Injectable and Preformed Osteoinductive Biodegradable Composites

描述（由申请人提供）：肌肉骨骼护理的许多临床情况需要骨重建策略。新型的骨科生物材料可以引导骨生长到可生物降解的聚合物复合支架中，这是解决这些需求的候选材料，而推动这些材料发展的目标是最终消除自体移植骨移植到骨骼再生部位。在过去的十年中，我们的实验室在原位可聚合材料的合成和表征，细胞-生物材料相互作用的体外评估以及小动物模型中支架功能的体内评估方面做了大量的工作。本提案的重点是通过三个综合目标将我们的骨组织工程工作转化为最初的人类应用。在Aim 1中，我们将血管内皮生长因子（VEGF）和骨形态发生蛋白-2 （BMP-2）包封在两个降解率不同的水凝胶孔隙原中，设计在自交联聚（富马酸丙烯）-共聚（己内酯）（PPF-co-PCL）复合生物材料支架中产生两个顺序的孔隙系统。这种双重孔隙的产生将影响血管生成因子和骨诱导因子的双重顺序传递，以提供初始血管网络，支持随后的成骨过程。在Aim 2中，我们将在兔后外侧脊柱融合模型中确定PPF-co-PCL复合支架对骨形成的体内影响。我们将在该模型中评估可注射和预制支架策略。可注射策略包括将聚合支架制剂注射到骨缺损中以形成复合生物材料。预制策略利用固体自由形状制造制造具有特定尺寸、形状和内部微结构的复合生物材料植入物。这种复合生物材料植入物的设计目标是制造一个三维支架，指导骨再生过程，并在聚合物降解和新骨形成过程中为重建区域提供机械支持。在Aim 3中，我们将在临床相关的人类外科手术的大型动物模型中评估PPF-co-PCL复合支架的骨再生性能，作为初步用于人类的转化步骤。我们选择了羊脊柱前后重建，包括后外侧横突融合和前骨间隙（椎间盘切除术/椎体切除术）重建，利用我们的可注射和预成型支架策略来实现这一目标。

DESCRIPTION (provided by applicant): Many clinical situations in musculoskeletal care require a bone reconstruction strategy. Novel orthopaedic biomaterials that effect guided bone growth into biodegradable polymeric composite scaffolds are candidates to address such requirements, and the goal that has motivated the development of these materials is the eventual elimination of autograft bone harvest for transplantation into skeletal regeneration sites. For the past decade, our laboratory has done extensive work on the synthesis and characterization of in situ polymerizable materials, in vitro evaluation of cell-biomaterial interactions, and in vivo assessment of scaffold function in small animal models. This proposal focuses on the translation of our bone tissue engineering work toward initial human use via three integrated aims. In Aim 1, we will encapsulate vascular endothelial growth factor (VEGF) and bone morphogenetic protein-2 (BMP-2) into two hydrogel porogens that have different degradation rates, designed to generate two sequential pore systems in the self-crosslinking poly(propylene fumarate)-co- poly(caprolactone) (PPF-co-PCL) composite biomaterial scaffold. This dual porosity generation will affect dual, sequential delivery of angiogenic and osteoinductive factors to provide an initial vascular network that will support the subsequent osteogenic process. In Aim 2, we will determine the in vivo effect of PPF-co-PCL composite scaffolds on bone formation in a rabbit posterolateral spine fusion model. We will evaluate both injectable and preformed scaffold strategies in this model. The injectable strategy involves injection of a polymerizing scaffold formulation into a bony defect to form a composite biomaterial. The preformed strategy utilizes solid freeform fabrication to manufacture a composite biomaterial implant that has a specified size, shape, and internal microarchitecture. The design goal for this composite biomaterial implant is to fabricate a three-dimensional scaffold that directs the bone regeneration process and provides mechanical support to the reconstructed region during polymer degradation and new bone formation. In Aim 3, we will assess the bone regeneration performance of PPF-co-PCL composite scaffolds in a large animal model of a clinically relevant human surgical procedure as a translational step toward initial human use. We have selected an anterior- posterior sheep spine reconstruction, consisting of both a posterolateral intertransverse process fusion and an anterior skeletal gap (discectomy/vertebrectomy) reconstruction, utilizing our injectable and preformed scaffold strategies to accomplish this goal.