Magnetic Capture of Osteoarthritis Biomarkers

骨关节炎生物标志物的磁捕获

基本信息

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
项目类别：
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

项目摘要

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，会带来重大的社会经济负担，如果能够在疾病早期应用，并且为了促进这种治疗的发展，许多潜在的 OA 治疗方法可能会更有效。早期 OA 的诊断是 OA 治疗未来的关键需求，不幸的是，评估小关节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诊断的能力。我们的团队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，我们已经证明了从大鼠膝盖中检测 OA 生物标志物的能力。该提案的目的是推进磁捕获作为评估动物安乐死后啮齿类 OA 模型中多种生物标志物的方法（目标 1）以及评估动物安乐死后生物标志物水平的方法。这些进展将有助于通过啮齿类动物 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体小关节 OA 生物标志物分析的长期潜力。，例如人手的那些，在目标 1 中，磁捕获将通过完成啮齿动物的联合级 OA 生物标志物评估来推进。实现以下目标：(1.1) 开发多重方法以在单个磁性捕获程序中检测多种 OA 生物标志物，(1.2) 完善磁性探针设计以提高磁性纳米粒子捕获的效率，(1.3) 展示磁性捕获在小鼠 OA 模型，以及 (1.4) 评估关节级 OA 生物标志物、关节退化的组织学证据和 OA 症状的行为证据之间的联系。在目标 2 中，磁捕获将被推进为通过完成以下目标，在啮齿类动物中进行联合级 OA 生物标志物评估的体内分析方法：（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）设计基于导管的注射/收集装置磁性纳米颗粒的体内捕获，（2.3）评估用于体内磁性捕获的磁性颗粒的清除率、安全性和生物相容性，以及（2.4）使用纵向评估大鼠中的关节级 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。