A Regenerative Medicine Approach for TMJ Meniscus Restoration

描述（由申请人提供）：该提案旨在寻求支持，以研究由细胞外基质（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）半月板的用途。强有力的初步研究表明，这种诱导模板可以刺激纤维软骨椎间盘的内源性形成，该纤维软骨椎间盘紧密模仿天然椎间盘材料的组成、结构和机械特性。大约3%至4%的人口寻求治疗TMJ疾病;其中90%是女性。大约70%的TMJ疾病患者患有椎间盘移位;这一事实表明TMJ椎间盘是导致TMJ病理学的级联事件中的关键组成部分。在体内不会发生自发性TMJ盘再生，并且随后的关节表面退化可导致需要全关节置换，对生活质量具有显著的负面影响。开发置换椎间盘将保护关节面，降低发病率，并减少后续关节置换的需要。所提出的工作的中心假设是，ECM支架朝向功能性TMJ椎间盘的建设性重塑是由于多能细胞向重塑部位的募集、先天免疫应答的调节而发生的，并且重塑过程的增强可以与相关的机械预处理一起发生。在一项涉及两个特定目标的为期4年的集中研究中，我们将检验这一假设。第一个具体目标将确定是否控制在体外机械负荷和接种与多能血管周围干细胞的人口可以增强ECM重塑过程。第二个特定目标将比较五种不同异种ECM构建体的体内重塑过程：1）非交联ECM支架，2）化学交联ECM支架，3）非交联细胞接种ECM支架，4）非交联机械调节ECM支架，和5）非交联细胞接种和机械调节支架。将确定重塑的时间-空间时间过程，并确定植入后4个不同时间点的关键事件的相关性和重要性：在双侧TMJ关节切除术的猪模型中植入后2周、1、3和6个月。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，以及一位有成就的口腔颌面外科医生的手术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学顾问来补充我们的团队。已经确定了明确的时间轴，研究以可靠的初步数据为基础。

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.