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Review
. 2025 Jun 1;11(6):424.
doi: 10.3390/gels11060424.

Hyaluronic Acid: Production Strategies, Gel-Forming Properties, and Advances in Drug Delivery Systems

Maciej Grabowski  1 , Dominika Gmyrek  1 , Maria Żurawska  1 , Anna Trusek  1
Affiliations
Review

Hyaluronic Acid: Production Strategies, Gel-Forming Properties, and Advances in Drug Delivery Systems

Maciej Grabowski et al. Gels. .

Abstract

Hyaluronic acid (HA) is a naturally occurring glycosaminoglycan widely recognised for its biocompatibility, biodegradability, and unique viscoelastic properties. Its structural versatility enables the formation of hydrogels with tuneable physicochemical characteristics, making it a valuable biomaterial in drug delivery and regenerative medicine. This review outlines HA properties, gel-forming approaches, and modern medicine and bioengineering applications. It provides a comprehensive overview of advances in HA production strategies, including microbial fermentation, animal tissue extraction, and production in vitro. Particular attention is given to gel-forming mechanisms, emphasising physical and chemical crosslinking methods like carbodiimide crosslinking, radical polymerisation, and enzymatic crosslinking. Advances in HA-based drug delivery systems and applications of HA-based materials in tissue engineering are also discussed, focusing on HA-based hydrogels with conjugates and combinations with compounds like collagen, alginate, and chitosan.

Keywords: drug delivery; hyaluronic acid; hyaluronic-acid-based hydrogels; microbial hyaluronic acid production.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
HA structure (d-glucuronic acid and N-acetyl-d glucosamine moieties alternate).
Figure 2
Figure 2
HA production pathways.
Figure 3
Figure 3
A stirred-tank bioreactor equipped with an aeration system, a thermal jacket, and integrated sensors [83].
Figure 4
Figure 4
Reactive functional groups of HA (illustration based on [107]).
Figure 5
Figure 5
The reaction of HA with BDDE under alkaline conditions.
Figure 6
Figure 6
The reaction of HA with BDDE under acidic conditions.
Figure 7
Figure 7
The cross-linking reaction of HA using DVS.
Figure 8
Figure 8
The reaction of HA with GTA.
Figure 9
Figure 9
The reaction of hydroxyl groups with maleic anhydride.
Figure 10
Figure 10
Ugi condensation reaction.
Figure 11
Figure 11
Reaction of amidation.
Figure 12
Figure 12
Reaction of ester formation.
Figure 13
Figure 13
Reaction of HA with an alkyl halide.
Figure 14
Figure 14
Reaction of HA with DA.
Figure 15
Figure 15
Ways of HA N-deacetylation.
Figure 16
Figure 16
Carbodiimide crosslinking reaction [117].
Figure 17
Figure 17
Formation of an amide product (based on [108,117]).
Figure 18
Figure 18
A diagram of photoinitiated polymerisation, using polymerisation of HA-SH and HAMA as an example [122].
Figure 19
Figure 19
A diagram of HA-Tyr crosslinking reaction catalysed by HRP [122].
Figure 20
Figure 20
Schematic of formation of a thiol-ene hydrogel [129].
Figure 21
Figure 21
A schematic of a disulfide bond creation [132].
See this image and copyright information in PMC

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