Hierarchically designed bone scaffolds: From internal cues to external stimuli

Bone tissue engineering utilizes three critical elements - cells, scaffolds, and bioactive factors - to recapitulate the bone tissue microenvironment, inducing the formation of new bone. Recent advances in materials development have enabled the production of scaffolds that more effectively mimic the hierarchical features of bone matrix, ranging from molecular composition to nano/micro-scale biochemical and physical features. This review summarizes recent advances within the field in utilizing these features of native bone to guide the hierarchical design of materials and scaffolds. Biomimetic strategies discussed in this review cover several levels of hierarchical design, including the development of element-doped compositions of bioceramics, the usage of molecular templates for in vitro biomineralization at the nanoscale, the fabrication of biomimetic scaffold architecture at the micro- and nanoscale, and the application of external physical stimuli at the macroscale to regulate bone growth. Developments at each level are discussed with an emphasis on their in vitro and in vivo outcomes in promoting osteogenic tissue development. Ultimately, these hierarchically designed scaffolds can complement or even replace the usage of cells and biological elements, which present clinical and regulatory barriers to translation. As the field progresses ever closer to clinical translation, the creation of viable therapies will thus benefit from further development of hierarchically designed materials and scaffolds.