Seamless Healing of Avascular Meniscus Tears by Stem Cell Recruitment

通过干细胞募集无缝愈合无血管半月板撕裂

• 批准号: 9560596
• 负责人: Chang Hun Lee
• 金额: $ 35.41万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-06 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9560596
• 关键词: Adhesives; Animal Model; Biomedical Engineering; Blood Vessels; Cartilage; Cell Differentiation process; Cell Transplantation; Cells; Chondrocyte-like Cell; Collagen; Country; Cues; Data; Defect; Degenerative polyarthritis; Disease; Dose; Encapsulated; Extracellular Matrix; Fibrin Tissue Adhesive; Fibroblasts; Fibrocartilages; Formulation; Foundations; Glues; Goals; Growth Factor; Hydrogels; In Vitro; Incidence; Injectable; Injections; Injury; Lead; Mechanics; Meniscus structure of joint; Mesenchymal; Modeling; Mussels; Outcome; Patients; Phenotype; Research Personnel; Research Project Grants; Site; Stem cells; Surgical incisions; Time; Tissues; Vascular blood supply; base; cell type; clinically relevant; connective tissue growth factor; design; disability; healing; improved; in vivo; mechanical properties; minimally invasive; novel; novel strategies; recruit; repaired; response; stem; tool

Project summary Meniscus injuries are extremely common with approximately one million patients undergoing treatment annually in the U.S. alone. Importantly, meniscal disorders inevitably lead to osteoarthritis (OA), which is the leading cause of disability in this country. As a multiphase fibrocartilage, the outer third of meniscus is a vascularized and collagen-rich fibrous tissue with fibroblast-like cells, whereas the inner third is avascular cartilaginous tissue with rounded chondrocyte-like cells. The middle zone is intermediate fibrocartilaginous tissue with a mixture of fibroblast-like cells and chondrocyte-like cells. Upon injury or defect, the outer zone of meniscus can reliably be repaired and expected to functionally heal. However, tears in the inner avascular region are hard to heal due to poor intrinsic healing capacity based on its highly differentiated cell type, specialized extracellular matrix and lack of blood supply. Despite many attempts to induce functional healing of avascular meniscus, no therapy currently exists that reliably results in seamless healing of inner-zone meniscus tears. Although delivery of stem/progenitor cells showed promise for improved avascular meniscus repair, cell delivery-based approaches have suffered from several translational barriers. Our preliminary study produced novel data showing that meniscus tears in the avascular zone can be healed by timely controlled recruitment and step-wise fibrochondrogenic differentiation of synovial mesenchymal stem/progenitor cells (MSCs). The recruitment and step-wise differentiation was successfully regulated by a single injection of CTGF-loaded bio-glue mixed with PLGA µS-encapsulating TGFβ3. Accordingly, the overall objective of the proposed projects is to establish a novel and efficient clinically relevant strategy for seamless healing of avascular meniscus tears by recruiting endogenous stem/progenitor cells. Our overarching hypothesis is that temporal control of stem cell recruitment into bio-glue and step-wise fibrocartilaginous differentiation leads to seamless healing of avascular meniscus tears. We here propose 1) to determine effective compositions of an injectable and adhesive hydrogel to guide avascular meniscus healing, 2) to determine effective doses and release rates of growth factors to enhance avascular meniscus healing in vitro, and 3) to enhance avascular meniscus healing by endogenous stem/progenitor cells in vivo. The expected outcome of the proposed studies will serve as an important foundation to develop a translational tool to improve treatment for avascular meniscus tears and defects, thus benefiting millions of patients with meniscus injuries and in turn lowering the incidence of osteoarthritis.

项目摘要 半月板受伤非常普遍，大约一百万吨接受治疗 仅在美国，一年一度。 该国的残疾主要原因是多相纤维球杆菌 具有成纤维细胞样细胞的血管化和富含胶原蛋白的裂变，而内部三分 带有圆形chon的细胞样细胞的软骨组织中间区域是中间区域 与成纤维细胞样细胞的混合物和孔状细胞的混合物。 半月板可以可靠地修复，并有效健康。 由于其高度分化的细胞类型，由于固有的愈合能力差而难以愈合，因此 专门的细胞外基质和缺乏血液疗法。 目前尚无疗法可靠地导致无缝无血液无血管， 半月板撕裂。 维修，基于细胞的方法已经遭受了我们的初步研究 产生的新数据表明，可以及时控制的血管区域的半月板撕裂可以治愈 滑膜间充质茎/祖细胞的募集和逐步的纤维软化差异化 （MSC）。 CTGF负载的生物胶与PLGA µS封闭TGFβ3的混合。 支撑项目是建立一种新颖有效的临床相关策略，以无缝治愈 通过招募内源性茎/祖细胞的血管半月板撕裂。 将干细胞募集到生物胶水和明智的纤维化脂肪分化中的时间控制导致 无缝治愈无血管弯；我们提出了1） 注射和粘合水凝胶可引导血管半月板愈合，2）确定有效剂量和 生长因子的释放速率增强体外血管弯板，3）增强血管 在体内通过内源性茎/祖细胞愈合。 研究将是开发转化工具以改善AvascularR治疗的重要基础 半月板撕裂和缺陷，因此受益于半月板受伤的患者，进而使您降低 骨关节炎的发生率。