Probing Osteoarthritis Pathogenesis by Noninvasive Imaging of Cartilage Strain

项目摘要/摘要 这项建议的目的是使用一种新的非侵入性方法在体内预测骨关节炎(OA)的发病机制 基于磁共振成像的关节软骨生物力学测量方法。磁共振研究的最新进展 磁共振成像(MRI)被引入到诊断和预测OA的进展方面具有令人兴奋的潜力， 最常见的退行性关节疾病。核磁共振方法试图发现骨关节炎的早期变化，当 新出现的改变疾病的干预措施(例如细胞移植)可能是最有效的。骨性关节炎病理生理学 通常涉及关节损伤(如韧带断裂)和退行性级联表达增加 炎性细胞因子和酶。此外，主要大分子的分解和损失，如 聚集素和II型胶原导致组织内的菌株和材料特性(例如模数)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 对骨性关节炎的诊断仍然很差，特别是在疾病的早期阶段，仍然存在一些挑战，包括 需要灵敏和特定的影像生物标记物来预测OA的结果，以及与影像相关的需求 组织功能和生物力学的生物标志物。在我们最初的拨款(AR063712)中，我们开创了双磁共振成像技术 用于软骨生物力学监测关节健康的核磁共振成像(外加载荷下的位移)。我们 发现双重核磁共振在检测受控酶消化或 对切除组织的机械损伤，以及在绵羊半月板切除术中的活体时间进程研究。相比较 对于定量磁共振成像(qMRI，例如T1ρ标测)，剪切应变与人类骨性关节炎严重程度的相关性更好 软骨。我们最近还进行了第一次人体活体和组织内软骨应变测量 临床3特斯拉(T)磁共振系统。在此续订申请中，我们将建立一个工作流来测量菌株和 并在多个模型系统中验证此工作流。在人类身上，我们也会 确定基于生物力学的MRI指标和生物标记物，预测时间进程软骨功能和 部分患者在韧带重建后出现症状性疼痛。我们将追求三个相关的 明确的目标。在目标1中，我们将为组织内应变的双重mri测量建立常规的临床工作流程。 和财产。我们将扩展我们现有的双核磁共振序列，以加快临床应变测量 在15分钟内，与反向建模相结合，可自动测量体内弹性成像。在目标2中， 我们将对照黄金标准基准验证双磁共振组织内应变和特性，确认 通过量化大量的误差指标，可重复性进行活体时间进程分析。在目标3中，我们将预测 韧带重建术后患者的功能结果和软骨健康状况。我们将确定 6个月的MRI指标预测患者报告的结果和一年和两年组织健康的程度 后处理。如果成功，我们将建立一种常规的软骨功能评估方法，并 支持将软骨生物力学作为关节损伤和修复的具体指标的新范式。

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.