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

描述（由申请人提供）：椎间盘退变是腰痛的主要或次要原因，相关医疗费用每年至少为200亿至1000亿美元，但手术治疗选择并不侧重于预防退变或修复椎间盘。本研究的最终临床目标是提供早期和微创干预，以减缓或逆转变性的进展，最终使ivd再生。有强有力的证据表明，诊断性椎间盘造影导致IVD变性，但相对而言，针头损伤如何损害IVD知之甚少。静脉内静脉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，使用大型动物和人类模型来告知如何优化此类治疗的基础科学知识很少。总的假设是，改变的生物力学、生物合成中的分解代谢变化和炎症是相互作用的因素，必须解决这些因素，以制定最佳的IVD退变修复策略。目的1将表征和验证早期退变的牛全IVD器官培养模型，同时提供与针头注射和炎症相关的合并症的更多机制理解。目的2将确定治疗干预牛损伤模型的最佳条件，重点是抗炎治疗，包括运输和摄取，剂量优化和修复实验。人类全IVD外植体模型的开发是一项重要的技术进步，已被专家公认为与临床状况具有高度相关性。因此，优化的治疗方法将在Aim 3中应用，以确定对退化的人类ivd进行有效治疗干预的潜力。初步结果表明，我们拥有丰富的经验，可以将大型动物的整个IVD外植体培养至少21天。针刺损伤和外源性TNFa的加入，测量了不同的生物力学和生物学变化。我们也有可靠的活体活体ivd来源，我们成功地在培养中保存了这些活体ivd。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：生长因子的功效如何依赖于IVD完整性和炎症状态？生长因子注射能刺激退化性ivd的合成代谢生物合成吗？刺激多长时间？生物力学修复和抗炎治疗是否可以优化以增强修复策略？解决这些问题将有助于通过对大型动物和人类IVD损伤和治疗策略的更机械的理解来告知和改进临床治疗。

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.