Recent Advances in Functionalization of Hyaluronic Acid for Biomedical Applications

Hyaluronic acid (HA) has emerged as a promising biopolymer for various biomedical applications due to its biocompatibility, biodegradability, and intrinsic ability to interact with cell surface receptors, making it an attractive candidate for numerous biological processes. Since HA cannot be gelled alone, it must be functionalized through different modification techniques, such as chemical, physical, bio-conjugative, and enzymatic, to activate the various sites present in it. This review analyzes these strategies and applications of HA in different biomedical fields. The first part of the review focuses on the different advanced functionalization strategies of HA, highlighting hydroxyl, amino, and carboxyl group-based reactions, as well as advanced techniques such as oxidation, sulfation, Cu-free click chemistry, thiol–ene coupling, hydrazone formation, bio-conjugation, nano-metal conjugation, and dynamic crosslinking methods. The second part of the review evaluates the use of functionalized HA in the development of advanced biomedical materials, including nano- and microparticles, hydrogels, and mucoadhesive materials with tailored drug release profiles, tissue engineering, skin wound healing, site-specific targeting, and stimuli-responsive behavior. Overall, this review critically consolidates the current advances and future perspectives in the functionalization of HA, underscoring its immense potential to drive the development of biomaterials with diverse biomedical applications.