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（由申请人提供）：该项目的目的是研究一种完全可生物吸收的整合结构/递送支架，以用于颈椎融合中的受控BMP2递送。仅在2008年，仅在美国就进行了超过230,000个颈椎融合，占所有脊柱融合的41％。由于腰椎融合的临床结局增强，同时消除了对移植收获的需求，因此在颈椎融合中，关闭标签使用率显着增加。然而，正如《纽约时报》和《华尔街日报》报道的那样，包括死亡在内的严重不良反应与颈椎融合中的BMP2使用有关，促使FDA警告不要在颈椎融合中使用BMP2。人们普遍认为，这些不良反应是由于当前批准的胶原蛋白海绵载体较高的BMP2剂量，较差的BMP2保留和不受控制的BMP2释放，从而允许BMP2扩散到周围的软组织中，并具有相关的血管水肿和电位骨形成增加。我们的实验室已经开发了整合拓扑优化，可生物吸收的聚合物固体自由形式制造，BMP2结合和可生物吸收固定的技术，以开发用于颈椎融合的新结构/递送系统。我们将设计这个新的结构/递送系统，并测试BMP2在颈椎融合的大型前（猪）动物模型中的递送。我们假设拓扑优化了具有表面积和机械模量的拓扑优化的多孔结构载体和接近椎骨小梁骨的机械模载体和大于10-8 m4/ns的渗透性与BMP2的临床剂量（0.5 mg）相结合的10-8 m4/ns通过融合量和融合量相比，将提供较低的临床剂量（0.5 mg），并提供融合量的较高量，并提供融合量的高度cag，并将其融合到融合量的情况下，并提供融合量的cciftic clifusion clifify cliftic和融合量。共轭或FDA批准的胶原海绵。我们将仅比较优化和临床笼设计，并与结合的BMP2递送以及胶原蛋白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BMP2递送方法提供更好的负载携带分布以及更好的控制骨形成。该提案的成功完成将为颈椎的生物吸收融合系统提供新的范式，以较低，更安全且价格较低的BMP2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的结构BMP2输送工具，该工具可同时针对机械负载轴承和BMP2交付进行优化。该项目旨在检验我们的假设，即这种集成的结构载体可以通过更有效地提供BMP2来提供更安全，更有效，更低的宫颈融合装置。具体而言，我们假设使用拓扑优化方法设计的该设备比传统的传统盒子融合笼设计的融合式设计可以提供出色的融合结局，而通过胶原蛋白海绵进行BMP2。