Infill-Modulated, Bioerodible, and Biocompatible Ocular Inserts for Tunable Acyclovir Release via Direct Powder Extrusion 3D Printing

Conventional treatment of herpetic keratitis via eye drops or ointments is limited by rapid precorneal elimination, frequent dosing requirements, and poor patient adherence. To overcome these challenges, this study explores the use of single-step direct powder extrusion (DPE) 3D printing for the fabrication of sustained-release, dissolvable ocular inserts composed of acyclovir, hydroxypropyl methylcellulose acetate succinate-high flow (HPMCAS-HF), and polyethylene glycol (PEG) 6000. Inserts were printed with varying infill densities (30%, 60%, and 90%) to modulate microstructural properties, drug release profiles, and transcorneal permeation. Lower infill density (OI30) exhibited higher porosity, enabling rapid matrix erosion and diffusion-driven release (∼95% over 24 h), along with enhanced permeation flux (0.33 ± 0.01 μg/cm²/min) and permeation coefficient (1.14 ± 0.05 × 10^-2 cm/s). Conversely, high-density constructs (OI90) showed compact microstructure, slower erosion (∼40% at 10 h), and extended release (∼58% over 24 h) with reduced transcorneal permeation flux (0.15 ± 0.01 μg/cm²/min). All formulations followed Weibull release kinetics (<i>R</i>² > 0.98), demonstrating a complex diffusion- and erosion-driven release behavior. The inserts maintained physiological pH, desired flexibility, and exhibited high biocompatibility in both <i>in vitro</i> and <i>ex vivo</i> studies, with no observable signs of irritancy in the hen's egg test on chorioallantoic membrane (HET-CAM), excellent hemocompatibility, >80% viability of ARPE-19 cells, and desired corneal tolerance. Apart from these, the 3D-printed ocular insert showed nearly 4-fold enhanced penetration and retention of Rhodamine B in the corneal layers compared to its aqueous solution during confocal laser scanning microscopy (CLSM) studies. These findings confirm the potential of DPE 3D printing for producing customizable, patient-centric, bioerodible ocular drug delivery systems offering sustained and tailored release, improved retention, and enhanced compliance for the management of keratitis.