Magnetic Collection of Joint-Level Osteoarthritis Biomarkers

项目摘要 2007年美国用于骨关节炎（OA）治疗的总医疗支出 1850亿美元，OA患者平均每年的自付费用约为2600美元 (the相当于一个普通美国公民3周的工资）。此外，OA患者人群 预计到2030年，由于美国人口老龄化， 肥胖症的流行尽管存在这种显著且不断增长的社会经济负担， 药物（DMOAD）很难从实验室转化到临床。DMOAD的缺乏部分是由于 到无法检测早期OA，这是一个疾病阶段，干预和生活方式的改变具有更大的 有可能逆转OA受累关节中发现的慢性级联关节破坏。临床上，OA是 通过X光片和体检诊断，但这些诊断在检测方面相对较差。 早期OA存在对促进早期OA诊断的技术的显著需求。分子 生物标志物具有巨大的潜力，可以在骨关节炎发生结构损伤之前诊断骨关节炎。 关节（X线检查前）。该提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OA生物标志物，而不需要从关节间隙中去除液体。使用 磁收集，关节破坏的潜在分子标记物可以从滑液中去除 并量化以检查关节疾病的严重程度。此外，由于该技术可以在广泛的 在关节液体积的范围内，生物标志物可以在OA的临床前啮齿动物模型和 临床设置。该提案的目标将通过两个具体目标实现。目标1是开发一个 增强的定量技术（磁采集）用于体外关节水平收集OA生物标志物。 目标1将通过三个子目标实现：1）定义体外磁采集的关键参数，2） 研究和实验验证模型，以将通过磁性收集的生物标志物的量与 收集到滑液内的初始生物标志物浓度，以及3）评估磁共振成像的灵敏度。 在一个虚幻的人类膝盖上采集目的2是收集和分析关节水平的生物标志物在大鼠模型中， 使用磁收集的膝关节OA。目标2将研究磁收集作为研究工具的实用性 对于小动物模型，将磁采集与其他可用方法进行比较，以恢复关节水平 用于分子分析的蛋白质（灌洗、液体芯吸）。这项工作的直接影响将是 开发一种创新的研究工具，能够对多个联合层面的 OA的小动物模型中的分子生物标志物。这项工作的长期影响是， 开发新的方法来诊断早期OA，并开发一种技术， 受OA影响的较小人体关节（包括掌指关节和 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.