Ophthalmic Applications Research Articles

Controlling Growth Factor Diffusion by Modulating Water Content in Injectable Hydrogels.

Recent advancements in the delivery of therapeutics for retinal diseases include the development of injectable hydrogels, networks of one or more hydrophilic polymers that contain a high-volume fraction of water. These systems are of particular interest due to their biocompatibility, permeability to water-soluble metabolites, and function as minimally invasive injectable delivery vehicles. Recently, hydrogels for ophthalmic applications have been developed that display a controlled release of factors necessary for cellular survival and proliferation. Understanding the relationship between the volume water fraction and the physical, chemical, and diffusion properties of the hydrogel scaffold could aid in the improvement of existing drug delivery treatments for retinal regeneration. In this study, we compared the diffusion and release of human epidermal growth factor (hEGF) encapsulated in different injectable homogenous and heterogenous hydrogels, namely gelatin-hydroxyphenyl propionic acid (Gtn-HPA) and hyaluronic acid-tyramine (HA-Tyr)-based hydrogels. These experimental results were compared with the measured stiffness and water content of these hydrogels and applied to different diffusion theories of polymers to determine the model of best fit. We find that the normalized diffusion and release of hEGF increases with free water content in injectable hydrogels: ranging from 0.176 at 41% free water in HA-Tyr to 0.2 at 53% free water in Gtn-HPA, whereas it decreases with hydrogel stiffness: 600 Pa for Gtn-HPA and 1440 Pa for HA-Tyr. Further, we compared our experimental data with theoretical diffusion models. We found that homogeneous theoretical models, notably the hydrodynamic model (giving a normalized diffusion close to 0.2), provide the most suitable explanation for the measured solute diffusion coefficient. Impact statement Diffusion in a three-dimensional system is a key factor in designing new hydrogel-based materials. It allows to control and predict diffusion in implants and delivery systems. However, very little is done to explore and test the diffusion since it is a complex process. Many models can predict solute diffusion; however, practical application using these models has not yet been done. We have shown the variation of these models in a practical extent, which could have a tremendous impact on designing biomaterial for biological application as it allows one to understand the diffusion of injected drugs and growth factors.

Preparation and detailed characterization of fusidic acid loaded in situ gel formulations for ophthalmic application

Preparation and detailed characterization of fusidic acid loaded in situ gel formulations for ophthalmic application

Customized anterior segment photoacoustic imaging for ophthalmic burn evaluation <i>in vivo</i>

Photoacoustic imaging has many advantages in ophthalmic application including high-resolution, requirement of no exogenous contrast agent, and noninvasive acquisition of both morphologic and functional information. However, due to the limited depth of focus of the imaging method and large curvature of the eye, it remains a challenge to obtain high quality vascular image of entire anterior segment. Here, we proposed a new method to achieve high quality imaging of anterior segment. The new method applied a curvature imaging strategy based on only one time scanning, and hence is time efficient and more suitable for ophthalmic imaging compared to previously reported methods using similar strategy. A custom-built photoacoustic imaging system was adapted for ophthalmic application and a customized image processing method was developed to quantitatively analyze both morphologic and functional information in vasculature of the anterior segment. The results showed that the new method improved the image quality of anterior segment significantly compared to that of conventional high resolution photoacoustic imaging. More importantly, we applied the new method to study ophthalmic disease in an <em>in vivo</em> mouse model for the first time. The results verified the suitability and advantages of the new method for imaging the entire anterior segment and the numerous potentials of applying it in ophthalmic imaging in future.

3D Image Generation From Single Image Using Color Filtered Aperture and 2.1D Sketch-A Computational 3D Imaging System and Qualitative Analysis

A new method for generating 3D images using both disparity parameters due to the color filtered aperture (CFA) and depth alignment of the multi-plane images for an acquired 2D image using a novel computational imaging system is presented. A CFA is created using add-on red, green, and blue color filters in front of the objective lens for a conventional 2D camera system. The multiple plane images are computed using various image regions identified by 2.1D sketch and the corresponding inter-region depth information with the aid of color disparities caused in the acquired 2D image. Our emphasis is to handle possible occlusions in single 2D image regions due to various object features for the acquired scene using ordered multiple plane images and to generate a 3D image by exploiting the order existing in the computed multiple plane images and compositing the region with aligned inter-image region depth information. The simulation and analysis demonstrate the elegance of the 3D image generation. Ultimately, the proposed computational imaging system is not only cost-effective but also an alternative to the stereo-based imaging system, which is not suited for ophthalmic or endoscopic imaging applications.

Theranostic Applications of Nanomaterials for Ophthalmic Applications

The development of theranostic applications of nanomaterials has presented researchers with a new form of diagnosing and treating diseases, such as cancer, Diabetic Retinopathy, and Age-Related Macular Degeneration. Theranostic have allowed for a bridge between conventional medicine and personalized medicine with the use of nanomaterials. The applications of nanomaterials within medicine (nanomedicine) have changed the diagnosis, monitoring, control, treatment, and prevention of diseases. The effects of the biological interaction of nanomaterials within the human body must be examined further to understand the efficacy, toxicity, and biodistribution. The use of theranostic application of nanomaterials has gained attention in the field of Ophthalmology. The use of theranostic nanomaterials to reduce current treatments, complications, diagnosis, reduce the effects and treat a visually threatening disease is appealing. The benefit of treating ocular diseases with theranostic will allow for better visibility and targeted treatment.

The glucocorticoid derivative with the phthalimide group cationic nanocrystal for ophthalmic application: a design space development approach

The glucocorticoid derivative of budesonide with a phthalimide group is a drug candidate to treat inflammatory eye diseases; nevertheless, it presents low water solubility. Drug nanocrystals have been proposed to overcome this hurdle. The development of an innovative ophthalmic anti-inflammatory nanosuspension was performed using a design space approach. We obtained the particle size reduction of this glucocorticoid derivative on a nanometer scale (approximately 165.0 nm), applying wet bead milling on a super reduced scale. The design of experiment supported the optimization of the formula evaluating the parameters that influence reducing the particle size and also allowed determining the design space. Considering the two statistical models developed and the size range obtained, we proposed that the optimized formulation for the glucocorticoid derivative nanosuspension may be 1.0 wt% glucocorticoid derivative and 0.092 wt% cetylpyridinium chloride. This formulation was characterized by the morphological, physical–chemical, and mucoadhesive in vitro test and showed potential for ophthalmic use with reduced frequency of product application, improved efficiency, and safety, which may promote better patient compliance.

AI-automated referral for patients with visual impairment

In the past 5 years, deep neural networks have been applied in several medical applications such as detecting pneumonia and lung consolidation from chest x-rays and CT scans,1 and melanoma from skin photographs.2 Deep learning has also been integrated into ophthalmic applications, especially with use of fundus and optical coherence tomography images because of their widespread use in clinical settings. Deep learning has been shown to detect diabetic retinopathy, glaucoma, age-related macular degeneration, diabetic macular oedema, and retinopathy of prematurity, and even to predict several systemic cardiovascular risk factors.

Gelatin scaffold with multifunctional curcumin-loaded lipid-PLGA hybrid microparticles for regenerating corneal endothelium

Corneal transplantation is currently the only approach to cure corneal blindness. Cell-based strategies that employ corneal endothelial cells (CECs) grown on supporting biomaterials hold great promise as possible alternative therapies for treating corneal endothelial dysfunction. Nevertheless, most biomaterials are used merely because of their robust mechanical properties, providing passive physical support for the transplantation of CEC monolayers. Based on the versatility of curcumin in ophthalmic applications, this study aims to develop a multifunctional scaffold system that can not only support the function and transplantation of CECs but also prevents post-engraftment complications by sustained curcumin release, thus enhancing the long-term success of CEC engraftment. Curcumin-loaded lipid-poly(lactic-co-glycolic acid) (PLGA; Cur@MPs) hybrid microparticles (MPs) fabricated using an oil-in-water single emulsion method are embedded into gelatin-based scaffolds. The anti-inflammatory, antioxidative, and anti-angiogenic potentials of the developed scaffolds and their capacity in supporting CEC monolayer formation are evaluated. The Cur@MPs are capable of promoting CEC proliferation, protecting CECs from oxidative stress-induced cell death via modulating Nrf2/HO-1 signaling axis, suppressing the secretion of pro-inflammatory cytokines by macrophages, and inhibiting the migration and angiogenesis of vascular endothelial cells. By incorporating the Cur@MPs into a thin gelatin membrane, the fabricated scaffold is able to support the growth and organization of CECs into a polygonal morphology with tight junctions. These experimental results demonstrate the potential of the Cur@MPs-loaded gelatin scaffold for actively supporting the survival and function of CEC monolayers after transplantation.

An Exploratory Study of a New Vancomycin Eye Drops Formulation for Extemporaneous Compounding.

Compounded eye drop solutions of vancomycin hydrochloride have important clinical applications, such as postoperative antimicrobial prophylaxis and bacterial keratitis. There exists a plethora of data to support the use of various liquid vehicles to compound vancomycin hydrochloride eye drops. However, there are a number of limitations for implementation, especially the frequent shortage or discontinuation of the vehicle products. This study was designed to investigate the use of an OTC eye wash product as the evergreen vehicle and to evaluate the physical and chemical stability of the new formulation. The Advance Eye Relief® eye wash and vancomycin hydrochloride for injection vials were used to prepare 10 and 50 mg/mL vancomycin eye drop solutions. The solutions were packaged in Steri-Droppers® bottles and stored in a freezer for 14 days followed by 28 days in refrigeration. The 14-day period of freezing was included to allow time for sterility testing. At pre-determined stability time points, samples were taken for visual inspection, pH and osmolality measurement, and analysis by a stability-indicating high performance liquid chromatography (HPLC) method. Freshly prepared vancomycin eye drops were clear, colorless, and free of particulates. The pH readings were 7.03 and 6.28 for the 10 and 50 mg/mL solutions, respectively. The osmolality of both solutions were within the range of 300-330 mOsmol/kg and considered isotonic. Initial drug concentrations of all samples were confirmed by HPLC to be within 100%-103% of the label claims. Throughout the stability study period, there were no significant changes in the appearance, pH, or osmolality of any samples. The HPLC results also confirmed that the drug concentrations in all stability samples were within 98%-101% of the initial time zero values and no significant degradation product peaks were observed. A new compounded vancomycin eye drop formulation was developed to mitigate vehicle sourcing issues. This eye drop formulation was easy to prepare, exhibited satisfactory properties for ophthalmic applications, and remained stable chemically and physically when stored for 14 days in freezer followed by 28 days in refrigerator.

Graphene Oxide Increases Corneal Permeation of Ciprofloxacin Hydrochloride from Oleogels: A Study with Cocoa Butter-Based Oleogels.

In this work, oleogels of cocoa butter (CB), rice bran oil (RBO), and graphene oxide (GO) were prepared. The prepared oleogels were subjected to various characterization techniques such as bright-field microscopy, X-ray diffraction (XRD), crystallization kinetics, differential scanning calorimetry (DSC), and mechanical studies. The influence of increasing GO content on the in vitro drug release and ex vivo corneal permeation of the model drug (ciprofloxacin HCl—CPH) from the oleogels was also investigated. Bright-field micrographs showed that increment in GO content reduced the size of the globular particles of CB. XRD analysis revealed that CB was crystallized in its β’ and β polymorphic forms in the oleogels, which was in agreement with thermal studies. The mechanical characterization demonstrated that the presence of GO improved the elastic nature and stress-bearing properties of the oleogels. Moreover, GO altered the crystallization kinetics of CB in the oleogels in a composition-dependent manner. The in vitro release of CPH from the oleogels occurred through either Fickian diffusion or fat network relaxation or a combination thereof. Furthermore, the inclusion of GO enhanced the ex vivo permeation of CPH molecules across the caprine cornea. Hence, we concluded that the prepared oleogels could be explored as potential delivery systems for ophthalmic applications.

Study on ITO Fresnel Pattern Liquid Crystal Lens

Everyone is getting old and the presbyopia arise. Conventional presbyopia correction lenses include convex lenses and progressive lenses, each of which has advantages and disadvantages. The convex lens is a short focal length lens, which has the advantage of being able to see immediately when looking at the close, but has the disadvantage that the lens is thick, heavy, and the glasses have to be removed when looking at the distance. Progressive Lens is a multifocal lens that can focus from near to far. It is relatively thin compared to convex lenses, but requires an adaptation period of about 1 to 2 months. To solve this problem, we developed light, thin, and variable refractive index ITO Fresnel pattern lenses using liquid crystals.[1] ITO Fresnel patterns were formed by photo lithography, and the voltages were applied differently for each pattern to drive the liquid crystals, and the focal length was changed as the applied voltage changed. The diopter (D) of the lens has changed over 9V, and showed the maximum diopter of 1 at 13V.[1] Li, Guoqiang, et al. "Switchable electro-optic diffractive lens with high efficiency for ophthalmic applications." Proceedings of the National Academy of Sciences 103 (16), pp.6100-6104 (2006)

Electro-optic diffractive multifocal lens with electrically reconfigurable multifocal planes

Despite the recent advances in correcting complex vision problems using the progressive addition lens, the narrow field of view of the lens often causes visual discomforts including dizziness and headache. The electro-optic lens technologies have shown promising potential for ophthalmic applications, but additional systems are needed to enable the time-multiplex switching of the focal power among multiple foci. Here, we demonstrate the electro-optic diffractive multifocal lens that provides multiple focal planes simultaneously by distributing the light pass through the lens to the zeroth and first-order diffraction focal planes of two LC diffractive lenses. The proposed LC diffractive lens offers six combinations of bifocal planes, nine combinations of trifocal planes, and 12 combinations of quadfocal planes that are electrically switchable without compromising the field of view when combined with a refractive lens such as a human crystalline lens. The diffractive multifocal lens technology shows promising potential for correcting ophthalmic vision problems as well as mitigating the vergence-accommodation conflict in augmented and virtual reality displays.

Nanotechnology for the Treatment of Allergic Conjunctival Diseases.

Allergic conjunctivitis is one of the most common external eye diseases and the prevalence has been increasing. The mainstay of treatment is topical eye drops. However, low bioavailability, low ocular drug penetration, transient resident time on the ocular surface due to tear turnover, frequent topical applications and dependence on patient compliance, are the main drawbacks associated with topical administration. Nanotechnology-based medicine has emerged to circumvent these limitations, by encapsulating the drugs and preventing them from degradation and therefore providing sustained and controlled release. Using a nanotechnology-based approach to load the drug is particularly useful for the delivery of hydrophobic drugs such as immunomodulatory agents, which are commonly used in allergic conjunctival diseases. In this review, different nanotechnology-based drug delivery systems, including nanoemulsions, liposomes, nanomicelles, nanosuspension, polymeric and lipid nanoparticles, and their potential ophthalmic applications, as well as advantages and disadvantages, are discussed. We also summarize the results of present studies on the loading of immunomodulators or nonsteroidal anti-inflammatory drugs to nano-scaled drug delivery systems. For future potential clinical use, research should focus on the optimization of drug delivery designs that provide adequate and effective doses with safe and satisfactory pharmacokinetic and pharmaco-toxic profiles.

Development and evaluation of doxycycline niosomal thermoresponsive in situ gel for ophthalmic delivery.

The present study was focused on the development of doxycycline niosomal thermosensitive in situ gel for ophthalmic application. For this purpose, in situ gel formulations based on Poloxamer 407 alone and in combination with hydroxypropyl methylcellulose were prepared by cold method and evaluated in terms of sol-gel transition temperature, gelling time and capacity. The addition of hydroxypropyl methylcellulose to the composition led to decrease in the phase transition temperature of the systems. Conversely, the inclusion of doxycycline niosomes to the formulations didn''t have a significant influence on their gelling and rheological properties. Doxycycline niosomal in situ gel based on 15%w/w Poloxamer and 1.5% w/w hydroxypropyl methylcellulose was characterized with gelation temperature of 34°C, appropriate for ophthalmic application, pseudoplastic flow behavior and very good physical stability. In vitro release studies indicated slower and sustained doxycycline release from the developed in situ gel as compared to niosomes. The conducted microbiological studies revealed its enhanced antibacterial activity with respect to doxycycline solution and doxycycline in situ gel. The obtained results indicate that the elaborated niosomal in situ gel may serve as a promising system for ophthalmic delivery of doxycycline, ensuring sufficient therapeutic concentration and sustained drug release.

Nanopharmaceuticals for Eye Administration: Sterilization, Depyrogenation and Clinical Applications.

Simple SummaryNanopharmaceuticals have revolutionized the way ophthalmic drugs are administered to overcome ocular delivery barriers and improve drug bioavailability. The design and production of an efficient ocular drug delivery system still remain a challenge. In this review, we discuss the sterilization and depyrogenation methods, commonly used for ophthalmic nanopharmaceuticals, and their clinical applications.As an immune-privileged target organ, the eyes have important superficial and internal barriers, protecting them from physical and chemical damage from exogenous and/or endogenous origins that would cause injury to visual acuity or even vision loss. These anatomic, physiological and histologic barriers are thus a challenge for drug access and entry into the eye. Novel therapeutic concepts are highly desirable for eye treatment. The design of an efficient ocular drug delivery system still remains a challenge. Although nanotechnology may offer the ability to detect and treat eye diseases, successful treatment approaches are still in demand. The growing interest in nanopharmaceuticals offers the opportunity to improve ophthalmic treatments. Besides their size, which needs to be critically monitored, nanopharmaceuticals for ophthalmic applications have to be produced under sterilized conditions. In this work, we have revised the different sterilization and depyrogenation methods for ophthalmic nanopharmaceuticals with their merits and drawbacks. The paper also describes clinical sterilization of drugs and the outcomes of inappropriate practices, while recent applications of nanopharmaceuticals for ocular drug delivery are also addressed.

Carbon Dots Fabrication: Ocular Imaging and Therapeutic Potential.

Vision loss is a major complication in common ocular infections and diseases such as bacterial keratitis, age-related macular degeneration (AMD) and diabetic retinopathy (DR). The prevalence of such ophthalmic diseases represents an urgent need to develop safe, effective, and long-term treatments. Current therapies are riddled with drawbacks and limitations which calls for the exploration of alternative drug delivery mechanisms. Toxicity of the inorganic metals and metal oxides used for drug delivery raise safety concerns that are alleviated with the alternate use of, a natural and organic polymer which is both biocompatible and environmentally friendly. Carbon dots (CDs) represent a great potential in novel biomedical applications due to their tunable fluorescence, biocompatibility, and ability to be conjugated with diverse therapeutic materials. There is a growing interest on the exploitation of these properties for drug delivery with enhanced bio-imaging. However, there are limited reports of CD applications for ophthalmic indications. In this review, we focus on the CD potential and the development of translational therapies for ophthalmic diseases. The current review presents better understanding of fabrication of CDs and how it may be useful in delivering anti-bacterial agents, anti-VEGF molecules as well as imaging for ophthalmic applications.

Amniotic membrane allografts maintain key biological properties post SCCO2 and lyophilization processing.

Amniotic membrane (AM) has been shown to enhance corneal wound healing due to the abundance of growth factors, cytokines, and extracellular matrix (ECM) proteins inherent to the tissue. As such, AM has garnered widespread clinical utility as a biological dressing for a number of ophthalmic and soft tissue applications. The preparation, sterilization, and storage procedures used to manufacture AM grafts are extremely important for the conservation of inherent biological components within the membrane. Current processing techniques use harsh chemicals and sterilization agents that can compromise the fundamental wound healing properties of AM. Furthermore, commercially available cryopreserved AM products require specific storage conditions (e.g., ultra-low freezers) thereby limiting their clinical availability in austere environments. Supercritical carbon dioxide (SCCO2) technology allows for the sterilization of biological tissues without the resulting degradation of integral ECM proteins and other factors often seen with current tissue sterilization processes. With this study we demonstrate that lyophilized AM, sterilized using SCCO2, maintains similar biochemical properties and biocompatibility as that of commercially available AM products requiring specialized cold storage conditions.

Particle swarm optimization for wavefront correction in ophthalmic applications

Many optical systems require the correction of the cumulative wavefront error of the system for performance optimization. In ophthalmology the wavefront error of the eye corresponds to the visual defect and can be measured up to high-order aberrations today. Lower orders of the wavefront error are usually corrected with spectacles, contact lenses or refractive surgery. In this paper we apply an optimization method called particle swarm optimization to calculate the optimal correction for visual defects based on measured high-order wavefront results. It is shown that an optimized conventional correction and in particular an extended wavefront correction including higher orders yields a better result for the visual Strehl ratio, as compared to a simple conjugate correction scheme.

Prolonged Distribution of Tranilast in the Eyes after Topical Application onto Eyelid Skin.

Tranilast, a lipophilic drug with various ophthalmic applications, was used as a model drug to establish the possibility of delivering lipophilic drugs through the eyelid skin. Pharmacokinetics and tissue distribution studies were conducted employing three application methods (topical application onto eyelid skin, eye drops, and intravenous injection in rats) to broaden the significance of delivering drugs through the eyelids. A two-compartment open model analysis was used for intravenous route while a non-compartmental evaluation was used for topical applications to estimate the pharmacokinetic parameters. Eyelid skin application, eye drops, and intravenous administration had mean residence times (MRTs) of 8.07, 1.79, and 3.25 h in the eyeball and 10.8, 1.29, and 2.97 h in the conjunctiva, correspondingly. In the eyeball, topical application of tranilast onto the eyelids corresponded to a 4.5- and 2.5-fold higher MRT compared with eye drops and intravenous administration, respectively. An 8.4- or 3.6-fold higher MRT was observed in the conjunctiva after topical application compared with eye drops or intravenous administration, respectively. This indicated a gradual penetration of tranilast into the eyeball and conjunctiva, subsequently a slow elimination from these target tissues.

Hydrogel-based ocular drug delivery systems for hydrophobic drugs

Conventional ophthalmic dosage forms such as eye drops pose a significant challenge because physiological barriers and clearance mechanisms limit ocular bioavailability. Hydrogels are promising therapeutic materials for ocular drug delivery because of their high biocompatibility and their ability to hold and release therapeutic agents. Even though they are generally associated with the delivery of hydrophilic drugs, several approaches have been developed to integrate hydrophobic ophthalmic drugs into hydrogels. Because of the limitations associated with the traditional topical eye drop delivery of hydrophobic drugs, hydrogel-based systems represent a viable alternative for controlled ocular drug delivery. This review presents an overview on the ophthalmic applications of hydrogels for the delivery of hydrophobic drugs, with special focus on diseases occurring in the anterior segment of the eye. We summarize the key hydrogels for incorporation and delivery of hydrophobic drugs, including soft contact lenses (SCLs), stimuli-responsive hydrogels, cyclodextrin-based polymeric hydrogels, and nanoparticle-loaded hydrogels. The strategies of integrating hydrophobic drugs into hydrogels as discussed in this review provide significant potential in ocular therapeutics.