A Regenerative Medicine Approach for TMJ Meniscus Restoration

描述（由申请人提供）：本提案寻求支持研究细胞外基质（ECM）组成的生物支架作为诱导支架在体内生成颞下颌关节（TMJ）半月板的使用。大量的初步研究表明，这种诱导模板可以刺激纤维软骨椎间盘的内源性形成，该纤维软骨椎间盘与天然椎间盘材料的组成、结构和力学性能非常相似。大约3%到4%的人寻求TMJ疾病的治疗；其中90%是女性。大约70%的颞下颌关节疾病患者患有椎间盘移位；这一事实表明，在导致TMJ病理的一系列事件中，TMJ椎间盘是一个关键组成部分。体内自发的TMJ椎间盘再生不会发生，随后的关节面退变可能导致需要全关节置换术，并对生活质量产生明显的负面影响。置换椎间盘的发展将保护关节关节面，减轻发病率，并避免后续关节置换的需要。本研究的中心假设是，ECM支架对功能性TMJ椎间盘的重构是多电位细胞聚集到重构部位、先天免疫反应的调节的结果，并且重构过程的增强可以通过相关的机械预处理发生。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。第一个特异性目标将确定体外控制机械负荷和多电位血管周围干细胞群体播种是否可以增强ECM重塑过程。第二个特定目标将比较五种不同异种ECM构建物的体内重塑过程：1)非交联ECM支架，2)化学交联ECM支架，3)非交联细胞植入ECM支架，4)非交联机械条件ECM支架，5)非交联细胞植入机械条件ECM支架。将确定重建的时空时间过程，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：植入后2周、1、3和6个月的猪双侧TMJ半月板切除术模型。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，以及一位成功的口腔颌面外科医生的外科专业知识来实现具体目标。我们有一位生物统计学家和一位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表，这些研究是基于可靠的初步数据。

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.