A Novel Contrast Agent for Post-Traumatic Osteoarthritis Imaging

项目摘要 摘要创伤后骨关节炎(PTOA)是急性膝关节后常见的严重并发症。 损伤，如前十字韧带(ACL)断裂。外科重建不能预防 PTOA的发展，表明损伤后关节的急性生化变化触发了 导致PTOA的一连串事件。对损伤的炎症反应的永久化被假设为 在关节退变过程中的重要因素，因此是一个有吸引力的治疗目标。在……里面 一般来说，在PTOA中观察到的炎症是慢性的、低级别的，主要由先天免疫调节。 系统。虽然已经确定了几种可以激活炎症反应的机制 在体外，关于炎症反应是如何在体内发生的鲜为人知，因为我们缺乏技术来 追踪体内的炎症反应。目前评估PTOA炎症反应的方法要么是破坏性的 组织学，不像炎症因子的分析那样具有组织特异性，或者缺乏这样的生物学特异性 就像影像一样。分子成像是解决PTOA发病机制的一种自然方法，因为它 可以在分子水平上成像炎症过程，并完全覆盖关节。我们的研究旨在 开发一种新的造影剂以成像体内PTOA的低级别炎症 特异性靶向细胞表面受体，在炎症信号和组织修复中发挥重要作用。 我们建议使用结合磁共振成像(MRI)和NEAR的多模式成像方法 红外(NIR)成像。我们将进行实验，在体外验证造影剂，并评估其 体内早期和晚期药代动力学研究。最后，我们将在纵向研究中测试造影剂。 这一建议的结果将为阐明PTOA的病理生理机制提供一个平台，有助于识别 新的治疗靶点，并跟踪治疗反应。在此应用中开发的分子探针具有 人类临床翻译的潜力，因为它的目标是跨物种保存的。

Project Summary Posttraumatic osteoarthritis (PTOA) is a common and serious complication that can occur following acute knee injury, such as anterior cruciate ligament (ACL) rupture. The inability of surgical reconstruction to prevent the development of PTOA, suggests that acute biochemical changes in the joint following injury trigger the cascade of events leading to PTOA. Perpetuation of the inflammatory response to injury is hypothesized as an important factor in the process of joint degeneration, thus representing an attractive target for therapy. In general, the inflammation observed in PTOA is chronic, low-grade, mediated primarily by the innate immune system. Although several mechanisms have been identified that can activate the inflammatory response in vitro, there is little known on how the inflammatory response occurs in vivo, since we lack the technology to track inflammation in vivo. Current methods to assess inflammation in PTOA are either destructive like histology, are not tissue-specific like the analysis of inflammatory factors, or lack the biological specificity such as imaging. Molecular imaging represents a natural approach to address the pathogenesis of PTOA, since it can image inflammation processes at the molecular level with complete joint coverage. Our research aims to develop a new contrast agent to image low-grade inflammation in PTOA in vivo by using a peptide that specifically target cell surface receptors, which play important roles in inflammatory signaling and tissue repair. We propose to use a multimodal imaging approach combining magnetic resonance imaging (MRI) and near infrared (NIR) imaging. We will conduct experiments to validate the contrast agent in vitro and to assess its pharmacokinetics at early and late stage in vivo. Lastly, we will test the contrast agent in a longitudinal study. The results of this proposal will provide a platform to elucidate the pathophysiology of PTOA, help identifying new therapeutic targets, and track therapy response. The molecular probe developed in this application has potential for human clinical translation since its targets are preserved cross-species.