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）：该提案寻求支持，以研究由细胞外基质（ECM）组成的生物支架的使用，作为在体内生成颞下颌关节（TMJ）弯板的诱导支架。强有力的试点研究表明，这种感应模板可以刺激纤维状脂肪盘的内源性形成，该圆盘密切模仿天然盘材料的组成，结构和机械性能。大约3％至4％的人口寻求TMJ疾病治疗；其中90％是女性。大约有70％的TMJ疾病患者患有椎间盘位移；将TMJ光盘识别为导致TMJ病理的事件级联中的关键组成部分的事实。没有发生自发的TMJ椎间盘再生，随后表达的表面变性可能导致需要总关节置换，并对生活质量产生明显的负面后果。置换光盘的开发将保护清晰的关节表面，减轻发病率，并消除随后的关节置换的需求。拟议工作的中心假设是，由于将多能细胞募集到重塑位点，对先天性免疫反应的调节，并且可以通过相关的机械预先调查发生重塑过程，因此将ECM支架朝向功能性TMJ盘的建设性重塑发生。在一项涉及两个特定目标的重点为4年的研究中，我们将检验这一假设。第一个具体目标将确定用多血管周围干细胞群体控制的体外机械负荷和播种是否可以增强ECM重塑过程。 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机械条件的支架。将确定重塑的颞空间时间过程，植入后4个单独的时间点关键事件的相关性和重要性：在植入后2周，1、3和6个月将在双边TMJ半月板切除术模型中确定。这项工作是高度跨学科的，将利用Thylak实验室的ECM脚手架专业知识，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手术专业知识来实现​​特定目标。我们有一个生物统计学家和兽医比较解剖顾问，可以补充我们的团队。已经建立了明确的时间表，研究基于稳定的初步数据。 公共卫生相关性：该提案描述了由哺乳动物细胞外基质组成的生物脚手架的工作，将用作颞叶叶肉进行的体内产生的诱导脚手架。试验研究表明，这种感应模板可以刺激纤维状圆盘的内源性形成，该椎间盘密切模仿天然盘材料的结构，组成和功能。猪模型将用于拟议的研究。