Tissue Engineered Total Disc Replacement in a Large Animal Model

大型动物模型中的组织工程全椎间盘置换术

• 批准号: 9889811
• 负责人: Robert L Mauck
• 金额: --
• 依托单位: PHILADELPHIA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9889811
• 关键词: Aging; Animal Model; Animals; Anterior; Architecture; Area; Articular Range of Motion; Biochemical; Biological; Biological Assay; Biomechanics; Bioreactors; Cell Maturation; Cells; Cervical; Cervical spine; Clinical Trials; Collagen; Custom; Data; Development; Devices; Dimensions; Economic Burden; Engineering; Environment; Extracellular Matrix; Failure; Fluoroscopy; Future; Goals; Goat; Growth; Head; Height; Histologic; Human; Hydration status; Imaging Techniques; Immobilization; Implant; In Vitro; Injury; Intervention; Intervertebral disc structure; Investigation; Magnetic Resonance Imaging; Mechanics; Mesenchymal Stem Cells; Metals; Modeling; Monitor; Motion; Operative Surgical Procedures; Outcome; Pain; Performance; Physiological; Procedures; Process; Property; Rattus; Replacement Arthroplasty; Risk; Spinal; Structure; Symptoms; Technology; Testing; Therapeutic; Tissue Engineering; Tissues; Torsion; Translating; Vertebral Bone; Vertebral column; Work; base; clinical practice; cohort; functional restoration; implantation; improved; improved outcome; in vivo; in vivo evaluation; instrumentation; intervertebral disk degeneration; mechanical device; novel; novel therapeutics; nucleus pulposus; response; translation to humans; treatment strategy; vertebra body

Title: Tissue Engineered Total Disc Replacement in a Large Animal Model The objective of this project is to develop a tissue-engineered construct including an engineered nucleus pulposus and annulus fibrosus to treat degenerative changes of the intervertebral disc (IVD). In Specific Aim 1, we will build on our preliminary small animal studies to construct cell- seeded DAPS whose geometric dimensions are comparable to human and goat IVDs. A novel compression-torsion bioreactor and simulated ex vivo disc-like microenvironment will be utilized to promote growth; we will also establish an endplate region to promote boney integration. In Specific Aim 2, we will investigate the impact of physiological loading on DAPS in vivo maturation and integration in a large animal (goat) cervical spine disc replacement model. Pre- matured DAPS constructs will be implanted into the goat cervical spine following a single-level cervical discectomy. Constructs will be implanted either with or without an integrated PCL foam endplate. Immediately after implantation, a cohort of animals will have their implanted motion segment stabilized using an anterior cervical plate. An additional cohort will undergo implantation without instrumentation. In vivo DAPS maturation will be assessed via MRI, based on our prior in vivo DAPS work. Motion of the goat cervical spine and head will be monitored using a custom large animal motion-tracking device that our group has developed. Terminal assays will assess motion segment mechanics and DAPS biochemical content and ECM distribution at 12 weeks post-implantation. In Specific Aim 3, we will investigate remobilization of the tissue-engineered motion segment and analysis of longer-term viability/segmental stability. The DAPS construct with best biomechanical performance in Aim 2 will be implanted after discectomy; at 12 weeks post-implantation, instrumentation will be removed, restoring unconstrained motion. Animals will continue free-range activity for 12 additional weeks, with regular acquisition of cervical motion and fluoroscopy data. At 24 weeks post-implantation, animals will be sacrificed and DAPS-implanted motion segments will be assessed via MRI analysis, biomechanical testing, histological analysis of matrix content and distribution, and biochemical analysis. The goal of this project is to develop tissue-engineered constructs and to assess their therapeutic potential in the treatment of degenerative disc disease. It is anticipated that the proposed study will offer an increased understanding of degenerative disc disease and demonstrate the potential of a novel therapeutic treatment.

标题：大型动物模型中的组织工程全椎间盘置换术 本项目的目标是开发一种组织工程化的结构，包括工程化的 髓核和纤维环来治疗椎间盘的退行性变化 （IVD）。在具体目标1中，我们将在我们初步的小动物研究的基础上构建细胞- 接种DAPS，其几何尺寸与人和山羊IVD相当。一种新型 将利用压缩-扭转生物反应器和模拟的离体盘状微环境 以促进生长;我们还将建立一个终板区域，以促进骨融合。在 具体目标2，我们将研究生理负荷对体内DAPS的影响 在大型动物（山羊）颈椎椎间盘置换模型中的成熟和整合。预处理 成熟的DAPS结构将在单节段后植入山羊颈椎， 颈椎间盘切除术植入结构时，可使用或不使用集成PCL泡沫 终板植入后，一组动物将立即进行植入运动 使用颈椎前路钢板稳定节段。另一个队列将接受 无器械植入。体内DAPS成熟将通过MRI评估，基于 在我们之前的体内DAPS工作中。将监测山羊颈椎和头部的运动 使用我们团队开发的定制大型动物运动跟踪设备。终端 测定将评估运动节段力学和DAPS生化含量以及ECM 植入后12周的分布。在具体目标3中，我们将研究再动员 的组织工程运动节段和分析的长期可行性/节段 稳定将植入目标2中生物力学性能最佳的DAPS结构 椎间盘切除术后;植入后12周，将取出内固定器械， 无约束运动动物将继续自由放养活动12周， 定期采集颈椎运动和透视数据。在植入后24周， 将处死动物，并通过MRI评估植入DAPS的运动节段 分析、生物力学测试、基质含量和分布的组织学分析，以及 生化分析该项目的目标是开发组织工程构建体， 评估其在退行性椎间盘疾病治疗中的治疗潜力。预计 拟议的研究将增加对退行性椎间盘疾病的了解， 证明了一种新的治疗方法的潜力。