LAUSR

Large bone defects represent a significant unmet medical challenge. Cost effectiveness and better stability make small molecule organic compounds a more promising alternative compared with biomacromolecules, for example, growth factors/hormones, in regenerative medicine. However, one common challenge for the application of these small compounds is their side‐effect issue. Phenamil is emerging as an intriguing small molecule to promote bone repair by strongly activating bone morphogenetic protein signaling pathway. In addition to osteogenesis, phenamil also induces significant adipogenesis based on some in vitro studies, which is a concern that impedes it from potential clinical applications. Besides the soluble chemical signals, cellular differentiation is heavily dependent on the microenvironments provided by the 3D scaffolds. Therefore, we developed a 3D nanofibrous biomimetic scaffold‐based strategy to harness the phenamil‐induced stem cell lineage differentiation. Based on the gene expression, alkaline phosphatase activity, and mineralization data, we indicated that bone‐matrix mimicking mineralized‐gelatin nanofibrous scaffold effectively improved phenamil‐induced osteoblastic differentiation, while mitigating the adipogenic differentiation in vitro. In addition to normal culture conditions, we also indicated that mineralized matrix can significantly improve phenamil‐induced osteoblastic differentiation in simulated inflammatory condition. In viewing of the crucial role of mineralized matrix, we developed an innovative and facile mineral deposition‐based strategy to sustain release of phenamil from 3D scaffolds for efficient local bone regeneration. Overall, our study demonstrated that biomaterials played a crucial role in modulating small molecule drug phenamil‐induced osteoblastic differentiation by providing a bone‐matrix mimicking mineralized gelatin nanofibrous scaffolds.