Conditions for modifying intraocular lenses as drug carriers for methotrexate using poly (lactic-co-glycolic acid).

INTRODUCTION: The intraocular lens (IOL) can be used as a slow-release drug carrier in cataract surgery to alleviate posterior capsular opacification (PCO). The following is a systematic development of an IOL using methotrexate and the solvent casting process with poly (lactic-co-glycolic acid) (PLGA) as a carrier polymer. METHODS: Different solvents for PLGA and methotrexate were tested for dissolution properties and possible damage to the IOL. The required biological concentration of methotrexate was determined in human capsular bags implanted with an IOL. To detect fibrosis, α-SMA, f-actin, and fibronectin were labelled by immunofluorescence staining. Cell proliferation and extracellular matrix contraction were observed in a lens epithelial cell line (FHL-124). Finally, the IOL was designed, and an ocular pharmacokinetic model was used to measure drug release. RESULTS: Solvent mixtures were found to allow coating of the IOL with drug and PLGA without damaging it. PCO in the capsular bag model was inhibited above 1 µM methotrexate (p = 0.02). Proliferation in FHL-124 was significantly reduced above a concentration of 10 nM (p = 0.04) and matrix contraction at 100 nM (p = 0.02). The release profile showed a steady state within therapeutic range. CONCLUSION: After determination of the required physicochemical manufacturing conditions, a drug releasing IOL was designed. A favourable release profile in an ocular pharmacokinetics model could be shown.

[Current aspects of vernal and atopic keratoconjunctivitis]. / Aktuelles zur Keratoconjunctivitis vernalis und atopica.

BACKGROUND: Vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC) are complex and rare diseases. Thus, their diagnosis and treatment are often a challenge. OBJECTIVE: Discussion on the epidemiology, new pathogenetic concepts, interesting clinical findings, diagnostic possibilities and new treatment options and their side effects in severe ocular allergies. Analysis of the presentation of VKC in the internet. MATERIAL AND METHODS: Evaluation of recent review articles, original publications, and case reports on the topics of VKC and AKC over the past 5 years. RESULTS: Ocular allergies have significantly increased over the last decades. Recent concepts discussed in the pathogenesis of VKC and AKC are the role of the local and gut microbiome as well as the influence of neuroinflammation. Keratoconus is significantly more common in patients with VKC and AKC compared to the normal population. It is associated with faster progression and a more severe course of disease. A conjunctival provocation test is only rarely necessary in the diagnosis of allergic conjunctivitis. Treatment of atopic dermatitis with dupilumab, an interleukin 4 receptor alpha (IL-4Ra) antagonist, can cause ocular side effects. Unfortunately, information available on the internet for patients and parents on the topic of VKC is sometimes dangerously incorrect. CONCLUSION: From the abovementioned new pathogenetic concepts, preventive and personalized treatment options could be developed in the future. Keratoconus in AKC/VKC must be recognized and treated early. Official guidelines are now available for a standardized conjunctival provocation test in the diagnosis of allergic conjunctivitis. The unwanted ocular side effects of dupilumab are often difficult to discriminate from the actual underlying AKC and respond well to anti-inflammatory treatment. Patients with VKC must be informed about the incorrect information on the internet regarding their disease.

[New and future treatment approaches for allergic conjunctivitis]. / Neue und zukünftige Therapieansätze in der Behandlung der allergischen Konjunktivitis.

BACKGROUND: In severe and recurrent ocular allergies conventional ophthalmic drugs can reach their limits, especially in chronic forms. The first novel immunomodulators and biologicals are already in clinical use and could provide relief. OBJECTIVE: Based on the immunopathophysiological mechanisms of ocular allergies, possible targets for innovative treatment approaches are presented. An overview of promising new and future immunomodulators and biologicals and their modes of action is also given. MATERIAL AND METHODS: Current reviews on ocular allergies and the treatment of systemic allergic diseases were screened. Case reports on the treatment of ocular allergy using immunomodulators and biologicals were analyzed. The clinical relevance and possible applications are presented. RESULTS: In chronic forms of ocular allergies, complex ocular surface inflammatory responses mediated via immunoglobulin E (IgE), mast cells, CD4-positive type 2 T­helper cells and eosinophilic granulocytes are predominant. Cyclosporine A 0.1% eyedrops have been approved in Europe since 2018 for children aged 4 years and older with severe vernal keratoconjunctivitis (VKC). In addition, case reports present promising data on the systemic off-label use of biologicals, such as dupilumab or omalizumab, in refractory VKC or atopic keratoconjunctivitis (AKC). CONCLUSION: A profound understanding of the immunopathophysiology of ocular allergies is necessary to detect further targets for future immunomodulators and biologicals. Currently, immunomodulatory therapy remains limited to cyclosporine A eyedrops. Other immunomodulatory agents, such as tacrolimus and biologicals can only be used off-label. Further studies on the controlled clinical use of these substances in the treatment of VKC or AKC are underway.

Long-term Outcomes of PreserFlo MicroShunt versus XEN45 Gel Stent in Open-Angle Glaucoma.

PURPOSE: To compare two glaucoma drainage devices with subconjunctival filtration (MicroShunt and XEN) for open-angle glaucoma (OAG), with respect to effectiveness and safety. PATIENTS AND METHODS: This is a single center, retrospective, interventional study. In total, 106 eyes of 95 patients with OAG underwent surgery. Of these patients, 51 eyes of 45 patients received a MicroShunt implantation and 55 eyes of 50 patients received an XEN implantation. Failure was defined as an intraocular pressure (IOP) lower than 5 or higher than 17 mmHg at the end of follow-up after 2 years, the need for surgical revision, secondary glaucoma surgery, or loss of light perception. Outcome was rated as complete success or qualified success, depending on whether it was achieved with or without anti-glaucomatous medications. Postoperative complications and interventions were also documented for both groups. RESULTS: In the MicroShunt group, mean IOP decreased from 20.6 ± 7.5 mmHg at baseline to 13.0 ± 3.9 mmHg (p < 0.0001) after 2 years. In the XEN group, mean IOP was lowered from 22.5 ± 7.9 mmHg to 13.5 ± 4.2 mmHg (p < 0.0001). In both groups, the mean number of medications was significantly reduced (MicroShunt 2.7 ± 1.2 to 0.9 ± 2.5; p < 0.0001 vs. XEN 3.2 ± 0.9 to 1.1 ± 1.5; p < 0.0001). In regard to success rates, 37% of MicroShunt patients achieved complete success and 57% qualified success at the end of follow-up. In the XEN group, rates were 25 and 45%, respectively. Patient demographics differed between the two groups with respect to age (MicroShunt 72.8 ± 8.7 vs. XEN 67.7 ± 9.0 years; p = 0.002). Postoperative complications were comparable between the two groups. CONCLUSION: Both MicroShunt and XEN are effective in significantly reducing IOP and glaucoma medications in OAG, and with a good safety profile.

Rotational stability of plate haptic toric intraocular lenses after combined 25-gauge vitrectomy and cataract surgery.

AIM: To evaluate the postoperative intraocular lens (IOL) rotational stability and residual refractive astigmatism following combined 25-gauge vitrectomy and cataract surgery with implantation of a plate haptic toric IOL. METHODS: In this retrospective case series, 32 eyes of 32 patients underwent a combined 25-gauge vitrectomy and phacoemulsification for vitreoretinal diseases and cataract with regular corneal astigmatism of at least 1 diopter (D). A plate haptic toric IOL (AT Torbi 709M, Carl Zeiss Meditec AG) was implanted in all eyes. The outcome measures were rotational stability and refractive astigmatism up to 6mo postoperatively as well as the best corrected visual acuity (BCVA). RESULTS: Preoperative refractive astigmatism was 2.14±1.17 D, which was significantly reduced to 0.77±0.37 D six to eight weeks postoperatively and remained stable throughout the observation period (0.67±0.44 D at three months and 0.75±0.25 D at six months; for all groups: P<0.0001 compared to baseline). BCVA improved significantly from 0.36±0.33 logMAR preoperatively to 0.10±0.15 logMAR following surgery (P=0.02). Mean IOL axis deviation from the target axis was 3.4°±2.9° after six to eight weeks and significantly decreased over time (2.4°±2.6° six months after surgery; P=0.04). In one patient IOL, re-alignment was performed. CONCLUSION: Corneal astigmatism is significantly reduced following combined 25-gauge vitrectomy and cataract surgery. The plate haptic toric IOL position and axis remain stable during the observation period of six months.

[Corneal disease in childhood-Hereditary, degenerative or infectious?] / Hornhauterkrankungen im Kindesalter ­ Hereditär, degenerativ oder infektiös?

BACKGROUND: Adequate visual acuity significantly contributes to the age-appropriate development of children's neurobehavior. Infantile corneal opacities are rare but implicate a high potential for amblyopia. OBJECTIVE: This review aims to provide an overview of the most common causes of infantile corneal opacities and highlights ophthalmopathological correlations. METHODS: The following review is based on an extensive literature search. RESULTS: If metabolic diseases, traumatic or infectious events can be excluded as a cause for an infantile corneal opacity, it is important to focus on the 3Ds, corneal dysgenesis, corneal dystrophy or corneal degeneration. DISCUSSION: If corneal opacities occur in childhood, early recognition, diagnosis, and initiation of treatment, including prophylaxis of amblyopia, are of utmost importance. In unexplained corneal opacities the histopathological work-up of the explanted cornea can contribute to the final diagnosis.

One-Year Outcomes of PreserfloTM MicroShunt Implantation versus Trabeculectomy for Pseudoexfoliation Glaucoma.

This retrospective, single-center study evaluates the safety and efficacy of PreserfloTM MicroShunt (MicroShunt) implantations compared to trabeculectomies (TETs) in patients diagnosed with pseudoexfoliation glaucoma (PEXG). A total of 31 eyes from 28 patients received a MicroShunt implantation, and 29 eyes from 26 patients received a TET. Surgical success was defined as an intraocular pressure (IOP) between 5 mmHg and 17 mmHg at the end of the follow-up period, no need for surgical revisions or secondary glaucoma surgery, and no loss of light perception. In the MicroShunt group, the mean IOP dropped from 20.8 ± 5.9 mmHg at baseline to 12.4 ± 2.8 mmHg (p < 0.0001) after one year. In the TET group, the mean IOP dropped from 22.3 ± 6.5 mmHg to 11.1 ± 3.7 mmHg (p < 0.0001) after 12 months. In both of the groups, the mean number of medications was reduced significantly (MicroShunt from 2.7 ± 1.2 to 0.2 ± 0.7; p < 0.0001 vs. TET from 2.9 ± 1.2 to 0.3 ± 0.9; p < 0.0001). Considering the success rates, 83.9% of the MicroShunt eyes achieved complete success, and 90.3% qualified for success at the end of the follow-up period. In the TET group, the rates were 82.8% and 93.1%, respectively. The postoperative complications were comparable between both groups. In conclusion, the MicroShunt implantation demonstrated non-inferiority regarding its efficacy and safety profile compared to TET in PEXG at a follow-up of one year.

Pharmacological Therapy of Proliferative Vitreoretinopathy: Systematic In Vitro Comparison of 36 Pharmacological Agents.

Purpose: Proliferative vitreoretinopathy (PVR) is currently treated surgically. Reliable pharmaceutical options would be desirable, and numerous drugs have been proposed. This in vitro study is intended to systematically compare and determine the most promising candidates for the treatment of PVR. Methods: A structured literature review was conducted in the "PubMed" database to identify previously published agents proposed for medical treatment of PVR -36 substances that met the inclusion criteria. Toxicity and antiproliferative effects were evaluated on primary human retinal pigment epithelial (hRPE) using colorimetric viability assays. The seven substances with the widest therapeutic range between toxicity and no longer detectable antiproliferative effect were then validated with a bromodeoxyuridine assay and a scratch wound healing assay using primary cells derived from surgically excised human PVR membranes (hPVR). Results: Among 36 substances, 12 showed no effect on hRPE at all. Seventeen substances had a significant (P < 0.05) toxic effect of which nine did not have an antiproliferative effect. Fifteen substances significantly reduced hRPE proliferation (P < 0.05). The seven most promising drugs with the highest difference between toxicity and antiproliferative effects on hRPE were dasatinib, methotrexate, resveratrol, retinoic acid, simvastatin, tacrolimus, and tranilast. Whereof resveratrol, simvastatin, and tranilast additionally showed antiproliferative and dasatinib, resveratrol, and tranilast antimigratory effects on hPVR (P < 0.05). Conclusion: This study presents a systematic comparison of drugs that have been proposed for PVR treatment in a human disease model. Dasatinib, resveratrol, simvastatin, and tranilast seem to be promising and are well-characterized in human use.

Comparison of Visual and Refractive Outcome between Two Methods of Corneal Marking for Toric Implantable Collamer Lenses (TICL) in Phakic Eyes.

PURPOSE: To compare the efficacy of digital-assisted reference marking for toric implantable collamer lenses (Callisto Eye System) with manual marking technique using a slit lamp markeur. METHODS: This study included patients that underwent implantation of a toric implantable collamer lens (EVO Visian toric ICL, Staar Surgical). Patients were included if they had a myopia above -3 diopters (D) and regular corneal astigmatism of 0.75 diopters or higher. Between both groups a 1:2 matching regarding similar preoperative level of myopia and astigmatism was performed. Visual and refractive outcomes were evaluated. Vector analysis was performed to evaluate total astigmatic changes. RESULTS: This study comprised 57 eyes of 57 patients with 19 eyes in the digital group and 38 eyes in the manual marking group. Postoperatively there were no statistically significant differences between both groups in UDVA (p = 0.467), spherical equivalent (SE) (p = 0.864), sphere (p = 0.761) and cylinder (p = 0.878). Vector analysis showed a slightly more accurate postoperative refractive astigmatism in the manual group (0.26 D at 107° ± 0.50 D) compared to the digital marking group (0.31 D at 107° ± 0.45 D), nevertheless with no statistically significant differences between both groups. CONCLUSIONS: A digital tracking approach for toric ICL alignment was an efficient and safe method for toric marking with similar results regarding visual and refractive outcomes compared to a conventional corneal marking method. Nevertheless, image-guided surgery helped to streamline the workflow in refractive ICL surgery.

Pharmacological drug screening to inhibit uveal melanoma metastatic cells either via EGF-R, MAPK, mTOR or PI3K.

AIM: To screen five potential pharmacological substances specifically targeting EGF-R, MAPK, mTOR, or PI3K for their antiproliferative effects, possible impact on cell viability, as well as cell death rates on three different uveal melanoma metastasis cell lines in vitro. METHODS: Three different uveal melanoma metastasis cell lines (OMM2.5, OMM2.3, and OMM1), that originated from human hepatic and subcutaneous metastasis, were exposed to inhibitors of different targets: erlotinib (EGF-R), everolimus (mTOR), selumetinib (MAPK), trametinib (MAPK) or the alkylphosphocholine erufosine (PI3K). Cell viability was assessed with a 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) dye reduction assay after 24h of treatment. Antiproliferative effects were evaluated separately after a 72-hour incubation of the cells with the pharmacological substance. Subsequently, the IC50 was calculated. Tumor cell death was investigated using a double stain apoptosis detection assay. RESULTS: Selumetinib, trametinib, and erufosine significantly decreased cell viability of all OMM cell lines (P<0.04). In addition, selumetinib and trametinib showed a significant inhibition of cell proliferation (P<0.05). Everolimus and erlotinib solely inhibited cell proliferation at the used concentrations (P<0.05). Besides an increase of necrotic cells after erufosine treatment (P<0.001), no changes in the number of dead cells for the other substances were observed. CONCLUSION: The preliminary drug screening demonstrates five new candidates, successfully targeting the canonical MAPK/ERK and PI3K/AKT/mTOR pathways in uveal melanoma metastasis cells in vitro. Hence, these findings provide an experimental basis to explore future single or combined therapy strategies for metastatic uveal melanoma.

Saving of Time Using a Software-Based versus a Manual Workflow for Toric Intraocular Lens Calculation and Implantation.

Background: To determine whether there is a significant saving of time when using a digital cataract workflow for digital data transfer compared to a manual approach of biometry assessment, data export, intraocular lens calculation, and surgery time. Methods: In total, 48 eyes of 24 patients were divided into two groups: 24 eyes were evaluated using a manual approach, whereas another 24 eyes underwent a full digital lens surgery workflow. The primary variables for comparison between both groups were the overall time as well as several time steps starting at optical biometry acquisition until the end of the surgical lens implantation. Other outcomes, such as toric intraocular lens misalignment, reduction of cylinder, surgically induced astigmatism, prediction error, and distance visual acuity were measured. Results: Overall, the total diagnostic and surgical time was reduced from 1364.1 ± 202.6 s in the manual group to 1125.8 ± 183.2 s in the digital group (p < 0.001). The complete time of surgery declined from 756.5 ± 82.3 s to 667.3 ± 56.3 (p < 0.0005). Compared to the manual approach of biometric data export and intraocular lens calculation (76.7 ± 12.3 s) as well as the manual export of the reference image to a portable external storage device (26.8 ± 5.5 s), a highly significant saving of time was achieved (p < 0.0001). Conclusions: Using a software-based digital approach to toric intraocular lens implantation is convenient, more efficient, and thus more economical than a manual workflow in surgery practice.

Femtosecond laser-assisted descemetorhexis for Descemet membrane endothelial keratoplasty: cell-based and tissue-based ex vivo analysis of precision and safety.

PURPOSE: To analyze precision and safety of femtosecond laser-assisted descemetorhexis and postoperative corneal wound healing in human ex vivo specimens. SETTING: Department of Ophthalmology, University Hospital, LMU Munich, Munich, Germany. DESIGN: Experimental ex vivo study. METHODS: 4 donor corneas underwent femtosecond laser-assisted descemetorhexis. The descemetorhexis was performed using the LDV Z8 femtosecond laser, followed by live/dead staining, phase contrast microscopy, and scanning electron microscopy. The descemetorhexis parameters were set using a modified optical coherence tomography image capturing of 8 segments within a focus of 100 µm at the posterior corneal stroma (reversed capsulotomy program). RESULTS: Live/dead sample staining analysis demonstrated that the femtosecond laser had minimal impact on the vitality of surrounding endothelial cells. Phase contrast microscopy and scanning electron microscopy evaluation showed that the laser produced precise, clear-cut edges, leaving no stromal tissue bridges. CONCLUSIONS: Femtosecond laser-assisted descemetorhexis could serve as a safe and precise technique with only minimal endothelial cell damage. To minimize stromal damage, further laser energy profile adjustments are necessary to optimize corneal treatment within different stages of corneal tissue swelling.

Advances in Imaging of Subbasal Corneal Nerves With Micro-Optical Coherence Tomography.

Purpose: To investigate the most peripheral corneal nerve plexus using high-resolution micro-optical coherence tomography (µOCT) imaging and to assess µOCT's clinical potential as a screening tool for corneal and systemic diseases. Methods: An experimental high-resolution (1.5 × 1.5 × 1 µm) µOCT setup was applied for three-dimensional imaging of the subbasal nerve plexus in nonhuman primates (NHPs) and swine within 3 hours postmortem. Morphologic features of subbasal nerves in µOCT were compared to ß3 tubulin-stained fluorescence confocal microscopy (FCM). Parameters such as nerve density, nerve distribution, and imaging repeatability were evaluated, using semiautomatic image analysis in form of a custom corneal surface segmentation algorithm and NeuronJ. Results: Swine and NHP corneas showed the species-specific nerve morphology in both imaging modalities. Most fibers showed a linear course, forming a highly parallel pattern, converging in a vortex with overall nerve densities varying between 9.51 and 24.24 mm/mm2. The repeatability of nerve density quantification of the µOCT scans as approximately 88% in multiple image recordings of the same cornea. Conclusions: Compared to the current gold standard of FCM, µOCT's larger field of view of currently 1 × 1 mm increases the conclusiveness of density measurements, which, coupled with µOCT's feature of not requiring direct contact, shows promise for future clinical application. The nerve density quantification may be relevant for screening for systemic disease (e.g., peripheral neuropathy). Translational Relevance: Technological advances in OCT technology may enable a quick assessment of corneal nerve density, which could be valuable evaluating ophthalmic and systemic peripheral innervation.