Seamless Healing of Avascular Meniscus Tears by Stem Cell Recruitment

项目摘要 半月板损伤非常常见，约有100万患者接受治疗 每年仅在美国。重要的是，关节紊乱不可避免地导致骨关节炎（OA），这是骨关节炎的主要原因。 是导致这个国家残疾的主要原因作为多相纤维软骨，半月板的外三分之一是一个 血管化和富含胶原的纤维组织，具有成纤维细胞样细胞，而内三分之一是无血管的 具有圆形软骨细胞样细胞的软骨组织。中间区为中间纤维软骨 具有成纤维细胞样细胞和软骨细胞样细胞的混合物的组织。在损伤或缺陷时， 半月板可以可靠地修复并预期功能性愈合。然而，眼泪在内心无血管 区域由于基于其高度分化的细胞类型的差的内在愈合能力而难以愈合， 特化细胞外基质和缺乏血液供应。尽管许多尝试诱导功能性愈合 对于无血管半月板，目前还没有可靠的治疗方法可以使内区无缝愈合 半月板撕裂尽管干/祖细胞的输送显示出改善无血管半月板的希望， 修复，基于细胞递送的方法遭受了几个翻译障碍。我们的初步研究 产生了新的数据，显示无血管区的半月板撕裂可以通过及时控制 滑膜间充质干/祖细胞的募集和逐步纤维软骨分化 （MSC）。募集和逐步分化成功地通过单次注射 载CTGF的生物胶与包封TGFβ3的PLGA µ S混合。因此， 建议的项目是建立一个新的和有效的临床相关的战略无缝愈合的 无血管半月板撕裂通过招募内源性干/祖细胞。我们的首要假设是 暂时控制干细胞募集到生物胶中和逐步纤维软骨分化导致 无血管半月板撕裂的无缝愈合。我们在这里提出1）确定有效组成的一个 用于引导无血管半月板愈合，2）确定有效剂量， 生长因子的释放速率，以增强无血管半月板的体外愈合，和3）增强无血管半月板的愈合， 半月板愈合的内源性干/祖细胞在体内。拟议方案的预期成果 研究将作为开发转化工具以改善无血管性心脏病治疗的重要基础。 半月板撕裂和缺陷，从而使数百万半月板损伤患者受益，从而降低了半月板损伤的发生率。 骨关节炎的发病率。

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.