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，直接导致组织损伤。 以及慢性疼痛。在临床上， 令人失望的是，传统的小分子和外源性抗氧化酶受到以下因素的困扰： 稳定性和生物利用度差，以及关节内注射后关节清除迅速。解决 这些限制，我们的父母R01工程二氧化锰纳米颗粒（MnO2 NPs），或“纳米酶”， 模拟抗氧化酶的活性氧（ROS）清除功能，但具有显著的 在稳定性、成本和生物利用度方面具有优势。事实上，我们证明了这些特性， 纳米材料可以针对关节组织保留和细胞吸收进行定制，这对于解决关键问题非常重要。 OA治疗的障碍。母体R01专注于优化MnO 2的抗氧化活性 NPs，在体外询问其软骨保护和抗炎机制，并评估其 在PTOA的啮齿动物模型中的体内疾病修饰能力。本附录扩展了这些研究，包括 全面评价MnO2 NP治疗的疼痛机制，特别关注 神经性疼痛OA患者可经历伤害性疼痛和神经性疼痛的组合。与 伤害性疼痛、组织损伤和炎症导致伤害感受器的激活和疼痛传递。 然而，神经性疼痛是由神经本身的损伤引起的，这可能与关节损伤或关节炎一起发生。 随着OA的进展，关节结构发生变化。神经性疼痛的治疗具有挑战性，因为 常用的抗炎药是无效的，治疗选择受到成瘾风险的限制， 严重的不良影响。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 和神经中的线粒体功能障碍。 鉴于其显著的抗氧化功能，稳定性， 由于MnO2纳米颗粒的生物利用度，我们假设MnO2纳米颗粒将有效缓解PTOA中的神经性疼痛。奠定 这一科学方向的基础，这一补充的目的是表征抗氧化功能的 MnO2 NPs与体外神经细胞，并评估体内神经性疼痛的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 的背根神经节，将补充行为分析，生化分析，和组织病理学 在母体R01中进行分析。这种对OA发病机制的综合评估，从关节结构方面， 功能和疼痛机制，可能有助于这种或其他方法从临床前成功转化为临床 抗氧化剂策略的肌肉骨骼疾病和慢性疼痛。

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.