Magnetic Capture of Osteoarthritis Biomarkers

骨关节炎生物标志物的磁捕获

• 批准号: 9109459
• 负责人: Kyle D Allen
• 金额: $ 31.83万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-11 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9109459
• 关键词: Address; Affect; Animal Euthanasia; Animals; Aspirate substance; Assessment tool; Behavioral; Binding; Biological Markers; Catheters; Clinic; Collection; Communication; Complex; Degenerative polyarthritis; Detection; Development; Diagnosis; Diagnostic; Disease; Early Diagnosis; Engineering; Equilibrium; Euthanasia; Fc Receptor; Future; Goals; Hand; Health; Human; Injection of therapeutic agent; Joints; Knee; Lead; Life; Link; Magnetic nanoparticles; Magnetism; Measurement; Measures; Methods; Modeling; Molecular; Monitor; Motivation; Mus; Nature; Pain; Pathogenesis; Patient-Focused Outcomes; Peer Review; Pre-Clinical Model; Procedures; Process; Prognostic Marker; Rattus; Rodent; Rodent Model; Safety; Serum; Staging; Surface; Symptoms; Synovial Fluid; Techniques; Technology; Testing; Therapeutic; Translating; United States National Institutes of Health; Urine; aptamer; base; biomarker development; biomarker discovery; biomaterial compatibility; chronic pain; design; diagnostic biomarker; disability; disabling symptom; improved; in vivo; iron oxide; joint destruction; nanoparticle; new technology; novel; novel diagnostics; particle; pre-clinical; prognostic; socioeconomics; targeted biomarker

 DESCRIPTION (provided by applicant): Osteoarthritis (OA) is a painful, debilitating disease associated with a significant socioeconomic burden. Many potential therapeutics for OA would likely be more effective if they could be applied at early disease stages, and to facilitate this, development of diagnostics for early stage OA is a critical need for the future of OA therapy. Unfortunately, technologies to assess joint-level changes in small articular joints are underdeveloped, and these technological limits impede our ability to effectively develop new diagnostic and prognostic biomarkers for OA. Our group has developed a new magnetic nanoparticle based technology to extract biomarkers directly from small articular joints without the need to aspirate synovial fluid. Using magnetic capture, we have demonstrated the ability to detect an OA biomarker from a rat knee with greater accuracy and sensitivity than current methods. The objective of this proposal is to advance magnetic capture as a method to assess multiple biomarkers in rodent OA models following animal euthanasia (Aim 1) and as a method to assess biomarker levels in live animals (Aim 2). These advances will help enable the development of prognostic biomarkers through rodent OA models, improve the preclinical assessment of emerging OA therapeutics, and demonstrate the long-term potential to apply magnetic capture to OA biomarker analysis in small human joints, such as those of the human hand. This application focuses on two, multi-objective specific aims. In Aim 1, magnetic capture will be advanced as post mortem analysis method of joint-level OA biomarker assessment in rodents by completing the following objectives: (1.1) Develop multiplex methods to detect multiple OA biomarkers in a single magnetic capture procedure, (1.2) Refine the magnetic probe design to increase the efficiency of the magnetic nanoparticle capture, (1.3) Demonstrate feasibility and utility of magnetic capture in a mouse OA model, and (1.4) Evaluate links between joint-level OA biomarkers, histological evidence of joint degeneration, and behavioral evidence of OA symptoms. In Aim 2, magnetic capture will be advanced as an in vivo analysis method of joint-level OA biomarker assessment in rodents by completing the following objectives: (2.1) Design particles and targeting molecules for the in vivo capture of OA biomarkers, (2.2) Design a catheter-based injection/collection apparatus for the in vivo capture of magnetic nanoparticles, (2.3) Assess the clearance, safety, and biocompatibility of magnetic particles used for in vivo magnetic capture, and (2.4) Longitudinally assess a joint-level OA biomarker in the rat using in vivo magnetic capture. Successful completion of these Aims and Objectives will lead to better understand the links between OA-related pathogenesis and OA-related pain and disability, and thereby an ability to develop diagnostic and prognostic OA biomarkers that will improve patient outcomes for OA. A major step toward this goal is the development of an enabling technology for longitudinal OA biomarker assessment in the synovial fluid of small articular joints. In this proposal, our novel magnetic capture technology will be advanced to address this need.

 描述（由申请人提供）：骨关节炎（OA）是一种痛苦的、使人衰弱的疾病，与显着的社会经济负担相关。许多潜在的 OA 治疗方法如果能够应用于早期疾病阶段，可能会更有效，为了促进这一点，开发早期 OA 的诊断方法是 OA 治疗未来的关键需求。不幸的是，评估小关节关节水平变化的技术尚不成熟，这些技术限制阻碍了我们有效开发新的 OA 诊断和预后生物标志物的能力。我们的小组开发了一种基于磁性纳米颗粒的新型技术，可以直接从小关节中提取生物标志物，而无需抽吸滑液。使用磁性捕获，我们已经证明能够从大鼠膝盖中检测 OA 生物标志物，其准确性和灵敏度比现有方法更高。该提案的目的是推进磁捕获作为评估动物安乐死后啮齿动物 OA 模型中多种生物标志物的方法（目标 1）和评估活体动物生物标志物水平的方法（目标 2）。这些进展将有助于通过啮齿动物 OA 模型开发预后生物标志物，改善新兴 OA 疗法的临床前评估，并证明将磁捕获应用于人类小关节（例如人手的关节）的 OA 生物标志物分析的长期潜力。该应用程序侧重于两个多目标特定目标。在目标 1 中，磁捕获将通过完成以下目标，作为啮齿动物联合级 OA 生物标志物评估的尸检分析方法得到发展：（1.1）开发多重方法以在单个磁捕获程序中检测多个 OA 生物标志物，（1.2）完善磁性探针设计以提高磁性纳米颗粒捕获的效率，（1.3）在小鼠 OA 模型中展示磁捕获的可行性和实用性，以及 (1.4) 评估关节级 OA 生物标志物、关节退变的组织学证据和 OA 症状的行为证据之间的联系。在目标 2 中，磁性捕获将通过完成以下目标，作为啮齿动物联合级 OA 生物标志物评估的体内分析方法得到发展：(2.1) 设计用于体内捕获 OA 生物标志物的颗粒和靶向分子，(2.2) 设计用于体内捕获磁性纳米粒子的基于导管的注射/收集装置，(2.3) 评估清除率、安全性和生物相容性 用于体内磁捕获的磁性颗粒的数量，以及（2.4）使用体内磁捕获纵向评估大鼠的关节水平 OA 生物标志物。成功完成这些目的和目标将有助于更好地了解 OA 相关发病机制和 OA 相关疼痛和残疾之间的联系，从而能够开发诊断和预后 OA 生物标志物，从而改善 OA 患者的预后。实现这一目标的一个重要步骤是开发一种用于小关节滑液中纵向 OA 生物标志物评估的支持技术。在本提案中，我们将改进新型磁捕获技术来满足这一需求。