Injectable and Moldable Composite Bone Scaffolds for Spinal Fusion

用于脊柱融合的可注射和可成型复合骨支架

基本信息

批准号：
10089684
负责人：
Lichun Lu
金额：
$ 5.05万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-05 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10089684
关键词：
3-Dimensional 3D Print Address Angiogenic Factor Animal Model Animals Anterior Applications Grants Arthrodesis Autologous Transplantation Biocompatible Materials Bone Growth Bone Regeneration Bone Transplantation Caring Chemistry Clinical Coupled Defect Dental Dental Models Development Devices Dorsal Encapsulated Esters Exhibits Formulation Fumarates Funding Generations Goals Gold Growth Factor Human Hydrogels Hydroxyapatites Implant In Situ Injectable Injections Institutional Review Boards Investigation Laboratories Ligaments Mandible Mechanics Medial Minimally Invasive Surgical Procedures Modality Modeling Molds Morbidity - disease rate Motion Musculoskeletal Natural regeneration Nerve Operative Surgical Procedures Oral Orthopedics Oryctolagus cuniculus Osteogenesis Otolaryngology Patients Performance Plant Roots Polymers Porosity Procedures Process Property Psoas Muscles Research Savings Shapes Sheep Site Solid Specific qualifier value Spinal Spinal Fusion Structure System Techniques Testing Time Translating Translations Transplantation United States National Institutes of Health Vascular Endothelial Growth Factors Vertebral column Viscosity Work allogenic bone transplantation base biodegradable polymer biomaterial compatibility bone bone morphogenetic protein 2 caprolactone catalyst clinically relevant controlled release craniofacial crosslink design first-in-human healing in vivo instrument maxillofacial mechanical properties member migration minimally invasive nano novel osteoinductive factor poly(propylene fumarate)pre-clinical programs reconstruction regenerative release factor repaired scaffold skeletal spine bone structure success three dimensional structure

项目摘要

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.

项目概要/摘要肌肉骨骼护理的许多临床情况，包括脊柱关节固定术，都需要骨头用于治疗包含性缺陷（骨头上的孔）、非包含性缺陷（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）的融合。新型骨科影响引导骨生长成可生物降解聚合物复合支架的生物材料是候选材料为了满足这些要求，推动这些材料开发的目标是增强并最终消除当前的自体移植和同种异体移植骨移植策略骨骼部位。在过去的十年中，我们的实验室在三维 (3-D) 方面做了广泛的工作预制骨支架并将其转化为临床相关的大型动物模型用于节段骨缺陷修复。当前提案的重点是我们的可注射和可模制骨支架的翻译通过三个综合目标，努力实现脊柱融合术在人类中的初步应用。在目标1中，我们将进一步优化我们的生物相容性、可生物降解性和可自交联的富马酸酯聚合物套件的成员通过聚（富马酸丙烯酯）（PPF）和聚（己内酯）（PCL）相互交联形成生物材料网络无催化剂点击化学（PPF/PCL）。该网络将采用骨传导纳米羟基磷灰石（纳米 HA）和可降解水凝胶致孔剂，封装血管内皮生长因子（VEGF）和骨形态发生蛋白-2 (BMP-2)。含有 VEGF 的水凝胶比 BMP 降解得更快含有水凝胶以实现血管生成和骨诱导因子的双重连续递送，并结合两阶段孔隙度生成。复合 PPF/PCL 配方将针对注射剂单独进行优化以及基于流变学和操作性能、机械性能的成功标准的可模制骨支架特性、孔隙率和互连性、降解率和生长因子释放曲线。在目标 2 中，我们将确定可注射和可模塑的 PPF/PCL 支架制剂在兔子体内的体内效果分别是椎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，并且在某些情况下可能具有次优的融合率，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，因此使我们能够批判性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体手术大型动物模型中的性能程序作为最初人类使用的转化步骤。我们选择了羊单侧后路脊柱椎弓根螺钉器械重建模型，包括后路椎间融合器、后外侧横突间融合，或同时结合这两种融合过程水平，利用我们的可注射和可模制支架策略来实现这些目标。