Cell‐Laden Scaffolds for Vascular‐Innervated Bone Regeneration

For regeneration of highly vascularized and innervated tissues, like bone, simultaneous ingrowth of blood vessels and nerves is essential but largely neglected. To address this issue, a “pre‐angiogenic” cell‐laden scaffold with durable angiogenic functions is prepared according to the bioactivities of silicate bioceramics and the instructive effects of vascular cells on neurogenesis and bone repair. Compared with traditional cell‐free scaffolds, the prepared cell‐laden scaffolds printed with active cells and bioactive inks can support long‐term cell survival and growth for three weeks. The long‐lived scaffolds exhibited durable angiogenic capability both in vitro and in vivo. The pre‐angiogenic scaffolds can induce the neurogenetic differentiation of neural cells and the osteogenic differentiation of mesenchymal stem cells by the synergistic effects of released bioactive ions and the ability of vascular cells to attract neurons. The enhanced bone regeneration with both vascularization and innervation is attributed to these physiological functions of the pre‐angiogenic cell‐laden scaffolds, which is defined as “vascular‐innervated” bone regeneration. It is suggested that the concept of “vascular‐innervated scaffolds” may represent the future direction of biomaterials for complex tissue/organ regeneration. The pre‐angiogenic cell‐laden scaffolds are 3D bioprinted with Li‐Mg‐Si (LMS) bioceramics‐based bioinks containing vascular endothelial cells. The cell‐laden scaffolds possessed the ability of modulating innervation and osteogenesis while holding long‐lived angiogenic functions. When implanted into bone defects, the cell‐laden scaffolds can promote ingrowth of blood vessels and nerve fibers and enhance bone formation, leading to the high efficiency of vascular‐innervated bone regeneration.