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

摘要摘要 半月板撕裂是发生创伤后骨关节炎(PTOA)的重要危险因素。长的- 该项目的学期目标是开发一种创新的生物疗法，以促进半月板撕裂的愈合 预防创伤后应激障碍。我们的实验室已经证明了利用软骨来源的祖细胞的有效性。 (CPCS)在小动物模型中促进半月板撕裂愈合。在努力将我们的成功转化为 将动物移植到临床相关的大动物模型，我们将优化并实施生物活性泪液接口 纤维蛋白水凝胶(FibroGel)，富含CPC，并注入趋化因子基质细胞衍生因子- 1(SDF-1)和小分子Kartogenin(Kgn)，共同增加CPC在撕裂部位的滞留 并分别增加其软骨基质的合成。拟议研究的目标是： 优化纤维凝胶作为半月板撕裂修复的新生物疗法；(2)确定其治疗半月板撕裂的疗效 刺激泪液愈合和降低PTOA的严重程度；以及(3)收集整个生物相容性数据 这项研究有助于这项技术的临床翻译。有三个独立的具体目标：(一)优化 纤维凝胶的细胞和生物活性成分可产生强健的纤维软骨基质重新合成，以桥接和 半月板撕裂愈合；(Ii)评价FibroGel促进半月板纤维软骨愈合的效果 在临床前大型动物模型中；以及(Iii)确定纤维凝胶增强的半月板修复在 减轻膝部的PTOA。研究设计将采用半月板组织外植体模型来优化 纤维凝胶，以最大限度地保留细胞和在撕裂部位重新合成软骨基质，以及 增加撕裂部位组织融合/愈合的强度。一种半月板损伤的猪模型将是 用于检测FibroGel的短期和长期疗效和生物相容性。成果评估将 包括半月板撕裂愈合评估、由生物标记物分析确定的PTOA严重程度评估 步态不对称分析及关节软骨和滑膜的宏观/微观评价 在纤维凝胶治疗后。成功完成将对促进发展产生积极影响 并翻译了一种新的策略，通过使用细胞生物制剂来刺激半月板损伤的修复。这 该项目与NIAMS的任务相关，因为它寻求寻找治疗肌肉骨骼疾病的创新方法 损伤和预防关节炎。

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.