Bridging Preclinical and Clinical Gaps in Ocular Therapeutics: Hydrogel Drug Delivery and 3D Tissue Models

Affecting over 2.2 billion people globally, ocular diseases represent a profound public health challenge, with vision loss projected to increase by 55% by 2050. Ocular drug delivery is fundamentally constrained by the eye's anatomical and physiological barriers, limiting bioavailability and necessitating repeated invasive administration. Hydrogel-based drug delivery systems (DDSs) have emerged as transformative platforms offering controlled drug release, mucoadhesive precorneal retention, and stimulus-responsive phase transitions for anterior and posterior segment diseases. Formulated from natural biopolymers (e.g., hyaluronic acid, chitosan, gelatin, and alginate) and synthetic platforms (e.g., thermosensitive poloxamers, pH-responsive carbomers, and photo-crosslinked polyethylene glycol systems), these networks sustain therapeutic concentrations while reducing the burden of invasive procedures. Despite these advances, clinical translation remains critically impeded by the limited predictive capacity of conventional two-dimensional cell cultures and animal models, which fail to replicate human ocular tissue architecture, barrier integrity, and disease pathophysiology. Three-dimensional (3D) ocular organoids (e.g., corneal epithelial, lens, lacrimal gland, and retinal constructs derived from patient-specific induced pluripotent stem cells) alongside eye-on-a-chip microfluidic platforms provide human-relevant microphysiological systems for evaluating hydrogel performance, drug transport, efficacy, and biocompatibility under normal conditions. Critically, the integration of hydrogel-based DDSs with advanced 3D tissue models offers a transformative strategy to bridge the persistent preclinical-to-clinical translation gap in ocular therapeutics. Herein, we critically appraise the current landscape of hydrogel-based ocular DDSs and their integration with 3D organoid and organ-on-chip platforms, identifying key opportunities and barriers along the translational pathway toward next-generation therapeutics for vision-threatening ocular diseases.