Hyaluronic Acid-Based Biomaterials in Tissue Engineering: From Molecular Properties to Re-Generative Applications.

Hyaluronic acid (HA), a native non-sulfated glycosaminoglycan of the extracellular matrix, has emerged as a central biomaterial in tissue engineering due to its biocompatibility, hydration capacity, and receptor-mediated bioactivity. Beyond its structural role, HA actively regulates cellular behaviors through interactions with receptors such as CD44 and RHAMM, with outcomes highly dependent on molecular weight, degradation state, and matrix context. Recent advances in chemical modification and crosslinking strategies have enabled the development of HA-based hydrogels, nanofibers, and composite systems with tunable mechanics and degradation profiles, supporting applications in bone, cartilage, vascular, and skin regeneration, as well as in emerging platforms such as 3D bioprinting and nanomedicine. However, inconsistent biological responses and limited clinical translation remain key challenges. This review integrates current understanding of HA synthesis, physicochemical properties, degradation, and receptor-mediated signaling, and establishes a mechanistic framework linking molecular characteristics, matrix mechanics, and cell responses. Building on this framework, we outline design strategies for multifunctional HA composites, advanced biofabrication approaches, and receptor-targeted systems, providing a basis for the rational engineering of next-generation HA-based biomaterials with improved translational potential.