Hyaluronic Acid in the Third Millennium

Abstract

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.

Keywords: biological activity; cosmetic; crosslinking; drug delivery; food-supplement; functionalization; hyaluronan applications; hyaluronan derivatives; hyaluronan synthases; hyaluronic acid; hyaluronidases; physico-chemical properties.

Figure 1

Chemical structures of HA disaccharide unit (A) and HA tetrasaccharide unit where the hydrophilic functional groups and the hydrophobic moieties are respectively evidenced in blue and yellow, while the hydrogen bonds are represented by green dashed lines (B).

Figure 2

Shear-thinning and non-thixotropic behavior of 0.5% HA solution (2 MDa) analyzed using the rotational rheometer AR2000 (TA instruments, New Castle, DE, USA), connected to the Rheology Advantage software (Version V7.20) and equipped with an aluminum cone/plate geometry (diameter 40 mm, angle 2°, 64-μm truncation). The viscosity decreases in response to gradual increases of the shear rate over time (upward ramp), and then, the viscosity increases in response to gradual decreases of the shear rate over time (downward ramp). The initial viscosity is recovered through the same intermediate states of the breakdown process: the breakdown of the polymeric network is transient and reversible, and therefore, the original structure of HA is recovered.

Figure 3

Schematic diagram showing HA key steps from its synthesis to its degradation.

Figure 4

Summary of HA cell surface receptors and of the actions that they control when linked by HA.

Figure 5

Chemical modifications of HA: conjugation and crosslinking (A). HA forms used for pharmaceutical, medical, food and cosmetic applications: native, conjugated and crosslinked (B).

Figure 6

Medical, pharmaceutical, cosmetic and dietary applications of HA and its derivatives.

Figure 7

Summary of the medical, pharmaceutical, cosmetic and dietary applications of HA and its derivatives, reporting some examples, the beneficial actions, the key features and the state of the art.