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。膝关节韧带具有多种重要功能，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]。由于半月板撕裂和破坏会导致退行性骨关节炎，因此人们普遍认为应积极尝试半月板修复，以保护半月板功能和随后的关节健康[2]。半月板修复的不完全和失败愈合率为50%[3]。仅部分愈合的半月板可能在临床上无症状[4]，因此临床医生可能会允许患者返回可能使修复处于风险中的活动。目前临床创伤愈合评估的敏感性和定性性质较差，无法准确决定是否恢复日常生活活动。磁共振成像（MRI）用于半月板修复的非侵入性评价，但半月板的可视化是困难的，因为半月板的高度组织化的超微结构在标准化成像期间由于短的横向弛豫时间（T2）而产生有限的信号强度。为关节软骨成像开发的T2标测的定量MRI（qMRI）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。这将是有益的，有一个有效的qMRI技术，医生客观和定量评估骨折愈合，并提供准确的康复方案和预后信息的病人。本研究的目的是在动物模型中评价使用UTE成像作为椎间盘完整性生物标志物的T2 * 标测的qMRI技术，以及相应的生物力学和组织学指标。将使用一个绵羊模型的尿道修复。在内侧半月板前角的血管区域内产生垂直方向的纵向撕裂，并立即修复。对侧肢体将用作非手术或假手术对照。将在术后0、4和8个月的时间点对动物实施安乐死。对膝关节内侧间室进行MR成像，以非侵入性评价修复的半月板。首先，将使用水敏脉冲序列来评估潜在的液体吸入修复部位。其次，将进行UTE成像以提供半月板内的对比度并计算组织的局部T2 * 值。成像后，将膝关节离断，并采集用于生物力学测试和修复组织学检查的组织样本。生物力学分析将量化修复部位间隙作为加载循环次数和失效载荷的函数。还将测量完整膝关节的失效载荷。修复半月板的组织学分析将使用多光子显微镜评价基质蛋白聚糖含量、血管渗透、胶原含量和胶原定向。然后，我们将在每个离散时间点将间接测量的股骨T2 * 值与直接测量的股骨结构（组织学）和功能（生物力学）相关联。本研究的长期目标是建立无创qMRI UTE T2 * 标测技术与生物力学特性和椎间盘组织的组织学外观之间的相关性。标准MR成像在评价尿道修复组织的结构完整性方面能力有限。我们预计，通过将T2 * 映射技术与组织学和机械性能相关联，我们将建立一个非侵入性生物标志物的组织成分和机械性能。在美国，超过35%的成年人有膝关节撕裂或破坏的证据[5]，并且更有可能发生膝关节骨关节炎。由于没有无创的、客观的和定量的方法来评价尿道修复，因此难以在体内评价尿道愈合。本提案将评价在临床相关场强下进行的完全无创定量MR技术评估椎间盘修复和功能的能力。

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.