Hyaluronan Hydrogels: Three Material States in Regenerative Orthopaedics

Hyaluronan-based materials are widely described as hydrogels, yet the term is applied without distinction to preparations that differ fundamentally in structure. This review addresses that imprecision by separating three material states of hyaluronan and by stating the criteria under which each may be called a gel: native linear hyaluronan, which forms a viscoelastic solution; the hexadecylamide derivative (HYADD-4), which self-assembles into a transient physical network through hydrophobic interactions; and hyaluronan cross-linked with 1,4-butanediol diglycidyl ether (BDDE), which forms a covalent three-dimensional network. A material is treated as a gel here only where both a percolated network and a solid-like mechanical response are documented. On that basis the covalent network qualifies; the derivative is elastic-dominated across the walking-to-running frequency band of the knee but has not been subjected to a formal Winter-Chambon analysis and is therefore described as gel-like; and the linear solution does not qualify at the molecular weights and concentrations used in marketed viscosupplements. We review the chemistry of network formation, the comparative physicochemical and rheological behavior, including viscosity, the storage and loss moduli, boundary lubrication, and resistance to enzymatic and oxidative degradation, and the receptor-mediated and anti-inflammatory mechanisms of action involving CD44 and molecular-weight-dependent signaling. Clinical and regenerative applications in osteoarthritis viscosupplementation and in scaffolds and carriers for cells and growth factors are summarized for each state. The networked materials show higher viscoelasticity and greater resistance to degradation than the linear solution, which provides a rationale for longer residence; the evidence for a clinical advantage over conventional hyaluronan, however, rests largely on preclinical and rheological data. A three-state framework is proposed, pending validation, to support clearer interpretation of the literature and more rational material selection.