A Regenerative Medicine Approach for TMJ Meniscus Restoration

描述(申请人提供)：这项建议寻求支持，以研究使用由细胞外基质(ECM)组成的生物支架作为诱导支架，用于体内生成颞下颌关节(TMJ)半月板。强有力的初步研究表明，这种诱导性模板可以刺激纤维软骨盘的内源性形成，这种内源性形成与天然椎间盘材料的成分、结构和机械性能非常相似。大约3%至4%的人口寻求治疗TMJ障碍；其中90%是妇女。大约70%的TMJ障碍患者患有关节盘移位；这一事实表明，TMJ椎间盘是导致TMJ病理的一系列事件中的关键组成部分。在活体内没有自发的TMJ盘再生，随后的关节表面退变可能导致需要全关节置换术，并对生活质量造成明显的负面后果。置换盘的开发将保护关节关节表面，减轻发病率，并消除后续关节置换术的需要。这项工作的中心假设是，ECM支架向功能性TMJ椎间盘的建设性重建是多潜能细胞招募到重建部位的结果，调节了先天免疫反应，并且相关的机械预适应可以增强重建过程。在一项涉及两个具体目标的为期4年的重点研究中，我们将检验这一假设。第一个具体目标将确定体外受控机械负荷和种植多潜能血管周围干细胞是否可以增强ECM重塑过程。第二个具体目的是比较五种不同异种ECM支架的体内重建过程：1)非交联型ECM支架，2)化学交联型ECM支架，3)非交联型细胞种植ECM支架，4)非交联型机械调节ECM支架，5)非交联型细胞种植机械调节支架。在猪双侧TMJ半月板切除模型中，将确定植入后2周、1周、3个月和6个月四个不同时间点的关键事件的相关性和重要性。这项工作是高度跨学科的，将利用Badylak实验室的ECM支架专业知识、Almarza实验室的机械生物学专业知识以及经验丰富的口腔颌面外科医生的外科专业知识来实现特定目标。我们有一名生物统计学家和一名兽医比较解剖顾问来补充我们的团队。已经确定了一个明确的时间表，这些研究以坚实的初步数据为基础。 公共卫生相关性：本提案描述了由哺乳动物细胞外基质组成的生物支架将作为诱导支架用于在体生成颞下颌关节半月板的工作。初步研究表明，这种诱导性模板可以刺激纤维软骨盘的内源性形成，这种内源性形成与天然盘材料的结构、组成和功能非常相似。在拟议的研究中将使用猪的模型。

DESCRIPTION (provided by applicant): This proposal seeks support to investigate the use of a biologic scaffold composed of extracellular matrix (ECM) as an inductive scaffold for the in vivo generation of a temporo- mandibular joint (TMJ) meniscus. Strong pilot studies indicate that this inductive template can stimulate the endogenous formation of a fibrocartilaginous disc that closely mimics the composition, structure, and mechanical properties of native disc material. Approximately 3% to 4% of the population seeks treatment for TMJ disorders; 90% of which are women. Approximately 70% of patients with TMJ disorders suffer from disc displacement; a fact that identifies the TMJ disc as a critical component in the cascade of events that lead to TMJ pathology. Spontaneous TMJ disc regeneration in vivo does not occur, and subsequent articulate surface degeneration can lead to the need for total joint replacement with marked negative consequences upon the quality of life. Development of a replacement disc would protect articulate joint surfaces, mitigate morbidity, and obviate the need for subsequent joint replacement. The central hypothesis of the proposed work is that constructive remodeling of an ECM scaffold toward a functional TMJ disc occurs as a result of recruitment of multipotential cells to the site of remodeling, modulation of the innate immune response, and that enhancement of the remodeling process can occur with associated mechanical preconditioning. In a focused 4-year study involving two Specific Aims, we will test this hypothesis. The first Specific Aim will determine whether controlled in vitro mechanical loading and seeding with a population of multipotential perivascular stem cells can enhance the ECM remodeling process. The second Specific Aim will compare the in vivo remodeling process of five different xenogeneic ECM constructs: 1) a non-crosslinked ECM scaffold, 2) a chemically cross-linked ECM scaffold, 3) a non-crosslinked cell seeded ECM scaffold, 4) a non-crosslinked, mechanically conditioned ECM scaffold, and 5) a non-crosslinked, cell seeded and mechanically conditioned scaffold. The temporo-spatial time course of remodeling will be determined and the relevance and importance of critical events at 4 separate time points post implantation: 2 weeks, 1, 3 and 6 months post implantation in a pig model of bilateral TMJ meniscectomy will be identified. This work is highly interdisciplinary and will utilize the ECM scaffold expertise of th Badylak laboratory, the mechanobiology expertise of the Almarza laboratory, and the surgical expertise of an accomplished oromaxillofacial surgeon to accomplish the Specific Aims. We have a biostatistician and a veterinary comparative anatomy consultant to complement our team. A clear timeline has been established and the studies are based upon solid preliminary data. PUBLIC HEALTH RELEVANCE: This proposal describes work in which a biologic scaffold composed of mammalian extracellular matrix will be used as an inductive scaffold for the in vivo generation of the temporo-mandibular joint meniscus. Pilot studies suggest that this inductive template can stimulate the endogenous formation of a fibrocartilaginous disc that closely mimics the structure, composition and function of native disc material. A pig model will be used in the proposed studies.