Osteoinductive Injectable Degradable Polymeric Scaffold

可以注射到骨缺损中并原位交联的可生物降解的聚合物支架可以提供 外科医生为几种临床情况提供微创治疗选择，其中包括节段性骨骼 缺损和后路脊柱融合。支架设计参数包括生物相容性、流变性能， 确定可注射性、降解速率和最终产物、机械性能和骨诱导性。我们 假设1）由聚丙烯互交联形成互穿聚合物网络（IPN 富马酸酯）（PPF），它含有不饱和双键的原位交联，和一种新的聚（己内酯 在其主链中含有柔性聚（己内酯）大分子单体的聚（富马酸酯）（PCLF）可以在聚合物中自交联。 不存在交联剂，2）使用可降解水凝胶微球作为孔隙率产生剂 该方法将改善支架的可注射性并消除固体致孔剂从支架扩散的步骤。 在用于孔隙生成的沥滤技术中所需的支架，和3）骨形态发生的受控递送 可以优化骨再生部位支架中的BMP-2蛋白，以最大限度地利用 这种分子的骨诱导特性。因此，我们建议解决自我交叉的问题， 生长因子的降解、可注射性和受控递送。在第一个目标中，自交联和 研究了一种新型PPF/PCLF IPN的降解特性，以消除交联剂的使用 在注射系统中。在这个目标中，我们也将合成天然的和合成的可生物降解的水凝胶， 作为致孔剂来改善支架在注射过程中的流变特性。在第二个目标中，BMP-2将是 包封在可生物降解的PPF/PLGA共混物微球中，微球将固定在微球中。 IPN/水凝胶复合支架，我们将研究生长因子的释放动力学以及其 生物活性在第三个目标中，作为致孔剂的水凝胶的组成将通过测量在多孔介质中的离子浓度来优化。 骨髓基质细胞（MSC）通过候选致孔剂的体外迁移率。MSC在体外的功能将 用于优化复合支架中BMP-2微球的负载量。这将发生在 测量MSC的增殖以及碱性磷酸酶和骨钙素的分泌， BMP从支架中释放。在第四个目标中，大鼠节段性缺损模型和兔后外侧脊柱 将使用融合模型来评估负载BMP-2的IPN/水凝胶复合支架的能力 微球以在体内诱导骨形成。

Biodegradable polymeric scaffolds that can be injected into a bone defect and crosslinked in situ may provide surgeons with minimally invasive treatment options for several clinical situations, among them segmental skeletal defects and posterior spinal fusion. Scaffold design parameters include biocompatibility, rheologic propertries that detrermine injectability, degradation rate and end products, mechanical properties, and osteoinductivity. We hypothesize that 1) interpenetrating polymer networks (IPN) formed by inter-crosslinking of poly(propylene fumarate) (PPF), which contains unsaturated double bonds for in situ crosslinking, and a novel poly(caprolactone fumarate) (PCLF), which contains flexible poly(caprolactone) macromers in its backbone, may self-crosslink in the absence of a crosslinking agent, 2) the use of degradable hydrogel microspheres as the porosity generating method would both improve the scaffold's injectability and eliminate the step of solid porogen diffusion from the scaffold needed in leaching techniques for pore generation, and 3) controlled delivery of bone morphogenic protein (BMP-2) from the scaffold at the bone regeneration site could be optimized to take maximum advantage of this molecule's osteoinductive properties. Therefore, we propose to address the issues of self-crossllnking, degradation, injectability, and controlled delivery of growth factors. In the first aim, the self-crosslinking and degradation characteristics of a novel PPF/PCLF IPN will be investigated to eliminate the use a crosslinking agent in injectable systems. In this aim, we will also sytnthesize natural and synthetic biodegradable hydrogels for use as porogens to improve the scaffold's rheological properties during injection. In the second aim, BMP-2 will be encapsulated in biodegradable PPF/PLGA blend microspheres, the microspheres will be immobilized in the IPN/hydrogel composite scaffold, and we will study the release kinetics of the growth factor as well as its bioactivity. In the third aim, the composition of the hydrogel as the porogen will be optimized by measuring the in vitro migration rate of marrow stromal cells (MSC) through candidate porogens. The function of MSCs in vitro will be used to optimize the loading dose of BMP-2 microspheres in the composite scaffold. This will occur by measuring the MSC's proliferation and secretion of both alkaline phosphatase and osteocalcin in response to BMP released from the scaffold. In the fourth aim, a rat segmental defect model and a rabbit posterolateral spine fusion model will be used to assess the ability of the IPN/hydrogel composite scaffold with loaded BMP-2 microspheres to induce bone formation in vivo.