Integrated Structural BMP2 Carrier Systems for Cervical Spine Fusion (resubmissi

描述（由申请人提供）：本项目的目的是研究一种新型的完全生物可吸收的集成结构/递送支架，用于颈椎融合术中的BMP 2受控递送。2008年仅在美国就进行了超过230，000例颈椎融合术，占所有脊柱融合术的41%。由于腰椎融合术的临床结局得到改善，同时无需采集移植物，因此颈椎融合术的标签外使用显著增加。然而，包括死亡在内的严重不良反应与BMP 2在颈椎融合中的使用有关，促使FDA警告不要在颈椎融合中使用BMP 2，如纽约和华尔街日报报道的那样。广泛假设这些不良反应是由于高BMP 2剂量、不良BMP 2保留和当前批准的胶原海绵载体不受控制的BMP 2释放，其允许BMP 2扩散到周围软组织中，伴随相关的血管水肿和异位骨形成增加。我们的实验室已经开发了整合拓扑优化，生物可吸收聚合物固体自由成型制造，BMP 2结合和生物可吸收固定的技术，以开发用于颈椎融合的新结构/递送系统。我们将设计这种新的结构/输送系统，并在颈椎融合的大型临床前（猪）动物模型中测试BMP 2的输送。我们假设拓扑优化的整合多孔结构载体具有接近椎骨小梁骨的表面积和机械模量，并且渗透性大于10-8 m4/Ns，结合低于临床剂量（0.5 mg）BMP 2将在融合时间方面提供上级融合，和融合块体积和刚度，与目前通过结合或FDA批准的胶原海绵递送BMP 2的临床颈椎融合器设计相比。我们将通过单独比较优化和临床融合器设计，结合BMP 2递送和胶原海绵递送来检验这一假设。这些实验组将使我们能够专门测试新系统是否使用不同的BMP 2输送方法提供更好的载荷分布以及更好的骨形成控制。该提案的成功完成将为颈椎生物可吸收融合系统提供新的范例，以更低，更安全，更便宜的BMP 2剂量实现脊柱融合。 公共卫生相关性：该提案旨在开发一种集成结构的BMP 2输送车辆，该车辆针对机械承载和BMP 2输送同时进行优化。该项目旨在验证我们的假设，即这种集成结构载体可以通过更有效地输送BMP 2提供更安全、更有效、更低成本的颈椎融合器械。具体而言，我们假设使用拓扑优化方法设计的该器械在减少下沉、更局部化的骨形成和机械稳定性方面比传统箱式融合器设计通过胶原海绵输送BMP 2可提供上级融合结局。

DESCRIPTION (provided by applicant): The purpose of this project is to investigate a novel completely bioresorbable integrated structural/delivery scaffold for controlled BMP2 delivery in cervical spine fusion. Over 230,000 cervical spine fusions were performed in the US alone in 2008, accounting for 41% of all spine fusions. Due to enhanced clinical outcomes in lumbar spine fusion while simultaneously eliminating the need for graft harvest, off label usage increased significantly in cervical spine fusion. However, severe adverse effects including death were associated with BMP2 usage in cervical spine fusion, prompting the FDA to warn against BMP2 use in cervical spine fusion, as reported by the New York Times and Wall Street Journal. It is widely hypothesized that these adverse effects are due to high BMP2 dosages, poor BMP2 retention and uncontrolled BMP2 release by the currently approved collagen sponge carrier that allows BMP2 diffusion into surrounding soft tissues, with associated increased vascular edema and ectopic bone formation. Our laboratory has developed technology integrating topology optimization, bioresorbable polymer solid free-form fabrication, BMP2 conjugation, and bioresorbable fixation to develop a new structural/delivery system for cervical spine fusion. We will engineer this new structural/delivery system and test the delivery of BMP2 in a large pre-clinical (pig) animal model of cervical spine fusion. We hypothesize that topology optimized integrated porous structural carriers with surface area and mechanical modulus close to vertebral trabecular bone and a permeability greater than 10-8 m4/Ns conjugated with lower than clinical dosages (0.5 mg) of BMP2 will provide superior fusion in terms of time to fusion, and fusion mass volume and stiffness compared to current clinical cervical cage designs delivering BMP2 via conjugation or FDA approved collagen sponge. We will test this hypothesis by comparing optimized and clinical cage designs alone, with conjugated BMP2 delivery and with collagen sponge delivery. These experimental groups will allow us to specifically test if the new system provides both better load carrying distribution as well as better controlled bone formation using a different BMP2 delivery method. Successful completion of this proposal will provide a new paradigm for bioresorbable fusion systems in the cervical spine, achieving spinal fusion with lower, safer, and less expensive doses of BMP2. PUBLIC HEALTH RELEVANCE: This proposal aims to develop an integrated structural BMP2 delivery vehicle that is optimized for mechanical load bearing and BMP2 delivery simultaneously. The project is designed to test our hypothesis that this integrated structural carrier can provide a safer, more effective, lower cost cervical fusion device by more efficaciously delivering BMP2. Specifically, we hypothesize that this device designed using topology optimization methods can provide superior fusion outcomes in terms of reduced subsidence, more localized bone formation, and mechanical stability than traditional box fusion cage designs delivering BMP2 via collagen sponges.