Treatment Of Various Ocular Diseases Research Articles

Wearable smart contact lenses: A critical comparison of three physiological signals outputs for health monitoring

Smart contact lenses (SCLs) have been considered as novel wearable devices for out-of-hospital and self-monitoring applications. They are capable of non-invasively and continuously monitoring physiological signals in the eyes, including vital biophysical (e.g., intraocular of pressure, temperature, and electrophysiological signal) and biochemical signals (e.g., pH, glucose, protein, nitrite, lactic acid, and ions). Recent progress mainly focuses on the rational design of wearable SCLs for physiological signal monitoring, while also facilitating the treatment of various ocular diseases. It covers contact lens materials, fabrication technologies, and integration methods. We also highlight and discuss a critical comparison of SCLs with electrical, microfluidic, and optical signal outputs in health monitoring. Their advantages and disadvantages could help researchers to make decisions when developing SCLs with desired properties for physiological signal monitoring. These unique capabilities make SCLs promising diagnostic and therapeutic tools. Despite the extensive research in SCLs, new technologies are still in their early stages of development and there are a few challenges to be addressed before these SCLs technologies can be successfully commercialized particularly in the form of rigorous clinical trials.

Rapidly Dissolving Trans-scleral Microneedles for Intraocular Delivery of Cyclosporine A

Cyclosporine A (CsA) is a cyclic peptide immunosuppressant drug that is beneficial in the treatment of various ocular diseases. However, its ocular bioavailability in the posterior eye is limited due to its poor aqueous solubility. Conventional CsA formulations such as a solution or emulsion permeate poorly across the eye due to various static and dynamic barriers of the eye. Dissolvable microneedle (MN)-based patches can be used to overcome barrier properties and, thus, enhance the ocular bioavailability of CsA in the posterior eye. CsA-loaded dissolvable MN patches were fabricated using polyvinylpyrrolidone (PVP) and characterized for MN uniformity and sharpness using SEM. Further characterization for its failure force, penetration force, and depth of penetration were analyzed using a texture analyzer. Finally, the dissolution time, ex vivo permeation, and ocular distribution of cyclosporine were determined in isolated porcine eyes. PVP MNs were sharp, uniform with good mechanical properties, and dissolved within 5 min. Ocular distribution of CsA in a whole porcine eye perfusion model showed a significant increase of CsA levels in various posterior segment ocular tissues as compared to a topically applied ophthalmic emulsion (Restasis®) (P < 0.001). Dissolving MNs of CsA were prepared, and the MN arrays can deliver CsA to the back of the eye offering potential for treating various inflammatory diseases.

Counteracting Data Bias and Class Imbalance-Towards a Useful and Reliable Retinal Disease Recognition System.

Multiple studies presented satisfactory performances for the treatment of various ocular diseases. To date, there has been no study that describes a multiclass model, medically accurate, and trained on large diverse dataset. No study has addressed a class imbalance problem in one giant dataset originating from multiple large diverse eye fundus image collections. To ensure a real-life clinical environment and mitigate the problem of biased medical image data, 22 publicly available datasets were merged. To secure medical validity only Diabetic Retinopathy (DR), Age-Related Macular Degeneration (AMD) and Glaucoma (GL) were included. The state-of-the-art models ConvNext, RegNet and ResNet were utilized. In the resulting dataset, there were 86,415 normal, 3787 GL, 632 AMD and 34,379 DR fundus images. ConvNextTiny achieved the best results in terms of recognizing most of the examined eye diseases with the most metrics. The overall accuracy was 80.46 ± 1.48. Specific accuracy values were: 80.01 ± 1.10 for normal eye fundus, 97.20 ± 0.66 for GL, 98.14 ± 0.31 for AMD, 80.66 ± 1.27 for DR. A suitable screening model for the most prevalent retinal diseases in ageing societies was designed. The model was developed on a diverse, combined large dataset which made the obtained results less biased and more generalizable.

Designing and making an open source, 3D-printed, punctal plug with drug delivery system.

With the advancement in the study of keratoconjunctivitis sicca and the scope of its treatment, punctal plugs are being widely used for the therapeutic management of dry eye disease. With the emergence of 3D printing in medicine, 3D printing of punctal plugs that have an inbuilt drug delivery system and also that can be personalized from patient to patient according to their punctum size can be a great therapeutic option. Another benefit of the device is that its printing takes a short period of time and is cost-effective. This study aimed at making an open source design and 3D printing an efficient model of a punctal plug with an inbuilt drug delivery system that can be eventually used for the treatment of various ocular diseases that require frequent drug instillation or blockage of the nasolacrimal pathway. The 3D design for the punctal plug was made using the open source application, FreeCAD, and slicing was done using the application ChituBox. After that, the plugs were printed using the LCD printer Crealty LD-002R. The material used was resin that was compatible with the Crealty LD-002R. Punctal plugs with satisfactory results were printed using the LCD printer. The punctal plugs showed suitable structure and were also easily reproduced in the 3D printer without any complications or setbacks.

AAV for Gene Therapy in Ocular Diseases: Progress and Prospects.

Owing to the promising therapeutic effect and one-time treatment advantage, gene therapy may completely change the management of eye diseases, especially retinal diseases. Adeno-associated virus (AAV) is considered one of the most promising viral gene delivery tools because it can infect various types of tissues and is considered as a relatively safe gene delivery vector. The eye is one of the most popular organs for gene therapy, since its limited volume is suitable for small doses of AAV stably transduction. Recently, an increasing number of clinical trials of AAV-mediated gene therapy are underway. This review summarizes the biological functions of AAV and its application in the treatment of various ocular diseases, as well as the characteristics of different AAV delivery routes in clinical applications. Here, the latest research progresses in AAV-mediated gene editing and silencing strategies to modify that the genetic ocular diseases are systematically outlined, especially by base editing and prime editing. We discuss the progress of AAV in ocular optogenetic therapy. We also summarize the application of AAV-mediated gene therapy in animal models and the difficulties in its clinical transformation.

Effectiveness of 3 MHz ultrasound in ex vivo scleral delivery of macromolecules of different sizes

Therapeutic ultrasound offers a novel approach for enhancing scleral delivery of macromolecules for treatment of various ocular diseases. Our previous in vitro diffusion cell studies showed that 3 MHz ultrasound could enhance scleral delivery of Avastin (MW: 149 kDa). We tested similar ultrasound parameters in an ex vivo whole eye rabbit model by using fluorescently labeled FITC-dextran of various sizes (40, 70, and 150 kDa) to mimic the sizes of the current macromolecules drugs for treatment of retinopathies. 3 MHz ultrasound was applied for 5 min on the sclera of the eye submersed in a macromolecule solution, and then the eyes were left in the solution for another 55 min while in the 34.6 °C water bath. Ultrasound was not turned on for the sham-treated group. Temperature modeling was performed to assess the safety of 5-min ultrasound application in the eye. The fluorescence intensity values of FITC-150 group were statistically different (p &amp;lt; 0.05) between the ultrasound-treated (1809.4, n = 8) and their sham-treated group (1185.8, n = 8). However, the FITC-70 and -50 groups lacked any appreciable difference between their ultrasound-treated (1313.6, n = 8) and (1646.3, n = 6), and their sham-treated groups (1431, n = 8) and (1121.8, n = 6), respectively. Thermal simulations demonstrated a temperature rise of 4.6 °C, while experimentally the maximum temperatures was 4.4 °C.

Deliver protein across bio-barriers via hexa-histidine metal assemblies for therapy: a case in corneal neovascularization model.

Because of their high specificity and low side effects, protein drugs possess a substantial global market. However, the low bioavailability of protein is still a major obstacle to their expanded applications, which is expected to be answered with proper protein formulations. Taking corneal neovascularization (CNV) as an example, we demonstrated a co-assembled system of hexa-histidine and Ava (Avastin) with metal ions (HmA@Ava) could cross the cornea, the most important bio-barrier during the treatment of most diseases of the anterior segment in clinics. We found that the nanosized HmA@Ava efficiently encapsulated Ava with impressive loading capacity without destroying the bioactivity of Ava and assisted Ava penetration through the corneal barriers to effectively inhibit CNV development in an alkali burn rat model with sustained and pH-dependent Ava release. Our results suggested that the co-assembled strategy of protein and HmA is a proper formulation to protein drugs, with promising penetration ability to deliver protein across bio-barriers, which could open a path for topical administration of protein drugs for treatment of various ocular diseases and hold enormous potential for delivery of therapeutic proteins not only for ocular diseases but also for other diseases that require protein treatment.

Contact Lenses as Ophthalmic Drug Delivery Systems: A Review.

Ophthalmic drugs used for the treatment of various ocular diseases are commonly administered by eye drops. However, due to anatomical and physiological factors, there is a low bioavailability of the active principle. In order to increase the drug residence time on the cornea to adequate levels, therapeutic contact lenses have recently been proposed. The polymeric support that constitutes the contact lens is loaded with the drug; in this way, there is a direct and effective pharmacological action on the target organ, promoting a prolonged release of the active principle. The incorporation of ophthalmic drugs into contact lenses can be performed by different techniques; nowadays, the soaking method is mainly employed. To improve the therapeutic performance of drug-loaded contact lenses, innovative methods have recently been proposed, including the impregnation with supercritical carbon dioxide. This updated review of therapeutic contact lenses production and application provides useful information on the most effective preparation methodologies, recent achievements and future perspectives.

Anterior lens capsule: biomechanical properties and biomedical engineering perspectives.

Anterior lens capsule, as the thickest basement membrane in the body, has its unique physiology characteristics. In ophthalmology, many attempts have been made to culture different kinds of cells including iris pigment epithelial cells, retinal pigment epithelial cells, corneal epithelium and endothelium cells, trabecular meshwork cells etc and anterior lens capsule has been confirmed to be served as an excellent scaffold for the growth and expansion of different ocular cells. Furthermore, anterior lens capsule also has unique potential in gestation evaluation and the treatment of various ocular diseases, including corneal ulcer, glaucoma, age-related macular degeneration and macular hole, etc. Here, we provide an overview of the biomechanical properties and biomedical engineering perspectives of anterior lens capsule.

Regulation of the Ocular Cell/Tissue Response by Implantable Biomaterials and Drug Delivery Systems.

Therapeutic advancements in the treatment of various ocular diseases is often linked to the development of efficient drug delivery systems (DDSs), which would allow a sustained release while maintaining therapeutic drug levels in the target tissues. In this way, ocular tissue/cell response can be properly modulated and designed in order to produce a therapeutic effect. An ideal ocular DDS should encapsulate and release the appropriate drug concentration to the target tissue (therapeutic but non-toxic level) while preserving drug functionality. Furthermore, a constant release is usually preferred, keeping the initial burst to a minimum. Different materials are used, modified, and combined in order to achieve a sustained drug release in both the anterior and posterior segments of the eye. After giving a picture of the different strategies adopted for ocular drug release, this review article provides an overview of the biomaterials that are used as drug carriers in the eye, including micro- and nanospheres, liposomes, hydrogels, and multi-material implants; the advantages and limitations of these DDSs are discussed in reference to the major ocular applications.

Umbilical Cord Blood and Serum for the Treatment of Ocular Diseases: A Comprehensive Review.

Several blood derivatives have been proposed for the treatment of various ocular diseases that affect either the anterior or the posterior segment of the eye. Blood sources may range from the patient’s own peripheral blood (autologous) to donor tissues, mainly allogeneic peripheral blood and umbilical cord blood (UCB). The utilization of the latter permits the collection of a large amount of serum all at once, and is characterized by therapeutic feasibility in patients with a poor general condition or anemia and blood dyscrasia. Products derived from UCB have two potential uses. First, serum in the form of eye drops can be applied topically onto the ocular surface to efficiently treat anterior segment disorders such as dry eye syndrome or corneal epithelial defects with different etiologies. The rationale for and efficacy of this application derive from the high concentrations of biologically active components and growth factors in UCB, which can nourish the ocular surface. Second, UCB is a source of stem cells, which are used in the field of regenerative medicine because they differentiate into various mature cells, including corneal and retinal cells. Therefore, UCB-derived stem cells have been proposed as a replacement therapy for the treatment of retinal and optic nerve diseases, given that current standard treatments often fail. The present review explores the clinical results that have been obtained using UCB-derived products in the field of ophthalmology, as well as the current limitations of those products in this field. Furthermore, given the promising development of UCB-based therapies, possible future directions in this area are discussed.

Fabrication and Characterization of Ocular Phase Transition Systems for Blepharitis: A Novel Approach

Introduction: In the present research, erythromycin estolate loaded in-situ gel was formulated and evaluated for blepharitis in order to improve its therapeutic efficacy, precorneal residence time of the system and to enhance the ocular bioavailability. Material and Methods: The developed formulation was characterized by several parameters viz. FTIR, clarity, pH, gelation temperature, rheological studies, drug content, in vitro drug release studies, transcorneal permeation studies, bioadhesion studies, isotonicity and stability studies. Results: The optimized formulation exhibited non-fickian release diffusion with a sustained release of drug 82.76 ± 0.94% up to 8h and drug content 93.64%. Isotonicity revealed that the formulation was isotonic in nature and there was no shrinkage and busting of cells. Bioadhesion study was performed to check the adherence of the prepared in situ gel to the corneal surface for 4h. Ex vivo transcorneal permeation was observed to be significantly higher when compared with market eye drops. Histopathological studies were conducted to confirm the presence of normal ocular surface tissues by maintaining their morphological structures without causing damage to the tissues. The formulation was nonirritant as confirmed by the HET-CAM test. Stability studies and accelerated stability studies were conducted for 13 weeks and 26 weeks respectively and formulations were analyzed for the visual appearance, pH, viscosity, gelling capacity, drug content and in vitro drug release and results showed no change in the formulations. Conclusion: The formulation was therapeutically efficacious, sterile, stable and provided controlled release over a period of time. The developed system could be a viable alternative to conventional eye drops for treatment of various ocular diseases.

Effects of intravitreal bevacizumab injection on the clinical manifestations of nonproliferative diabetic retinopathy in patients with macular edema: a systematic review

Introduction: Bevacizumab (Avastin) is considered as an effective strategy in the treatment of various ocular diseases. As a vascular endothelial growth factor (VEGF) inhibitor, Avastin is used to control macular edema in patients with nonproliferative diabetic retinopathy (NPDR). Therefore, in this study, we systematically reviewed the effects of intravitreal bevacizumab injections on nonproliferative stage of diabetic retinopathy. Methods: Scopus and PubMed were systematically searched to find articles in which the effect of Avastin (bevacizumab) had been evaluated in nonproliferative stage of diabetic retinopathy. Literature search was performed using “Avastin OR bevacizumab”, “nonproliferative stage” and “diabetic retinopathy” as keyterms in the title, keywords, and abstract.Result: All 47 articles were found in all databases, two additional records were found through reference list screening, and only 10 articles were relevant to the purpose of this study. According to the inclusion/exclusion criteria, 39 articles were excluded in several step processes of article selection. The results revealed that intravitreal injection of bevacizumab could be safely used to treat various ocular disease, particularly NPDR stage of diabetic retinopathy with macular edema.Discussion: Bevacizumab is considered as a novel and effective modality in the treatment of various ocular diseases such as retinal neovascularization, neovascular glaucoma, macular edema, and other ocular complications. Findings also suggested that bevacizumab is a suitable therapeutic approach in clinical use.Conclusion: According to the results of included documents, intravitreal injection of bevacizumab could be considered as a promising treatment modality in the clinical management of NPDR stage of diabetic retinopathy.

Thermal safety of ultrasound-enhanced ocular drug delivery: A modeling study.

Delivery of sufficient amounts of therapeutic drugs into the eye for treatment of various ocular diseases is often a challenging task. Ultrasound was shown to be effective in enhancing ocular drug delivery in the authors' previous in vitro and in vivo studies. The study reported here was designed to investigate the safety of ultrasound application and its potential thermal effects in the eye using PZFlex modeling software. The safety limit in this study was set as a temperature increase of no more than 1.5 °C based on regulatory recommendations and previous experimental safety studies. Acoustic and thermal specifications of different human eye tissues were obtained from the published literature. The tissues of particular interest in this modeling safety study were cornea, lens, and the location of optic nerve in the posterior eye. Ultrasound application was modeled at frequencies of 400 kHz-1 MHz, intensities of 0.3-1 W/cm(2), and exposure duration of 5 min, which were the parameters used in the authors' previous drug delivery experiments. The baseline eye temperature was 37 °C. The authors' results showed that the maximal tissue temperatures after 5 min of ultrasound application were 38, 39, 39.5, and 40 °C in the cornea, 39.5, 40, 42, and 43 °C in the center of the lens, and 37.5, 38.5, and 39 °C in the back of the eye (at the optic nerve location) at frequencies of 400, 600, 800 kHz, and 1 MHz, respectively. The ocular temperatures reached at higher frequencies were considered unsafe based on current recommendations. At a frequency of 400 kHz and intensity of 0.8 W/cm(2) (parameters shown in the authors' previous in vivo studies to be optimal for ocular drug delivery), the temperature increase was small enough to be considered safe inside different ocular tissues. However, the impact of orbital bone and tissue perfusion should be included in future modeling efforts to determine the safety of this method in the whole orbit especially regarding potential adverse optic nerve heating at the location of the bone.

Intracellular pathways following uptake of bevacizumab in RPE cells

The anti-VEGF antibody bevacizumab is widely used off-label for the treatment of various ocular diseases, most commonly in age-related macular degeneration and diabetic macular edema. Bevacizumab is able to penetrate the retina and is found in the choroid after intravitreal injection in a time dependent manner. It has previously been shown to be taken up by the retinal pigment epithelium (RPE). In this study, we have investigated the intracellular pathway following uptake of bevacizumab in RPE cells, tested both in primary porcine RPE cells and in the human cell line ARPE19. Bevacizumab displays a characteristic, time-dependent pattern of intracellular distribution, as detected by immunofluorescence and pulse chase experiments. In both primary cells and the cell line, intracellular bevacizumab can be found after seven days, as detected by immunofluorescence and Western blotting. Immediately after application, bevacizumab partially colocalizes with Rab5, indicating some uptake in early endosomes. Intracellularly, bevacizumab is detected in the cytoskeletal fraction, aligning with actin filaments, as revealed by subcellular fractioning and immunofluorescence. Bevacizumab seems to travel along actin filaments by myosin7a, as determined by triple staining immunofluorescence. Interestingly, over a period of seven days, bevacizumab seems to accumulate in certain storage areas, as observed by immunofluorescence. Furthermore, results obtained with immunocytochemistry, Western blotting and flow cytometry indicate that bevacizumab may be released from the RPE cells via exosomes. In conclusion, bevacizumab is taken up by and transported in the retinal pigment epithelial cells in a characteristic, time-dependent manner, where it seems to move along actin filaments by myosin7a and seem to be partially released from the cells via exosomes.

Noncontact depth-resolved micro-scale optical coherence elastography of the cornea.

High-resolution elastographic assessment of the cornea can greatly assist clinical diagnosis and treatment of various ocular diseases. Here, we report on the first noncontact depth-resolved micro-scale optical coherence elastography of the cornea achieved using shear wave imaging optical coherence tomography (SWI-OCT) combined with the spectral analysis of the corneal Lamb wave propagation. This imaging method relies on a focused air-puff device to load the cornea with highly-localized low-pressure short-duration air stream and applies phase-resolved OCT detection to capture the low-amplitude deformation with nano-scale sensitivity. The SWI-OCT system is used here to image the corneal Lamb wave propagation with the frame rate the same as the OCT A-line acquisition speed. Based on the spectral analysis of the corneal temporal deformation profiles, the phase velocity of the Lamb wave is obtained at different depths for the major frequency components, which shows the depthwise distribution of the corneal stiffness related to its structural features. Our pilot experiments on ex vivo rabbit eyes demonstrate the feasibility of this method in depth-resolved micro-scale elastography of the cornea. The assessment of the Lamb wave dispersion is also presented, suggesting the potential for the quantitative measurement of corneal viscoelasticity.

Herbal therapeutic strategies for diabetic retinopathy using nobiletin

Diabetes mellitus is one of the most challenging and prevalent metabolic diseases results in microvascular complications such as retinopathy, neuropathy and macrovascular complications such as heart attack, stroke and peripheral vascular diseases. Diabetic retinopathy (DR) is a major cause of blindness in diabetes which can be avoidable with good glycemic control. There are number of factors that contribute to vascular permeability and angiogenesis in DR including the oxidative damage of the retinal neuronal cells, vascular endothelial growth factor (VEGF), prostaglandins, cyclooxygenase-2 (COX-2) and nitric oxide (NO) synthase. Despite the standards of care, laser photocoagulation and pars plana vitreous surgery for DR, recent successful use of several molecules is bringing a paradigm shift in favor of pharmacotherapy. There is an increasing interest in natural products in pharmacotherapy as the chemical diversity of natural products has better matches than the diversity of synthetic compounds. Flavonoids a common group of plant polyphenols are known for their antioxidant, anti-inflammatory, anti-angiogenic activities also shown their potential in the prevention and treatment of various ocular diseases

Ritonavir inhibits HIF-1α-mediated VEGF expression in retinal pigment epithelial cells in vitro

Retinal hypoxia-mediated activation of the hypoxia-inducible factor (HIF pathway) leading to angiogenesis is a major signaling mechanism underlying a number of sight-threatening diseases. Inhibiting this signaling mechanism with an already approved therapeutic molecule may have promising anti-angiogenic role with fewer side effects. Hence, the primary objective of this study was to examine the expression of HIF-1α and VEGF in human retinal pigment epithelial cells treated with ritonavir under hypoxic and normoxic conditions. ARPE-19 and D407 cells were cultured in normoxic or hypoxic conditions, alone or in the presence of ritonavir. Quantitative real-time polymerase chain reaction, immunoblot analysis, sandwich ELISA, endothelial cell proliferation, and cytotoxicity were performed. A 12-h hypoxic exposure resulted in elevated mRNA expression levels of both HIF-1α and VEGF in ARPE-19 and D407 cells. Hence, this time point was selected for subsequent experiments. Presence of ritonavir in the culture medium strongly inhibited VEGF expression in a concentration-dependent manner under hypoxic conditions. Immunoblot analysis demonstrated a substantially reduced protein expression of HIF-1α in the presence of ritonavir. Further, hypoxic exposure-induced VEGF secretion was also inhibited by ritonavir, as demonstrated using ELISA. Finally, ritonavir significantly diminished the proliferation of choroid-retinal endothelial (RF/6A) cells demonstrating potential anti-angiogenic activity. Cytotoxicity studies showed that ritonavir is non-toxic to RPE cells. This study demonstrates for the first time that ritonavir can inhibit HIF-1α and VEGF in ARPE-19 and D407 cells. Such inhibition may form a platform for application of ritonavir in the treatment of various ocular diseases.

Ion- and pH-activated novel in-situ gel system for sustained ocular drug delivery

Poor bioavailability (<1%) of drugs from conventional eye drops is mainly due to the various precorneal loss factors which include rapid tear turnover, systemic drug absorption through naso-lachrymal duct, transient residence time of the drug solution in the cul-de-sac and the relative impermeability of the drugs to corneal epithelial membrane. The present study describes the formulation and evaluation of chitosan and gellan gum based novel in-situ gel system activated by dual physiological mechanisms. Chitosan (a pH-sensitive polymer) in combination with gellan gum (an ion-activated polymer) were used as gelling agent. Timolol maleate, the drug which is frequently used for glaucoma therapy was used as model drug to check the efficacy of the formulation. The developed formulation was characterized for various in vitro parameters, for example, clarity, gelation pH, isotonicity, sterility, viscosity, transcorneal permeation profile, and ocular irritation. Ocular retention was studied by gamma scintigraphy and a significant increase in retention time was observed. The formulation was also found to be nonirritant and well tolerable. The developed system can be a viable alternative to conventional eye drops for the treatment of various ocular diseases and is suitable for clinical application.

Formulation, characterization and testing of tetracaine hydrochloride-loaded albumin-chitosan microparticles for ocular drug delivery

Most ocular surgical procedures take ∼60 min to complete, the anaesthetic property of the safest drug, tetracaine, is initiated in a few minutes and lasts ∼10–15 min. The purpose of the present study was to develop an ocular tetracaine formulation which can produce an immediate onset of action and/or longer duration of action during the entire surgical procedure. Tetracaine-loaded microparticle formulation was prepared by the method of spray-drying and characterized in terms of size, zeta potential, morphology, thermal stability and release pattern. The study reports a microparticulate ocular formulation with minimum cytotoxicity and optimum cellular uptake. In addition, microencapsulated tetracaine was found to significantly increase the duration of action of the drug up to 4-fold. Taken together, the results presented in this work described albumin-chitosan microparticles to be an effective delivery platform for ocular anaesthetic agents and a potential treatment of various ocular diseases.