Bone tissue is a highly vascularized tissue and concomitant development of the vascular system and mineralized matrix requires a synergistic interaction between osteogenesis and angioblasts. Several strategies have been applied to achieve vascularized tissue‐engineered bone, including the addition of cytokines as well as pre‐vascularization strategies and co‐culture systems. However, the scaffold is another extremely important component to consider, and development of vascularized bone scaffolds remains one of the greatest challenges for engineering clinically relevant bone substitutes. Here, this review highlights the biomaterial selection, preparation of pre‐vascularized scaffolds, composition modification of the scaffold, structural design, and the comprehensive use of the above synergistic modifications of scaffold materials for vascular scaffolds in bone tissue engineering. Moreover, a strategy is proposed for the design of future scaffold structures, in which promoting the regeneration of vascularized bone by regulating the microenvironment should be the main focus. This overview can help illuminate progress in this field and identify the most recently developed scaffolds that show the greatest potential for achieving clinically vascularized bone.

The redevelopment/regeneration pattern of amputated limbs from a blastema in salamander suggests that enhanced regeneration might be achieved by mimicking the developmental microenvironment. Inspired by the discovery that the expression of magnesium transporter‐1 (MagT1), a selective magnesium (Mg) transporter, is significantly upregulated in the endochondral ossification region of mouse embryos, a Mg‐enriched 3D culture system is proposed to provide an embryonic‐like environment for stem cells. First, the optimum concentration of Mg ions (Mg 2+ ) for creating the osteogenic microenvironment is screened by evaluating MagT1 expression levels, which correspond to the osteogenic differentiation capacity of stem cells. The results reveal that Mg 2+ selectively activates the mitogen‐activated protein kinase/extracellular regulated kinase (MAPK/ERK) pathway to stimulate osteogenic differentiation, and Mg 2+ influx via MagT1 is profoundly involved in this process. Then, Mg‐enriched microspheres are fabricated at the appropriate size to ensure the viability of the encapsulated cells. A series of experiments show that the Mg‐enriched microenvironment not only stimulates the osteogenic differentiation of stem cells but also promotes neovascularization. Obvious vascularized bone regeneration is achieved in vivo using these Mg‐enriched cell delivery vehicles. The findings suggest that biomaterials mimicking the developmental microenvironment might be promising tools to enhance tissue regeneration.

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