Seamless Healing of Avascular Meniscus Tears by Stem Cell Recruitment

项目总结 半月板损伤非常常见，大约有100万名患者正在接受治疗。 每年仅在美国。重要的是，半月板疾病不可避免地会导致骨关节炎(OA)，这是 这是这个国家导致残疾的主要原因。半月板外1/3为多时相纤维软骨。 血管化的富胶原纤维组织中含有成纤维细胞样细胞，而内三分之一为无血管的。 软骨组织，有圆形的软骨细胞样细胞。中间带为中间纤维软骨。 成纤维细胞样细胞和软骨细胞样细胞混合的组织。在受伤或缺陷时， 半月板可以可靠地修复并有望在功能上愈合。然而，内无血管的撕裂 由于其高度分化的细胞类型的内在愈合能力较差，区域很难愈合， 专门的细胞外基质和缺乏血液供应。尽管多次尝试诱导功能性愈合 对于无血管半月板，目前还没有可靠地导致内区无缝愈合的治疗方法。 半月板撕裂。尽管干细胞/祖细胞的移植显示出改善无血管半月板的前景 修复，基于细胞交付的方法受到了几个翻译障碍的影响。我们的初步研究 产生的新数据表明，无血管区的半月板撕裂可以通过及时控制愈合 滑膜间充质干细胞/祖细胞的募集和向纤维软骨方向的分化 (MSCs)。通过一次注射成功地调节了招募和逐步分化 负载CTGF的生物胶与PLGA-S包裹的转化生长因子β3混合。因此， 提出的项目是建立一种新的和有效的临床相关战略，以无缝修复 无血管半月板通过招募内源性干细胞/祖细胞撕裂。我们最重要的假设是 干细胞募集到生物胶中的时间控制和逐步纤维软骨分化导致 无血管半月板撕裂的无缝愈合。我们在这里建议1)确定一个有效的组成 可注射和粘附性水凝胶引导无血管半月板愈合，2)确定有效剂量和 生长因子的释放率促进体外无血管半月板愈合，以及3)促进无血管半月板愈合 内源性干/祖细胞体内修复半月板的实验研究建议的预期结果 这项研究将成为开发一种改进无血管治疗的翻译工具的重要基础 半月板撕裂和缺陷，从而使数以百万计的半月板损伤患者受益，并反过来降低 骨性关节炎的发病率。

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.