Zinc-containing biomaterials for bone disease therapy and tissue repair: Design principles, mechanistic insights, and...

Bone tissue engineering has emerged as a promising strategy not only for treating bone defects and related diseases but also for supporting bone regeneration. However, its success relies on the development of effective biomaterials that can simultaneously fulfill therapeutic needs and replicate the natural extracellular matrix of bone tissue. Zinc (Zn) is an essential nutrient that plays a crucial role in bone metabolism. Indeed, it is known to enhance bone formation and regeneration. Unlike conventional bioactive ions that primarily contribute to mineral deposition or antimicrobial activity, Zn plays a multifaceted regulatory role in bone regeneration by simultaneously modulating osteogenesis, angiogenesis, immune responses, and cellular enzymatic pathways, while also enabling controlled biodegradation and therapeutic functionality. Zn-containing biomaterials have shown great potential for bone tissue engineering applications due to their unique properties, including high biocompatibility, biodegradability, antibacterial activity, and osteogenic properties. This review provides an overview of the synthesis, design, and recent advancements in various types of biomaterials combined with Zn, including Zn-based metal-organic frameworks (MOFs), Zn oxide nanoparticles (ZnO NPs), Zn-doped hydroxyapatite (ZnHA), Zn-functionalized magnetic nanostructures, scaffolds/implants, hydrogels, and cements, among others, for the treatment of bone diseases and tissue regeneration. The present review also focuses on the mechanisms by which Zn-containing biomaterials promote bone regeneration, including regulation of osteoblast differentiation, stimulation of angiogenesis, and inhibition of osteoclast activity. Furthermore, we discuss the clinical translation of Zn-containing platforms, including commercially available products, ongoing clinical trials, and preclinical systems. Ultimately, Zn-containing biomaterials hold promise as therapeutic and regenerative agents with strong potential to treat bone-related diseases and induce regeneration in the near future.