCVA was the strongest predictor for AUCBCVA, while no association with baseline OCT features was observed. Overall, improvement of BCVA and CMT after FAc injection was maintained over 24 months. This study is registered in the German Clinical Trials Register under the DRKS-ID: DRKS00024399.

Comparison of a Presbyopia-Correcting Supplementary Intraocular Lens Combination and a Capsular-Bag Lens: An In Vitro Study.

We evaluated the optical quality of two approaches to trifocality: polypseudophakia versus monopseudophakia. The combination (polypseudophakia) of a monofocal Basis Z B1AWY0 and AddOn Trifocal A4DW0M intraocular lens (IOL) was compared to using one Basis Z Trifocal B1EWYN IOL, all from 1stQ GmbH. In both approaches, we measured modulation transfer function (MTF) and Strehl Ratio (SR) values at 3.0 and 4.5 mm pupil sizes. We determined the through-focus (TF) MTF at 25, 50 and 100 lp/mm for the 3 mm aperture. United States Air Force (USAF) target images were recorded. MTF measurement of the trifocal lens and the combined monofocal and trifocal AddOn IOL showed good performance at the far and near focus for the 3 mm aperture. For the 4.5 mm aperture the MTF improved for the far focus but decreased for the intermediate and near focus. TF MTF showed better contrast at the far focus for the polypseudophakic setup but at the expense of the efficiency at the near focus. However, the USAF chart images revealed only minimal differences between both approaches. The optical quality of the polypseudophakic approach was not affected by the presence of two IOLs instead of one and proved to be comparable with the performance of one capsular-bag-fixated trifocal IOL. Differences between the single vs. two-lens approach seen in the TF MTF analysis could be attributed to the optical design that varied between the trifocal models.

[Hydrophobic surface properties of hydrophilic acrylic lenses do not protect against calcification]. / Hydrophobe Oberflächeneigenschaften hydrophiler Acryllinsen schützen nicht vor Kalzifikation.

BACKGROUND: Opacification through calcification of hydrophilic acrylic intraocular lenses is a serious complication of cataract surgery, which usually results in explantation of the lens. In the process of calcification, the intraocular lens material plays a crucial role: calcification only occurs in hydrophilic acrylic lenses. Hydrophobic acrylic lenses show no crystal formation within the polymer. Hydrophilic acrylic lenses from some manufacturers have hydrophobic surface properties. The question arises as to what influence these surface properties have on the risk of calcification. OBJECTIVE: The present study investigated whether the hydrophobic surface properties of hydrophilic acrylic lenses can prevent calcification. MATERIAL AND METHODS: Using an electrophoretic in vitro model of calcification, two hydrophilic lenses with hydrophobic surface properties were compared to two hydrophilic lenses and a hydrophobic negative control to determine the risk of calcification. The lenses were then analyzed by optical microscopy, Alizarin Red and Von Kossa staining, scanning electron microscopy (SEM) and energy dispersive X­ray spectroscopy (EDX). RESULTS: All four hydrophilic lens models showed calcification within the polymer. No difference was found between the hydrophilic lenses and the hydrophilic lenses with hydrophobic surface properties in terms of crystal formation. The hydrophobic negative control showed no calcification. CONCLUSION: The investigation conducted in this study under standardized conditions could show that hydrophobic surface properties of hydrophilic acrylic lenses do not protect against calcium phosphate crystal formation within the polymer. There also is a risk of calcification in these lens models.