A Regenerative Medicine Approach for TMJ Meniscus Restoration

颞下颌关节半月板修复的再生医学方法

• 批准号: 8365369
• 负责人: Alejandro Jose Almarza
• 金额: $ 62.89万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8365369
• 关键词: Affect; Bilateral; Biochemical; Biological; Biomechanics; Canis familiaris; Cells; Cellular Infiltration; Chemicals; Chondrocytes; Collagen; Comparative Anatomy; Complement; Custom; Data; Deposition; Development; Environment; Event; Excision; Extracellular Matrix; Family suidae; Frequencies; Generations; Glycosaminoglycans; Healed; Immune response; In Situ; In Vitro; Infiltration; Joints; Laboratories; Lead; Location; Mechanical Stimulation; Mechanics; Meniscus structure of joint; Methods; Modeling; Morbidity - disease rate; Operative Surgical Procedures; Outcome; Pathology; Patients; Pattern; Peptides; Phenotype; Pilot Projects; Population; Process; Property; Quality of life; Recruitment Activity; Regenerative Medicine; Relative (related person); Replacement Arthroplasty; Replacement Therapy; Role; Shapes; Site; Solid; Source; Spatial Distribution; Stem cells; Stimulus; Structure; Surface; Surgeon; Temporomandibular Joint; Temporomandibular Joint Disorders; Testing; Time; TimeLine; Tissues; Vascularization; Woman; Work; base; crosslink; disc regeneration; healing; implantation; in vivo; macrophage; migration; pre-clinical; preconditioning; prototype; reconstruction; response; restoration; scaffold; soft tissue; stem; stem cell population

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.

描述（由申请人提供）：本提案寻求支持研究使用由细胞外基质（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。强有力的试点研究表明，这种诱导模板可以刺激纤维软骨盘的内源性形成，该纤维软骨盘密切模仿天然椎间盘材料的成分、结构和机械性能。大约 3% 至 4% 的人口寻求颞下颌关节疾病的治疗；其中90%是女性。大约 70% 的颞下颌关节紊乱患者患有椎间盘移位；这一事实表明，颞下颌关节盘是导致颞下颌关节病理的一系列事件中的关键组成部分。体内不会发生自发的颞下颌​​关节盘再生，随后的关节表面退化可能导致需要进行全关节置换，对生活质量产生明显的负面影响。更换椎间盘的开发将保护关节表面，减轻发病率，并消除随后关节置换的需要。这项工作的中心假设是，ECM 支架向功能性 TMJ 盘的建设性重塑是由于将多能细胞募集到重塑部位、调节先天免疫反应而发生的，并且重塑过程的增强可以通过相关的机械预处理来实现。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受控体外机械负荷和接种多能血管周围干细胞群是否可以增强 ECM 重塑过程。第二个具体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，5）非交联细胞接种和 机械调节支架。将确定重塑的时空时间过程，并确定植入后 4 个不同时间点关键事件的相关性和重要性：在双侧 TMJ 半月板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熟练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学顾问来补充我们的团队。明确的时间表已经确定，并且研究基于可靠的初步数据。 公共健康相关性：该提案描述了由哺乳动物细胞外基质组成的生物支架将用作颞下颌关节半月板体内生成的诱导支架的工作。初步研究表明，这种诱导模板可以刺激纤维软骨盘的内源性形成，该纤维软骨盘密切模仿天然椎间盘材料的结构、组成和功能。拟议的研究将使用猪模型。