Bioactive Injectable Implants for Functional Intervertebral Disc Regeneration

说明： 高达85%的人在一生中的某个时候会受到腰痛的影响，导致 医疗保健和相关费用每年给美国经济造成超过1000亿美元的损失。在退伍军人中，慢性下腰痛占脊椎按摩就诊的70%以上，在许多情况下与他们的服务期限直接相关。椎间盘退变是一种进行性炎症驱动的级联反应，导致结构和机械故障，与下腰痛的原因密切相关。2001至2010年间，超过13万名现役军人被诊断为椎间盘退行性变，在此期间，年发病率增加了一倍多。因此，开发新的椎间盘退变治疗策略对现役军人和退伍军人来说都是高度相关的。目前治疗椎间盘退变的一个关键限制是它们不寻求维持或恢复自然的组织结构和机械功能。因此，迫切需要通过直接解决潜在原因和机制来保留和/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)减轻局部炎症导致组织分解代谢；4)促进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，在没有外源性交联剂的情况下快速聚合，支持间充质干细胞的存活和生物合成，并使椎间盘机械功能正常化。我们还开发了一种使用从聚合物微球释放的白细胞介素1受体拮抗剂(IL-1R)来治疗椎间盘炎症的新型缓释疗法。这项建议的目的是协同这些技术来开发一种微创疗法，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，只有解决了这些标准，才能使治疗腰椎间盘退变具有长期疗效。在目标1中，我们将建立体外预适应干细胞以在恶劣的体内微环境中存活的技术，验证 体内预适应的有效性，并建立最佳的体内种植密度，以平衡最大的再生潜力和植入环境固有的有限营养可获得性。在目标2中，我们将扩展我们之前的工作，开发和测试一种抗炎疗法，该疗法可以减弱退变椎间盘中存在的复杂炎症细胞因子的表达谱，具有保留干细胞再生潜力和阻止持续的自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，我们将在已建立的椎间盘退变的大型动物模型中评估这一治疗策略。

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.