Injectable and Preformed Osteoinductive Biodegradable Composites

描述（由申请人提供）：肌肉骨骼护理中的许多临床情况需要骨重建策略。新型骨科生物材料，影响引导骨生长到可生物降解的聚合物复合材料支架是候选人，以解决这些要求，和目标，促使这些材料的发展是最终消除自体移植骨移植到骨骼再生部位的收获。在过去的十年中，我们的实验室已经做了大量的工作，在原位可聚合材料的合成和表征，在体外评价细胞生物材料的相互作用，并在小动物模型中的支架功能的体内评估。该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初步的人类使用。在目标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）包封到具有不同降解速率的两种水凝胶致孔剂中，设计用于在自交联聚（富马酸丙二醇酯）-共-聚（己内酯）（PPF-co-PCL）复合生物材料支架中产生两个连续孔系统。这种双重孔隙率的产生将影响血管生成和骨诱导因子的双重顺序递送，以提供将支持随后的成骨过程的初始血管网络。在目标2中，我们将确定PPF-co-PCL复合支架在兔后外侧脊柱融合模型中对骨形成的体内作用。我们将在该模型中评估可注射和预成型支架策略。可注射策略涉及将聚合支架制剂注射到骨缺损中以形成复合生物材料。预成型策略利用固体自由成型制造来制造具有指定尺寸、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种三维支架，在聚合物降解和新骨形成期间指导骨再生过程并为重建区域提供机械支撑。在目标3中，我们将在临床相关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，作为初步人类使用的转化步骤。我们选择了前后路羊脊柱重建，包括后外侧横突间融合和前骨骼间隙（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。 公共卫生相关性：本项目开发的新型可生物降解聚合物复合支架将为各种大小和形状的骨骼缺损提供新的治疗选择。生物材料将通过在植入预成型支架或注射原位可聚合制剂后诱导骨形成来提供缺损部位的生物重建。这两种应用模式具有明显的优势。预成型支架允许精确控制支架几何形状和内部结构，而可注射支架利用微创手术技术，可以缩短患者的住院时间和更快的恢复。生物材料的可降解性质将不需要植入物回收，节省他们的时间，费用和不便。

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. PUBLIC HEALTH RELEVANCE: The novel biodegradable polymeric composite scaffolds to be developed in this project will offer new treatment options for skeletal defects of various size and shape. The biomaterial will provide biological reconstruction of the defect site by inducing bone formation following either implantation of preformed scaffolds or injection of in situ polymerizable formulations. These two application modalities offer distinct advantages. The preformed scaffolds allow precise control over scaffold geometry and internal architecture, while the injectable scaffolds utilize minimally invasive surgical techniques that can lead to shortened hospital stay and faster recovery for patients. The degradable nature of the biomaterial will not require implant retrieval, saving them time, expense, and inconvenience.