Development of Drug Delivery Technology for Stem Cell Based TMJ Regeneration

1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呼吸和言语。TMJ由肌肉、韧带和 4纤维软骨盘和髁突。颞下颌关节紊乱病(TMD)困扰着1000多万人 5名美国人，根据NIDCR，每年的费用约为40亿美元。退行性TMD类型，包括 6 TMJ骨关节炎(OA)，使人虚弱，影响生活质量，并导致永久性组织 7损失。目前的TMJ骨关节炎治疗通常是双重的，要么涉及疼痛管理，要么涉及侵入性治疗 8例手术，如全关节置换术失败率高。缺乏最低限度的 9种促进组织再生的侵入性TMJ疗法。 再生医学承诺了因疾病而失去的娱乐功能组织。因此， 11利用常驻干细胞的再生能力来修复TMJ可能代表着最低限度的 12侵袭性干细胞治疗TMJ骨关节炎。我们已经鉴定出纤维软骨干细胞 13个(FCSCs)，位于TMJ关节浅表区。移植的FCSCs自组织和 14再生软骨。Wnt/连环蛋白信号通路促进细胞增殖和抑制软骨形成 15胚胎干细胞的分化。然而，过度激活的Wnt/连环蛋白会耗尽FCSCs并导致TMJOA 16在小鼠、兔子和人类中。这些数据表明，抑制FCSCs中的Wnt/连环蛋白可能起作用 17作为一种以干细胞为基础的治疗TMJ OA的策略。事实上，我们展示了 18通过每周关节腔内注射WNT抑制剂skerostin改善TMJ来阻断WNT 19兔TMJ损伤模型。然而，主席一方的药物输送系统， 20人TMJ骨关节炎患者接受硬化剂缓释治疗的定义尚不明确。 根据我们的初步数据，我们假设可注射的缓释制剂 22透明质酸-硬化素水凝胶将靶向TMJ纤维软骨干细胞再生 23 TMJ。

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.