Liquid Crystalline Hydroxyapatite Nanorods Orchestrate Hierarchical Bone‐Like Mineralization

Abstract Bone matrix exhibits exceptional mechanical properties due to its unique nanocomposite structure of type I collagen fibrils and hydroxyapatite (HAp) nanoparticles in hierarchical liquid crystalline (LC) order. However, the regeneration mechanism of this LC structure is elusive. This study investigates the role of the LC structure of HAp nanorods in guiding aligned mineralization and its underlying molecular mechanism. A unidirectionally oriented LC phase of HAp nanorods is developed through engineering‐assisted self‐assembling. This is used to study the growth direction of long‐range aligned extracellular matrix (ECM) and calcium deposit formation during the osteogenic differentiation of human bone marrow‐derived mesenchymal stem cells. It is found that 2 key regulatory genes, COL1A1 and COL4A6, lead to the formation of aligned ECM. Activation of the PI3K‐Akt pathway enhances osteogenesis and promotes ordered calcium deposits. This study provides evidence for elucidating the mechanism of LC‐induced ordered calcium deposition at hierarchical levels spanning from the molecular to macro‐scale, as well as the switch from ordered to disordered mineralization. These findings illuminate bone regeneration, contribute to the development of biomimetic artificial bone with long‐range ordered structures, and suggest a basis for therapeutic targeting of microstructure‐affected bone disorders and the broader field of cell‐ECM interactions.