Hyaluronic acid as a versatile building block for the development of biofunctional hydrogels: In vitro models and preclinical innovations

Hyaluronic acid (HyA) is a non-sulphated linear polysaccharide found abundantly in the extracellular matrix, known for its biocompatibility and versatility in tissue engineering. Chemical modifications of HyA, including methacrylate, acrylate, click chemistry, norbornene, or host-guest chemistry, are necessary for the formation of stable hydrogels with tuneable biophysical characteristics. These modifications enable precise control over stiffness, swelling, degradation, and advanced functionalities such as shear-thinning, self-healing, and injectability. Functionalisation further enhances hydrogel bioactivity, enabling controlled cell adhesion, modulation of cell behaviour, hydrogel degradation, and release profiles, as well as inflammation modulation or bacterial growth inhibition. These are achieved by conjugating proteins, peptides, antibodies, or reactive chemical groups. HyA hydrogels find broad applications both <i>in vitro</i> and <i>in vivo</i>. <i>In vitro</i>, HyA-based hydrogels can support the development of models to understand fundamental processes in health and mechanisms behind disease progression, serving as highly tuneable extracellular matrix mimetics. As therapeutic interventions, injectable or implantable HyA-based hydrogels have been developed to repair a range of tissues, including cartilage, bone, muscle, and skin defects. However, issues remain to be addressed before widespread adoption of HyA-based hydrogels as clinical options. Future innovations for HyA hydrogels include its establishment as an enabling technology for the delivery of novel therapeutics, with a particular focus on immunomodulatory molecules, and the development of more dynamic, tissue-mimetic HyA-based hydrogels.