Bond-Centric Modifications of Hyaluronic Acid: Synthesis, Processing, and Biomedical Applications

Hyaluronic acid (HA), a natural polysaccharide present in human connective tissues, is widely used in biomedicine because of its excellent biocompatibility and biodegradability. However, products based on natural HA have several drawbacks, leading to widespread studies on the modification and processing of HA to improve its clinical use. This review discusses common methods of modifying HA, including physical and chemical modification as well as crosslinking. It focuses in detail on various chemical modification strategies from the perspective of the resultant chemical bonds, systematically organizes HA chemistry according to bond types, and refines the design rules for linking chemistry in relation to degradability, mechanical properties, responsiveness, and safety. It then summarizes the latest applications of HA-based products in the fields of ophthalmology, bone and joint treatment, aesthetic medicine, wound healing, and drug delivery. Finally, it explores challenges for the clinical application of HA and provides an outlook on future research directions. By summarizing the applications of HA across distinct biomedical domains, we hope to provide new ideas and directions for its further development and use.