Since its first isolation in 1934, hyaluronic acid (HA) has been studied across a variety of research areas. This unbranched glycosaminoglycan consisting of repeating disaccharide units of N-acetyl-d-glucosamine and d-glucuronic acid is almost ubiquitous in humans and in other vertebrates. HA is involved in many key processes, including cell signaling, wound reparation, tissue regeneration, morphogenesis, matrix organization and pathobiology, and has unique physico-chemical properties, such as biocompatibility, biodegradability, mucoadhesivity, hygroscopicity and viscoelasticity. For these reasons, exogenous HA has been investigated as a drug delivery system and treatment in cancer, ophthalmology, arthrology, pneumology, rhinology, urology, aesthetic medicine and cosmetics. To improve and customize its properties and applications, HA can be subjected to chemical modifications: conjugation and crosslinking. The present review gives an overview regarding HA, describing its history, physico-chemical, structural and hydrodynamic properties and biology (occurrence, biosynthesis (by hyaluronan synthases), degradation (by hyaluronidases and oxidative stress), roles, mechanisms of action and receptors). Furthermore, both conventional and recently emerging methods developed for the industrial production of HA and its chemical derivatization are presented. Finally, the medical, pharmaceutical and cosmetic applications of HA and its derivatives are reviewed, reporting examples of HA-based products that currently are on the market or are undergoing further investigations.

Over the last years, hyaluronic acid (HA) injectable dermal fillers (DFs) have become the most popular agents for soft tissue contouring and volumizing. HA fillers are characterized by most of the properties that an ideal DF should have, due to HA unique chemical-physical properties, biocompatibility, biodegradability, and versatility. Therefore, HA DFs have revolutionized the filler market with a high number of products, which differ in terms of HA source, cross-linkage (agent and degree), HA concentration, hardness, cohesivity, consistency, inclusion or lack of anesthetic, indication, and longevity of correction. The article first provides a general introduction to DF world, and an overview of the different materials is available for fillers. Second, it describes the characteristics and the peculiarities of HA fillers, their differences from the other available materials, and therefore the reasons at the base of their success. Moreover, an update regarding the main Food and Drug Administration (FDA) approved fillers is presented.

Dry eye syndrome is a common disease which can damage the corneal epithelium. It is treated with eye drops to stimulate tear production and hydrate the corneal surface. The most prescribed artificial tear remedies contain hyaluronic acid (HA), which enhances epithelial wound healing, improving tissue health. To the best of our knowledge, only a few recent studies have investigated cross-linked HA (HA-CL) in eye drops for human applications. This work consists in an in vitro evaluation of the re-epithelialization ability of two different preparations containing a recently synthetized HA cross-linked with urea: 0.02% (w/v) HA-CL (solution 1, S1), and 0.4% (w/v) HA-CL (solution 2, S2). The study was conducted on both 2D human corneal cells (HCEpiC) and 3D reconstructed tissues of human corneal epithelium (HCE). Viability by 3(4,5-dimethylthiazol-2)2,5-diphenyltetrazolium bromide (MTT) test, pro-inflammatory cytokine release (interleukin-8, IL-8) by ELISA, and morphology by hematoxylin and eosin (HE) staining were evaluated. In addition, to understand the molecular basis of the re-epithelialization properties, cyclin D1 levels were assessed by western blot. The results showed no cellular toxicity, a slight decrease in IL-8 release, and restoration of epithelium integrity when the wounded 3D model was treated with S1 and S2. In parallel, cyclin D1 levels increased in cells treated with both S1 and S2.

The present work evaluates for the first time the use of urea-crosslinked hyaluronic acid (HA-CL), a novel derivative of native hyaluronic acid (HA), to produce microspheres (MS) by emulsification-solvent evaporation, for dermal delivery of sodium ascorbyl phosphate (SAP). As the term of comparison, HA MS were prepared. A pre-formulation study—investigation of the effects of polymers solutions properties (pH, viscosity) and working conditions—led to the production of optimized HA-CL MS and HA-CL—SAP MS with: almost unimodal size distributions; mean diameter of 13.0 ± 0.7 and 9.9 ± 0.8 µm, respectively; spherical shape and rough surface; high yield, similar to HA MS and HA–SAP MS (≈ 85%). SAP was more efficiently encapsulated into HA-CL MS (78.8 ± 2.6%) compared to HA MS (69.7 ± 4.6%). Physical state, thermal properties, relative moisture stability of HA-CL MS and HA-CL–SAP MS were comparable to those of HA MS and HA–SAP MS. However, HA-CL–SAP MS exhibited an extended drug release compared to HA–SAP MS, despite the same kinetic mechanism—contemporaneous drug diffusion and polymer swelling/dissolution. Therefore, HA-CL formulation showed a greater potential as microcarrier (for encapsulation efficiency and release kinetic), that could be improved, in future, using suitable excipients.