Hyaluronic Acid

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PIPE-0078

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General Description

Hyaluronic acid (HA) is an unbranched glycosaminoglycan (GAG) polymer with an unusually high molecular weight (up to 10⁸ Da) present in vertebrate tissues. The HA polymer is composed of repeating disaccharide units of N-acetyl-d-glucosamine and d-glucuronic acid joined through β-1,4-linkages. Intrachain β-1,3-linkages stabilize HA by placing bulky substituent groups equatorially with hydrogen atoms axially minimizing rotation. Alternating hydrophobic/hydrophilic surfaces result, which are held together by hydrogen bonding. In neutral solutions, HA becomes anionic as carboxyl groups dissociate. The resulting salts of hyaluronan with Na⁺ or Ca²⁺ give HA exceptional hydrophilicity. Once hydrated, the rigid HA secondary structure predominates as a left-handed helix. HA tends to form duplexes in solution by intermolecular hydrogen bonding and hydrophobic interactions, which further collapse the structure into a β-sheet tertiary structure forming an extended polymeric mesh.

Application

Hyaluronic Acid (HA) is a multifunctional biopolymer utilized across diverse industries due to its exceptional biocompatibility and moisture-retention properties. In aesthetic medicine and skincare, it serves as the gold standard for dermal fillers to restore facial volume and as a premier humectant in topical formulations to enhance skin hydration and elasticity.
Beyond cosmetics, HA plays a critical role in healthcare: it is used in ophthalmic surgery to protect delicate eye tissues, in orthopedics as a viscosupplement to lubricate osteoarthritic joints, and in advanced wound care to accelerate tissue regeneration. Furthermore, its ability to form hydrogels makes it a cutting-edge tool in drug delivery systems and tissue engineering, where it acts as a scaffold for growing new cells.

Hyaluronic acid (HA) hydrogels formed through cross-linking have potential as a mechanically stable 3D matrix for controlled delivery systems as well as tissue engineering applications. However, traditional cross-linking strategies require toxic catalysts. Thus, researchers developed injectable HA hydrogels with tunable cross-linker length and density using three cross-linkers, BDDE, ferulic acid (FA), and pluronic (PLU), for the treatment of wrinkles on the skin of mice. HA hydrogels cross-linked with FA and PLU demonstrated enzyme- and temperature-dependent sol-to-gel properties. HA-FA and HA-PLU hydrogels were both injectable and biocompatible with RAW 264.7 cells and HDF cells in vitro. HA-PLU hydrogels increased growth rates of HDF and HaCaT cells and inhibited expression of collagen-degrading proteins (ERK/JNK/p38 kinases and MMP-1/3/9), allowing for increased Collagen I deposition in vitro. When injected subcutaneously into mice, all three hydrogels formed stable gels in the dermis with no cytotoxicity. HA-PLU showed superior anti-wrinkling capabilities. By tuning cross-linking density, desired properties such as injectability, biocompatibility, and therapeutic properties can be tailored to desired applications throughout soft tissues.

Fig. 2 Biocompatible, injectable HA hydrogels that effectively reduce skin wrinkles by inhibiting collagen degradation and promoting tissue regeneration. (Murugesan M, et al. 2025)

References

Murugesan M, et al. Tailoring hyaluronic acid hydrogels: Impact of cross-linker length and density on skin rejuvenation as injectable dermal fillers and their potential effects on the MAPK signaling pathway suppression. Bioactive Materials. 2025, 49: 154-171.

How does the molecular weight of Hyaluronic Acid affect its physical viscosity?

Higher molecular weight Hyaluronic Acid typically results in increased viscosity and superior lubricating properties.

What functional groups are responsible for the hydrophilicity of Hyaluronic Acid?

The numerous hydroxyl and carboxyl groups within Hyaluronic Acid allow it to bind water molecules extensively.

Is Hyaluronic Acid considered a protein or a carbohydrate?

Hyaluronic Acid is a carbohydrate, specifically a long-chain polysaccharide, rather than a protein or lipid.

Are there different grades of Hyaluronic Acid available?

Yes, Hyaluronic Acid is categorized into cosmetic, food, and pharmaceutical grades based on purity and standards.