Integrated Structural BMP2 Carrier Systems for Cervical Spine Fusion (resubmissi

用于颈椎融合的集成结构 BMP2 载体系统（重新提交

• 批准号: 8239266
• 负责人: Scott J Hollister
• 金额: $ 52.03万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-17 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8239266
• 关键词: Accounting; Adverse effects; Allografting; Animal Model; Anterior; Area; Autologous Transplantation; BMP2 gene; Binding; Blood Vessels; Bolus Infusion; Bone Matrix; Bone Regeneration; Boxing; Cervical; Cervical spine; Cessation of life; Characteristics; Clinical; Clinical Research; Collagen; Collagen Type I; Deglutition Disorders; Device Designs; Devices; Diffusion; Dose; Edema; Effectiveness; Engineering; FDA approved; Family suidae; Fatigue; Harvest; Health; Histology; Human; Journals; Label; Laboratories; Left; Life; Mechanics; Methods; Modeling; Morbidity - disease rate; New York; Osteogenesis; Outcome; Outcome Measure; Pain; Permeability; Porifera; Procedures; Reporting; Risk; Rosa; Safety; Sales; Solid; Solutions; Spinal; Spinal Fusion; Surface; Swelling; System; Technology; Testing; Time; Tissue Engineering; Titania; Titanium; Treatment Efficacy; Vertebral column; Weight-Bearing state; biodegradable polymer; controlled release; cost; design; disease transmission; dosage; innovation; novel; pre-clinical; recombinant human bone morphogenetic protein-2; sample fixation; scaffold; soft tissue; spine bone structure; substantia spongiosa; success

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.

描述(申请人提供)：本项目的目的是研究一种新型的可完全生物吸收的一体化结构/输送支架，用于在颈椎融合术中控制BMP2的输送。2008年，仅在美国就进行了超过230,000例颈椎融合手术，占所有脊柱融合手术的41%。由于腰椎融合术中临床结果的改善，同时消除了对移植物采集的需要，非标记物在颈椎融合术中的使用显著增加。然而，据《纽约时报》和《华尔街日报》报道，在颈椎融合术中使用BMP2会产生包括死亡在内的严重不良反应，促使FDA警告不要在颈椎融合术中使用BMP2。人们普遍认为，这些不良反应是由于BMP2剂量高、BMP2保留率低以及目前批准的胶原海绵载体释放BMP2不受控制所致，这种载体允许BMP2扩散到周围软组织，并伴随着血管水肿和异位骨形成的增加。我们实验室开发了集拓扑优化、生物可吸收聚合物固体自由形式制造、BMP2连接和生物可吸收固定于一体的技术，开发了一种新的颈椎融合结构/输送系统。我们将设计这一新的结构/传递系统，并在大型临床前(猪)动物颈椎融合模型中测试BMP2的传递。我们假设，拓扑优化的集成多孔性结构载体具有接近椎体松质骨的表面积和机械模数，渗透性大于10-8M4/NS，结合低于临床剂量(0.5 mg)的BMP2将在融合时间、融合质量和硬度方面提供更好的融合，与目前通过结合或FDA批准的胶原海绵提供BMP2的临床颈椎融合器设计相比。我们将通过比较优化的和临床的支架设计，结合BMP2输送和胶原海绵输送来检验这一假说。这些试验组将允许我们专门测试新系统是否使用不同的BMP2输送方法提供更好的承载分布和更好的骨形成控制。这项提议的成功完成将为颈椎的生物可吸收融合系统提供一个新的范例，用更低、更安全、更便宜的BMP2剂量实现脊柱融合。 与公共健康相关：这项提议旨在开发一种集成的结构性BMP2输送工具，该载体同时优化了机械承载和BMP2输送。该项目旨在验证我们的假设，即这种集成的结构载体可以通过更有效地传递BMP2来提供更安全、更有效、更低成本的颈椎融合器。具体地说，我们假设，使用拓扑优化方法设计的这种装置在减少下沉、更局部的骨形成和机械稳定性方面可以提供比传统的通过胶原海绵输送BMP2的盒式融合器设计更好的融合结果。