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.

中文翻译：

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矿化的纳米纤维支架可促进苯甲酰胺诱导的成骨细胞分化，同时减轻成脂分化。

大的骨缺损代表了巨大的医学难题。与再生医学中的生物大分子（例如生长因子/激素）相比，成本效益和更好的稳定性使小分子有机化合物成为更有前途的替代品。然而，这些小化合物的应用面临的一个共同挑战是它们的副作用问题。Phenamil逐渐成为一种有趣的小分子，通过强烈激活骨骼形态发生蛋白信号传导途径来促进骨骼修复。除成骨作用外，基于一些体外研究，苯那非还可以诱导显着的脂肪形成，这是潜在的临床应用所困扰的一个问题。除可溶性化学信号外，细胞分化在很大程度上还取决于3D支架提供的微环境。所以，我们开发了一种基于3D纳米纤维仿生支架的策略，以利用苯那米尔诱导的干细胞谱系分化。基于基因表达，碱性磷酸酶活性和矿化数据，我们表明模仿矿化明胶纳米纤维支架的骨基质有效改善了苯那非诱导的成骨细胞分化，同时减轻了体外成脂分化。除了正常的培养条件外，我们还表明矿化的基质可以在模拟的炎症条件下显着改善苯甲酰胺诱导的成骨细胞分化。鉴于矿化基质的关键作用，我们开发了一种基于矿物质沉积的创新且简便的策略，可维持3D支架中苯甲酰胺的释放，从而实现有效的局部骨再生。全面的，