Magnetic Collection of Joint-Level Osteoarthritis Biomarkers

项目摘要 2007年美国用于骨关节炎(OA)治疗的医疗支出总额 为1850亿美元，一个OA患者每年的平均自付费用约为2600美元 (相当于一个普通美国公民3周的工资)。此外，骨性关节炎患者人数为 预计到2030年，患者将从2700万人增加到6700万人，原因是美国人口老龄化和 肥胖症的流行。尽管有这种重大且不断增长的社会经济负担，但疾病改变了骨关节炎 药物(DMOADs)很难从实验室转移到临床。缺乏DMOAD在一定程度上是由于 无法检测到早期骨性关节炎，这是一种疾病阶段，干预措施和生活方式的改变 有可能扭转在受骨性关节炎影响的关节中发现的慢性关节破坏。临床上，骨性关节炎是 通过X光片和体检确诊，但这些诊断方法在发现方面相对较差 早期骨性关节炎。存在着对促进早期OA诊断的技术的重大需求。分子 生物标志物有巨大的潜力在骨关节炎的结构损伤发生之前进行诊断。 关节(放射前)。该方案的目标是开发一种新的基于磁性纳米颗粒的技术 从滑液中收集骨性关节炎的生物标志物，而不需要从关节间隙取出液体。vbl.使用 磁采集，关节破坏的潜在分子标记可以从滑液中移除 并量化以检查关节疾病的严重程度。此外，因为这项技术可以在广泛的范围内工作 关节液体积的范围，生物标志物可以在临床前的OA啮齿动物模型中和在 临床环境。提案目标将通过两个具体目标来实现。目标1是开发一种 增强的定量技术(磁采集)用于体外联合水平收集骨性关节炎生物标记物。 目标1将通过三个子目标来实现：1)确定体外磁采集的关键参数；2) 调查和实验验证模型，以关联通过磁力收集的生物标记物的量 采集滑液中的初始生物标志物浓度，以及3)评估磁感应强度的敏感性 在幽灵般的人类膝盖上收割。目标2是收集和分析大鼠模型中关节水平的生物标志物。 膝关节骨关节炎采用磁力收割法。目标2将研究磁收获作为一种研究工具的效用 对于小动物模型，将磁采集与其他可用的方法进行比较，以恢复关节水平 用于分子分析的蛋白质(灌洗液、液芯)。这项工作的直接影响将是 开发一种创新的研究工具，使多个联合层面的定量评估成为可能 小动物骨性关节炎模型中的分子生物标志物。这项工作的长期影响是有可能 开发诊断早期骨性关节炎的新方法，并开发一种能够使 受骨性关节炎影响的人体小关节的生物标志物分析，包括掌指和 手的指间关节和脊柱的小关节。

Project Summary The 2007 aggregate healthcare expenditures attributed to osteoarthritis (OA) treatment in the United States were $185 billion, with an average out-of-pocket expense for an OA patient of approximately $2600 annually (the equivalent of 3 wks pay for an average American citizen). Moreover, the OA patient population is anticipated to grow from 27 million patients to 67 million patients in 2030, due to an aging US population and an epidemic of obesity. Despite this significant and growing socioeconomic burden, disease modifying OA drugs (DMOADs) have been difficult to translate from the lab to the clinic. The lack of DMOADs is due in part to an inability to detect early-stage OA, a disease stage where interventions and lifestyle changes have greater potential to reverse a chronic cascade of joint destruction found in the OA-affected joint. Clinically, OA is diagnosed through radiographs and physical exams, yet these diagnostics are relatively poor at detecting early-stage OA. A significant need exists for technologies that facilitate early-stage OA diagnosis. Molecular biomarkers have tremendous potential to diagnose OA prior to the development of structural damage in the joint (pre-radiographic). The goal of this proposal is to develop a novel magnetic nanoparticle-based technique to collect OA biomarkers from synovial fluid without the need to remove fluid from the joint space. Using magnetic harvesting, potential molecular markers of joint destruction can be removed from the synovial fluid and quantified to examine the severity of joint disease. Moreover, because the technique can work in a wide range of joint fluid volumes, biomarkers could be quantified in both preclinical rodent models of OA and in the clinical setting. The proposal goal will be achieved through two specific aims. Aim 1 is to develop an enhanced, quantitative technique (magnetic harvesting) for the joint-level collection of OA biomarkers in vitro. Aim 1 will be achieved through three sub-aims: 1) Define key parameters for magnetic harvesting in vitro, 2) Investigate and experimentally verify models to relate the amount of biomarker collected via magnetic harvesting to the initial biomarker concentration within synovial fluid, and 3) Assess the sensitivity of magnetic harvesting in a phantom human knee. Aim 2 is to collect and analyze joint-level biomarkers in a rat model of knee OA using magnetic harvesting. Aim 2 will examine the utility of magnetic harvesting as a research tool for small animal models, comparing magnetic harvesting to other available methods to recover joint-level proteins for molecular analysis (lavage, fluid wicking). The immediate impact of this work will be the development of an innovative research tool that will enable the quantitative assessment of multiple joint-level molecular biomarkers in small animal models of OA. The long-term impact of this work is the potential to develop new methods to diagnosis early-stage OA and the development of a technology that would enable biomarker analysis in smaller human joints affected by OA, including the metacarpophalangeal and interphalangeal joints of the hand and the facet joints of the spine.