Evaluation of an MRI Biomarker for Meniscal Repair

描述（由申请人提供）：本申请涉及广泛的挑战领域（03）：生物标志物的发现和验证以及特定的挑战主题，03- ar -104：成像生物标志物。膝关节半月板具有几个重要的功能，包括增加股骨远端和胫骨近端不一致关节面之间的接触面积，关节润滑，软骨细胞营养和关节稳定性[1]。由于撕裂和半月板破坏导致退行性骨关节炎[2]，人们普遍认为应该积极尝试半月板修复，以保持半月板功能和随后的关节健康。半月板修复的不完全和失败愈合率为50%。只有部分愈合的半月板在临床上可能是无症状的，因此临床医生可能会允许患者恢复可能危及修复的活动。目前临床半月板愈合评估的敏感性和定性较差，妨碍了对恢复日常生活活动的准确决定。磁共振成像（MRI）用于半月板修复的非侵入性评估，但半月板的可视化是困难的，因为半月板高度组织化的超微结构在标准化成像中由于短的横向松弛时间（T2）而产生有限的信号强度。用于关节软骨成像的定量MRI (qMRI) T2定位技术无法捕获半月板的非常短的T2值。最近，超短回波（UTE）序列已被开发用于显示半月板内的图像对比度以及产生用于定量T2*计算的多回波图像。有一个有效的qMRI技术将有利于医生客观和定量地评估半月板愈合，并为患者提供准确的康复方案和预后信息。本研究的目的是在动物模型中评估使用ut成像的T2*定位技术作为半月板完整性的生物标志物，以及相应的半月板修复的生物力学和组织学测量。将使用绵羊半月板修复模型。垂直方向，纵向撕裂将在内侧半月板前角的血管区产生，并立即修复。对侧肢体将用作非手术或假手术对照。动物将在术后0、4和8个月的时间点实施安乐死。对膝关节内侧腔室进行磁共振成像，对修复后的半月板进行无创评估。首先，将使用水敏感脉冲序列来评估修复部位的潜在流体吸收率。其次，将进行UTE成像以提供半月板内的对比，并计算组织的局部T2*值。成像后，膝关节将被分离，组织样本用于生物力学测试和修复的组织学检查。生物力学分析将量化修复点间隙作为加载周期数和失效载荷的函数。对于完整的膝盖，也将测量到失效的载荷。修复后半月板的组织学分析将利用多光子显微镜评估基质蛋白聚糖含量、血管穿透性、胶原含量和胶原取向。然后，我们将在每个离散时间点将半月板T2*值的间接测量与半月板结构（组织学）和功能（生物力学）的直接测量相关联。本研究的长期目标是建立无创qMRI UTE T2*定位技术与半月板组织生物力学特性和组织学外观之间的相关性。标准磁共振成像在评估半月板修复组织的结构完整性方面是有限的。我们预计，通过将T2*定位技术与组织学和力学性能相关联，我们将建立半月板组成和力学性能的无创生物标志物。在美国，超过35%的成年人有半月板撕裂或破裂的迹象，并且更有可能发展成膝关节骨关节炎。由于没有无创、客观、定量的评估半月板修复的方法，很难评估半月板在体内的愈合情况。本提案将评估在临床相关场强下进行的完全无创、定量MR技术评估半月板修复和功能的能力。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (03): Biomarker Discovery and Validation and specific Challenge Topic, 03-AR-104: Imaging Biomarkers. The menisci of the knee perform several important functions including increasing the contact area between the incongruent articular surfaces of the distal femoral and proximal tibial, joint lubrication, chondrocyte nutrition and joint stability [1]. It is widely accepted that aggressive attempts at meniscal repair should be made in order to preserve meniscus function and subsequent joint health since tears and disruption of the meniscus lead to degenerative osteoarthritis [2]. Meniscal repairs have an incomplete and failed healing rate of 50% [3]. A meniscus that is only partially healed may be clinically asymptomatic [4], thus a clinician might potentially allow patients to return to activities that can put the repair at risk. The current poor sensitivity and qualitative nature of clinical meniscal healing evaluation precludes accurate decisions about return to activities of daily living. Magnetic resonance imaging (MRI) is used for non-invasive evaluation of meniscal repairs, but visualization of the meniscus is difficult because the highly organized ultrastructure of the meniscus produces limited signal intensity during standardized imaging due to short transverse relaxation times (T2). The quantitative MRI (qMRI) technique of T2 mapping developed for articular cartilage imaging is unable to capture the very short T2 values of the meniscus. Recently, ultra-short echo (UTE) sequences have been developed to display image contrast within the meniscus as well as producing multi-echo images for quantitative T2* calculation. It would be beneficial to have a validated qMRI technique for physicians to objectively and quantitatively assess meniscal healing and to provide accurate rehabilitation protocols and prognostic information for the patient. The goal of this study is to evaluate the qMRI technique of T2* mapping using UTE imaging as a biomarker of meniscal integrity with corresponding biomechanical and histological measures of meniscal repair in an animal model. An ovine model of meniscal repair will be used. Vertically oriented, longitudinal tears will be created in the vascular region of the anterior horn of the medial meniscus and immediately repaired. The contralateral limbs will be used as non-operative or sham- operated controls. Animals will be euthanized at times points of 0, 4 and 8 months post-operatively. The medial compartment of the knee will have MR imaging performed to non-invasively evaluate the repaired meniscus. First, a water-sensitive pulse sequence will be used to evaluate potential fluid imbibition into the repair site. Second, UTE imaging will be performed to provide contrast within the meniscus and to calculate the local T2* values of the tissue. After imaging, the knee joints will be disarticulated and tissue samples for biomechanical testing and histological examination of the repair will be acquired. The biomechanical analysis will quantify repair site gapping as a function of number of loading cycles and the load to failure. The load to failure will also be measured for intact knees. The histologic analysis of the repaired meniscus will evaluate matrix proteoglycan content, vascular penetration, collagen content and collagen orientation using multiphoton microscopy. We will then correlate the indirect measurements of meniscal T2* values with direct measurements of meniscal structure (histology) and function (biomechanics) at each discrete time point. The long term objective of this study is to establish a correlation between the non-invasive qMRI UTE T2* mapping technique with biomechanical properties and histological appearance of meniscal tissue. Standard MR imaging is limited in its ability to evaluate the structural integrity of meniscal repair tissue. We anticipate that by correlating the T2* mapping technique to histology and mechanical properties, we will establish a noninvasive biomarker of meniscal composition and mechanical performance. Over 35% of adults in the US have evidence of meniscal tears or disruption [5], and are more likely to develop osteoarthritis in the knee. It is difficult to evaluate meniscal healing in-vivo since no non-invasive, objective and quantitative method for evaluating meniscal repair exists. This proposal will evaluate the ability of a completely noninvasive, quantitative MR technique, performed at clinically relevant field strengths, to assess meniscal repair and function.