Integrated Structural BMP2 Carrier Systems for Cervical Spine Fusion

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，用于颈椎融合中BMP2的可控递送。2008年仅在美国就进行了超过23万例颈椎融合手术，占所有脊柱融合手术的41%。由于腰椎融合的临床结果增强，同时消除了移植物收获的需要，因此在颈椎融合中的非标签使用显著增加。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对颈椎融合术中使用BMP2发出警告。人们普遍假设，这些不良反应是由于BMP2剂量高、BMP2潴持差以及目前批准的胶原海绵载体释放BMP2不受控制，使BMP2扩散到周围软组织，从而增加血管水肿和异位骨形成。我们的实验室已经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结合和生物可吸收固定的技术，以开发一种新的颈椎融合结构/递送系统。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，其表面积和力学模量接近椎小梁骨，渗透率大于10-8 m4/Ns，结合低于临床剂量（0.5 mg）的BMP2，与目前临床设计的通过结合或FDA批准的胶原海绵提供BMP2的颈椎笼设计相比，在融合时间、融合质量、体积和刚度方面提供更好的融合。我们将通过比较优化和临床笼设计，结合BMP2传递和胶原蛋白海绵传递来验证这一假设。这些实验组将允许我们专门测试新系统是否提供更好的负载分布以及使用不同的BMP2传递方法更好地控制骨形成。该建议的成功完成将为颈椎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。

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.