Infectious ocular diseases like keratitis, conjunctivitis, and endophthalmitis pose significant clinical challenges due to the complexities of delivering drugs to the eye. Recent advancements in drug delivery systems offer promising improvements for treating these conditions. Key strategies include targeted delivery through physicochemical modifications, magnetic nanoparticles, and ligand-receptor interactions. This review explores the safety and biocompatibility of ocular drug delivery systems through in vivo ocular toxicity studies, in vitro cytotoxicity assays, hemocompatibility studies, ocular tolerance tests, and genotoxicity assays. It also examines combination therapies and stimuli-responsive delivery systems for their potential to enhance therapeutic efficacy. Furthermore, we discuss tailored and optimized drug delivery approaches for infectious ocular diseases, outlining current challenges and future directions for developing effective ocular drug delivery systems. 

Drug Delivery Systems for Infectious Eye Diseases: Advancements and Prospects

Dry eye disease (DED) is a growing public health concern affecting millions of people worldwide and causing ocular discomfort and visual disturbance. Developing its therapeutic drugs based on animal models suffer from interspecies differences and poor prediction of human trials. Here, we established long-term 3D human corneal epithelial organoids, which recapitulated the cell lineages and gene expression signature of the human corneal epithelium. Organoids can be regulated to differentiate ex vivo, but the addition of FGF10 inhibits this process. In the hyperosmolar-induced DED organoid model, the release of inflammatory factors increased, resulting in damage to the stemness of stem cells and a decrease in functional mucin 1 protein. Furthermore, we found that the organoids could mimic clinical drug treatment responses, suggesting that corneal epithelial organoids are promising candidates for establishing a drug testing platform ex vivo. In summary, we established a functional, long-term 3D human epithelial organoid that may serve as an ex vivo model for studying the functional regulation and disease modelling. 

Establishment of human corneal epithelial organoids for ex vivo modelling dry eye disease

Zoonotic viruses with the ability to replicate in the human respiratory tract pose a threat to public health. Organoids, which are highly representative, multicellular models representing specific organs or tissues, can aid in our understanding of the pathogenesis, pathogenicity, transmissibility, and reservoir circulation dynamics of zoonotic viruses. Organoid studies can facilitate the rapid selection of antiviral therapies identification of potential reservoir species and intermediate hosts, and inform the selection of suitable laboratory animal models. We review the use of human- and animal-derived organoid models from multiple organs to investigate the threat of emerging zoonotic viruses that cause respiratory disease. 

Advancing zoonotic respiratory virus research through the use of organoids

Recently, significant strides have been made in the development of high-fidelity skin organoids, encompassing techniques such as 3D bioprinting, skin-on-a-chip systems, and models derived from pluripotent stem cells (PSCs), replicating appendage structures and diverse skin cell types. Despite the emergence of these state-of-the-art skin engineering models, human organotypic cultures (OTCs), initially proposed in the 1970s, continue to reign as the predominant in vitro cultured three-dimensional skin model in the field of tissue engineering. This enduring prevalence is owed to their cost-effectiveness, straight forward setup, time efficiency, and faithful representation of native human skin. In this review, we systematically delineate recent advances in skin OTC models, aiming to inform future efforts to enhance in vitro skin model fidelity and reproducibility.

Diversity of human skin three-dimensional organotypic cultures

Aims To report an epidemiological update of bacterial keratitis (BK) in a tertiary ophthalmology centre over 20 months compared with a previous study on the same timeframe from 1998 to 1999. Methods 354 patients with BK documented by microbiological corneal scraping or resolutive under antibiotics treatment from January 2020 to September 2021 were analysed retrospectively. Results One or several risk factors were found in 95.2% of patients: contact lens wear (45.2%), ocular surface disease (25.0%), systemic disease (21.8%), ocular trauma (11.9%) and ocular surgery (8.8%). The positivity rate of corneal scrapings was 82.5%, with 18.2% polybacterial. One hundred seventy-five (59.9%) bacteria were Gram-negative, and 117 (40.1%) were Gram-positive. The most common bacteria were Pseudomonas aeruginosa (32.5%), Moraxella spp (18.1%) and Staphylococcus aureus (8.2%). Final visual acuity (logarithm of the minimum angle of resolution) was associated with age (r=+0.48; p=0.0001), infiltrate size (r=+0.32; p&lt;0.0001), ocular surface disease (r=+0.13; p=0.03), ocular trauma (r=-0.14; p=0.02) and contact lens wear (r=−0.26; p&lt;0.0001). Gram-negative bacteria were responsible for deeper (r=+0.18; p=0.004) and more extensive infiltrates (r=+0.18; p=0.004) in younger patients (r=−0.19; p=0.003). Compared with the previous period, the positivity rate of corneal scrapings and the proportion of Gram-negative bacteria, especially Moraxella spp, increased. All P. aeruginosa and Moraxella spp were sensitive to quinolones, and all S. aureus were sensitive to both quinolones and methicillin. Conclusion Contact lens wear remained the leading risk factor. The bacteria distribution was reversed, with a predominance of Gram-negative bacteria and increased Moraxella spp. 

pdf/predisposing-factors-clinical-and-microbiological-insights-2s3w4ow1ua.pdf

Predisposing factors, clinical and microbiological insights of bacterial keratitis: analysis of 354 cases from a leading French academic centre

The conjunctival epithelium covering the eye contains two main cell types: mucus-producing goblet cells and water-secreting keratinocytes, which present mucins on their apical surface. Here, we describe long-term expanding organoids and air-liquid interface representing mouse and human conjunctiva. A single-cell RNA expression atlas of primary and cultured human conjunctiva reveals that keratinocytes express multiple antimicrobial peptides and identifies conjunctival tuft cells. IL-4/-13 exposure increases goblet and tuft cell differentiation and drastically modifies the conjunctiva secretome. Human NGFR+ basal cells are identified as bipotent conjunctiva stem cells. Conjunctival cultures can be infected by herpes simplex virus 1 (HSV1), human adenovirus 8 (hAdV8), and SARS-CoV-2. HSV1 infection was reversed by acyclovir addition, whereas hAdV8 infection, which lacks an approved drug therapy, was inhibited by cidofovir. We document transcriptional programs induced by HSV1 and hAdV8. Finally, conjunctival organoids can be transplanted. Together, human conjunctiva organoid cultures enable the study of conjunctival (patho)-physiology. 

Human conjunctiva organoids to study ocular surface homeostasis and disease.

Practice patterns in the management of bacterial keratitis: a five-continent survey

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Human conjunctiva organoids to study ocular surface homeostasis and disease.

Practice patterns in the management of bacterial keratitis: a five-continent survey