Therapeutic contact lenses for the treatment of corneal and ocular surface diseases: Advances in extended and targeted drug delivery.

The eye is one of the most important organs in the human body providing critical information on the environment. Many corneal diseases can lead to vision loss affecting the lives of people around the world. Ophthalmic drug delivery has always been a major challenge in the medical sciences. Since traditional methods are less efficient (∼5%) at delivering drugs to ocular tissues, contact lenses have generated growing interest in ocular drug delivery due to their potential to enhance drug bioavailability in ocular tissues. The main techniques used to achieve sustained release are discussed in this review, including soaking in drug solutions, incorporating drug into multilayered contact lenses, use of vitamin E barriers, molecular imprinting, nanoparticles, micelles and liposomes. The most clinically relevant results on different eye pathologies are presented. In addition, this review summarizes the benefits of contact lenses over eye drops, strategies for incorporating drugs into lenses to achieve sustained release, results of in vitro and in vivo studies, and recent advances in the commercialization of therapeutic contact lenses for allergic conjunctivitis.

Observational study of cenegermin for the treatment of limbal stem cell deficiency associated with neurotrophic keratopathy.

Background: Neurotrophic keratopathy (NK) and limbal stem cell deficiency (LSCD) have high morbidity and require aggressive management to prevent permanent vision loss. Cenegermin, a recombinant human nerve growth factor, was approved by the Federal Drug Administration in 2018 for the treatment of NK. Objectives: To determine the efficacy and safety of cenegermin in the treatment of LSCD associated with NK. Design: Prospective cohort study. Methods: Patients diagnosed with LSCD and NK who had failed conventional treatment were enrolled in this prospective open-label study. Patients were treated with cenegermin for 8 weeks. The primary objective was to determine whether the area of abnormal epithelium decreased following treatment. Corneal sensation, visual acuity (VA), and LSCD severity were also evaluated. Results: Six eyes of 5 patients were included in the study. Cenegermin significantly improved the area of abnormal corneal epithelium in 5 of 6 eyes, measuring 73% of total corneal area at the initial visit and 48% at the final visit (P = .036). Corneal sensation improved in all patients, Cochet-Bonnet aesthesiometry measured 14.7 and 26.7 mm at the initial and final visit, respectively (P = .009). VA improved in 4 out of 6 eyes, with mean initial logMAR VA of 1.67 and final logMAR VA of 1.19 (P = .045). Finally, LSCD grading improved using the Aravena scoring system; however, this difference was not statistically significant (P = .14). One patient presented with an epithelial defect at baseline, which resolved following treatment. No patient withdrew from the study due to adverse effects. Conclusions: Cenegermin effectively improved the cornea epithelium, VA, and corneal sensation in patients with LSCD and NK who had failed prior treatment. Further studies are necessary to better understand the anatomical changes and to confirm our results with a larger randomized control trial. Registration: The study was registered at ClinicalTrials.gov with identifier NCT04552730 (https://clinicaltrials.gov/ct2/show/NCT04552730).

Reactivation of Herpes Zoster Keratitis Following Shingrix Vaccine.

We present a case of herpes zoster keratitis reactivation shortly following the Shingrix vaccine. In our patient, reactivation of herpes zoster keratitis occurred a few weeks following the herpes zoster subunit (HZ/su) vaccine. The development of herpes zoster ophthalmicus following HZ/su is exceedingly rare, with only one prior reported case found in the literature. Reporting of this potential correlation is important in understanding the full risks of vaccines and can help elucidate the etiology of such responses.

Molecular mechanisms and treatments for ocular symblephara.

There are currently no effective methods to prevent or durably treat ocular symblephara, the adhesions between the palpebral and bulbar conjunctiva. How symblephara form at the molecular level is largely unknown. We present here an overview of current clinical symblephara treatments and describe potential molecular mechanisms behind conjunctival adhesion formation that may inform future symblephara treatment and prevention options. Understanding how symblephara form at the molecular level will facilitate treatment development. Preventative therapies may be possible by targeting symblephara progenitor cells immediately after injuries, while novel therapeutics should be aimed at modulating TGF-ß pathways and effector cells in conjunctival scarring to treat symblephara formation more effectively.

Drug delivery to the anterior segment of the eye: A review of current and future treatment strategies.

Research in the development of ophthalmic drug formulations and innovative technologies over the past few decades has been directed at improving the penetration of medications delivered to the eye. Currently, approximately 90% of all ophthalmic drug formulations (e.g. liposomes, micelles) are applied as eye drops. The major challenge of topical eye drops is low bioavailability, need for frequent instillation due to the short half-life, poor drug solubility, and potential side effects. Recent research has been focused on improving topical drug delivery devices by increasing ocular residence time, overcoming physiological and anatomical barriers, and developing medical devices and drug formulations to increase the duration of action of the active drugs. Researchers have developed innovative technologies and formulations ranging from sub-micron to macroscopic size such as prodrugs, enhancers, mucus-penetrating particles (MPPs), therapeutic contact lenses, and collagen corneal shields. Another approach towards the development of effective topical drug delivery is embedding therapeutic formulations in microdevices designed for sustained release of the active drugs. The goal is to optimize the delivery of ophthalmic medications by achieving high drug concentration with prolonged duration of action that is convenient for patients to administer.

A Prospective, Randomized Trial of Povidone-Iodine 0.6% and Dexamethasone 0.1% Ophthalmic Suspension for Acute Bacterial Conjunctivitis.

PURPOSE: To evaluate the efficacy and safety of a topical ophthalmic suspension combination of povidone-iodine 0.6% (PVP-I) and dexamethasone 0.1% (DEX) for infectious and inflammatory components of bacterial conjunctivitis. DESIGN: Randomized, double-masked, multicenter, phase 3 clinical trial. METHODS: Subjects of all ages (those <3 months had to be full-term) with a diagnosis of bacterial conjunctivitis were randomized 3:1:3 to either PVP-I/DEX, PVP-I alone, or placebo. The primary endpoint was clinical resolution in the study eye, and the key secondary efficacy endpoint was bacterial eradication, both at the day 5 visit. Adverse events (AEs) were documented at all visits. RESULTS: Overall, 753 subjects were randomized (intent-to-treat [ITT] population; PVP-I/DEX [n = 324]; PVP-I [n = 108]; placebo [n = 321]); mean and standard deviation (SD) age was 44.3 (22.9) years, and most were female (61.2%) and white (78.1%). In all treatment groups, mean treatment compliance was >98%. The modified ITT population for the efficacy analysis comprised 526 subjects. In the study eye at the day 5 visit, clinical resolution was achieved by 50.5% (111/220) subjects in the PVP-I/DEX group vs 42.8% (95/222) in the placebo group (P = .127), and bacterial eradication was achieved by 43.3% (94/217) and 46.8% (102/218), respectively (P = .500). Treatment-emergent AEs were experienced by 32.8% (106/323), 39.8% (43/108), and 19.0% (61/321) of subjects in the safety population treated with PVP-I/DEX, PVP-I, and placebo, respectively (most mild in severity). CONCLUSION: In this study, PVP-I/DEX did not demonstrate additional benefit in clinical efficacy compared with placebo in subjects with bacterial conjunctivitis.

Content validity of a novel patient-reported and observer-reported outcomes assessment to evaluate ocular symptoms associated with infectious conjunctivitis in both adult and pediatric populations.

BACKGROUND: Acute infectious conjunctivitis is a common condition most frequently caused by viruses or bacteria. Clinical outcome assessments have been used to assess signs and symptoms of bacterial and viral conjunctivitis, but have not been evaluated for content validity. We aimed to develop content-valid patient- (PRO) and observer-reported outcome (ObsRO) instruments to assess symptoms of ocular discomfort associated with viral or bacterial conjunctivitis in adult and pediatric patients. METHODS: Draft items were developed from a previous review of published studies from 2001 to 2015. Patients and caregivers of patients with a diagnosis of viral or bacterial conjunctivitis within the past 6 months were recruited. Concept elicitation with open-ended questions explored signs and symptoms, followed by cognitive interviewing to assess clarity and relevance of the draft items. Patients aged ≥8 years were interviewed for the PRO; parents/caregivers of children aged 1-10 years were interviewed for the ObsRO. Interviews were conducted in three rounds to allow changes. Concept saturation was documented using a saturation grid. Cognitive interview data were analyzed iteratively and focused on clarity, relevance and inconsistent interpretation of the instrument's content. RESULTS: Overall, 23 patients or parents/caregivers participated (round 1, n = 10; round 2, n = 6; round 3, n = 7). Data saturation was reached by the 16th interview. The most frequent spontaneously reported signs/symptoms were: discharge, red/pink eyes, itchiness, swelling/puffiness, watery eyes, pain, burning and foreign body sensation. Itching, pain/burning/stinging and foreign body sensation were most commonly reported as the top three most bothersome symptoms. Interview results indicated that items on pain, itching and foreign body sensation for the PRO and pain or discomfort for the ObsRO were relevant to the patients' experience of conjunctivitis and were clear and easy to understand. CONCLUSIONS: PRO and ObsRO items were found to be clear, relevant and appropriate in assessing key viral and bacterial conjunctivitis symptoms in adult and pediatric patients.

Oral miltefosine for refractory Acanthamoeba keratitis.

PURPOSE: To report the first case of Acanthamoeba keratitis treated with oral miltefosine in the United States. OBSERVATIONS: A 17-year-old female with a history of orthokeratology contact lens wear presented after five months of left eye pain, redness, and photophobia. She was previously treated with antivirals and topical corticosteroids for presumed herpetic disease. She was found to have a large central ring infiltrate and corneal cultures were positive for Acanthamoeba. The infection progressed despite hourly PHMB 0.02% and chlorhexidine 0.02%, and oral vorizonazole. The patient was started on oral miltefosine 50 mg 3 times per day. Following one week of treatment, repeat cultures were positive for Acanthamoeba and therefore, the concentration of chlorhexidine was increased from 0.02% to 0.06% and PHMB was changed to propamidine isetionate (Brolene 0.1%). There was definite clinical improvement after five weeks of treatment with oral miltefosine, topical chlorhexidine 0.06% and propamidine isetionate 0.1%. CONCLUSIONS AND IMPORTANCE: Acanthamoeba keratitis is a challenging entity to treat and often associated with a poor prognosis. Oral miltefosine may offer additional therapeutic benefit in cases of refractory Acanthamoeba keratitis.

Chronic Electrical Stimulation for Tear Secretion: Lacrimal vs. anterior ethmoid nerve.

PURPOSE: To evaluate and compare the effect of lacrimal nerve stimulation (LNS) and anterior ethmoid nerve stimulation (AENS) on aqueous tear secretion, and tissue condition following chronic implantation. METHODS: A neurostimulator was implanted in rabbits adjacent to the (1) lacrimal nerve, and (2) anterior ethmoid nerve. Tear volume was measured with Schirmer test strips after stimulation (2.3-2.8 mA pulses at 30 Hz for 3-5 min), and scores were compared to sham stimulation. Lacrimal gland and nasal septal tissue were evaluated histologically after chronic stimulation (2 weeks-7 months). RESULTS: LNS increases tear volume by 32% above sham (p < 0.05, n = 5), compared with 133% for AENS (p ≤ 0.01, n = 6). AENS also significantly increases tear secretion in the fellow, non-stimulated eye (p ≤ 0.01, n = 6), as expected from the tearing reflex pathway. Histologically, chronic LNS is well tolerated by surrounding tissues while chronic AENS results in nasal mucosal fibrosis and implant extrusion within 3 weeks. CONCLUSIONS: AENS is significantly more effective than LNS at enhancing aqueous tear secretion, including the fellow eye. The lacrimal implant is well tolerated, while the nasal implant requires further design optimization to improve tolerability.

Enhanced Tearing by Electrical Stimulation of the Anterior Ethmoid Nerve.

Purpose: Electrical neurostimulation enhances tear secretion, and can be applied to treatment of dry eye disease. Using a chronic implant, we evaluate the effects of stimulating the anterior ethmoid nerve on the aqueous, lipid, and protein content of secreted tears. Methods: Neurostimulators were implanted beneath the nasal mucosa in 13 New Zealand white rabbits. Stimulations (2.3-2.8 mA pulses of 75-875 µs in duration repeated at 30-100 Hz for 3 minutes) were performed daily, for 3 weeks to measure changes in tear volume (Schirmer test), osmolarity (TearLab osmometer), lipid (Oil-Red-O staining), and protein (BCA assay, mass spectrometry). Results: Stimulation of the anterior ethmoid nerve in the frequency range of 30 to 90 Hz increased tear volume by 92% to 133% (P ≤ 0.01). Modulating the treatment with 50% duty cycle (3 seconds of stimulation repeated every 6 seconds) increased tear secretion an additional 23% above continuous stimulation (P ≤ 0.01). Tear secretion returned to baseline levels within 7 minutes after stimulation ended. Tear film osmolarity decreased by 7 mOsmol/L, tear lipid increased by 24% to 36% and protein concentration increased by 48% (P ≤ 0.05). Relative abundance of the lacrimal gland proteins remained the same, while several serum and corneal proteins decreased with stimulation (P ≤ 0.05). Conclusions: Electrical stimulation of the anterior ethmoid nerve increased aqueous tear volume, reduced tear osmolarity, added lipid, and increased the concentration of normal tear proteins. Human studies with an intranasal stimulator should verify these effects in patients with aqueous- and lipid-deficient forms of dry eye disease.

Biocompatibility of poly(ethylene glycol) and poly(acrylic acid) interpenetrating network hydrogel by intrastromal implantation in rabbit cornea.

We evaluated the biocompatibility of a poly(ethylene glycol) and poly(acrylic acid) (PEG/PAA) interpenetrating network hydrogel designed for artificial cornea in a rabbit model. PEG/PAA hydrogel measuring 6 mm in diameter was implanted in the corneal stroma of twelve rabbits. Stromal flaps were created with a microkeratome. Randomly, six rabbits were assigned to bear the implant for 2 months, two rabbits for 6 months, two rabbits for 9 months, one rabbit for 12 months, and one rabbit for 16 months. Rabbits were evaluated monthly. After the assigned period, eyes were enucleated, and corneas were processed for histology and immunohistochemistry. There were clear corneas in three of six rabbits that had implantation of hydrogel for 2 months. In the six rabbits with implant for 6 months or longer, the corneas remained clear in four. There was a high rate of epithelial defect and corneal thinning in these six rabbits. One planned 9-month rabbit developed extrusion of implant at 4 months. The cornea remained clear in the 16-month rabbit but histology revealed epithelial in-growth. Intrastromal implantation of PEG/PAA resulted in a high rate of long-term complications.

Interpenetrating polymer network hydrogel scaffolds for artificial cornea periphery.

Three-dimensional scaffolds based on inverted colloidal crystals (ICCs) were fabricated from sequentially polymerized interpenetrating polymer network (IPN) hydrogels of poly(ethyleneglycol) and poly(acrylic acid). This high-strength, high-water-content IPN hydrogel may be suitable for use in an artificial cornea application. Development of a highly porous, biointegrable region at the periphery of the artificial cornea device is critical to long-term retention of the implant. The ICC fabrication technique produced scaffolds with well-controlled, tunable pore and channel dimensions. When surface functionalized with extracellular matrix proteins, corneal fibroblasts were successfully cultured on IPN hydrogel scaffolds, demonstrating the feasibility of these gels as materials for the artificial cornea porous periphery. Porous hydrogels with and without cells were visualized non-invasively in the hydrated state using variable-pressure scanning electron microscopy.

Successful DMEK after intraoperative graft inversion.

PURPOSE: Hardiness of a Descemet membrane endothelial keratoplasty (DMEK) graft is not well established. The aim of this study was to report a case of graft survival after intraoperative inversion. METHODS: We describe a case of a 76-year-old man with Fuchs corneal dystrophy who underwent DMEK in the left eye. After deployment of the graft and a 15-minute sulfur hexafluoride gas fill, the graft was noted to be inverted. The graft was then reoriented and properly positioned. RESULTS: Because of progressive graft detachment, rebubble was required at 2 weeks after surgery. At 2 months after surgery, the graft was clear and fully adherent. Specular microscopy revealed 27.9% endothelial cell loss of the donor cornea. CONCLUSIONS: Despite intraoperative inversion, this DMEK graft remained viable without excessive endothelial cell loss.

Incidence of postoperative endophthalmitis from 1990 to 2009 using povidone-iodine but no intracameral antibiotics at a single academic institution.

PURPOSE: To correlate the incidence of postoperative endophthalmitis with changes in the preoperative prophylaxis over a 20-year period. SETTING: Department of Ophthalmology, Ludwig-Maximilians-University, Munich, Germany. DESIGN: Retrospective chart review. METHODS: Patients diagnosed with postoperative endophthalmitis from 1990 to 2009 after intraocular surgery performed at the same institution were included. Because of changes in the preoperative prophylaxis during the study period, 3 groups were formed for data analysis: Period 1 (1990 to 1992), no standardized prophylaxis regimen; period 2 (1993 to 1998), preoperative topical medication, povidone-iodine 10.0% periorbitally, and 1 drop of povidone-iodine 1.0% in the conjunctiva sac; and period 3 (1999 to 2009), similar to period 2 except with irrigation of the conjunctival sac with 10 mL of povidone-iodine 1.0%. RESULTS: The overall rate of postoperative endophthalmitis was 0.113% (77/68,323) for all intraocular surgeries. It decreased significantly from 0.291% (16/5505) in period 1 to 0.170% (33/19,413) in period 2 to 0.065% (28/43,405) in period 3 (P < .001). In cataract surgery, the overall rate of postoperative endophthalmitis was 0.125% (30/24,034). It decreased in each subsequent period, from 0.338% (9/2662) in period 1 to 0.224% (15/6696) in period 2 to 0.041% (6/14,676) in period 3 (P < .001). Coagulase-negative Staphylococcus was the most commonly isolated organism (47.4%). CONCLUSIONS: The rate of postoperative endophthalmitis decreased over a 20-year period at a single academic institution. Although multiple factors might have contributed to this decline, implementation of a preoperative prophylaxis protocol using copious povidone-iodine might have been the most important contributor. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.

Intravitreal injection technique and monitoring: updated guidelines of an expert panel.

PURPOSE: To review evidence and provide updated guidelines on intravitreal (IVT) injection technique and monitoring. METHODS: A review of the published literature on IVT injection from 2004 to 2014 formed the basis for round table deliberations by an expert panel of ophthalmologists. RESULTS: The dramatic increase in the number of IVT injections has been accompanied by a comparable increase in evidence surrounding IVT practice patterns and techniques. The expert panel identified a number of areas that have evolved since publication of the original IVT injection guidelines in 2004, the most notable of which were a lack of evidence to support the routine use of pre-, peri-, and postinjection antibiotics to reduce the risk of endophthalmitis, and the role of aerosolized droplets containing oral contaminants from the patient and/or providers as a potential source of infection. The panel emphasized the continued importance of applying povidone-iodine to and avoiding eyelid contact with the intended injection site and needle. CONCLUSION: Updated guidelines on IVT injection technique and monitoring are proposed based on a review of published literature and expert panel deliberations.

Prevention and treatment of injection-related endophthalmitis.

BACKGROUND: Intravitreal injections are the fastest growing cause of endophthalmitis and can result in severe vision loss. The prevention, diagnosis and management of such infections remain unclear and at times controversial. METHODS: We searched Pubmed for keywords "prophylaxis," "endophthalmitis," "intravitreal injection." We focused on studies published in the last 2 years as well as other recent studies with particular attention to data on the incidence, microbiology, prevention, and treatment of injection-related endophthalmitis. RESULTS: Over 20 relevant studies were found. With povidone-iodine preparation, the per-injection endophthalmitis rate is low at about 0.03%. Antibiotics do not appear to be beneficial for prevention of post-injection endophthalmitis. The best timing of vitrectomy is unclear. CONCLUSIONS: Antibiotic prophylaxis is probably not needed when giving intravitreal injections. More data is needed to help determine the proper treatment for post-injection endophthalmitis.

In vivo biocompatibility of two PEG/PAA interpenetrating polymer networks as corneal inlays following deep stromal pocket implantation.

This study compared the effects of implanting two interpenetrating polymer networks (IPNs) into rabbit corneas. The first (Implant 1) was based on PEG-diacrylate, the second (Implant 2) was based on PEG-diacrylamide. There were inserted into deep stromal pockets created using a manual surgical technique for either 3 or 6 months. The implanted corneas were compared with normal and sham-operated corneas through slit lamp observation, anterior segment optical coherence tomography, in vivo confocal scanning and histological examination. Corneas with Implant 1 (based on PEG-diacrylate) developed diffuse haze, ulcers and opacities within 3 months, while corneas with Implant 2 (based on PEG-diacrylamide) remained clear at 6 months. They also exhibited normal numbers of epithelial cell layers, without any immune cell infiltration, inflammation, oedema or neovascularisation at post-operative 6 month. Morphological studies showed transient epithelial layer thinning over the hydrogel inserted area and elevated keratocyte activity at 3 months; however, the epithelium thickness and keratocyte morphology were improved at 6 months. Implant 2 exhibited superior in vivo biocompatibility and higher optical clarity than Implant 1. PEG-diacrylamide-based IPN hydrogel is therefore a potential candidate for corneal inlays to correct refractive error.

Diffusion of protein through the human cornea.

AIMS: To determine the rate of diffusion of myoglobin and bovine serum albumin (BSA) through the human cornea. These small proteins have hydrodynamic diameters of approximately 4.4 and 7.2 nm, and molecular weights of 16.7 and 66 kDa, for myoglobin and BSA, respectively. METHODS: Diffusion coefficients were measured using a diffusion chamber where the protein of interest and balanced salt solution were in different chambers separated by an ex vivo human cornea. Protein concentrations in the balanced salt solution chamber were measured over time. Diffusion coefficients were calculated using equations derived from Fick's law and conservation of mass in a closed system. RESULTS: Our experiments demonstrate that the diffusion coefficient of myoglobin is 5.5 ± 0.9 × 10(-8) cm(2)/s (n = 8; SD = 1.3 × 10(-8) cm(2)/s; 95% CI: 4.6 × 10(-8) to 6.4 × 10(-8) cm(2)/s) and the diffusion coefficient of BSA is 3.1 ± 1.0 × 10(-8) cm(2)/s (n = 8; SD = 1.4 × 10(-8) cm(2)/s; 95% CI: 2.1 × 10(-8) to 4.1 × 10(-8) cm(2)/s). CONCLUSIONS: Our study suggests that molecules as large as 7.2 nm may be able to passively diffuse through the human cornea. With applications in pharmacotherapy and the development of an artificial cornea, further experiments are warranted to fully understand the limits of human corneal diffusion and its clinical relevance.

Application of 10% povidone iodine reduces conjunctival bacterial contamination rate in patients undergoing cataract surgery.

PURPOSE: To determine the efficacy of 10% povidone iodine (PVI) drops given before cataract extraction in addition to routine irrigation of the conjunctival sac with 1% PVI. METHODS: This prospective, randomized, single-center study at the Department of Ophthalmology, Ludwig-Maximilians-University, Munich, includes 263 eyes of 242 patients undergoing cataract surgery. Patients were randomized to receive 3 drops of 10% PVI into the conjunctival sac (study group) or no PVI drops (control group). All patients underwent periorbital disinfection with 10% PVI followed by irrigation of the conjunctiva with 10 mL of 1% PVI. Specimens were obtained prior to the application of PVI, after antibiotic administration (T1), after irrigation with PVI but before surgery (T2), and at the conclusion of surgery (T3). RESULTS: After PVI disinfection, the number of positive cultures was significantly reduced in all groups (p<0.0001) from 69%-93% at T1 to 1%-16% at T3. In outpatients, the study group showed significantly fewer positive cultures at the conclusion of surgery compared to the control group (4% vs 16%; p=0.03). Also in inpatients significant fewer positive cultures were found in the study group compared to the control group at T2 (12% vs 28%; p=0.03) and at T3 (1% vs 10%; p=0.03). CONCLUSIONS: Three additional drops of 10% PVI prior to surgery provided additional benefit by reducing the conjunctival bacterial contamination rate even in the setting of preoperative irrigation of the conjunctiva with 1% PVI.