Tianjin Key Laboratory of Composite and Functional Materials, School of Materials Science and Engineering, Tianjin University, Tianjin 300072, China.
Biomater Sci. 2019 Mar 26;7(4):1675-1685. doi: 10.1039/c8bm01632a.
Accelerating the healing of bone fractures by local delivery of growth factors possessing osteoinductive activity has been extensively demonstrated. Unfortunately, for some complex clinical fractures, such as osteoporotic vertebral compression fracture, it is not possible to adopt such a strategy because of access restrictions. Systemic administration of growth factors is considered to be an appropriate alternative method due to its easy operability and precise spatiotemporal compatibility at fracture sites. But this therapy method was hampered by the poor in vivo stability, inefficient distribution at the fracture site and potential side effects of growth factors. To address these challenges, we conceived a systemic delivery platform of growth factors based on nanocapsules, taking advantage of the unique physiological character of bone fracture, i.e., the malformed blood vessels and the over-expression of matrix metalloproteinases (MMPs). In this work, bone morphogenetic protein-2 (BMP-2), 2-(methacryloyloxy)ethyl phosphorylcholine (MPC) and the bisacryloylated VPLGVRTK peptide were respectively used as the model growth factor, monomer, and MMP-cleavable crosslinker. Nanocapsules were formed by in situ free radical polymerization on the surface of BMP-2 with MPC and peptides. The structure and function of BMP-2 were well maintained during the preparation process. BMP-2 nanocapsules (n(BMP-2)) were of uniform small size (∼30 nm) possessing a long circulation time (half-life is ∼48 h) and could be passively targeted to the fracture site through malformed blood vessels after systemic administration. Once accumulated at the fracture site, the shells of nanocapsules could be degraded by MMP and thus BMP-2 was released. Animal experiments proved that n(BMP-2) showed a better ability of bone repair than native BMP-2. In addition, n(BMP-2) showed a much lower inflammatory irritation. The results demonstrated that the systemic administration of growth factor nanocapsules could enhance their in vivo stability and fracture site delivery efficiency, realizing the efficient repair of a bone fracture. This rational delivery system may expand the bone repair types which can be administered with growth factors. Furthermore, the concept of taking advantage of the malformed vascular structure to deliver drugs potentially inspires researchers for the therapy of other diseases, especially sudden disease (such as cerebral hemorrhage).
通过局部递送具有成骨活性的生长因子来加速骨折愈合已经得到了广泛的证实。不幸的是，对于一些复杂的临床骨折，如骨质疏松性椎体压缩性骨折，由于进入受限，无法采用这种策略。由于其易于操作和在骨折部位具有精确的时空调控性，全身给予生长因子被认为是一种合适的替代方法。但这种治疗方法受到生长因子体内稳定性差、在骨折部位分布效率低和潜在副作用的限制。为了解决这些挑战，我们基于纳米胶囊设计了一种生长因子的全身递送平台，利用骨折的独特生理特征，即畸形血管和基质金属蛋白酶（MMPs）的过度表达。在这项工作中，骨形态发生蛋白 2（BMP-2）、2-（甲基丙烯酰氧基）乙基磷酸胆碱（MPC）和双丙烯酰化 VPLGVRTK 肽分别用作模型生长因子、单体和 MMP 可切割交联剂。纳米胶囊通过 BMP-2 表面的原位自由基聚合与 MPC 和肽形成。在制备过程中，BMP-2 的结构和功能得到了很好的保持。BMP-2 纳米胶囊（n（BMP-2））具有均匀的小尺寸（约 30nm）、长循环时间（半衰期约为 48h），并可通过全身给药后畸形血管被动靶向骨折部位。一旦在骨折部位积累，纳米胶囊的外壳可被 MMP 降解，从而释放 BMP-2。动物实验证明，n（BMP-2）在骨修复能力方面优于天然 BMP-2。此外，n（BMP-2）表现出低得多的炎症刺激。结果表明，生长因子纳米胶囊的全身给药可以增强其体内稳定性和骨折部位的递送效率，实现骨骨折的有效修复。这种合理的递药系统可能会扩大可以用生长因子治疗的骨修复类型。此外，利用畸形血管结构递药的概念可能会为治疗其他疾病（特别是突发性疾病，如脑出血）的研究人员提供启示。
