Ophthalmic Applications Research Articles

Fluorescence Sensing Technologies for Ophthalmic Diagnosis.

Personalized and point-of-care (POC) diagnoses are critical for ocular physiology and disease diagnosis. Real-time monitoring and continuous sampling abilities of tear fluid and user-friendliness have become the key characteristics for the applied ophthalmic techniques. Fluorescence technologies, as one of the most popular methods that can fulfill the requirements of clinical ophthalmic applications for optical sensing, have been raised and applied for tear sensing and diagnostic platforms in recent decades. Wearable sensors in this case have been increasingly developed for ocular diagnosis. Contact lenses, as one of the commercialized and popular tools for ocular dysfunction, have been developed as a platform for fluorescence sensing in tears diagnostics and real-time monitoring. Numbers of biochemical analytes have been examined through developed fluorescent contact lens sensors, including pH values, electrolytes, glucose, and enzymes. These sensors have been proven for monitoring ocular conditions, enhancing and detecting medical treatments, and tracking efficiency of related ophthalmic surgeries at POC settings. This review summarizes the applied ophthalmic fluorescence sensing technologies in tears for ocular diagnosis and monitoring. In addition, the cooperation of fabricated fluorescent sensor with mobile phone readout devices for diagnosing ocular diseases with specific biomarkers continuously is also discussed. Further perspectives for the developments and applications of fluorescent ocular sensing and diagnosing technologies are also provided.

Recent large-scale philophthalmosis outbreak in Portugal: inefficacy of common antihelminthic agents

BackgroundParasitic conjunctivitis caused by Philophthalmus spp. is a common ophthalmic disease in birds, with localized outbreaks occurring worldwide. There is no consensus on treating this disease; mechanical removal is considered a standard recommendation, but is associated with disease relapses within days or weeks.MethodsFrom 2015 to 2020, we examined 4295 Larus michahellis and Larus fuscus gulls in southern Portugal for the presence of Philophthalmus spp. Due to the need to treat dozens of infected gulls in the rescue station, we tested three treatment regimens aimed at targeting Philophthalmus lucipetus in the infected gulls: (I) the ophthalmic application of levamisole; (II) the oral application of milbemycin in combination with praziquantel; and (III) the subcutaneous application of ivermectin.ResultsThe outbreak of philophthalmosis in gulls in southern Portugal has been ongoing since the first cases were reported in 2015–2016. The prevalence of philophthalmosis has fluctuated annually, peaking a maximum of 10.3% in L. fuscus in 2017 and at 2.1% in L. michahellis in 2016. The infection intensity peaked at a median of 11.5 eye-flukes per host bird in L. fuscus in 2016 and a median of six eye-flukes per host bird in L. michahellis in 2017. Nine gulls were infected with >50 eye-flukes. None of the treatment options were effective at treating P. lucipetus infections: the numbers of eye-flukes in the infected birds did not decrease, and the clinical signs of the disease did not change.ConclusionsAn outbreak of philophthalmosis in southern Portugal has massively affected two species of gulls in the region. Two previously suggested philophthalmosis treatments (ocular levamisole and praziquantel given orally), as well as a third mode of treatment with a previously failed compound (ivermectin administered subcutaneously) were used. However, the treatments did not affect the numbers of P. lucipetus in the eyes of the treated gulls. Further research should address ophthalmic gel formulations or sub-conjunctival delivery mode for antihelminthic drugs that are effective against Philophthalmus spp. in vitro.Graphical abstract

EyeScreen: Development and Potential of a Novel Machine Learning Application to Detect Leukocoria.

PurposeEarly diagnosis and treatment of retinoblastoma are of paramount importance for a positive clinical outcome. The most common sign of retinoblastoma is leukocoria, or white pupil. Effective, easy-to-perform, community-based screening is needed to improve outcomes in lower-income regions. The EyeScreen (developed by Joshua Meyer from the University of Michigan) Android (Google LLC) smartphone application is an important step toward addressing this need. The purpose of this study was to examine the potential of the novel use of low-cost technologies—a cell phone application and machine learning—to identify leukocoria.DesignA cell phone application was developed and refined with the feedback from on-site, single-population use in Ethiopia. Application performance was evaluated in this technology validation study.ParticipantsOne thousand four hundred fifty-seven participants were recruited from ophthalmology and pediatric clinics in Addis Ababa, Ethiopia.MethodsPhotographs obtained with inexpensive Android smartphones running the EyeScreen Application were used to train an ImageNet (ResNet) machine learning model and to measure the performance of the app. Eighty percent of the images were used in training the model, and 20% were reserved for testing.Main Outcome MeasuresPerformance of the model was measured in terms of sensitivity, specificity, receiver operating characteristic (ROC) curve, and precision-recall curve.ResultsAnalyses of the participant images resulted in the following at the participant level: sensitivity, 87%; specificity, 73%; area under the ROC curve, 0.93; and area under the precision-recall curve, 0.77.ConclusionsEyeScreen has the potential to serve as an effective screening tool in the areas of the world most affected by delayed retinoblastoma diagnosis. The relatively high initial performance of the machine learning model with small training datasets in this early-phase study can serve as a proof of concept for future use of machine learning and artificial intelligence in ophthalmic applications.

Prednisolone and dexamethasone are systemically absorbed after topical application of ophthalmic suspensions in healthy dogs.

To quantify plasma concentrations of prednisolone and dexamethasone (peripheral and jugular) and cortisol following topical ophthalmic application of 1% prednisolone acetate and 0.1% dexamethasone to healthy adult dogs. 12 purpose-bred Beagles. Dogs received 1 drop of 1% prednisolone acetate (n = 6) or neomycin polymyxin B dexamethasone (ie, 0.1% dexamethasone; 6) ophthalmic suspension in both eyes every 6 hours for 14 days. Blood samples (peripheral and jugular) were collected on days 0, 1, 7, and 14 and analyzed for plasma prednisolone and dexamethasone concentrations. Plasma cortisol concentrations were measured at the beginning of the study and following topical drug administration. Both drugs demonstrated systemic absorption. Prednisolone was detected on days 1, 7, and 14 (median plasma concentration, 24.80 ng/mL; range, 6.20 to 74.00 ng/mL), and dexamethasone was detected on days 1, 7, and 14 (2.30 ng/mL; 0 to 17.70 ng/mL). Neither prednisolone nor dexamethasone were detected in plasma samples on day 0 (baseline). Sampling from the jugular vein resulted in higher plasma drug concentrations than from a peripheral vein when samples from each day were combined. Plasma cortisol concentrations were significantly lower than baseline following 14 days of treatment with topical prednisolone acetate and dexamethasone. Prednisolone and dexamethasone are detected in the plasma of healthy dogs following topical ophthalmic administration 4 times/d with prednisolone concentrations being close to a physiologic dose of orally administered prednisolone. Additional research is needed to evaluate the systemic absorption of these medications in dogs with ocular inflammation.

Retinal blood flow imaging with combined full-field swept-source optical coherence tomography and laser Doppler holography.

Full-field swept-source optical coherence tomography (FF-SS-OCT) and laser Doppler holography (LDH) are two holographic imaging techniques presenting unique capabilities for ophthalmology. We report on interlaced FF-SS-OCT and LDH imaging with a single instrument. Effectively, retinal blood flow and pulsation could be quasi-simultaneously monitored. This instrument holds potential for a wide scope of ophthalmic applications.

Trade-Off Asymmetric Profile for Extended-Depth-of-Focus Ocular Lens

We explore the possibility of extending the depth of focus of an imaging lens with an asymmetric quartic phase-mask, while keeping the aberration within a relatively low level. This can be intended, for instance, for ophthalmic applications, where no further digital processing can take place, relying instead on the patient’s neural adaptation to their own aberrations. We propose a computational optimization method to derive the design-strength factor of the asymmetric profile. The numerical and experimental results are shown. The optical experiment was conducted by means of a modulo-2π phase-only spatial light modulator. The proposed combination of the asymmetric mask and the lens can be implemented in a single refractive element. An exemplary case of an extended-depth-of focus intraocular lens based on the proposed element is described and demonstrated with a numerical experiment.

Topical timolol enhances surgical wound healing in the lower portion of the leg in older patients with comorbidities: A retrospective review

Topical timolol enhances surgical wound healing in the lower portion of the leg in older patients with comorbidities: A retrospective review

Recent developments of temperature‐responsive polymers for ophthalmic applications

AbstractBlindness is one of the most feared disabilities. From cataracts and glaucoma to age‐related macular degeneration and retinal vascular diseases, ocular diseases have adverse impacts on patients and pose a huge burden to the healthcare system. The World Health Organization estimates that out of 2.2 billion people with visual impairment, almost half of the cases can be prevented or has yet to be addressed. This presents an urgent clinical and societal need to be met. Temperature‐sensitive hydrogels are one of the most biocompatible materials, which can be applied into the eye. By exploiting physiological temperature as a stimulus for in situ gel formation, control of the mechanical properties, rate of drug release, and biomechanical interactions can be tuned. They are very versatile and have immense potential in ocular applications by acting as vitreous substitutes in retinal surgery or topical eye drops and lenses for ocular discomfort and inflammation. In this article, we provide a review of the recent developments in temperature‐responsive polymers in ophthalmic therapy in the past 5 years including retinal detachment, retinal vascular diseases, dry eyes, cataracts, age‐related macular degeneration, and glaucoma.

Miniaturizing optical coherence tomography

AbstractOptical coherence tomography (OCT) has revolutionized ophthalmic diagnosis as a non‐invasive, cross‐sectional imaging technique in the last 30 years and hence is one of the fastest adopted advanced imaging technologies in the history of medicine. A miniaturization of OCT devices would not only reduce size but ideally also reduce costs and therefore create potential new markets. OCT systems based on photonic integrated circuits (PIC) could enable a significant miniaturization of complex systems with high degree of integration as well as low costs of goods. These therefore have a potential to enable portable, cost‐effective, high performing, real handheld OCT devices. This review identifies three main categories towards miniaturized OCT devices: Handheld imaging probes interfaced to a (mobile) base station, compact home/self‐ OCT and PIC‐based OCT. Imaging performance parameters and technical readiness levels of the identified miniaturized OCT systems for (non‐) ophthalmic applications are presented. Special attention is paid to PIC‐based OCT applications and their progress.Picture: First in vivo human retinal tomogram using a PIC‐based subcomponent (arrayed waveguide grating, AWG) of a spectral domain OCT system. Adapted with permission from E. A. Rank et al., Light Sci Appl. 2021, 10, 1, CC By 4.0. Copyright © 2021, The Author(s).

Development and Characterization of Nanoemulsions for Ophthalmic Applications: Role of Cationic Surfactants.

The eye is a very complex organ comprising several physiological and physical barriers that compromise drug absorption into deeper layers. Nanoemulsions are promising delivery systems to be used in ocular drug delivery due to their innumerous advantages, such as high retention time onto the site of application and the modified release profile of loaded drugs, thereby contributing to increasing the bioavailability of drugs for the treatment of eye diseases, in particular those affecting the posterior segment. In this review, we address the main factors that govern the development of a suitable nanoemulsion formulation for eye administration to increase the patient’s compliance to the treatment. Appropriate lipid composition and type of surfactants (with a special emphasis on cationic compounds) are discussed, together with manufacturing techniques and characterization methods that are instrumental for the development of appropriate ophthalmic nanoemulsions.

Development of Microchip Laser for Ophthalmic Therapy Application

We have recently developed a several milli-joule, sub-nanosecond laser source for ophthalmic therapy application which allows to lower a laser breakdown threshold, less than half, and more stably/effectively yield the breakdown phenomenon compared to that based on conventionally employed source, implying the developed source has a potential to realize more minimally invasive ophthalmic treatment for secondary cataract. For further laser performance, the use of a photonic crystal device as an output coupler of the laser source has been also demonstrated. With this system, pulse width shortening and polarization control of the laser output could be achieved simultaneously. This paper presents these recent ophthalmic laser developments.

Femtosecond lasers for eye surgery applications: historical overview and modern low pulse energy concepts

Abstract This review provides an overview of the historical development and modern applications of femtosecond (fs) lasers in ophthalmology, with a focus on the optical concepts involved. fs-Laser technology is unique because it allows very precise cutting inside the eye through optically transparent tissue, without a need for any mechanical openings. fs-Lasers were historically first used for refractive cornea surgery, later also for therapeutic cornea procedures and lens surgery. Further new areas of ophthalmic application are under development. The latest laser system concept is low pulse energy and high pulse frequency: by using larger numerical aperture focusing optics, the pulse energy required for optical breakdown decreases, and athermal tissue cutting with minimal side effects is enabled.

Mucoadhesive phenylboronic acid conjugated chitosan oligosaccharide-vitamin E copolymer for topical ocular delivery of voriconazole: Synthesis, in vitro/vivo evaluation, and mechanism

Topical eye drops still face challenges of low-drug treatment effects and frequent dosing in ophthalmic applications due to the low preocular retention rate and low transcorneal permeability. Thus, we designed and synthesized a phenylboronic acid conjugated chitosan oligosaccharide-vitamin E copolymer (PBA-CS-VE) for use in mucoadhesive voriconazole (VRC)-loaded nanomicelles for fungal keratitis. In vitro mucin binding and ex vivo eyeball adhesion tests show that the copolymer has strong mucoadhesion. The transportation of coumarin-6 (C6) across a monolayer of HCE-T cells and 3D cell spheroids confirm the strong corneal penetration ability of PBA-CS-VE. The mechanism of promoting corneal penetration was studied in terms of intracellular calcium-ion concentration, cell membrane potential, cell membrane fluidity, and the tight junctions of cells. The pharmacokinetics in the aqueous humor were examined to evaluate the ability of nanomicelles in promoting corneal penetration and prolonging ocular retention. VRC-loaded PBA-CS-VE nanomicelles (PBA-CS-VE-VRC) yielded a very favorable therapeutic effect on a rabbit model of fungal keratitis in vivo as compared to the free drug. Overall, the results indicate that PBA-CS-VE nanomicelles are a mucoadhesive candidate with enhanced transcorneal permeability and prolonged preocular retention for efficient delivery of topical ocular drugs. Statement of significanceAlthough eye drops are widely used in ocular drug delivery, the disadvantages such as short retention time and weak corneal penetrating ability still seriously affect the therapeutic effect of the drug. Therefore, the mucoadhesive carrier seems to be an interesting strategy for ocular drug delivery. Herein, a novel phenylboronic acid conjugated chitosan oligosaccharide-vitamin E copolymer was designed and constructed as mucoadhesive nanomicelles loaded with voriconazole for fungal keratitis. These nanomicelles were able to improve the in vitro mucin binding and to prolong the residence time of the drug on the surface of the eyeball. Moreover, the nanomicelles exhibited an enhanced drug permeability in cell monolayer models and 3D cell culture models. This work provides a promising ocular drug delivery system.

In vivo human retinal swept source optical coherence tomography and angiography at 830\xa0nm with a CMOS compatible photonic integrated circuit

Photonic integrated circuits (PIC) provide promising functionalities to significantly reduce the size and costs of optical coherence tomography (OCT) systems. This paper presents an imaging platform operating at a center wavelength of 830 nm for ophthalmic application using PIC-based swept source OCT. An on-chip Mach–Zehnder interferometer (MZI) configuration, which comprises an input power splitter, polarization beam splitters in the sample and the reference arm, and a 50/50 coupler for signal interference represents the core element of the system with a footprint of only (12 times 5);{text {mm}}^2. The system achieves 94 dB imaging sensitivity with 750 upmu W on the sample, 50 kHz imaging speed and 5.5 upmu m axial resolution (in soft tissue). With this setup, in vivo human retinal imaging of healthy subjects was performed producing B-scans, three-dimensional renderings as well as OCT angiography. These promising results are significant prerequisites for further integration of optical and electronic building blocks on a single swept source-OCT PIC.

Enhanced medical diagnosis for dOCTors: a perspective of optical coherence tomography.

.Significance: After three decades, more than 75,000 publications, tens of companies being involved in its commercialization, and a global market perspective of about USD 1.5 billion in 2023, optical coherence tomography (OCT) has become one of the fastest successfully translated imaging techniques with substantial clinical and economic impacts and acceptance.Aim: Our perspective focuses on disruptive forward-looking innovations and key technologies to further boost OCT performance and therefore enable significantly enhanced medical diagnosis.Approach: A comprehensive review of state-of-the-art accomplishments in OCT has been performed.Results: The most disruptive future OCT innovations include imaging resolution and speed (single-beam raster scanning versus parallelization) improvement, new implementations for dual modality or even multimodality systems, and using endogenous or exogenous contrast in these hybrid OCT systems targeting molecular and metabolic imaging. Aside from OCT angiography, no other functional or contrast enhancing OCT extension has accomplished comparable clinical and commercial impacts. Some more recently developed extensions, e.g., optical coherence elastography, dynamic contrast OCT, optoretinography, and artificial intelligence enhanced OCT are also considered with high potential for the future. In addition, OCT miniaturization for portable, compact, handheld, and/or cost-effective capsule-based OCT applications, home-OCT, and self-OCT systems based on micro-optic assemblies or photonic integrated circuits will revolutionize new applications and availability in the near future. Finally, clinical translation of OCT including medical device regulatory challenges will continue to be absolutely essential.Conclusions: With its exquisite non-invasive, micrometer resolution depth sectioning capability, OCT has especially revolutionized ophthalmic diagnosis and hence is the fastest adopted imaging technology in the history of ophthalmology. Nonetheless, OCT has not been completely exploited and has substantial growth potential—in academics as well as in industry. This applies not only to the ophthalmic application field, but also especially to the original motivation of OCT to enable optical biopsy, i.e., the in situ imaging of tissue microstructure with a resolution approaching that of histology but without the need for tissue excision.

Stretchable Nanostructures as Optomechanical Strain Sensors for Ophthalmic Applications

Stretchable Nanostructures as Optomechanical Strain Sensors for Ophthalmic Applications

Olive Pomace Phenolic Compounds Stability and Safety Evaluation: From Raw Material to Future Ophthalmic Applications.

Nowadays, increasing interest in olive pomace (OP) valorization aims to improve olive’s industry sustainability. Interestingly, several studies propose a high-value application for OP extracts containing its main phenolic compounds, hydroxytyrosol and oleuropein, as therapy for ocular surface diseases. In this work, the stability and accessibility of OP total phenolic and flavonoid content, main representative compounds, and antioxidant activity were assessed under different pretreatment conditions. Among them, lyophilization and supercritical CO2 extraction were found to increase significantly most responses measured in the produced extracts. Two selected extracts (CONV and OPT3) were obtained by different techniques (conventional and pressurized liquid extraction); Their aqueous solutions were characterized by HPLC-DAD-MS/MS. Additionally, their safety and stability were evaluated according to EMA requirements towards their approval as ophthalmic products: their genotoxic effect on ocular surface cells and their 6-months storage stability at 4 different temperature/moisture conditions (CPMP/ICH/2736/99), together with pure hydroxytyrosol and oleuropein solutions. The concentration of hydroxytyrosol and oleuropein in pure or extract solutions was tracked, and possible degradation products were putatively identified by HPLC-DAD-MS/MS. Hydroxytyrosol and oleuropein had different stability as standard or extract solutions, with oleuropein also showing different degradation profile. All compounds/extracts were safe for ophthalmic use at the concentrations tested.

Evaluating of Two Type of Cyclosporine-A Containing Nanosuspension for Ophthalmic Administration

Dry eye is both a common symptom and a disease. It is known that the ophthalmic emulsion of the immunomodulator cyclosporine-A (Cyc-A) has a positive effect on this condition but its’ absorption to intraocular tissues is limited. Nanosuspension is a drug formulation that aims to increase the bioavailability. The aim of this study was to develop a Cyc-A nanosuspension formulation for a better intraocular absorption via ocular delivery and to investigate the effectiveness of the formulation by comparing it with two marketed ophthalmic emulsions (Restasis® and Depores®). Two type of Cyc-A loaded Eudragit S100 nanosuspension (A and B) were prepared. Drug formulations were applied to both eyes of 20 male Albino New Zealand rabbits with an interval of 12 hours for 14 days. In vitro drug release was tested using a dialysis sac and quantitative analysis was performed by HPLC for evaluating Cyc-A amounts in all formulations. Although all four formulations had similar particle size and polydispersity indexes, nanosuspension B which had a positive zeta potential value, had released more Cyc-A than other formulations. It was showed that Cyc-A loaded nanosuspension formulations which had good ocular tolerability could be a better alternative to commercial formulations for the treatment of dry eye. The nanosuspensions have ideal mean particle size range with a positive surface charge for ophthalmic applications of Cyc-A.

Effect of corneal stromal lenticule customization on neurite distribution and excitatory property

IntroductionRefractive stromal lenticules from Small Incision Lenticule Extraction (SMILE), though usually discarded, hold a potential for various ophthalmic applications, including refractive correction, stromal volume expansion, and biomechanical strengthening of the cornea. ObjectivesTo investigate the effect of lenticule customization on lenticule neurite length profile and the excitatory response (calcium signaling) and the potential of reinnervation. MethodsHuman and porcine stromal lenticules were treated by (1) excimer laser reshaping, (2) ultraviolet A-riboflavin crosslinking (CXL), and (3) decellularization by sodium dodecyl sulfate (SDS), respectively. The overall neurite scaffold immuno-positive to TuJ1 (neuron-specific class III β-tubulin) expression and population of active neurite fragments with calcium response revealed by L-glutamate-induced Fluo-4-acetoxymethyl ester reaction were captured by wide-field laser-scanning confocal microscopy, followed by z-stack image construction. The NeuronJ plugin was used to measure neurite lengths for TuJ1 (NL-TuJ1) and calcium signal (NL-Ca). Reinnervation of lenticules was examined by the ex vivo grafting of chick dorsal root ganglia (DRG) to the decellularized human lenticules. Differences between groups and controls were analyzed with ANOVA and Mann-Whitney U test. ResultsThe customization methods significantly eliminated neurites inside the lenticules. NL-TuJ1 was significantly reduced by 84% after excimer laser reshaping, 54% after CXL, and 96% after decellularization. The neurite remnants from reshaping and CXL exhibited calcium signaling, indicative of residual excitatory response. Re-innervation occurred in the decellularized lenticules upon stimulation of the grafted chick embryo DRG with nerve growth factor (NGF 2.5S). ConclusionAll of the lenticule customization procedures reduced lenticule neurites, but the residual neurites still showed excitatory potential. Even though these neurite remnants seemed minimal, they could be advantageous to reinnervation with axon growth and guidance after lenticule reimplantation for refractive and volume restoration of the cornea.

Recent Advances in Hydrogels: Ophthalmic Applications in Cell Delivery, Vitreous Substitutes, and Ocular Adhesives.

With the prevalence of eye diseases, such as cataracts, retinal degenerative diseases, and glaucoma, different treatments including lens replacement, vitrectomy, and stem cell transplantation have been developed; however, they are not without their respective shortcomings. For example, current methods to seal corneal incisions induced by cataract surgery, such as suturing and stromal hydration, are less than ideal due to the potential for surgically induced astigmatism or wound leakage. Vitrectomy performed on patients with diabetic retinopathy requires an artificial vitreous substitute, with current offerings having many shortcomings such as retinal toxicity. The use of stem cells has also been investigated in retinal degenerative diseases; however, an optimal delivery system is required for successful transplantation. The incorporation of hydrogels into ocular therapy has been a critical focus in overcoming the limitations of current treatments. Previous reviews have extensively documented the use of hydrogels in drug delivery; thus, the goal of this review is to discuss recent advances in hydrogel technology in surgical applications, including dendrimer and gelatin-based hydrogels for ocular adhesives and a variety of different polymers for vitreous substitutes, as well as recent advances in hydrogel-based retinal pigment epithelium (RPE) and retinal progenitor cell (RPC) delivery to the retina.