Hyaluronic Acid Hydrogels Crosslinked in Physiological Conditions: Synthesis and Biomedical Applications

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.

Keywords: cross-linking; hyaluronic acid; physiological conditions.

Figure 1

Number of papers that contain the terms ‘Hyaluronic’ and ‘Hydrogel’ (2011–2020) (Source: SCOPUS).

Figure 2

(a) Schematic representation of an experiment for the determination of G′ and G″ of hydrogels through shear rheometry. (b) Oscillatory frequency experiments performed on polymer hydrogels with different relaxation times starting from polymer solutions (with no crosslinks) to fully gel-like materials in which G′ > G″. Adapted with permission from [33].

Figure 3

Formation of reversible boronic esters bond through reactions between boronic acids and diols.

Figure 4

Reversible Schiff-base formation, (a) imine, (b) hydrazone, (c) acyl-hydrazone, and (d) oxime bonds through reactions between aldehyde groups and primary amine, hydrazide, acyl-hydrazide, or oxyamine groups, respectively.

Figure 5

Thiol Chemistry: (a) Disulfide formation through oxidation reaction, (b) disulfide-exchange reaction, (c) Michael addition reaction, and (d) thiol–yne addition reaction.

Figure 6

Strain-promoted azide–alkyne cycloaddition (SPAAC) reaction between azide and (a) oxanorbonadiene and (b) cyclooctune groups.

Figure 7

Diels–Alder formation: (a) Diels–Alder general [4 + 2] cycloaddition reaction. (b) DA cycloaddition reaction between furan and maleimide groups.

Figure 8

Inverse electron demand Diels–Alder (IEDDA) cycloaddition reaction between tetrazine and norbornene groups.

Figure 9

The figure shows that BMP-2 mimicking peptide (BP) loaded within an injectable ‘Diels Alder’ hyaluronic acid hydrogel induces the osteogenic differentiation of human dental pulp stem cells (hDPSC). Adapted with permission from [100].

Figure 10

Schematic representation of the experimental procedure for the preparation of thermosensitive hyaluronic (HA) hydrogels prepared through blending of solutions of chitosan (CS) and β-sodium glycerophosphate (GP) at 37 °C. Taken with permission from [114].