Hyaluronic acid-based in situ injectable crosslinked hydrogels as next-generation vitreous substitutes: A review

Replacement of the vitreous body remains a major unmet need in vitreoretinal surgery. Currently used tamponade agents, such as gases and silicone oils, provide mechanical support but fail to replicate the optical, viscoelastic, and biological functions of the native vitreous and are associated with significant clinical limitations. Injectable hydrogels have therefore emerged as promising alternatives, particularly systems that undergo network formation directly within the vitreous cavity. This review provides a focused, concept-driven analysis of in situ forming hydrogel vitreous substitutes, with a primary emphasis on hyaluronic acid (HA)-based systems, which currently represent the most advanced and translationally promising candidates. Rather than presenting a systematic survey, we apply a structured selection strategy centered on HA-based hydrogels that gel in situ, complemented by injectable pre-formed HA hydrogels and a limited number of representative non-HA systems included for comparative benchmarking. This framework enables a clear distinction between pre-gelled and in situ approaches and highlights the added value of in situ network formation. Beyond material composition and crosslinking chemistry, the review integrates translational insights from reported failure cases, current clinical and regulatory considerations, and methodological benchmarking challenges. Particular emphasis is placed on emerging process-level innovations, including microfluidic-assisted precursor preparation, standardized in vitro testing workflows, and physiologically relevant eye models. By synthesizing material design, gelation mechanisms, processing strategies, and translational requirements, this review clarifies why in situ crosslinked HA-based hydrogels currently represent the leading direction for next-generation vitreous substitutes, while identifying critical gaps and future research priorities required for successful clinical translation.