Injectable and Moldable Composite Bone Scaffolds for Spinal Fusion

项目总结/摘要 肌肉骨骼护理中的许多临床情况，包括脊柱关节固定术， 治疗包含性缺损（骨中的孔）、非包含性缺损（缺失节段）的重建策略 或通过骨生成空间（骨通常不会生长的地方）进行融合。新型矫形器 可生物降解的聚合物复合支架中的生物材料是候选材料， 满足这些要求，而推动这些材料开发的目标是 增强并最终消除目前自体移植和同种异体骨移植策略， 骨骼部位。在过去的十年里，我们的实验室在三维（3-D）方面做了大量的工作 预成型骨支架并将其转化为临床相关的节段性骨的大型动物模型 缺陷修复目前的建议集中在翻译我们的可注射和可塑性骨支架 通过三个综合目标，致力于脊柱融合的初步人类应用。在目标1中，我们将进一步优化 我们的生物相容性，可生物降解和自交联富马酸酯聚合物套件的成员 生物材料网络，通过聚（富马酸丙二醇酯）（PPF）和聚（己内酯）（PCL）的交联， 无催化剂点击化学（PPF/PCL）。该网络将纳入骨传导纳米羟基磷灰石 （纳米HA）和可降解水凝胶致孔剂，包裹血管内皮生长因子（VEGF）， 骨形态发生蛋白-2（BMP-2）。含有VEGF的水凝胶将比BMP降解得更快- 包含水凝胶以实现血管生成和骨诱导因子的双重、顺序递送， 两阶段孔隙生成复合PPF/PCL制剂将分别优化用于注射 和可模制的骨支架，其基于流变学和处理性能、机械 性能、孔隙率和互连性、降解速率和生长因子释放曲线。在目标2中， 将确定可注射和可模塑的PPF/PCL支架制剂在兔中的体内作用 椎体间和后外侧脊柱融合模型。由于黄金标准自体移植 骨，可能会导致供体部位发病，并且在某些情况下融合率可能不佳，脊柱融合是 通常被认为是骨移植替代品最具挑战性的应用之一，因此我们可以批判性地 评估优化的候选支架植入物制剂。在目标3中，我们将评估 PPF/PCL复合材料支架在临床相关人类外科手术的大型动物模型中的性能 程序作为向最初人类使用的转化步骤。我们选择了一只羊单侧后 脊柱椎弓根螺钉内固定重建模型，包括后路椎间融合术、 后外侧横突间融合，或同时合并这些融合过程 水平，利用我们的可注射和可成型的支架策略来实现这些目标。

Project Summary/Abstract Many clinical situations in musculoskeletal care, including spinal arthrodesis procedures, require a bone reconstruction strategy to treat contained defects (a hole in a bone), non-contained defects (a missing segment of bone), or fusion across bone generation spaces (where bone would not normally grow). 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 augmentation and eventual elimination of current autograft and allograft bone strategies for transplantation into skeletal sites. For the past decade, our laboratory has done extensive work on three-dimensional (3-D) preformed bone scaffolds and transitioned them to clinically relevant large animal models for segmental bone defect repair. The current proposal focuses on the translation of our injectable and moldable bone scaffold work toward initial human use in spinal fusion via three integrated aims. In Aim 1, we will further optimize members of our suite of biocompatible, biodegradable, and self-crosslinkable fumarate ester polymeric biomaterial networks by inter-crosslinking of poly(propylene fumarate) (PPF) and poly(caprolactone) (PCL) via catalyst-free click chemistry (PPF/PCL). The network will incorporate osteoconductive nano-hydroxyapatite (nano-HA) and degradable hydrogel porogens that encapsulate vascular endothelial growth factor (VEGF) and bone morphogenetic protein-2 (BMP-2). The VEGF-containing hydrogel will degrade faster than the BMP- containing hydrogel to achieve dual, sequential delivery of angiogenic and osteoinductive factors coupled with two-stage porosity generation. The composite PPF/PCL formulations will be optimized separately for injectable and moldable bone scaffolds based on success criteria in rheological and handling properties, mechanical properties, porosity and interconnectivity, degradation rates, and growth factor release profiles. In Aim 2, we will determine the in vivo effect of the injectable and moldable PPF/PCL scaffold formulations in rabbit interbody and posterolateral spinal fusion models, respectively. Due to the fact that the gold standard, autograft bone, may incur donor site morbidity and can have a suboptimal fusion rate in some situations, spinal fusion is often considered one of the most challenging applications of bone graft substitutes, thus allowing us to critically evaluate the optimized candidate scaffold implant formulations. In Aim 3, we will assess the bone regeneration performance of PPF/PCL composite scaffolds in a large animal model of clinically relevant human surgical procedures as a translational step toward initial human use. We have selected a sheep unilateral posterior spine pedicle screw instrumented reconstruction model, consisting of either a posterior interbody fusion, a posterolateral intertransverse process fusion, or a combination of both these fusion processes at the same level, utilizing our injectable and moldable scaffold strategies to accomplish these goals.