Probing Osteoarthritis Pathogenesis by Noninvasive Imaging of Cartilage Strain

项目总结/摘要 本提案的目的是使用一种新的非侵入性方法预测体内骨关节炎（OA）的发病机制。 基于MRI的关节软骨生物力学测量方法。磁共振的最新进展 磁共振成像（MRI）已被引入，具有诊断和预测OA进展的令人兴奋的潜力， 最常见的退行性关节疾病。MRI方法试图发现OA的早期变化， 新出现的改善疾病的干预措施（例如细胞植入）可能是最有效的。OA病理生理学 通常涉及关节损伤（例如韧带断裂）和退行性级联反应， 炎性细胞因子和酶。此外，主要大分子如 聚集蛋白聚糖和II型胶原导致组织内应变和材料性质（例如模量）改变， 提示软骨生物力学的MRI可能对退变敏感。不幸的是，非侵入性 OA的诊断仍然很差，特别是在疾病的早期阶段，仍然存在一些挑战，包括 需要敏感和特异的影像学生物标志物来预测OA的结果， 生物标志物对组织功能和生物力学的影响。在我们最初的资助（AR 063712）中，我们率先推出了dualMRI （通过MRI在施加的载荷下的位移）用于软骨生物力学以监测关节健康。我们 发现dualMRI在检测受控酶消化后的应变增加方面是稳健的， 对切除组织的机械创伤，以及在绵羊体内的时间过程的椎间盘切除术研究中。相比 与定量MRI（qMRI，例如T1ρ标测）相比，剪切应变与人类OA严重程度更相关 软骨我们最近还进行了第一次在人体内和组织内软骨应变措施， 临床3特斯拉（T）MRI系统。在此更新申请中，我们将建立一个工作流程来测量应变， 模量（即弹性成像），并在多个模型系统中验证此工作流程。在人类中，我们也会 识别基于生物力学的MRI指标和生物标志物，预测时间进程软骨功能， 一部分患者韧带重建后出现症状性疼痛。我们将追踪三个相关的 具体目标。在目标1中，我们将建立一个常规的临床工作流程，用于组织内应变的双重MRI测量 及特性.我们将扩展现有的双MRI序列，以加速应变的临床测量 在15分钟内，并结合逆向建模，自动测量体内弹性成像。在目标2中， 我们将根据金标准基准验证双MRI组织内应变和特性， 通过量化众多误差指标，可实现体内时程分析的重现性。在目标3中，我们将预测 韧带重建后患者的功能结果和软骨健康。康贝特人将以 6个月时的MRI指标预测1年和2年时患者报告的结局和组织健康的程度 后处理。如果成功，我们将建立一个常规的方法来评估软骨的功能， 支持以软骨生物力学作为关节损伤和修复的具体指标的新范例。

PROJECT SUMMARY / ABSTRACT The objective of this proposal is to predict osteoarthritis (OA) pathogenesis in vivo using a novel noninvasive MRI-based method of measuring articular cartilage biomechanics. Recent advances in magnetic resonance imaging (MRI) have been introduced with exciting potential to diagnose and predict the progression of OA, the most common degenerative joint disease. MRI methods have sought to discover early changes in OA, when emerging disease-modifying interventions (e.g. cell implantation) may be most effective. OA pathophysiology often involves joint injury (e.g. ligament rupture) and a degenerative cascade of increased expression of inflammatory cytokines and enzymes. Moreover, the breakdown and loss of major macromolecules such as aggrecan and type II collagen leads to altered strains and material properties (e.g. moduli) within the tissue, suggesting MRI of cartilage biomechanics may be sensitive to degeneration. Unfortunately, noninvasive diagnosis of OA remains poor, especially in early disease stages, and several challenges remain, including the need for sensitive and specific imaging biomarkers that predict OA outcomes, and the need to relate imaging biomarkers to tissue function and biomechanics. In our original grant (AR063712), we pioneered dualMRI (displacements under applied loading by MRI) for cartilage biomechanics to monitor joint health. We discovered that dualMRI is robust to detect strain increases following controlled enzyme digestions or mechanical trauma to excised tissues, and in an in vivo time-course meniscectomy study in sheep. Compared to quantitative MRI (qMRI, e.g. T1ρ mapping), shear strains better correlated with OA severity in human cartilage. We also recently performed first-in-human in vivo and intra-tissue cartilage strain measures on a clinical 3 Tesla (T) MRI system. In this renewal application, we will establish a workflow to measure strains and moduli (i.e. elastography), and validate this workflow in multiple model systems. In humans, we will also identify biomechanics-based MRI metrics and biomarkers that predict time-course cartilage function and symptomatic pain following ligament reconstruction in a subset of patients. We will pursue three related specific aims. In Aim 1, we will establish a routine, clinical workflow for dualMRI measures of intra-tissue strain and properties. We will extend our existing dualMRI sequence to accelerate clinical measurement of strain within 15 minutes, and coupled to inverse modeling, automate measurement of in vivo elastography. In Aim 2, we will validate dualMRI intra-tissue strain and properties against gold-standard benchmarks, confirming reproducibility for in vivo time course analyses by quantifying numerous error metrics. In Aim 3, we will predict functional outcomes and cartilage health in patients following ligament reconstruction. We will determine the extent that MRI metrics at six months predict patient-reported outcomes and tissue health at one and two years post treatment. If successful, we will establish a routine method for functional assessment of cartilage, and support a new paradigm targeting cartilage biomechanics as specific indicators of joint damage and repair.