Model of Human Disc Regeneration in the spectrum of Degenerative Disc Disease

描述(申请人提供)：腰间盘(IVD)退变是腰痛的主要或次要原因，相关的医疗费用每年至少从200到1000亿美元不等，但手术治疗方案并不侧重于防止退变或修复腰椎间盘。这项研究的最终临床目标是提供早期和微创的干预措施，以减缓或逆转退变的进展，并最终再生IVD。有强有力的证据表明，诊断性椎间盘造影术导致了IVD的退变，但对于针损伤如何损害IVD，人们知之甚少。向IVD内注射治疗药物是一项非常有前途的技术，正在进行生长因子和抗炎治疗的临床试验，但令人惊讶的是，使用大型动物和人体模型来告知如何优化此类治疗方法的基础科学知识很少。总的假设是，生物力学改变、生物合成的分解代谢变化和炎症都是相互作用的因素，必须解决这些因素才能为IVD变性制定最佳修复策略。目的1将描述和验证牛整个IVD器官培养模型的早期变性，同时提供与注射和炎症相关的共同发病的更多机制的理解。目的2将确定以抗炎治疗为重点的牛损伤模型的治疗干预的最佳条件，包括运输和摄取、剂量优化和修复实验。人类完整IVD外植体模型的开发是一项重要的技术进步，已被专家们公认为与临床条件具有高度相关性。因此，将在目标3中应用优化的治疗方法，以确定对退行性人类静脉畸形进行有效治疗干预的可能性。初步结果表明，我们在大型动物体外培养中保持完整的IVD外植体至少21天的丰富经验。针刺损伤和外源性TNFa的加入引起了不同的生物力学和生物学变化。我们还从身体解剖中获得了可靠的活体人类IVD来源，并成功地在培养中保持了这一来源。我们的因变量测量侧重于生物力学、分解代谢变化、炎症和疼痛相关因素。拟议的工作将解决：生长因子的疗效如何依赖于IVD的完整性和炎症状态？注射生长因子能刺激退行性人类IVD的合成代谢吗？能持续多久？生物力学修复和抗炎治疗能否优化以增强修复策略？解决这些问题将有助于了解和改进临床治疗，对大型动物和人类IVD的IVD损伤和治疗策略有更多的机械性理解。

DESCRIPTION (provided by applicant): Intervertebral disc (IVD) degeneration is a primary or secondary cause of low back pain with associated medical costs ranging from at least $20 to $100 billion annually, yet surgical treatment options do not focus on preventing degeneration or repairing discs. The ultimate clinical goal of this research is to provide early and minimally invasive interventions to slow or reverse progression of degeneration and eventually regenerate IVDs. There is strong evidence of IVD degeneration caused by diagnostic discography yet relatively little is known about how needle injury damages IVDs. Needle injection of therapeutics into the IVD is a very promising technique that is reaching clinical trials for growth factor and anti-inflammatory treatments yet there is surprisingly little basic science knowledge using large animal and human models to inform how such treatments should be optimized. The overall hypothesis is that altered biomechanics, catabolic shifts in biosynthesis, and inflammation are interacting factors that must all be addressed to develop optimal repair strategies for IVD degeneration. Aim 1 will characterize and validate bovine whole IVD organ culture models of early degeneration while providing a more mechanistic understanding of co-morbidity associated with needle injection and inflammation. Aim 2 will determine optimal conditions for therapeutic interventions into bovine injury models focused on anti-inflammatory treatments including transport and uptake, dose optimization, and repair experiments. The development of a human whole IVD explant model is an important technical advance that has been acknowledged by experts to have high relevance to the clinical condition. The optimized treatment methods will therefore be applied in Aim 3 to determine the potential for effective treatment interventions on degenerated human IVDs. Preliminary results demonstrate our extensive experience maintaining whole IVD explants from large animals in culture at least 21 days. Distinct biomechanical and biological alterations were measured in response to needle puncture injuries and the addition of exogenous TNFa. We also have a reliable source of live human IVDs from autopsy that we successfully maintained in culture. Our dependent variable measurements focus on biomechanics, catabolic shifts, inflammation, and pain-related factors. The proposed work will address: How does growth factor efficacy depend on IVD integrity and inflammatory state? Does growth factor injection stimulate anabolic biosynthesis in degenerated human IVDs and for how long? Can biomechanical repair and anti-inflammatory treatments be optimized to enhance repair strategies? Addressing these questions will help inform and improve clinical treatments with a more mechanistic understanding of IVD injuries and treatment strategies in large animal and human IVDs.