Macrophage polarization and immunomodulation strategies for bone tissue engineering via hyaluronic acid-based biomaterials

Bone tissue engineering (BTE) is one of the promising solutions that have emerged to challenge the shortcomings of the traditional grafting method by combining biomaterials, cells, and signalling molecules to produce functional bone. Hyaluronic acid (HA) has grown to be a versatile biomaterial among natural polymers due to its biocompatibility, biodegradation, and inherent immunomodulatory properties. This review highlights how HA-based scaffolds and hydrogels can encourage osteoimmunomodulation by polarizing macrophages, the primary factor in signaling the effectual response on inflammatory and reparative responses in bone healing. The capacity of HA to bind macrophage surface receptors, including cluster of differentiation 44 (CD44), and receptor for hyaluronan-mediated motility (RHAMM) enables the reorganization of intracellular signaling pathways (NF-Kβ, STAT6, and TGF-2/SMAD) to promote the induction of pro-regenerative M2 phenotypes by deactivating pro-inflammatory M1 macrophages. Furthermore, incorporation of HA with bioactive ceramics, polymers, and nanoparticles improves the mechanical strength, osteoconductivity, and immunoregulatory functions of the scaffold. In addition, HA-CD44/RHAMM interaction inhibits NF-κB-induced inflammatory cytokine production and induces STAT6-mediated polarization of M2 macrophages. The HA-mediated signaling also stimulates the secretion of IL-10 and TGF-β to form a regenerative osteoimmune environment that promotes bone repair and tissue regeneration. This is due to controlled degradation, sustained release of growth factors, and adaptive immunogenicity attributed to modified and composite HA hydrogels, which support angiogenesis and osteogenesis in critical bone defects and inflammatory bone diseases. 3D bioprinting and stimuli-responsive HA scaffolds that could be used to achieve patient-specific, tunable immunomodulation are also discussed in the present review. In spite of all preclinical advances, there are still translational issues based on the variability in biology, complexity in production, and regulatory restrictions. The future trends include the incorporation of smart, tailored HA-based scaffolds with biosensing, gene modulatory, and exosomes delivery systems to promote precision bone regeneration. Altogether, HA-based biomaterials are the new generation of bioactive and immuno-instructive scaffolds that have the potential to coordinate immune response and tissue repair, which redefines the landscape of regenerative bone medicine.