Administrative Supplement for R01AR080687

摘要 氧化应激在骨关节炎(OA)的发病机制中起着关键作用，直接对组织起作用 精神崩溃以及慢性疼痛。增强关节中抗氧化剂防御的尝试已经在临床上得到了应用 令人失望--传统的小分子和外源提供的抗氧化酶受到 稳定性和生物利用度差，关节内注射后关节清除迅速。致信地址 在这些限制下，我们的母公司R01设计了二氧化锰纳米颗粒(MnO2 NPs)，或称纳米酶 模拟抗氧化酶清除活性氧(ROS)的功能，但具有显著 在稳定性、成本和生物利用度方面的优势。事实上，我们演示了这些特性 纳米材料可以为关节组织保留和细胞摄取量身定做，这对于解决关键的 骨关节炎治疗性交付的障碍。母体R01致力于优化MnO2的抗氧化活性 NPS，体外询问其软骨保护和抗炎机制，并评价其 PTOA啮齿动物模型的体内疾病修正能力。本补编对这些研究进行了扩展，包括 全面评估对MnO2 NP治疗反应的疼痛机制，特别关注 神经性疼痛。骨性关节炎患者可能会经历伤害性和神经性疼痛的组合。使用 伤害性疼痛、组织损伤和炎症导致伤害性感受器的激活和疼痛的传递。 然而，神经性疼痛是由神经本身的损伤引起的，这种损伤可能发生在关节损伤或 随着骨性关节炎的进展，关节的结构发生变化。神经性疼痛的治疗是具有挑战性的，因为 常用的消炎药是无效的，治疗选择受到成瘾风险和 严重的不良反应。已知氧化应激通过诱导损伤来触发和维持神经病理性疼痛 以及神经中的线粒体功能障碍。 鉴于它们显著的抗氧化功能，稳定性和 生物利用度，我们假设MnO2纳米粒将有效地缓解PTOA的神经病理性疼痛。铺设 为这一科学方向奠定基础，本附录旨在表征黄连蛋白的抗氧化功能 MnO2纳米粒子与神经细胞的体外作用，并评价神经病理性疼痛的体内生物标志物对治疗的反应 在PTOA模型中使用MnO2 NP。这些生物标志物，如关节神经支配模式和细胞组成 背根神经节，将补充行为分析，生化分析，和组织病理学 父R01中的分析。这个对骨性关节炎发病机制的综合评估，从关节结构的角度来看， 功能和疼痛机制，可以促进这或其他成功的临床前到临床转换 肌肉骨骼疾病和慢性疼痛的抗氧化策略。

ABSTRACT Oxidative stress plays a key role in the pathogenesis of osteoarthritis (OA), contributing directly to tissue breakdown as well as to chronic pain. Attempts to boost antioxidant defenses in the joint have been clinically disappointing - conventional small molecules and exogenously delivered antioxidant enzymes are plagued by poor stability and bioavailability, as well as rapid joint clearance following intra-articular injections. To address these limitations, our parent R01 engineers manganese dioxide nanoparticles (MnO2 NPs), or “nanozymes”, that mimic the reactive oxygen species (ROS) scavenging functions of antioxidant enzymes, but have significant advantages in terms of stability, cost, and bioavailability. Indeed, we demonstrated the properties of these nanomaterials can be tailored for joint tissue retention and cell uptake, which is important for addressing critical barriers to therapeutic delivery in OA. The parent R01 focuses on optimizing the antioxidant activity of the MnO2 NPs, interrogating their chondroprotective and anti-inflammatory mechanisms in vitro, and evaluating their disease-modifying ability in vivo in a rodent model of PTOA. This supplement expands on these studies to include comprehensive evaluation of pain mechanisms in response to MnO2 NP treatment, with particular focus on neuropathic pain. OA patients can experience a combination of nociceptive and neuropathic pain. With nociceptive pain, tissue damage and inflammation leads to activation of nociceptors and pain transmission. Neuropathic pain, however, is caused by damage to the nerves themselves, which can occur with joint injury or as a result of structural changes in the joint as OA progresses. Treatment of neuropathic pain is challenging, as commonly used anti-inflammatories are ineffective, and therapeutic options are limited by risk of addiction and serious adverse effects. Oxidative stress in known to trigger and maintain neuropathic pain, by inducing damage and mitochondrial dysfunction in nerves. Given their pronounced antioxidant functions, stability, and bioavailability, we hypothesize that MnO2 NPs will be effective at alleviating neuropathic pain in PTOA. To lay the groundwork for this scientific direction, this supplement aims to characterize the antioxidant functions of MnO2 NPs with neural cells in vitro, and evaluate biomarkers for neuropathic pain in vivo in response to treatment with MnO2 NP in a PTOA model. These biomarkers, such as joint innervation patterns and cellular composition of the dorsal root ganglion, will complement the behavior analyses, biochemical analyses, and histopathologic analyses in the parent R01. This comprehensive assessment of OA pathogenesis, in terms of joint structure, function, and pain mechanisms, may facilitate successful preclinical to clinical translation of this or other antioxidant strategies for musculoskeletal diseases and chronic pain.