Therapy For Ocular Diseases Research Articles

Exploring Hydrogel Nanoparticle Systems for Enhanced Ocular Drug Delivery.

Drug delivery to the ocular system is affected by anatomical factors like the corneal epithelium, blinking reflex, aqueous blood barrier, and retinal blood barrier, which lead to quick removal from the site and inefficient drug delivery. Developing a drug delivery mechanism that targets specific eye tissue is a major hurdle for researchers. Our study examines the challenges of drug absorption in these pathways. Hydrogels have been researched as a suitable delivery method to overcome some obstacles. These are developed alone or in conjunction with other technologies, such as nanoparticles. Many polymer hydrogel nanoparticle systems utilizing both natural and synthetic polymers have been created and investigated; each has pros and cons. The complex release mechanism of encapsulated agents from hydrogel nanoparticles depends on three key factors: hydrogel matrix swelling, drug-matrix chemical interactions, and drug diffusion. This mechanism exists regardless of the type of polymer. This study provides an overview of the classification of hydrogels, release mechanisms, and the role of controlled release systems in pharmaceutical applications. Additionally, it highlights the integration of nanotechnology in ocular disease therapy, focusing on different types of nanoparticles, including nanosuspensions, nanoemulsions, and pharmaceutical nanoparticles. Finally, the review discusses current commercial formulations for ocular drug delivery and recent advancements in non-invasive techniques. The objective is to present a comprehensive overview of the possibilities for enhancing ocular medication delivery through hydrogel nanoparticle systems.

Mesenchymal stem cell therapy in veterinary ophthalmology: clinical evidence and prospects.

Mesenchymal stem cell (MSC) therapy presents a promising strategy for treating various ocular conditions in veterinary medicine. This review explores the therapeutic potential of MSCs in managing corneal ulcers, immune-mediated keratitis, chronic superficial keratitis, keratoconjunctivitis sicca, retinal degeneration, and ocular burns in feline, equine, and canine patients. Studies have demonstrated the immunomodulatory and regenerative properties of MSCs, highlighting their ability to mitigate inflammation and promote tissue regeneration. Experimental studies have shown the potential of MSC therapy in reducing corneal opacity and vascularization, indicating significant therapeutic advantages. Delivery methods play a crucial role in optimizing the therapeutic efficacy of MSCs in ocular diseases. Various delivery methods, such as intravitreal injection, subconjunctival injection, topical administration, and scaffold-mediated delivery, are being explored to optimize MSC delivery to the target ocular tissues. Clinical trials have shown significant improvements in clinical signs following MSC therapy, underscoring its efficacy in treating ocular diseases. Additionally, tissue engineering approaches incorporating MSCs, growth factors, and scaffolds offer innovative strategies for corneal regeneration and tissue repair. Despite challenges such as standardization of protocols and long-term safety assessment, ongoing research endeavours seek to unlock the full therapeutic potential of MSC therapy in ocular diseases. Future prospects in MSC therapy involve exploring scaffold and hydrogel-based approaches and cell-free therapies leveraging the bioactive molecules released by MSCs. Continued research and development efforts are essential to unlock the full therapeutic potential of MSCs and realize their transformative impact on ocular diseases in veterinary patients.

Achyranthis radix Extract Enhances Antioxidant Effect of Placenta-Derived Mesenchymal Stem Cell on Injured Human Ocular Cells.

Age-related ocular diseases such as age-related macular degeneration, glaucoma, and diabetic retinopathy are major causes of irreversible vision impairment in the elderly. Conventional treatments focus on symptom relief and disease slowdown, often involving surgery, but fall short of providing a cure, leading to substantial vision loss. Regenerative medicine, particularly mesenchymal stem cells (MSCs), holds promise for ocular disease treatment. This study investigates the synergistic potential of combining placenta-derived MSCs (PD-MSCs) with Achyranthis radix extract (ARE) from Achyranthes japonica to enhance therapeutic outcomes. In a 24-h treatment, ARE significantly increased the proliferative capacity of PD-MSCs and delayed their senescence (* p < 0.05). ARE also enhanced antioxidant capabilities and increased the expression of regeneration-associated genes in an in vitro injured model using chemical damages on human retinal pigment epithelial cell line (ARPE-19) (* p < 0.05). These results suggest that ARE-primed PD-MSC have the capability to enhance the activation of genes associated with regeneration in the injured eye via increasing antioxidant properties. Taken together, these findings support the conclusion that ARE-primed PD-MSC may serve as an enhanced source for stem cell-based therapy in ocular diseases.

Enhancing Ocular Drug Delivery: The Effect of Physicochemical Properties of Nanoparticles on the Mechanism of Their Uptake by Human Cornea Epithelial Cells.

This study investigates the effect of nanoparticle size and surface chemistry on interactions of the nanoparticles with human cornea epithelial cells (HCECs). Poly(lactic-co-glycolic) acid (PLGA) nanoparticles were synthesized using the emulsion-solvent evaporation method and surface modified with mucoadhesive (alginate [ALG] and chitosan [CHS]) and mucopenetrative (polyethylene glycol [PEG]) polymers. Particles were found to be monodisperse (polydispersity index (PDI) below 0.2), spherical, and with size and zeta potential ranging from 100 to 250 nm and from -25 to +15 mV, respectively. Evaluation of cytotoxicity with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay indicated that incubating cells with nanoparticles for 24 h at concentrations up to 100 μg/mL caused only mild toxicity (70-100% cell viability). Cellular uptake studies were conducted using an in vitro model developed with a monolayer of HCECs integrated with simulated mucosal solution. Evaluation of nanoparticle uptake revealed that energy-dependent endocytosis is the primary uptake mechanism. Among the different nanoparticles studied, 100 nm PLGA NPs and PEG-PLGA-150 NPs showed the highest levels of uptake by HCECs. Additionally, uptake studies in the presence of various inhibitors suggested that macropinocytosis and caveolae-mediated endocytosis are the dominant pathways. While clathrin-mediated endocytosis was found to also be partially responsible for nanoparticle uptake, phagocytosis did not play a role within the studied ranges of size and surface chemistries. These important findings could lead to improved nanoparticle-based formulations that could improve therapies for ocular diseases.

Advancement in Nanobiotechnology for Human Health Care: Focus on Ocular Diseases and Future Prospects

Abstract: Nanotechnology involves the study of different materials on the nanometer scale, typical-ly less than 100 nm in size. Nanomedicine is the creation of nanotechnology, a new science and technology area. Similarly, various nanomaterials, such as nanostructure, nanotubes, and nanoparticles, were also found to have significant applications in the human biological system at the molecu-lar level to achieve healthcare advantage. Nanotechnology is rapidly expanding in the field of medicine with a special emphasis on ophthalmology. Nanotechnology advancements need to be translated into a new and exciting platform for diagnosis, treatment, and therapeutics for ocular disease. The application of nanotechnology in ocular disease and cancer, such as nanoparticle-based drug delivery system, drug development, gene therapy, and tissue engineering, helps overcome many oc-ular problems. In particular, one of the most important applications of the emerging nanoscience system is used in ocular cancer diagnosis and therapy with the help of carbon nanotubes, nanocrys-tals, nanowires, etc. Several approaches have been developed for treatment and therapy for ocular disease. Moreover, these tremendous approaches have been safely used and effective for a broad range of applications. In this study, the focus is to discuss recent findings and various constraints and summarize the applications of nanotechnology-mediated systems for treating various ocular diseases.

Efficacy and Safety of the Melanocortin Pan-Agonist PL9643 in a Phase 2 Study of Patients with Dry Eye Disease.

Purpose: The melanocortin receptor pan-agonist PL9643, a potential therapy for ocular diseases, was investigated in a phase 2, 12-week study in patients with dry eye disease (DED). Methods: This was a placebo-controlled study evaluating efficacy and safety of thrice-daily PL9643. Placebo (vehicle) was similar to tears. Primary endpoints were intra-patient changes in inferior corneal fluorescein staining and ocular discomfort after 12 weeks. Secondary endpoints were changes in additional DED signs or symptoms. Multiple secondary endpoints were not adjusted for multiplicity. Patients with moderate or severe DED were analyzed in addition to the overall intent-to-treat (ITT) population. Results: In the ITT population (n = 160) the PL9643 group did not demonstrate significant treatment difference versus placebo at week 12/day 85 for the primary endpoints (P > 0.05). In patients with moderate or severe DED (n = 53), PL9643 treatment demonstrated either nominally significant (P < 0.05) or trending (P < 0.1) improvement over placebo in mean change from baseline at week 12/day 85 in several sign endpoints, including fluorescein staining in inferior, superior, corneal sum, and total sum regions; Lissamine Green staining in temporal, nasal, conjunctival sum, and total sum regions; and tear film breakup time. Conjunctival redness also showed (nonsignificant) improvement at week 12/day 85. There were no drug-related adverse events (AEs) and no drug-related discontinuations. Conclusions: PL9643 showed no significant efficacy for the ITT population; however, efficacy results across several signs and symptoms in the subpopulation of moderate to severe DED patients, the low number of ocular AEs, and no tolerability issues suggest that PL9643 shows promise as a therapeutic for DED. Clinical Trial Registration number: NCT04268069.

Current Innovations in Intraocular Pressure Monitoring Biosensors for Diagnosis and Treatment of Glaucoma—Novel Strategies and Future Perspectives

Biosensors are devices that quantify biologically significant information required for diverse applications, such as disease diagnosis, food safety, drug discovery and detection of environmental pollutants. Recent advancements in microfluidics, nanotechnology and electronics have led to the development of novel implantable and wearable biosensors for the expedient monitoring of diseases such as diabetes, glaucoma and cancer. Glaucoma is an ocular disease which ranks as the second leading cause for loss of vision. It is characterized by the increase in intraocular pressure (IOP) in human eyes, which results in irreversible blindness. Currently, the reduction of IOP is the only treatment used to manage glaucoma. However, the success rate of medicines used to treat glaucoma is quite minimal due to their curbed bioavailability and reduced therapeutic efficacy. The drugs must pass through various barriers to reach the intraocular space, which in turn serves as a major challenge in glaucoma treatment. Rapid progress has been observed in nano-drug delivery systems for the early diagnosis and prompt therapy of ocular diseases. This review gives a deep insight into the current advancements in the field of nanotechnology for detecting and treating glaucoma, as well as for the continuous monitoring of IOP. Various nanotechnology-based achievements, such as nanoparticle/nanofiber-based contact lenses and biosensors that can efficiently monitor IOP for the efficient detection of glaucoma, are also discussed.

Non-adherence and non-persistence to intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy: a systematic review and meta-analysis

BackgroundIntravitreal anti-vascular endothelial growth factor (anti-VEGF) injections play a key role in treating a range of macular diseases. The effectiveness of these therapies is dependent on patients’ adherence (the extent to which a patient takes their medicines as per agreed recommendations from the healthcare provider) and persistence (continuation of the treatment for the prescribed duration) to their prescribed treatment regimens. The aim of this systematic review was to demonstrate the need for further investigation into the prevalence of, and factors contributing to, patient-led non-adherence and non-persistence, thus facilitating improved clinical outcomes.MethodsSystematic searches were conducted in Google Scholar, Web of Science, PubMed, MEDLINE, and the Cochrane Library. Studies in English conducted before February 2023 that reported the level of, and/or barriers to, non-adherence or non-persistence to intravitreal anti-VEGF ocular disease therapy were included. Duplicate papers, literature reviews, expert opinion articles, case studies, and case series were excluded following screening by two independent authors.ResultsData from a total of 409,215 patients across 52 studies were analysed. Treatment regimens included pro re nata, monthly and treat-and-extend protocols; study durations ranged from 4 months to 8 years. Of the 52 studies, 22 included a breakdown of reasons for patient non-adherence/non-persistence. Patient-led non-adherence varied between 17.5 and 35.0% depending on the definition used. Overall pooled prevalence of patient-led treatment non-persistence was 30.0% (P = 0.000). Reasons for non-adherence/non-persistence included dissatisfaction with treatment results (29.9%), financial burden (19%), older age/comorbidities (15.5%), difficulty booking appointments (8.5%), travel distance/social isolation (7.9%), lack of time (5.8%), satisfaction with the perceived improvement in their condition (4.4%), fear of injection (4.0%), loss of motivation (4.0%), apathy towards eyesight (2.5%), dissatisfaction with facilities 2.3%, and discomfort/pain (0.3%). Three studies found non-adherence rates between 51.6 and 68.8% during the COVID-19 pandemic, in part due to fear of exposure to COVID-19 and difficulties travelling during lockdown.DiscussionResults suggest high levels of patient-led non-adherence/non-persistence to anti-VEGF therapy, mostly due to dissatisfaction with treatment results, a combination of comorbidities, loss of motivation and the burden of travel. This study provides key information on prevalence and factors contributing to non-adherence/non-persistence in anti-VEGF treatment for macular diseases, aiding identification of at-risk individuals to improve real-world visual outcomes. Improvements in the literature can be achieved by establishing uniform definitions and standard timescales for what constitutes non-adherence/non-persistence.Systematic review registrationPROSPERO CRD42020216205.

Innovative advancement of contact lenses for noninvasive diagnosis and therapy: A mini review

AbstractWith the growth of the market and the number of wearers, contact lenses have been widely used for vision correction and cosmetic purposes for a few years. The current study opens up a new path for their applications. On the one hand, contact lenses are ideal sensing platforms due to advances in the monitoring of relevant indicators in tears such as glucose and intraocular pressure. Aside from detecting a single analyte at a time, multifunctional contact lens sensors were proposed to monitor two or more indicators at the same time. Contact lenses, on the other hand, are also suitable drug delivery platforms due to their good biocompatibility and long contact duration with the cornea. Different drug delivery approaches are being investigated to increase drug duration and bioavailability. In addition, the integration of these novel drug delivery methods into wearable sensors has become a topic for a complete closed‐loop program for disease management. We began this review by summarizing the categories and properties of current contact lenses. Then, innovative applications of contact lenses such as biosensors and drug delivery systems were also summarized. In general, the current progress in the applications of contact lenses provides a new possibility for noninvasive diagnosis and therapy of ocular diseases.

Lipid nanoparticles for gene therapy in ocular diseases.

Lipid nanoparticles, as a nucleic acid delivery system, have been used as an alternative to treat ocular diseases, since they can cross the ocular barrier and efficiently transfecting nucleic acids to various cells of the eye. The size influences the transfection of genes, biological distribution, diffusion, and cellular uptake. It is therefore important to establish a relationship between size, formulation, and encapsulation percentage. In this review, we used a search strategy to compare studies of nanomedicine systems aimed at eye diseases where the size of the nanoparticles and the efficiency of encapsulation of genetic material are reported based on the criteria of Preferred Reporting Items for Systematic Reviews (PRISMA ScR 2020 guidelines). Out of the initial 5932, 169 studies met the inclusion criteria and were included to form the basis of the analysis. Nanoparticles reported are composed mainly of PEG-modified lipids, cholesterol, and cationic lipids, that in combination with messenger or interference RNA, allow the formulation of a nanoparticle with an encapsulation efficiency greater than 95%. The diseases treated mainly focus on conditions related to the retina and cornea. Certain characteristics of nanoparticles increase encapsulation efficiency, such as the size of the nanoparticle and the charge of the outer layer of the nanoparticle. It is still unknown what characteristics lipid nanoparticles should have to successfully treat human eye illnesses. The in vitro and in vivo investigations covered in this review, however, present encouraging results. To improve encapsulation effectiveness and disease gene silencing, nanoparticle formulation is essential. The most stable nanoparticles are those made mostly of cationic lipids, PEG lipids, and cholesterol, which also effectively encapsulate RNA. The encapsulation efficiency is not only influenced by size, but also by other factors such as methods of preparation.

Antiangiogenic therapy for ocular diseases: Current status and challenges

AbstractAngiogenesis is the process of new blood vessel growth from pre‐existing ones involving vascular endothelial cell activation, proliferation, migration, and tube formation. The vascular endothelial growth factor A (VEGF‐A) is known to be a key factor that promotes angiogenesis. Pathological angiogenesis is a key and common feature of numerous ocular neovascular diseases, such as wet age‐related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, and corneal neovascularization. Although anti‐VEGF treatment has been a great success for the treatment of such ocular neovascular diseases, many challenges exist, such as limited efficacy, unresponsiveness in many patients, drug resistance, treatment burden due to repeated intravitreous injection, all of which incent much effort and enthusiasm to find new and better treatment for ocular neovascular diseases. In recent years, new antiangiogenic drug, targets and drug delivery methods have been developed. This perspective discusses the status of currently available therapies, challenges, opportunities, and potential new directions toward better therapies for ocular neovascular diseases.

Systemic Outcomes of Intravitreal Injections of Dexamethasone and Anti-Vascular Endothelial Growth Factor.

Intravitreal dexamethasone and anti-vascular endothelial growth factor (anti-VEGF) medications have revolutionized ocular disease management and favorable ocular safety profiles, but few studies have compared their systemic adverse events (SAEs). This study investigated the SAEs of intravitreal dexamethasone and anti-VEGFs by using real-world data. This retrospective cohort study sourced medical records from the largest multi-institutional database in Taiwan. Patients who received intravitreal dexamethasone (n = 137) or anti-VEGFs (n = 10,345) between 2014 and 2019 were enrolled. Propensity score matching was performed to achieve homogeneity between the two groups. Subdistribution hazard ratios (SHRs) and 95% confidence intervals (CIs) were calculated using the Fine-Gray model. Systemic as well as ocular clinical events and systemic biomarkers after 1-year follow-up were compared. Both groups demonstrated comparable risks of major cardiac adverse events (SHR 1.57, 95% CI 0.29-8.55), heart failure (SHR 0.62, 95% CI 0.07-5.33), major bleeding (SHR 0.23, 95% CI 0.03-1.77), all-cause admission (SHR 0.73, 95% CI 0.41-1.30), and all-cause death (SHR 2.11, 95% CI 0.35-12.71). There were no significant differences in longitudinal changes in systolic and diastolic blood pressure, glycated hemoglobin, low-density lipoprotein, estimated glomerular filtration rate, or alanine aminotransferase between the groups. Both groups had a similar incidence of cataract surgery. Although the dexamethasone group exhibited a relatively high prevalence of antiglaucomatous medication use, there was not a significantly higher incidence of glaucoma surgery. Intravitreal dexamethasone and anti-VEGF medications had comparable systemic safety profiles in our study. Both drugs represent efficacious and safe therapies for ocular diseases.

Possibilities and prospects for antioxidant therapy in ocular diseases

The eye is particularly vulnerable to oxidative stress due to its constant exposure to atmospheric oxygen, sunlight, ultraviolet and ionizing radiation, chemicals, pollutants, and microorganisms that may shift the physiological balance towards oxidation. Today, oxidative stress is considered a major pathogenetic feature of a wide spectrum of ocular conditions including diseases of the lens (cataract), anterior chamber (glaucoma), cornea (keratoconus, traumatic injuries, post-operative conditions), eye surface (pterygium, dry eye syndrome), retina (uveitis, retinopathies), and optic nerve (optic neuropathies, glaucoma). Potential strategies for pathogenetic therapy in conditions, associated with oxidative stress, include direct inhibition of lipid peroxidation, induction of Nrf2 transcription factor signaling, repression and sequestration of vascular endothelial growth factor (VEGF), and the use of agents with direct antioxidant effect. Methylethylpyridinol or 3-oxy-6-methyl-2-ethylpyridine hydrochloride, a potent free radical scavenger, is often regarded as a major antioxidant agent for ophthalmological purposes. Methylethylpyridinol is characterized by a possibility of being used in different types of dosage forms. In ophthalmology, it is given by injection, as well as by instillation in the form of eye drops. Methylethylpyridinol can be used for the treatment and prevention of inflammation and burn injuries of the cornea, hemorrhages into the anterior chamber of the eye and into the sclera, thrombosis of the central retinal vein and its branches, diabetic retinopathy and complications in myopia, as well as for the protection of the cornea when exposed to high intensity light and wearing contact lenses. This paper reviews the main features of oxidative stress as the leading pathogenetic factor in ocular diseases, and the possibilities of antioxidant therapy using methylethylpyridinol.

Optimisation of AAV-NDI1 Significantly Enhances Its Therapeutic Value for Correcting Retinal Mitochondrial Dysfunction

AAV gene therapy for ocular disease has become a reality with the market authorisation of LuxturnaTM for RPE65-linked inherited retinal degenerations and many AAV gene therapies currently undergoing phase III clinical trials. Many ocular disorders have a mitochondrial involvement from primary mitochondrial disorders such as Leber hereditary optic neuropathy (LHON), predominantly due to mutations in genes encoding subunits of complex I, to Mendelian and multifactorial ocular conditions such as dominant optic atrophy, glaucoma and age-related macular degeneration. In this study, we have optimised the nuclear yeast gene, NADH-quinone oxidoreductase (NDI1), which encodes a single subunit complex I equivalent, creating a candidate gene therapy to improve mitochondrial function, independent of the genetic mutation driving disease. Optimisation of NDI1 (ophNdi1) substantially increased expression in vivo, protected RGCs and increased visual function, as assessed by optokinetic and photonegative response, in a rotenone-induced murine model. In addition, ophNdi1 increased cellular oxidative phosphorylation and ATP production and protected cells from rotenone insult to a significantly greater extent than wild type NDI1. Significantly, ophNdi1 treatment of complex I deficient patient-derived fibroblasts increased oxygen consumption and ATP production rates, demonstrating the potential of ophNdi1 as a candidate therapy for ocular disorders where mitochondrial deficits comprise an important feature.

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.

DCZ19931, a novel multi-targeting kinase inhibitor, inhibits ocular neovascularization

Neovascularization is a prominent cause of irreversible blindness in a variety of ocular diseases. Current therapies for pathological neovascularization are concentrated on the suppression of vascular endothelial growth factors (VEGF). Despite the remarkable efficacy of anti-VEGF drugs, several problems still exist, including ocular complications and drug resistance. Thus, it is still required to design novel drugs for anti-angiogenic treatment. This study aimed to investigate the anti-angiogenic effects of a small molecule multi-target tyrosine kinase inhibitor, DCZ19931, on ocular neovascularization. The results showed that administration of DCZ19931 at the tested concentrations did not cause obvious cytotoxicity and tissue toxicity. DCZ19931 could reduce the size of choroidal neovascularization (CNV) lesions in laser-induced CNV model and suppress ocular neovascularization in oxygen-induced retinopathy (OIR) model. DCZ19931 could suppress VEGF-induced proliferation, migration, and tube formation ability of endothelial cells, exhibiting similar anti-angiogenic effects as Ranibizumab. DCZ19931 could reduce the levels of intercellular cell adhesion molecule-1 (ICAM-1) expression in vivo and in vitro. Network pharmacology prediction and western blots revealed that DCZ19931 exerted its anti-angiogenic effects through the inactivation of ERK1/2-MAPK signaling and p38-MAPK signaling. In conclusion, this study indicates that DCZ19931 is a promising drug for anti-angiogenic therapy for ocular diseases.

Neutrophil Extracellular Traps (NETs) in Ocular Diseases: An Update.

Neutrophil extracellular traps (NETs) are net-like complexes expelled from neutrophils, composing cell-free deoxyribonucleic acid (DNA), histones, and neutrophil granule proteins. Besides capturing and eliminating pathogens, NETs also exacerbate the inflammatory response associated with various diseases, including systemic lupus erythematosus, rheumatoid arthritis, and psoriasis. Currently, there are growing reports about NETs involved in the pathogenesis of ocular diseases. This review primarily focuses on the pathogenesis of NETs in the ophthalmology field, highlighting their importance in serving as potential targets for the therapy of ocular diseases.

Nanoparticles in ocular applications and their potential toxicity.

Nanotechnology has been developed rapidly in recent decades and widely applied in ocular disease therapy. Nano-drug delivery systems overcome the bottlenecks of current ophthalmic drug delivery and are characterized with strong biocompatibility, stability, efficiency, sustainability, controllability, and few side effects. Nanoparticles have been identified as a promising and generally safe ophthalmic drug-delivery system based on the toxicity assessment in animals. Previous studies have found that common nanoparticles can be toxic to the cornea, conjunctiva, and retina under certain conditions. Because of the species differences between humans and animals, advanced in vitro cell culture techniques, such as human organoids, can mimic the human organism to a certain extent, bringing nanoparticle toxicity assessment to a new stage. This review summarizes the advanced application of nanoparticles in ocular drug delivery and the potential toxicity, as well as some of the current challenges and future opportunities in nanotoxicological evaluation.

Mesenchymal stem cell-derived extracellular vesicles for cell-free therapy of ocular diseases

Mesenchymal stem cells-derived extracellular vesicles (MSC-EVs) have noticeably attracted clinicians’ attention in treating ocular diseases. As the paracrine factor of MSCs and an alternative for cell-free therapies, MSC-EVs can be conveniently dropped over the ocular surface or diffused through the retina upon intravitreal injection, without increasing the risks of cellular rejection and tumor formation. For clinical translation, a standardized and scalable production, as well as reprogramming the MSC-EVs, are highly encouraged. This review aims to assess the potential approaches for EV production and functional modification, in addition to summarizing the worldwide clinical trials initiated for various physiological systems and the specific biochemical effects of MSC-EVs on the therapy of eye diseases. Recent advances in the therapy of ocular diseases based on MSC-EVs are reviewed, and the associated challenges and prospects are discussed as well.

Rapidly separable microneedle patches for controlled release of therapeutics for long-acting therapies

Microneedle (MN) patches have become an appealing approach for transdermal drug delivery due to their unique properties, such as enabling self-administration, causing no pain, increasing patient compliance, eliminating biohazardous sharps disposal and avoiding risk of needle-stick injury. Although dissolvable MN patches have achieved great success in bolus drug delivery in the skin, rapidly separable MN patches have recently attracted strong interest, especially in the treatment of chronic diseases, because of the short application time, long-acting efficacy and less frequent administration. In this review, we summarized three types of rapidly separable long-acting MN patches with different working mechanisms, followed by discussion of biomedical applications of those MN patches, including antigen delivery for vaccination, contraceptives delivery for long-term contraception, insulin delivery for diabetes treatment, ocular drug delivery for long-term therapy of ocular diseases, anti-tumor drug delivery for cancer therapy, pain relief drug delivery for analgesia, drug delivery for bacterial killing, and anti-obesity drug delivery for weight loss. Finally, we provided our perspectives on the future development of rapidly separable long-acting MN patches.