Injectable and Moldable Composite Bone Scaffolds for Spinal Fusion

项目摘要/摘要 肌肉骨骼护理中的许多临床情况，包括脊柱关节融合术，都需要骨骼。 治疗包含的缺陷(骨头上的洞)、非包含的缺陷(缺失的节段)的重建策略 骨)，或跨骨生成空间(骨通常不会生长的地方)融合。新型骨科 影响引导骨生长成为可生物降解的聚合物复合支架的生物材料是候选材料 以满足这些要求，而推动这些材料开发的目标是 增强和最终消除当前移植自体骨和同种异体骨的策略 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 预制骨支架并将其移植到临床相关的节段性骨的大型动物模型 缺陷修复。目前的提案集中在我们的可注射和可模塑的骨支架的翻译上 通过三个综合目标致力于人类在脊柱融合中的初步应用。在目标1中，我们将进一步优化 我们的生物相容、可生物降解和可自交联富马酸酯聚合物套件的成员 聚富马酸丙二酯(PPF)和聚己内酯(PCL)通过交联形成生物材料网络 无催化剂点击化学(PPF/PCL)。该网络将包括具有骨传导功能的纳米羟基磷灰石。 (Nano-HA)和可降解的水凝胶造孔剂，包裹血管内皮生长因子(VEGF)和 骨形态发生蛋白2(BMP-2)。含有血管内皮生长因子的水凝胶的降解速度会快于骨形态发生蛋白- 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 两段式孔隙度生成。PPF/PCL复合配方将分别针对注射用进行优化 以及基于成功标准的流变性和可操作性、机械性能的可模塑骨支架 特性、孔隙率和互连性、降解率和生长因子释放谱。在目标2中，我们 将确定可注射和可模塑的PPF/PCL支架配方在兔体内的效果 椎间融合模型和后外侧融合模型。因为金本位，自体移植 骨，可能导致供区病变，在某些情况下融合率可能不佳，脊柱融合术是 通常被认为是骨移植替代品最具挑战性的应用之一，因此允许我们关键地 评估优化的候选支架植入物配方。在目标3中，我们将评估骨再生 PPF/PCL复合支架在临床相关人类外科大动物模型中的应用 程序作为人类最初使用的翻译步骤。我们选择了一只单侧后部的绵羊 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，或同时进行这两种融合 利用我们的可注射和可模塑支架战略来实现这些目标。

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.