AIM: To develop a new material for retina filling and to investigate its effect on intraocular structure and histocompatibility in rabbit eyes. METHODS: The polymer-derived hyaluronic acid (HA) was formed by UV light cross-linked with N-vinyl-pyrrolidone. Vitrectomy was performed in the rabbits, and then cross-linked HA hydrogels at different concentrations were injected. Intraocular pressure measurements, cornea check-up, and B-ultrasound examination were performed during the follow-up period. After six weeks’ follow-up, the rabbits were sacrificed, and both eyes were removed for hematoxylin-eosin (HE) staining, and the polymer materials were observed under electron microscopy. RESULTS: The particle size of the cross-linked HA hydrogels was mainly around at 100 nm. After vitrectomy and injection into vitreous cavity optical coherence tomography showed that the polymeric material HA had no significant effect on the overall thickness of the retina. The intraocular pressure returned to the normal level gradually at week 4. B-ultrasound results revealed that there is no significant change in the eye tissue given to HA material. The pathological and transmission electron microscopy results showed no obvious pathological change in the primary cells and rod cells under the retina tissue. CONCLUSION: HA-based cross-linked biopolymers has good biocompatibility in rabbit eyes, showing a promising potential as vitreous substitutes.