Engineering Large‐Scale Self‐Mineralizing Bone Organoids with Bone Matrix‐Inspired Hydroxyapatite Hybrid Bioinks

Addressing large bone defects remains a significant challenge owing to the inherent limitations in self‐healing capabilities, resulting in prolonged recovery and suboptimal regeneration. Although current clinical solutions are available, they have notable shortcomings, necessitating more efficacious approaches to bone regeneration. Organoids derived from stem cells show great potential in this field; however, the development of bone organoids has been hindered by specific demands, including the need for robust mechanical support provided by scaffolds and hybrid extracellular matrices (ECM). In this context, bioprinting technologies have emerged as powerful means of replicating the complex architecture of bone tissue. The research focused on the fabrication of a highly intricate bone ECM analog using a novel bioink composed of gelatin methacrylate/alginate methacrylate/hydroxyapatite (GelMA/AlgMA/HAP). Bioprinted scaffolds facilitate the long‐term cultivation and progressive maturation of extensive bioprinted bone organoids, foster multicellular differentiation, and offer valuable insights into the initial stages of bone formation. The intrinsic self‐mineralizing quality of the bioink closely emulates the properties of natural bone, empowering organoids with enhanced bone repair for both in vitro and in vivo applications. This trailblazing investigation propels the field of bone tissue engineering and holds significant promise for its translation into practical applications. This innovative study has introduced a new method for bone regeneration, employing hybrid bioinks inspired by the natural bone matrix to develop large‐scale, self‐mineralizing bone organoids with excellent mechanical properties, capable of extensive in vitro and in vivo cultivation, and multicellular differentiation. It has addressed limitations in mechanical support and extracellular matrix replication, advancing bone tissue engineering.