Bioactive Injectable Cell Scaffold for Meniscus Injury Repair in a Large Animal Model

用于大型动物模型半月板损伤修复的生物活性可注射细胞支架

• 批准号: 10586596
• 负责人: Chathuraka Teekshana Jayasuriya
• 金额: $ 28.2万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-04 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586596
• 关键词: Affect; Animal Model; Animals; Arthritis; Attenuated; Behavior; Biocompatible Materials; Biological Markers; Biological Products; Biological Response Modifier Therapy; Cartilage; Cells; Cellular Structures; Chemotactic Factors; Chondrogenesis; Collagen; Collagen Fiber; Complex; Control Animal; Data; Degenerative polyarthritis; Development; Dose; Effectiveness; Evaluation; Exhibits; Extracellular Matrix; Fast Green; Fibrin; Fibrinogen; Fibrocartilages; Flow Cytometry; Gait; Gel; Gene Proteins; Goals; Green Fluorescent Proteins; Histologic; Histology; Histopathology; Human; Hydrogels; Image; Injectable; Injury; Knee; Knee Injuries; Knee joint; Knowledge; Laboratories; Magnetic Resonance Imaging; Measures; Mechanics; Medial meniscus structure; Mediator; Meniscus structure of joint; Mesenchymal Stem Cells; Microscopic; Miniature Swine; Mission; Modeling; National Institute of Arthritis, and Musculoskeletal, and Skin Diseases; Nature; Organ Culture Techniques; Organism; Orthopedics; Outcome Assessment; Outcome Measure; Patients; Plasma; Prevention; Production; Proteoglycan; Public Health; Rattus; Reporting; Research; Research Design; Risk Factors; Severities; Sirius Red F3B; Site; Stains; Stromal Cell-Derived Factor 1; Surgical sutures; Synovial Fluid; Synovial Membrane; Technology; Testing; Thrombin; Time; Tissue Model; Tissues; Translating; Translations; Traumatic Arthropathy; United States National Institutes of Health; Urine; Visualization; articular cartilage; base; biomaterial compatibility; chemokine; clinical translation; clinically relevant; disability; efficacy evaluation; experimental group; healing; improved; in vivo evaluation; injury and repair; innovation; lymph nodes; meniscal tear; meniscus injury; musculoskeletal injury; novel; polarized light; porcine model; pre-clinical; prevent; repaired; response; scaffold; small molecule; stem cells; success; treatment response

SUMMARY ABSTRACT Meniscal tearing is a significant risk factor for the development of posttraumatic osteoarthritis (PTOA). The long- term goal of this project is to develop an innovative biologic therapy to improve meniscus tear healing for the prevention of PTOA. Our laboratory has demonstrated the efficacy of utilizing cartilage-derived progenitor cells (CPCs) to stimulate healing of meniscal tears in a small animal model. In efforts to translate our success in small animals to a clinically relevant large animal model, we will optimize and implement a bioactive tear interfacing fibrin hydrogel (FibroGel) that is laden with CPCs and infused with the chemokine Stromal Cell Derived Factor- 1 (SDF-1) and the small molecule Kartogenin (KGN), which collectively increases CPC retention at the tear site and increases their chondrogenic matrix synthesis, respectively. The objectives of the proposed study are: To optimize FibroGel as a novel biologic therapy for meniscus tear repair; (2) To determine its efficacy for stimulating tear reunification and reduction of PTOA severity; and (3) To collect biocompatibility data throughout the study to aid in clinical translation of this technology. There are three independent specific aims: (I) Optimize cellular and bioactive components of FibroGel to produce robust fibrocartilage matrix re-synthesis to bridge and reunify meniscus tears; (II) Evaluate the efficacy of using FibroGel for improving meniscal fibrocartilage healing in a preclinical large animal model; and (III) Determine the efficacy of FibroGel-augmented meniscus repair in attenuating PTOA in the knee. The research design will employ a meniscus tissue explant model to optimize FibroGel in order to maximize cell retention and chondrogenic matrix re-synthesis at the tear site, as well as increase the strength of tissue reintegration/reunion at the tear site. A porcine model of meniscal injury will be used to examine the short- and long-term efficacy and biocompatibility of FibroGel. Outcome assessments will include evaluation of meniscus tear healing, evaluation of PTOA severity as determined by biomarker analysis, gait asymmetry analysis, and macroscopic/microscopic assessment of the articular cartilage and synovium following FibroGel treatment. Successful completion will have a positive impact by facilitating the development and translation of a new strategy to stimulate meniscus injury repair through the use of cellular biologics. This project is relevant to the mission of NIAMS because it seeks to find innovative ways to treat musculoskeletal injuries and prevent arthritis.

摘要摘要 半月板撕裂是创伤后骨关节炎（PTOA）发展的重要危险因素。长期 该项目的术语目标是开发一种创新的生物疗法，以改善弯月面撕裂愈合 预防PTOA。我们的实验室证明了利用软骨衍生的祖细胞的功效 （CPC）刺激小动物模型中半月板撕裂的愈合。为了翻译我们的成功 动物到临床上相关的大型动物模型，我们将优化和实施生物活性撕裂接口 纤维蛋白水凝胶（纤维凝胶）载有CPC，并注入趋化因子基质细胞衍生因子 - 1（SDF-1）和小分子卡尔生蛋白（KGN），共同增加了撕裂部位的CPC保留率 并分别增加其软骨基质合成。拟议的研究的目标是： 优化纤维状素作为一种新型生物疗法，以修复半月板撕裂； （2）确定其功效 刺激泪水统一和PTOA严重程度的降低； （3）在整个过程中收集生物相容性数据 这项研究有助于该技术的临床翻译。有三个独立的特定目的：（i）优化 纤维凝胶的细胞和生物活性成分，以产生稳健的纤维球基质基质重新合成到桥和 重新拟合半月板的眼泪； （ii）评估使用纤维凝胶改善半月板纤维球治疗的功效 在临床前大动物模型中； （iii）确定在 膝盖衰减PTOA。研究设计将采用半月板组织外植物模型来优化 纤维凝胶为了最大化细胞保留和软骨基质在撕裂部位的重新合成，以及 提高撕裂部位的组织重新整合/团聚的强度。半月板损伤的猪模型将是 用于检查纤维凝胶的短期和长期功效和生物相容性。结果评估将 包括评估半月板撕裂愈合，通过生物标志物分析确定的PTOA严重程度的评估， 步态不对称分析以及关节软骨和滑膜的宏观/微观评估 纤维凝胶治疗后。成功完成将通过促进发展产生积极的影响 以及通过使用细胞生物制剂来刺激半月板损伤修复的新策略的翻译。这 项目与Niams的使命相关，因为它试图找到创新的方法来治疗肌肉骨骼 受伤并预防关节炎。