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

Abstract

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 in vitro and in vivo . In vitro , 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. Created in BioRender. Chang, J. (2025) https://BioRender.com/z32q422 . Hyaluronic acid is a versatile building block for the development of biofunctional hydrogels. Chemical modifications of hyaluronic acid enable tunable biophysical and biochemical properties, facilitating diverse functionalities such as cell adhesion, controlled degradation, and immune modulation. These engineered hydrogels support applications in in vitro models, neural tissue engineering, cartilage and bone regeneration, muscle repair, and skin tissue engineering. • Hyaluronic acid (HyA)'s biocompatibility and tuneability enable diverse applications. • A range of modifications facilitate formation of hydrogels with tuneable properties. • HyA hydrogels can be functionalised with biomolecules for added bioactivity. • HyA hydrogels are widely used in vitro for modelling healthy and diseased tissue. • HyA hydrogels are used as implantable or injectable biomaterials for tissue repair.

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