Bioactive Injectable Implants for Functional Intervertebral Disc Regeneration

产品说明： 下背痛会影响高达85%的人在某些时候在他们的生活，导致 美国的医疗保健和相关成本每年超过1000亿美元。在退伍军人中，慢性腰痛占脊椎按摩治疗的70%以上，在许多情况下与他们的服务期直接相关。椎间盘退变是一种渐进的炎症驱动级联反应，导致结构和机械故障，强烈暗示是腰痛的原因。2001年至2010年期间，超过13万名现役军人被诊断出椎间盘退变，这一时期的年发病率翻了一番多。因此，为椎间盘退变开发新的治疗策略与现役军人和退伍军人高度相关。目前椎间盘退变治疗的一个关键限制是它们不寻求维持或恢复天然组织结构和机械功能。因此，强烈需要通过直接解决根本原因和机制来保持和/或恢复椎间盘结构和机械功能的椎间盘退变的新疗法。椎间盘退变的理想治疗方法是：1）微创; 2）恢复生物力学功能; 3）减轻局部炎症驱动组织catalysis; 4）增强长期细胞外基质再生。我们最近开发了一种新型的可注射水凝胶，其在不存在外源性交联剂的情况下快速聚合，支持间充质干细胞存活和生物合成，并使椎间盘机械功能正常化。我们还开发了一种新的持续释放治疗椎间盘炎症使用白细胞介素-1受体拮抗剂（IL-1 R？）提供的聚合物微球。该提案的目的是协同这些技术以开发微创治疗，其同时使椎间盘机械功能正常化，减轻局部炎症，并促进干细胞驱动的天然组织再生。我们假设，只有通过解决这些标准将椎间盘退变的治疗有长期的疗效。在目标1中，我们将建立预处理干细胞在椎间盘的苛刻体内微环境中存活的体外技术，验证预处理干细胞在椎间盘微环境中的作用。 体内预处理的功效，并建立最佳体内接种密度，其平衡最大再生潜力与植入环境固有的有限营养可用性。在目标2中，我们将扩展我们以前的工作，以开发和测试一种抗炎疗法，该疗法可减弱退行性椎间盘中存在的复杂炎症细胞因子表达谱，具有保留干细胞再生潜力和停止持续天然组织破坏的双重目标。最后，在目标3中，作为关键的临床前步骤，我们将在已建立的大型椎间盘退变动物模型中评估这种治疗策略。

DESCRIPTION: Low back pain will affect up to 85 percent of people at some point during their lives, resulting in healthcare and related costs to the United States economy in excess of $100 billion every year. Among Veterans, chronic low back pain accounts for over 70 percent of chiropractic visits and in many cases is directly connected to their period of service. Intervertebral disc degeneration, a progressive, inflammation driven cascade that leads to structural and mechanical failure, is strongly implicated as a cause of low back pain. Between 2001 and 2010, more than 130,000 active service members received diagnoses of disc degeneration, with annual incidence rates more than doubling over this period. Developing new treatment strategies for disc degeneration is therefore highly relevant to both active military personnel and Veterans. A key limitation of current treatments for disc degeneration is that they do not seek to maintain or restore native tissue structure and mechanical function. There is therefore a strong need for new therapies for disc degeneration that retain and/or restore disc structure and mechanical function by directly addressing the underlying causes and mechanisms. The ideal therapy for disc degeneration would: 1) be minimally invasive; 2) restore biomechanical function; 3) attenuate localized inflammation driving tissue catabolism; and 4) potentiate long term extracellular matrix regeneration. We have recently developed a novel injectable hydrogel that polymerizes rapidly in the absence of exogenous cross-linking agents, supports mesenchymal stem cell survival and biosynthesis, and normalizes disc mechanical function. We have also developed a novel sustained release therapy for disc inflammation using interleukin-1 receptor antagonist (IL-1R¿) delivered from polymeric microspheres. The objective of this proposal is to synergize these technologies to develop a minimally invasive therapy that simultaneously normalizes disc mechanical function, attenuates localized inflammation, and promotes stem- cell driven native tissue regeneration. We hypothesize that only by addressing these criteria will a therapy for disc degeneration have long-term efficacy. In Aim 1 we will establish in vitro techniques for preconditioning stem cells to survive in the harsh in vivo microenvironment of the disc, verify the efficacy of preconditioning in vivo, and establish the optimum in vivo seeding density which balances maximum regeneration potential with the limited nutritional availability inherent to the implantation environment. In Aim 2 we will extend our previous work to develop and test an anti-inflammatory therapy that attenuates the complex inflammatory cytokine expression profile present in the degenerate disc, with the dual objectives of preserving stem cell regenerative potential and halting continued native tissue destruction. Finally, in Aim 3, as a critical pre-clinical step we will evaluate this therapeutic strategy in an established large animal model of disc degeneration.