Development of Drug Delivery Technology for Stem Cell Based TMJ Regeneration

1篇摘要 2颞下颌关节（TMJ）是一个复杂的关节系统，对牙齿的咬合、咀嚼、 3呼吸和说话颞下颌关节是由肌肉，韧带，和一个网络， 4纤维软骨盘和髁突。颞下颌关节紊乱病（TMD）困扰着超过1000万人 根据NIDCR，每年花费约40亿美元的美国人。退行性TMD，包括 6颞下颌关节骨关节炎（OA），使人衰弱，影响生活质量，并导致永久性组织 7损失目前的TMJ OA治疗通常是双重的，涉及疼痛管理或侵入性治疗。 8例手术，如失败率较高的全关节置换术。有一个最低限度的缺乏 9侵入性TMJ疗法，促进组织再生。 10再生医学承诺重建因疾病而丧失的功能组织。因此 利用常驻干细胞的再生能力来修复TMJ可能代表了最低限度的 12基于干细胞的侵袭性治疗颞下颌关节OA。我们已经鉴定出纤维软骨干细胞 13（FCSC）位于TMJ髁突浅区。移植的FCSC自我组织， 14例再生软骨。Wnt/β-Catenin信号促进增殖并抑制软骨形成 15 FCSC的分化。然而，过度活跃的Wnt/β-Catenin消耗FCSCs并导致TMJ OA 16在小鼠、兔子和人类中。这些数据表明，抑制FCSC中的Wnt/β-连环蛋白可能有助于 17作为治疗TMJ OA的基于干细胞的治疗策略。事实上，我们发现 18通过每周TMJ关节内注射Wnt抑制剂sclerostin阻断Wnt改善TMJ 19 OA在兔TMJ损伤模型中的作用。然而，用于椅旁的药理学药物递送系统， 持续释放sclerostin施用至人类TMJ OA患者尚未被定义。 21基于我们的初步数据，我们假设注射缓释剂的递送 22透明质酸-sclerostin水凝胶将靶向驻留的TMJ纤维软骨干细胞再生 颞下颌关节23度。

1 ABSTRACT 2 The temporomandibular joint (TMJ) is a complex joint system critical for dental occlusion, mastication, 3 respiration and speech. The TMJ is comprised of a network of muscles, ligaments, and a 4 fibrocartilaginous disc and condyle. Temporomandibular disorders (TMDs) afflict over 10 million 5 Americans at an annual cost of ~$4 billion, per the NIDCR. Degenerative types of TMDs, including 6 TMJ osteoarthritis (OA), are debilitating, compromise quality of life, and causes permanent tissue 7 loss. Current TMJ OA treatments are typically two-fold, involving either pain management or invasive 8 surgeries, such as total joint replacements with high failure rates. There is a paucity of minimally 9 invasive TMJ therapies that promote tissue regeneration. 10 Regenerative medicine promises the recreation functional tissue that is loss from disease. Thus 11 exploiting the regenerative capabilities of resident stem cells to repair TMJ may represent a minimally 12 invasive stem cell-based treatment for TMJ OA. We have identified fibrocartilage stem cells 13 (FCSCs) that reside in the TMJ condyle superficial zone. Transplanted FCSCs self-organize and 14 regenerate cartilage. Wnt/Catenin signaling promotes proliferation and inhibits chondrogenic 15 differentiation of FCSCs. However, over-active Wnt/Catenin deplete FCSCs and cause TMJ OA 16 in mice, rabbits and humans. These data suggest that inhibiting Wnt/Catenin in FCSCs may serve 17 as a stem cell-based therapeutic strategy for the treatment of TMJ OA. In fact, we showed that 18 blocking Wnt via weekly TMJ intra-articular injections of the Wnt inhibitor sclerostin ameliorated TMJ 19 OA in a rabbit TMJ injury model. However, a pharmacological drug delivery system for chairside, 20 sustained release sclerostin administration to human TMJ OA patients has not been defined. 21 Based on our preliminary data, we hypothesize that delivery of an injectable, sustained release 22 hyaluronic acid-sclerostin hydrogel will target resident TMJ fibrocartilage stem cells to regenerate 23 TMJ.