Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness, primarily due to progressive damage to the optic nerve head (ONH) driven by elevated and fluctuating intraocular pressure (IOP). A critical component of this process is the remodeling of the ONH in response to these mechanical stressors. Our research focuses on replicating the complex biomechanical environment of the ONH using advanced 3D hydrogel systems and 3D cell cultures, allowing us to simulate the effects of dynamic mechanical loading and IOP fluctuations. By closely examining how these mechanical forces influence cellular behavior and tissue remodeling, we aim to uncover the underlying mechanobiological pathways that contribute to ONH damage in POAG. This understanding could open doors to innovative therapeutic approaches designed to protect or restore ONH function and slow the progression of glaucoma.