Poor initial stability at the first four weeks after surgery is becoming the major causes for metal implant failure. Previous attempts neglected the control release of insulin for the bone regeneration among nondiabetic subjects. The major reason may lie in the adverse effects, such as attenuated bone formation, hypoglycemia or hyperinsulinemia, that caused by the excessive insulin. Thus, spatiotemporal release of insulin may serve as the promising strategy. To address this, through solvent extraction (EMS), solvent evaporation (SMS) and cosolvent methods (CMS), we prepared three types of PLGA microspheres with various internal structures, but similar size distribution. The effects of the preparation methods on the properties of the microspheres, such as their release behavior, degradation of molecular weight, and structural evolution, were investigated. Human bone marrow mesenchymal stromal cells (BMSCs) and rabbit implant models were used to test the bioactivity of the microspheres in vitro and in vivo, respectively. The result demonstrated that these three preparation methods did not influence the polymer degradation but instead affected the internal structural evolution, which plays a crucial role in the release behavior, osteogenesis and peri-implant bone regeneration. Compared with EMS and CMS microspheres, SMS microspheres exhibited a relatively steady release rate in the first four weeks, which evidently stimulated the osteogenic differentiation of the stem cells and peri-implant bone regeneration. Meanwhile, SMS microspheres significantly enhanced the stability of the implant at Week 4, which is promising to reduce early failure rate of the implant without inducing adverse effects on the serum biochemical indices.

中文翻译：

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均一大小的载有胰岛素的PLGA微球可改善早期植入物周围的骨再生。

术后头四个星期初期稳定性差，正成为金属植入物失败的主要原因。先前的尝试忽略了非糖尿病受试者中骨再生的胰岛素的控制释放。主要原因可能是由于过量胰岛素引起的不良反应，例如骨骼形成减弱，低血糖或高胰岛素血症。因此，胰岛素的时空释放可能是有前途的策略。为了解决这个问题，我们通过溶剂萃取（EMS），溶剂蒸发（SMS）和助溶剂方法（CMS），制备了三种类型的PLGA微球，其内部结构各异，但粒径分布相似。制备方法对微球性质的影响，例如其释放行为，分子量降低和结构演变，被调查了。使用人骨髓间充质基质细胞（BMSC）和兔植入模型分别在体外和体内测试微球的生物活性。结果表明，这三种制备方法不影响聚合物降解，而影响内部结构演变，这在释放行为，成骨和植入物周围骨再生中起着至关重要的作用。与EMS和CMS微球相比，SMS微球在开始的四周内显示出相对稳定的释放速率，这显然刺激了干细胞的成骨分化和植入物周围的骨再生。同时，SMS微球在第4周显着增强了植入物的稳定性。