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.
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.
| Koff, M F; Shah, P; Pownder, S et al. (2013) Correlation of meniscal T2* with multiphoton microscopy, and change of articular cartilage T2 in an ovine model of meniscal repair. Osteoarthritis Cartilage 21:1083-91 |
