Integrated Structural BMP2 Carrier Systems for Cervical Spine Fusion

用于颈椎融合的集成结构 BMP2 载体系统

• 批准号: 8544773
• 负责人: Scott J Hollister
• 金额: $ 61.35万
• 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/8544773
• 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.

描述（由申请人提供）：该项目的目的是研究一种新型完全生物可吸收的集成结构/递送支架，用于颈椎融合中受控的 BMP2 递送。 2008年仅在美国就进行了超过23万例颈椎融合术，占所有脊柱融合术的41%。由于腰椎融合的临床效果得到改善，同时消除了移植物采集的需要，颈椎融合中的标签外使用显着增加。然而，据《纽约时报》和《华尔街日报》报道，包括死亡在内的严重不良反应与 BMP2 在颈椎融合中的使用有关，促使 FDA 对 BMP2 在颈椎融合中的使用发出警告。人们普遍认为，这些不良反应是由于 BMP2 剂量高、BMP2 保留差以及当前批准的胶原海绵载体不受控制的 BMP2 释放造成的，该载体允许 BMP2 扩散到周围的软组织中，从而导致血管水肿和异位骨形成增加。我们的实验室开发了集成拓扑优化、生物可吸收聚合物固体自由形状制造、BMP2接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/输送系统。我们将设计这种新的结构/递送系统，并在大型临床前（猪）颈椎融合动物模型中测试 BMP2 的递送。我们假设，拓扑优化的集成多孔结构载体，其表面积和机械模量接近椎骨小梁，渗透性大于 10-8 m4/Ns，与低于临床剂量 (0.5 mg) 的 BMP2 结合，将在以下方面提供优异的融合：与目前通过接合或 FDA 批准的胶原海绵提供 BMP2 的临床颈椎融合器设计相比，融合时间、融合质量体积和硬度。我们将通过单独比较优化的笼子设计和临床笼子设计、结合 BMP2 递送和胶原海绵递送来测试这一假设。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分布以及更好控制的骨形成。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、更便宜剂量的 BMP2 实现脊柱融合。