Abstract
Hyaluronic acid (HA) hydrogels display a wide variety of biomedical applications ranging from tissue engineering to drug vehiculization and controlled release. To date, most of the commercially available hyaluronic acid hydrogel formulations are produced under conditions that are not compatible with physiological ones. This review compiles the currently used approaches for the development of hyaluronic acid hydrogels under physiological/mild conditions. These methods include dynamic covalent processes such as boronic ester and Schiff-base formation and click chemistry mediated reactions such as thiol chemistry processes, azide-alkyne, or Diels Alder cycloaddition. Thermoreversible gelation of HA hydrogels at physiological temperature is also discussed. Finally, the most outstanding biomedical applications are indicated for each of the HA hydrogel generation approaches.
Highlights
Hyaluronic acid (HA) is a non-sulfated glycosaminoglycan composed of repeating units of the disaccharide β-1,4-D-glucuronic acid–β-1,3 N-acetyl-D-glucosamine
The thiol group can undergo several reactions; in the present work, we focus our efforts on those that can be carried out in physiological conditions and that require no catalysis to occur: disulfide formation/exchange reactions, Michael addition type reactions, and thiol–yne addition reactions
Many of the hyaluronic acid hydrogel formulations, commercialized mostly as injectable biomaterials, are obtained through reaction conditions that are not compatible with cell culture which hinders some of their bio-applications
Summary
Hyaluronic acid (HA) is a non-sulfated glycosaminoglycan composed of repeating units of the disaccharide β-1,4-D-glucuronic acid–β-1,3 N-acetyl-D-glucosamine. For the use of hyaluronic acid as temporary scaffolds for tissue engineering applications, it is necessary to adjust the rate of degradation to the rate of formation of the new tissue To overcome these drawbacks, the HA chains can be cross-linked, either chemically or physically to form hydrogels. HA crosslinking can be carried out in two ways: by directly adding a cross-linker and forming the three-dimensional (3D) network, or by pre-modifying the HA chains with functional groups liable to be crosslinked The latter leads to the generation of active moieties that add new functionalities to the hydrogel [3]. The hydrogels obtained at low HA:DVS weight ratios were non-cytotoxic and showed an adopted that predefines the properties of the targeted hydrogel Such an approach is excellent capacity toby load antibiotics and anti-inflammatory agents [13]. Different approaches for the preparation of thermoreversible hyaluronic hydrogels at physiological temperature including grafting or combination with thermoresponsive synthetic polymers (poly-N isopropylamide or pluronics) and natural polymers (gelatin or dextran among others) are reviewed as well
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