Revisiting the sclera as a target for glaucoma therapy.

The pursuit of improved intraocular pressure (IOP) control in glaucoma continues to drive innovation beyond conventional trabecular-based therapies. While minimally invasive glaucoma surgery (MIGS) has focused attention on enhancing conventional outflow, increasing evidence suggests that the sclera represents a biologically active and potentially modifiable interface influencing unconventional aqueous drainage and transscleral drug delivery. Traditionally regarded as a passive structural barrier, the sclera is now recognized as a spatially heterogeneous, mechanosensitive tissue with region-specific extracellular matrix composition and biomechanical properties. Emerging data demonstrate that pharmacologic agents such as prostaglandin analogues can remodel scleral extracellular matrix architecture, increasing molecular permeability and facilitating uveoscleral outflow. At the same time, advances in transscleral drug delivery including iontophoresis, ultrasound-assisted diffusion, biodegradable matrices, and extracellular vesicle-based platforms highlight the sclera's dual role as both a hydraulic regulator and a therapeutic conduit. However, translational challenges including diffusion-dominated transport, episcleral clearance, fibrotic encapsulation, and dose variability have, to date, limited the widespread clinical adoption of transscleral strategies. In this review, we synthesize structural, biomechanical, pharmacologic, and translational evidence to propose a refined framework: the sclera as a dynamically remodeling hydraulic interface that may be selectively modulated to influence aqueous outflow and enable targeted posterior segment delivery. This integrative perspective expands the therapeutic paradigm for glaucoma beyond trabecular intervention alone.