Institute of Pharmaceutical Sciences, Drug Formulation & Delivery Group, Swiss Federal Institute of Technology Zurich, Switzerland.
Eur J Pharm Biopharm. 2013 Sep;85(1):99-106. doi: 10.1016/j.ejpb.2013.03.004.
Spatiotemporal release of growth factors from a delivery device can profoundly affect the efficacy of bone growth induction. Here, we report on a delivery platform based on the encapsulation of insulin-like growth factor I (IGF-I) in different poly(D,L-lactide) (PLA) and poly(D,L-lactide-co-glycolide) (PLGA) microsphere (MS) formulations to control IGF-I release kinetics. In vitro IGF-I release profiles generally exhibited an initial burst (14-36% of total IGF-I content), which was followed by a more or less pronounced dormant phase with little release (2 to 34 days), and finally, a third phase of re-increased IGF-I release. The osteoinductive potential of these different IGF-I PL(G)A MS formulations was tested in studies using 8-mm metaphyseal drill hole bone defects in sheep. Histomorphometric analysis at 3 and 6 weeks after surgery showed that new bone formation was improved in the defects locally treated with IGF-I PL(G)A MS (n=5) as compared to defects filled with IGF-I-free PL(G)A MS (n=4). The extent of new bone formation was affected by the particular release kinetics, although a definitive relationship was not evident. Local administration of IGF-I resulted in down-regulation of inflammatory marker genes in all IGF-I treated defects. The over-expression of growth factor genes in response to IGF-I delivery was restricted to formulations that produced osteogenic responses. These experiments demonstrate the osteoinductive potential of sustained IGF-I delivery and show the importance of delivery kinetics for successful IGF-I-based therapies.
生长因子从递送装置中的时空释放可以深刻影响骨生长诱导的效果。在这里，我们报告了一种基于将胰岛素样生长因子 I（IGF-I）包封在不同的聚（D，L-乳酸）（PLA）和聚（D，L-乳酸-共-乙醇酸）（PLGA）微球（MS）制剂中的递送平台，以控制 IGF-I 释放动力学。体外 IGF-I 释放曲线通常表现出初始突释（总 IGF-I 含量的 14-36%），随后是或多或少明显的休眠期，释放很少（2 至 34 天），最后是 IGF-I 重新释放的第三阶段。这些不同的 IGF-I-PL（G）A MS 制剂的成骨潜力在使用绵羊 8-mm 干骺端钻孔骨缺损的研究中进行了测试。手术后 3 周和 6 周的组织形态计量学分析表明，与用不含 IGF-I 的 PL（G）A MS 填充的缺陷（n=4）相比，局部用 IGF-I-PL（G）A MS 处理的缺陷中的新骨形成得到了改善（n=5）。尽管没有明显的关系，但新骨形成的程度受到特定释放动力学的影响。局部给予 IGF-I 导致所有接受 IGF-I 治疗的缺陷中炎症标志物基因的下调。生长因子基因的过表达是对 IGF-I 递送的反应，仅限于产生成骨反应的制剂。这些实验证明了持续 IGF-I 递送的成骨潜力，并表明递送动力学对于成功的 IGF-I 基疗法的重要性。
