Development and Characterization of a Photocrosslinkable, Chitosan-Based, Nerve Growth Factor-Eluting Hydrogel for the Ocular Surface.

Purpose: Recombinant human nerve growth factor (rhNGF; cenegermin-bkbj, OXERVATE) is the first and only U.S. Food and Drug Administration-approved treatment for moderate to severe neurotrophic keratopathy. The aim of this study was to determine the feasibility of incorporating a version of rhNGF in a mucoadhesive hydrogel capable of sustained drug release to the ocular surface. Methods: Hydrogels loaded with rhNGF were synthesized by conjugating chitosan with azidobenzoic acid (Az-Ch), adding rhNGF, and exposing the solution to ultraviolet (UV) radiation to induce photocrosslinking. Az-Ch hydrogels were evaluated for physical properties and rhNGF release profiles. Cytocompatbility of Az-Ch was assessed using immortalized human corneal limbal epithelial (HCLE) cells. TF1 erythroleukemic cell proliferation and HCLE cell proliferation and migration were used to assess the bioactivity of rhNGF released from Az-Ch hydrogels. Results: Az-Ch formed hydrogels in <10 seconds of UV exposure and demonstrated high optical transparency (75-85 T%). Az-Ch hydrogels exhibited good cytocompatibility with no demonstratable effect on HCLE cell morphology or viability. rhNGF was released gradually over 24 hours from Az-Ch hydrogels and retained its ability to induce TF1 cell proliferation. No significant difference was observed between rhNGF released from Az-Ch and freshly prepared rhNGF solutions on HCLE cell proliferation or percent wound closure after 12 hours; however, both were significantly better than control (P < 0.01). Conclusions: rhNGF-loaded Az-Ch hydrogels exhibited favorable physical, optical, and drug-release properties, as well as retained drug bioactivity. This drug delivery system has the potential to be further developed for in vivo and translational clinical applications. Translational Relevance: Az-Ch hydrogels may be used to enhance rhNGF therapy in patients with NK.

Relaxing descemetotomy: microscope-integrated OCT-guided technique for acute corneal hydrops.

Introduction: 3 cases are used to illustrate the technique of Descemet membrane (DM) relaxing incisions followed by air descemetopexy for the management of patients with acute corneal hydrops. Patients and Clinical Findings: In each case, anterior-segment optical coherence tomography (OCT) demonstrated taut DM detachments and hydrops was refractory to conservative medical management and intracameral air injection. Diagnosis Intervention and Outcomes: To facilitate the reapproximation of DM and potentiate corneal deturgescence, intraoperative OCT-guided descemetotomy was performed with bent surgical scissors and a bent 30-gauge needle. Subsequent air descemetopexy was successful, and DM reattachment was maintained postoperatively. Corneal edema improved in all patients relatively rapidly postoperatively. Conclusions: Relaxing descemetotomy with air descemetopexy may be useful in cases of acute corneal hydrops with taut DM detachments that are unresponsive to air tamponade alone.

Topical Sustained Delivery of Miltefosine Via Drug-Eluting Contact Lenses to Treat Acanthamoeba Keratitis.

This study aimed to develop a miltefosine-eluting contact lens (MLF-CL) device that would allow sustained and localized miltefosine release for the treatment of Acanthamoeba keratitis. MLF-CLs were produced in three different miltefosine doses by solvent-casting a thin miltefosine-polymer film around the periphery of a methafilcon hydrogel, which was then lathed into a contact lens. During seven days of in vitro testing, all three formulations demonstrated sustained release from the lens at theoretically therapeutic levels. Based on the physicochemical characterization of MLF-CLs, MLF-CL's physical properties are not significantly different from commercial contact lenses in terms of light transmittance, water content and wettability. MLF-CLs possessed a slight reduction in compression modulus that was attributed to the inclusion of polymer-drug films but still remain within the optimal range of soft contact lenses. In cytotoxicity studies, MLF-CL indicated up to 91% viability, which decreased proportionally as miltefosine loading increased. A three-day biocompatibility test on New Zealand White rabbits revealed no impact of MLF-CLs on the corneal tissue. The MLF-CLs provided sustained in vitro release of miltefosine for a week while maintaining comparable physical features to a commercial contact lens. MLF-CL has a promising potential to be used as a successful treatment method for Acanthamoeba keratitis.

Experience with netarsudil 0.02% and latanoprostene bunod 0.024% as adjunctive therapy for glaucoma.

PURPOSE: To assess the effectiveness and safety of adjunctive topical netarsudil 0.02% and latanoprostene bunod 0.024% in patients with glaucoma. METHODS: A retrospective, multi-center, cohort study of patients with glaucoma treated with netarsudil 0.02% or latanoprostene bunod from five tertiary care centers. Inclusion criteria included patients with glaucoma treated with either medication as adjunctive therapy. Outcomes included mean absolute intraocular pressure (IOP) reduction and relative IOP reduction from baseline. Adverse reactions and reasons for discontinuation were reported. One-way analysis of variance, Kruskal-Wallis rank sum test, and Mann Whitney U test compared the outcomes. RESULTS: A total of 95 eyes (95 patients) on netarsudil and 41 eyes (41 patients) on latanoprostene bunod were analyzed. Mean duration of use was 54.3 ± 28 days for netarsudil and 82.9 ± 51.2 days for latanoprostene bunod. At the final visit, mean IOP reduction was 3.9 ± 4.6 mmHg (17.5 ± 6.0%) (p < 0.0001) with netarsudil and 2.9 ± 3.7 mmHg (13.6 ± 16.3%) (p < 0.0001) with latanoprostene bunod. IOP lowering did not depend on baseline number of IOP-lowering medications. The most common reason for discontinuation was non-effectiveness in both groups. CONCLUSION: Similar to monotherapy, netarsudil and latanoprostene bunod demonstrated efficacy in lowering IOP when used as adjunctive therapy.

Outcomes of Repository Corticotropin Gel for Ocular Sarcoidosis.

PURPOSE: To evaluate the utility and side effect profile of subcutaneous repository corticotropin gel (RCI) in ocular sarcoidosis. METHODS: Retrospective chart review. RESULTS: Among six identified patients on RCI therapy, 4 had uveitis, one had optic neuritis and one had uveitis and optic neuritis secondary to sarcoidosis. The average follow-up was 43.5 months. RCI therapy was continuous in 4 patients (average 7.7 months) and intermittent in 2 patients (24 and 12 months). Five of the 6 patients continued with local and/or systemic corticosteroids for ocular inflammation control while on RCI therapy.  Two-thirds of patients experienced adverse effects including hyperpigmentation, alopecia, and severe hypertension. RCI therapy was discontinued in 5 of the 6 patients due to continued inflammation and side/adverse effects (4 patients) and loss of follow-up (1 patient). CONCLUSION: In this small cohort, the majority of patients failed to achieve adequate steroid-sparing ocular inflammation control and experienced side effects while on RCI therapy. Additional studies are needed to elucidate the role of RCI in ocular inflammation.

A novel, sensitive, and widely accessible besifloxacin quantification method by HPLC-fluorescence: Application to an ocular pharmacokinetic study.

Besifloxacin has been embraced for the treatment of ocular bacterial infections. While LC-MS/MS has been used in investigating BSF pharmacokinetics, those costly instruments are not universally available and have complicated requirements for operation and maintenance. Additionally, pharmacokinetics of besifloxacin in dose-intense regimens are still unknown. Herein, a new quantification method was developed employing the widely accessible HPLC with fluorescence detection and applied to an ocular pharmacokinetic study with an intense regimen. Biosamples were pre-treated using protein precipitation. Chromatographic separation was achieved on a C18 column using mobile phase of 0.1% trifluoroacetic acid and acetonitrile. To address the weak fluorescence issue of besifloxacin, effects of detection parameters, elution pattern, pH of mobile phase, and reconstitution solvents were investigated. The method was fully validated per US-FDA guidelines and demonstrated precision (<13%), accuracy (91-112%), lower limit of quantification (5 ng/mL), linearity over clinically relevant concentrations (R2 > 0.999), matrix-effects (93-105%), recoveries (95-106%), and excellent selectivity. The method showed agreement with agar disk diffusion assays for in vitro screening and comparable in vivo performance to LC-MS/MS (Deming Regression, y = 1.010x + 0.123, r = 0.997; Bland-Altman analysis, mean difference was -6.3%; n = 21). Pharmacokinetic parameters suggested superior surface-retentive properties of besifloxacin. Maximum concentrations were 1412 ± 1910 and 0.15 ± 0.12 µg/mL; area under the curve was 1,637 and 1.08 µg·h/g; and half-life was 4.9 and 4.1 h; and pharmacokinetic-to-pharmacodynamic ratios were ≥ 409 and ≤ 17.8 against ocular pathogens in tears and aqueous humor, respectively. This readily available method is sensitive for biosamples and practical for routine use, facilitating besifloxacin therapy development.

Glaucoma Care of Incarcerated Patients at an Academic Institution: A Case-Control Study.

PURPOSE: To evaluate medication and follow-up adherence in incarcerated patients examined at an academic glaucoma clinic, in comparison to nonincarcerated controls. METHODS: Retrospective, case-control study. Consecutive prisoners presenting for initial visits in the Glaucoma Clinic at the Illinois Eye and Ear Infirmary between December 2015 and December 2017 were included in the study. Nonincarcerated patients seen in the same Glaucoma Clinic with similar initial visit dates, age, race, sex, and disease severity were selected as controls. Glaucoma Clinic visits from each patient were reviewed until December 2018. Examination information, surgical intervention, follow-up and treatment recommendations, and patient-reported medication usage were recorded for each visit. Number of visits, loss to follow-up, follow-up delays, and medication nonadherence were studied as primary outcome measures. RESULTS: Twenty-four prisoners and 24 nonincarcerated controls were included. Prisoners had an average of 2.46 ± 2.38 visits during the study period, compared to 5.04 ± 3.25 for controls (P = 0.001). Follow-up visits occurred more than 30 days after the recommended follow-up time in 57.4% (95% confidence interval [CI]: 44.2%-70.6%) of prisoners, compared to 17.9% (95% CI: 10.2%-25.6%) of controls (P < 0.00001). 70.8% of prisoners (95% CI: 66.3-74.5%) were lost to follow-up, compared to 29.2% of controls (95% CI: 25.5%-32.9%; P < 0.01). Medication nonadherence rates were similar between prisoners (13.6%; 95% CI: 12.1%-15.2%) and controls (12.0%; 95% CI: 11.4%-12.6%; P = 0.78). CONCLUSIONS: Glaucoma follow-up adherence was significantly worse in prisoners compared to a nonincarcerated control population. Further study into causative factors is needed.

Nerve Growth Factor as an Ocular Therapy: Applications, Challenges, and Future Directions.

Nerve growth factor (NGF), the prototypical neurotrophin first discovered in the 1950s, has recently garnered increased interest as a therapeutic agent promoting neuronal health and regeneration. After gaining orphan drug status within the last decade, NGF-related research and drug development has accelerated. The purpose of this article is to review the preclinical and clinical evidence of NGF in various applications, including central and peripheral nervous system, skin, and ophthalmic disorders. We focus on the ophthalmic applications including not only the FDA-approved indication of neurotrophic keratitis but also retinal disease and glaucoma. NGF represents a promising therapy whose therapeutic profile is evolving. The challenges related to this therapy are reviewed, along with possible solutions and future directions.

Design of a navigational catheter system for the targeted delivery of therapeutics within the suprachoroidal space.

Diseases of the posterior segment of the eye are common causes of blindness and can be difficult to treat due to their location. Recently, there has been increased interest in the use of the suprachoroidal space to deliver therapeutics to the posterior segment. This space is accessible through a trans-scleral approach and blunt dissection of the adjacent scleral and choroidal tissues. However, despite recent commercial interest, there are few tools designed specifically to provide targeted delivery of therapeutics to a localised region within the suprachoroidal space. Therefore, we designed and prototyped a novel navigational catheter system for the targeted delivery of payloads within the suprachoroidal space. The system consists of a customised catheter tip designed to minimise blunt dissection stresses on neighbouring tissues, a mechanism for controlled catheter navigation, and a method for targeted delivery of large payloads. A customised in vitro model of the eye was also designed to visually demonstrate the capability of the catheter system to controllably navigate within the suprachoroidal space and deliver a targeted payload. This system can enable the delivery of large therapeutic payloads to the eye for the treatment of posterior eye diseases, thereby impacting the development and availability of vision-saving treatments.

Reproducible Derivation and Expansion of Corneal Mesenchymal Stromal Cells for Therapeutic Applications.

Purpose: A reproducible protocol for the production of corneal mesenchymal stem/stromal cells (cMSCs) is necessary for potential clinical applications. We aimed to describe successful generation and expansion of cMSCs using an explant method. Methods: Corneoscleral rims of human cadaveric eyes were divided into four pieces and used as explants to allow outgrowth of cMSCs (passage 0, or P0). The cells were subcultured at a 1:10 ratio until passage 5 (P5). The characteristics as well as therapeutic effects of expanded cMSCs were evaluated both in vitro, using a scratch assay, and in vivo using epithelial debridement and chemical injury mouse models. Results: All explants demonstrated outgrowth of cells by 7 days. Although the initial outgrowth included mixed mesenchymal and epithelial cells, by P1 only cMSCs remained. By subculturing each flask at a ratio of 1:10, the potential yield from each cornea was approximately 12 to 16 × 1010 P5 cells. P5 cMSCs demonstrated the cell surface markers of MSCs. The secretome of P5 cMSCs induced faster closure of wounds in an in vitro scratch assay. Subconjunctival injection of P5 cMSCs in mouse models of mechanical corneal epithelial debridement or ethanol injury led to significantly faster wound healing and decreased inflammation, relative to control. Conclusions: cMSCs can be reproducibly derived from human cadaveric corneas using an explant method and expanded with preservation of characteristics and corneal wound healing effects. Translational Relevance: The results of our study showed that cMSCs produced using this scheme can be potentially used for clinical applications.

Predictive factors of Boston Type I Keratoprosthesis outcomes: A long-term analysis.

PURPOSE: To study the long-term visual- and device retention-related outcomes and complications of the Boston Type I Keratoprosthesis (KPro). METHODS: Single-center, retrospective cohort study of all patients undergoing KPro implantation from February 2007 to April 2014 with at least 5 years of follow-up. RESULTS: 68 eyes from 65 patients underwent KPro implantation during the study period. At 5 and 10 years, the probability of maintaining or improving visual acuity (VA) was 75.0% and 66.7%, respectively, and the probability of KPro retention was 89.2% and 89.2%, respectively. Initial device retention rate at 10 years was significantly lower in those with underlying ocular surface disease (46.8% [30.6-63.2] vs 75.8% [61.0-90.7], P = 0.03), while other baseline characteristics showed no significant association. Final VA was more likely to be stable or improved in patients with fewer failed grafts (2 [1-6] vs 3 [1-6], P < 0.01), and a final VA of 20/200 or better was more likely in primary KPro eyes (44.8% [26.7-62.9] vs 19.4% [6.5-32.3], P = 0.03). Combined KPro-vitrectomy eyes were more likely to have stable or improved final VA than non-vitrectomy eyes (88.5% [76.2-100.0] vs 64.1% [49.1-79.1], P = 0.04). All complications had increasing incidence beyond 5 years; in particular, corneal melt, surgical glaucoma interventions, and endophthalmitis tended to have late presentations, with 79.0%, 78.6%, and 88.9% of these complications occurring beyond one year, respectively. CONCLUSIONS: KPro devices show favorable long-term visual and retention outcomes in select patients. Careful long-term, multidisciplinary follow-up is warranted to address potential complications.

Therapeutic Effects of Lyophilized Conditioned-Medium Derived from Corneal Mesenchymal Stromal Cells on Corneal Epithelial Wound Healing.

Objectives: The conditioned-medium derived from corneal mesenchymal stromal cells (cMSCs) has been shown to have wound healing and immunomodulatory effects in corneal injury models. Here, the therapeutic effects of lyophilized cMSC conditioned-medium were compared with fresh conditioned-medium. Methods: The epithelial wound healing effects of fresh and lyophilized cMSC conditioned-medium were compared with conditioned-medium from non-MSC cells (corneal epithelial cells) using scratch assay. To evaluate the anti-inflammatory effects of fresh and lyophilized cMSC conditioned-media, macrophages were stimulated by a Toll-Like Receptor (TLR) ligand followed by treatment with the conditioned-media and measuring the expression of inflammatory genes. In vivo wound healing effects of fresh and lyophilized cMSC conditioned-media were assessed in a murine model of cornea epithelial injury. Results: Both fresh and lyophilized cMSCs-derived conditioned-medium induced significantly faster closure of in vitro epithelial wounds compared to conditioned-medium from non-MSC cells (P < .0001). Treating stimulated macrophages with fresh or lyophilized cMSCs-derived conditioned-media significantly decreased the expression of inflammatory genes compared to control (P < .0001). Murine corneal epithelial wounds were healed by 87.6 ± 2.7% and 86.2 ± 4.6% following treatment with fresh and lyophilized cMSC conditioned-media, respectively, while the control was healed by 64.7 ± 16.8% (P < .05). Conclusion: Lyophilized cMSC-derived conditioned-medium is as effective as fresh conditioned-medium in promoting wound healing and modulating inflammation. The results of this study support the application of lyophilized cMSCs-derived conditioned-medium, which allows for more extended storage, as a promising non-invasive option in the treatment of corneal wounds.

Glaucoma Care of Prison Inmates at an Academic Hospital.

Importance: Glaucoma care for prison inmates is underrepresented in the literature even though managing the treatment of such patients may provide unique challenges. Objectives: To evaluate the glaucoma profile of prison inmates treated at an academic ophthalmology center and to report on the medical and surgical management and follow-up metrics. Design, Setting, and Participants: This retrospective cohort study assessed data from 82 incarcerated patients treated at the glaucoma clinic, an academic referral center at the University of Illinois at Chicago, between January 2013 and December 2017. Main Outcomes and Measures: Diagnosis, glaucoma severity, medical and surgical interventions, and patient-reported medication adherence were recorded for each visit. Recommended and actual follow-up times were recorded and compared. Data analyses were conducted from January 2013 to December 2018. Results: In total, 82 patients (161 eyes) had 375 visits during the study period. All patients were male and ranged from 20 to 75 years of age (mean [SD] age, 50.8 [11.9] years). Most participants were black patients (65 [79.3%]). The most common diagnoses were primary open-angle glaucoma (POAG; 53 eyes [32.9%]) and POAG suspect (52 eyes [32.3%]). Glaucoma severity ranged from mild (25 of 77 eyes [32.5%]) to advanced (41 of 77 eyes [53.2%]). Overall, 59 patients (73.2%) were treated medically with up to 4 topical agents (40.0%). Of those treated, 70.0% of patients (95% CI, 57.7%-81.2%) reported medication nonadherence during at least 1 visit. Medication nonadherence was more common among those taking 4 different topical medications (21 of 24 [87.5%]) compared with others taking fewer medications (20 of 35 [57.1%]), for a difference of 30.4% (95% CI, 7.0%-53.6%; P = .02), and among those with advanced disease (22 of 26 [84.6%]) compared with glaucoma suspect (6 of 13 [46.2%]), for a difference of 38.4% (95% CI, 9.3%-67.5%; P = .02). Nineteen office procedures, including laser peripheral iridotomy and laser trabeculoplasty, were performed on 14 eyes. Seventeen incisional glaucoma procedures were performed on 15 eyes, including glaucoma drainage device implant (11 procedures [64.7%]) and trabeculectomy (3 procedures [17.6%]). Only 26.6% of return office visits (95% CI, 21.3%-32.3%) occurred within the recommended follow-up time frame. Furthermore, 93 patients (34.8%; 95% CI, 28.2%-40.0%) were seen more than 1 month after the recommended follow-up. Conclusions and Relevance: Despite incarceration in prison, where medication administration and appointment attendance are theoretically controlled, the results of this study suggested that substantial medication and follow-up nonadherence exists among inmates.

Characterization of an Electronic Corneal Prosthesis System.

PURPOSE: Corneal opacity is a leading cause of reversible blindness worldwide. An electronic corneal prosthesis, or intraocular projector, could potentially restore high-quality vision without need for corneal clarity. MATERIALS AND METHODS: Four intraocular projection systems were constructed from commercially available electronic components and encased in biocompatible plastic housing. They were tested for optical properties, biocompatibility, heat dissipation, waterproofing, and accelerated wear. A surgical implantation technique was developed. RESULTS: Intraocular projectors were produced of a size that can fit within the eye. Their optics produce better than 20/200 equivalent visual acuity. MTT assay demonstrated no cytotoxicity of devices in vitro. Temperature testing demonstrated less than 2°C increase in temperature after 1 h. Three devices lasted over 12 weeks under accelerated wear conditions. Implantation surgery was demonstrated via corneal trephination insertion in a cadaver eye. CONCLUSION: This is the first study to demonstrate and characterize fully functional intraocular projection systems. This technology has the potential to be an important new tool in the treatment of intractable corneal blindness.

Visual and Anatomic Outcomes in Perforating Ocular Injuries.

PURPOSE: This article reports the presentation, management, and outcomes in patients suffering perforating ocular injuries. METHODS: A retrospective review was conducted at a single ophthalmology Level 1 trauma center. Patients with evidence of traumatic ocular perforation, with surgical intervention attended by a single vitreoretinal surgeon (W.F.M.), were reviewed between 2009 and 2017. RESULTS: Six eyes from 6 patients with perforating ocular injuries were studied. All patients were male, between ages 11 and 56 years. Perforation was the result of gunshots (3), other accidental injury (2), or surgical complication (1). Varying degrees of retinal detachments were seen in all 6 patients. Pars plana vitrectomy, with endolaser around posterior entry or exit wounds, was performed on average 21.7 ± 8.9 days from the time of injury (range, 0-58 days). In all cases with intraorbital foreign bodies, the foreign bodies were left in place. The most recent postoperative visual acuity ranged from 20/25 to counting fingers. Missile injuries tended to have poorer vision. All cases achieved full anatomic attachment at most recent follow-up. There have been no orbital complications related to retained intraorbital foreign bodies, including endophthalmitis, orbital infections, or mechanical strabismus. CONCLUSION: This study demonstrates successful anatomic outcomes of 6 cases of perforating ocular injuries. Visual outcomes were variable, though missile injuries demonstrated worse prognosis, whereas several nonmissile macula-involving cases achieved quite favorable results. Although traumatic perforating injuries generally have guarded visual prognoses, favorable results may be achieved in select scenarios.

Sudden-onset Blindness from a Spontaneous Carotid-cavernous Fistula with Secondary Central Retinal Artery Occlusion and Posterior Ischemic Optic Neuropathy.

Our case describes a patient diagnosed with a carotid-cavernous fistula (CCF) secondary to a spontaneously ruptured cavernous carotid aneurysm, presenting with sudden vision loss, and a concomitant central retinal artery occlusion as visualized by a cherry-red spot in the macula and posterior ischemic optic neuropathy. Computed tomography of the brain and orbits showed mild hydrocephalus, orbital fat haziness, and proptosis with concern for fluid in the basal cisterns. Cerebral angiography confirmed the suspected diagnosis of CCF. After angiography, a Magnetic resonance imaging of the brain demonstrated abnormal diffusion restriction in the posterior right optic nerve confirmed on the apparent diffusion coefficient map, consistent with ischemia of the optic nerve in this location. Two weeks after discharge, outpatient fundus photography showed resolution of her cherry-red spot, and optical coherence tomography showed thinning of the entire retinal nerve fiber layer as compared to the contralateral eye. In CCFs, congestive symptoms of proptosis, pain, and even central retinal vein occlusion findings are frequently described. However, our patient's no light perception vision and imaging findings suggest associated central retinal artery occlusion and ischemic optic neuropathy. These findings underscore the multitude of serious visual effects of high flow CCFs.