Emerging quantitative MR imaging biomarkers in inflammatory arthritides

PURPOSE: To review quantitative magnetic resonance imaging (qMRI) methods for imaging inflammation in connective tissues and the skeleton in inflammatory arthritis. This review is designed for a broad audience including radiologists, imaging technologists, rheumatologists and other healthcare professionals. METHODS: We discuss the use of qMRI for imaging skeletal inflammation from both technical and clinical perspectives. We consider how qMRI can be targeted to specific aspects of the pathological process in synovium, cartilage, bone, tendons and entheses. Evidence for the various techniques from studies of both adults and children with inflammatory arthritis is reviewed and critically appraised. RESULTS: qMRI has the potential to objectively identify, characterize and quantify inflammation of the connective tissues and skeleton in both adult and pediatric patients. Measurements of tissue properties derived using qMRI methods can serve as imaging biomarkers, which are potentially more reproducible and informative than conventional MRI methods. Several qMRI methods are nearing transition into clinical practice and may inform diagnosis and treatment decisions, with the potential to improve patient outcomes. CONCLUSIONS: qMRI enables specific assessment of inflammation in synovium, cartilage, bone, tendons and entheses, and can facilitate a more consistent, personalized approach to diagnosis, characterisation and monitoring of disease

MRI Mapping for Cartilage Repair Follow-up

Patients, who benefit from cartilage repair surgery, need a non-invasive and high-quality imaging modality to assess the structure and the biochemical property of the repair tissue. Magnetic resonance imaging (MRI), which provides better tissue contrast and high spatial resolution, is currently the best imaging technique available for the assessment of articular cartilage pathologies. In addition to MR morphology sequences, that allow cartilage lesions detection as well as repair tissue evaluation from the articular surface of the joint to the bone-cartilage interface, MRI mapping techniques help to assess the technical success of the procedure of cartilage repair and the state of cartilage healing, as well the identification of possible complications after cartilage repair surgery. MRI mapping techniques such as T1, T2 and T2* mapping help to assess the biochemical property of the repair tissue using delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) to assess the proteoglycan content and T2/T1rho (T1ρ) mapping to assess the collagen content and the fiber matrix arrangement. This chapter gives an overview about the MRI mapping techniques used for Cartilage Repair Tissue Follow-up

Assessing patterns of T2/T1rho change in grade 1 cartilage lesions of the distal femur using an angle/layer dependent approach.

PURPOSE:To assess changes in the patterns of T2 and T1rho values within grade 1 cartilage lesions of osteoarthritis (OA) patients compared to healthy controls. MATERIALS AND METHODS:Twenty healthy knees and 25 OA knees were examined on a 3 T scanner. Areas of signal heterogeneity within the cartilage of the distal femur were identified using fat suppressed proton density-weighted imagines. T2 and T1rho values in each OA patient with grade 1 lesions were compared to average T2 and T1rho values of the corresponding areas in healthy subjects. RESULTS:A total of 28 areas including grade 1 lesion were identified. Compared to normal cartilage, the majority of grade 1 cartilage lesions demonstrated either no significant change or a statistically significant increase in both T2 values (18/28, 64%) and T1rho values (23/28, 82%). Compared to T2, T1rho demonstrated a greater proportion of statistically significantly higher values in OA patients than those from the normal controls. However, T2 and T1rho values in grade 1 lesions can be decreased, or demonstrate mixed patterns compared to those in healthy cartilage. CONCLUSION:Our results suggest that early degenerative cartilage lesions can demonstrate various patterns of T2 and T1rho changes

Investigation of Quantitative Magnetization Transfer Magnetic Resonance Imaging as a Non-Invasive Technique to Assess the Biochemical, Mechanical, and Histologic Properties of Healthy and Osteoarthritic Meniscus and Cartilage

Osteoarthritis is a degenerative disease affecting entire joints and leading to pain, stiffness, and loss of mobility. It affects around 13% of the Canadian population and commonly presents in the knee. Traditionally, osteoarthritis has been visualized using radiography because it is the most accessible imaging method and can detect bone alterations, but this method is unable to show changes to the articular cartilage and meniscus, which have been shown to play an important role in the disease process. Quantitative magnetic resonance imaging (qMRI) is able to provide images of the soft tissue within the knee joint as well as numerical values representative of the state of the tissue health. One particular qMRI technique is quantitative magnetization transfer (qMT), and it allows for the determination of the properties of the bound pool within tissues (macromolecules such as proteoglycan and collagen) that has resonance too short to be captured with conventional MRI. Because qMT probes the properties of the hydrogen bound to macromolecules, it is expected to be more sensitive to the changes in composition of a tissue associated with osteoarthritis. The primary objective of this research is to establish a relationship between qMT parameters (f, k, T2b relaxation time, T2f relaxation time, and T1f relaxation time) and the biochemical, histological, and mechanical properties of human articular cartilage and meniscus, and a secondary objective is to compare in vivo to ex situ qMT parameters. Two separate studies were conducted using differing populations in order to accomplish these objectives. The first study assessed six human cadaver knees with no history of injury or illness in order to validate the methods and gain a baseline of values to be expected in a healthy population. Intact cadaver knees were imaged using qMT MRI techniques and qMT parameters extracted. Subsequent to imaging, core samples were taken from each meniscus and digested and assayed to determine the liquid, collagen, and proteoglycan contents. Menisci were dissected into pieces for histology and scored using an established histological scoring system customized to the meniscus. Pearson product moment and Spearman’s rho correlation coefficients were calculated for the biochemistry and histology results respectively compared to the qMT parameters to determine if any of the imaging metrics were predictive of the biochemical content or histological score. Results of this study showed several significant correlations between the qMT parameters and tissue properties. Some of these key findings included correlations in the collective samples where increasing liquid content was associated with decreasing bound pool fraction (r=-0.248, p<0.5); increasing collagen per dry mass showed increasing T1f (r=0.413, p<0.01) and T2f (r=0.510, p<0.01); and an increase in total histology score was related to a decrease in T1f (ρ=-0.232, p<0.05), T2f (ρ=-0.277, p<0.01), and T2b (ρ=-0.207, p<0.05). In the medial side samples, key correlations were observed between increasing collagen per dry mass and increasing T1f (r=0.477, p<0.01), T2f (r=0.585, p<0.01), and T2b (r=0.415, p<0.05); and increasing histology score and decreasing T1f (ρ=-0.232, p<0.05), T2f (ρ=-0.277, p<0.01), and T2b (ρ=-0.207, p<0.05). In the lateral side samples, key correlations were between increasing liquid content and decreasing f (r=-0.380, p<0.05) and increasing sulfated glycosaminoglycan (sGAG) per wet mass was associated with increases in f (r=0.391, p<0.05) and kf (r=0.404, p<0.05). The second study focused on an end-stage osteoarthritis population by assessing total knee arthroplasty patients. The aim of this study was to explore the relationships between qMT parameters and tissue properties in damaged tissue. Two patients were scanned using the qMT MRI protocol prior to their surgery, and the excised tissues were scanned post-operatively using the same sequence. From these samples, seven separate articular cartilage and meniscus surfaces (both medial and lateral) were assessed. After imaging, the surfaces underwent mechanical indentation testing and the instantaneous modulus, elastic fit mean squared error, and tissue thicknesses were determined. Core samples were then removed from the surfaces for biochemical and histological analysis. Biochemistry protocols were the same as utilized in the cadaver study, and histology preparation was the same as well with different scoring methods used depending on the tissue type (articular cartilage versus meniscus). Pearson and Spearman correlation coefficients were once again determined in order to assess correlations between the qMT parameters and the tissue properties. A Wilcoxon signed rank test was performed to assess differences between in vivo and ex situ qMT results. The key results of this study showed significant correlations in the in vivo cartilage between increasing instantaneous modulus and decreasing T1f (r=-0.221, p<0.05) and T2f (r=-0.233, p<0.05) in the lateral side samples; increasing liquid content and T1f (r=0.836, p<0.05) in the lateral samples; and histology score and f in the combined samples (ρ=0.670, p<0.05) and medial samples (ρ=1.000, p<0.01). In the ex situ cartilage, significant correlations were found between increasing histology score and decreasing T2b (ρ=-0.896, p<0.01) in the lateral samples. In the lateral menisci samples in vivo, key correlations were found between increasing liquid content and decreasing kf (r=-0.890, p<0.05); increasing sGAG/dry mass and increasing T2b (r=0.869, p<0.05); and increasing collagen/wet mass and increasing kf (r=0.820, p<0.05). In the lateral ex situ menisci, a negative correlation was observed between instantaneous modulus and T2f (r=-0.563, p<0.05). In the global surface analysis (combining all cartilage and meniscus surfaces), key correlations were between increasing liquid content and increasing T1f (r=0.926, p<0.01) and T2f (r=0.864, p<0.05); increasing sGAG/dry mass and increasing T1f (r=826 p<0.05) and T2f (r=0.964, p<0.01); increasing collagen/dry mass and decreasing T1f (r=-0.780, p<0.05); and increasing histology score and increasing T2f (ρ=0.893, p<0.01). Significant decreases in T1obs, T1f, T2f and T2b were also found from in vivo to ex situ scanning environments. The findings in the correlation analysis of this project show the potential of qMT MRI imaging as a valuable modality for determining the structure, function, and composition of osteoarthritic articular cartilage and meniscus. It has been shown that ex situ qMT parameters are not the same as in vivo but steps have been made in a direction towards quantifying the relationships between the differing environments. Possible uses of this technique lie in early diagnosis of OA, monitoring of disease progression, and evaluation of potential treatments

Investigation of Subchondral Bone Abnormalities associated with Osteoarthritis using Image-Based Biomechanics

Osteoarthritis (OA) is degenerative disease caused by a mechanical failure of bone and cartilage. Common risk factors for developing OA include: being over-weight, female, having joint malalignment, or a history of prior joint injury. Post-traumatic OA is extremely common in the knee as individuals frequently suffer injuries to structures that provide stability to the joint. To enhance our understanding about OA, animal models are employed where the injury can be and monitored in a controlled environment. When used in conjunction with pre-clinical imaging techniques the longitudinal degradation of bone and cartilage can be quantitatively monitored in vivo. Recent evidence has identified cystic lesions within the subchondral bone as the possible source of painful symptoms and accelerated disease progression, but little is known about their etiology. The purpose of this thesis was to improve knowledge regarding the mechanism that causes subchondral cysts. OA was induced in the rodent knee via surgery, and the pathological changes were quantified with micro-CT and MRI. The composition of the cysts was correlated with end-stage histology. Thus, an accurate definition of OA bone cysts was achieved. To assess the effect of cysts in human bone, a study was conducted using a patient data set restrospectively. Using finite element (FE) analysis, higher stress values were found within bone surrounding cysts. Therefore, the probable mechanism of cyst expansion, stress induced resorption, was identified. Finally, the FE models of the bones were combined with soft tissue structures – from a co-registered MRI – to produce comprehensive patient-specific models of the knee

Engineering zonally organized articular cartilage

textCartilage regeneration is one of the most widely studied areas in tissue-engineering. Despite significant progress, most efforts to date have only focused on generating homogenous tissues whose bulk properties are similar to articular cartilage. However, anatomically and functionally, articular cartilage consists of four spatially distinct regions: the superficial, transitional, deep, and calcified zones. Each zone is characterized by unique extra-cellular matrix (ECM) compositions, mechanical properties, and cellular organization. The ECM is primarily composed of type II collagen and glycosaminoglycans (GAGs), whose relative concentrations vary between zones and therefore lead to distinctive mechanical properties. One of the major unsolved challenges in engineering cartilage has been the inability to regenerate tissue that mimics the zonal architecture of articular cartilage. Recent studies have attempted to imitate this spatial organization using zone-specific chondrocytes isolated from donor animal cartilage. Directed differentiation of a single stem population into zonally organized native-like articular cartilage has not yet been reported. This dissertation reports that hydrogels, incorporating both synthetic and natural polymers as well as cell-induced degradability, are suitable for generating zone-specific chondrogenic phenotypes from a single MSC population. Specifically, cues provided from the unique combinations of chondroitin sulfate (CS), hyaluronic acid (HA), and MMP-sensitive peptide (MMP-pep) within a PEG-based hydrogel, direct the chondrogenic differentiation of MSCs. The findings of this dissertation demonstrate the capability of creating native-like and mechanically relevant articular cartilage consisting of zone specific layers. This ability provides a new direction in cartilage tissue engineering and could be invaluable for cartilage repair if incorporated with current minimally invasive surgical techniques.Biomedical Engineerin