Multi-parametric visualization of knee joint ultra-structure

Sophisticated surgical techniques in the treatment of cartilage defects, degenerative cartilage, meniscus pathologies, or anterior cruciate ligament (ACL) tears, need high quality follow-up. As these pathologies are most frequently combined with each other, a combination in diagnostics and follow-up measurements is desirable. In addition to conventional morphological MRI sequences, compositional (biochemical) MRI represents a novel approach for a more comprehensive analysis of joint tissues. Recent publications have employed these modern biochemical MRI techniques for the visualization of native cartilage, degenerative cartilage and cartilage repair tissue after different surgical cartilage repair techniques. Currently, also the meniscus and, within initial approaches, the ACL are targets for biochemical MRI. Advanced morphological and biochemical MRI has shown its capability to visualize the constitution and also the composition of these important joint structures. While morphological MRI focuses on the shape, the structure and possible changes in signal intensity, biochemical MRI aims at assessing the ultra-structure and the composition of the tissue on a molecular level. However, most of these functional MR techniques have not been sufficiently validated by histomorphological analysis so far, which limits their applicability in pre-clinical or clinical studies. While visualisation of cartilage by dGEMRIC or T2 relaxation mapping are the subject of current validation studies, the analysis of repaired or degenerative cartilage using newer techniques, such as 23Na(sodium) imaging, T2* mapping, T2d mapping, ultra-short echo-time (UTE) imaging, magnetization transfer contrast (MTC), diffusion-weighted imaging (DWI), or T1rho, has, to date, not been satisfactorily validated. Furthermore, very little histological confirmation has been available for the meniscus or the ACL with regard these MR methodologies. Goal of the present grant is to validate these novel biochemical MR techniques by conventional histomorphology and ultra high-field MR microscopy using two established animal models and to implement the findings into clinical MR follow-up protocols. In the knee joints of 20 sheep, healthy articular cartilage will either be compared with degenerated articular cartilage induced by meniscectomy (osteoarthritis group), or with two different types of cartilage repair tissues induced by the microfracture technique (MFX), or matrix-associated autologous chondrocyte transplantation (MACT) (cartilage repair group). Additionally, the above-mentioned biochemical MR methodologies (dGEMRIC, sodium MRI, T2 mapping, T2* mapping, T2d mapping, UTE, MTC, DWI and T1rho) will be used to assess the associated joint structures, including the menisci and anterior cruciate ligament (ACL) in a multi-parametric approach at different time points after surgery. Tissues from untreated healthy joints will serve as controls. The MR measurements will be performed at a clinical 3 Tesla MR system (to ensure the clinical applicability) and a 7 Tesla gradient insert enabling for MR microscopy and sodium MRI (to ensure the best possible image quality and resolution). The results can thus be downgraded from histology and MR microscopy to clinical 3 Tesla MRI. The visualization and non-destructive biochemical analysis of these musculoskeletal tissues should provide a basis for new clinical protocols in the follow-up of chondroprotective strategies, as well as cartilage repair surgery, meniscal surgery and ACL surgery.

Conventional morphological Magnetic Resonance Imaging (MRI) is already frequently used as a non-invasive tool to analyze the human knee joint. However diseases of the knee joint often have already started long before morphological changes can be seen. Novel compositional (biochemical) MRI can be applied for a more comprehensive analysis of joint tissues in order to improve diagnosis. It was the aim of this project to develop a combination of morphological and biochemical MRI which is beneficial to analyse early onset of cartilage defects, meniscus pathologies and anterior crucial ligament tears. Innovative MRI methods were designed on the 7 Tesla Scanner of the MR Center of Excellence in Vienna to get additional information of the main composites of the tissue. Briefly summarised we can get quantitative information on water content, the tissue structure, like the collagen fibre orientation (T2/T2*) and the loss or build up of critical biochemical substances (biomarkers) like proteoglycan (dGEMRIC, 23Na, gag-CEST). Additionally an improved imaging (UTE,vTE) of bone tissue interfaces of cartilage, menisci and bone-ligaments insertion was possible. To validate these methods we simulated selected diseases of the knee joint like osteoarthritis (OA) and different cartilage repair surgical procedures using an animal model. Additionally to the whole knee imaging MR microscopy was used to improve image resolution. Side by side comparison of MRI/MR microscopy at high fields with gold standard histo-morphological examination revealed a more detailed view of what changes can be analyzed and how they should be interpreted. Generally we can assume that diseases of the knee joint like osteoarthritis are very common and will become more frequently because of the demographic development of western societies. Often injuries of major parts of the knee joint like anterior crucial ligament (ACL) tears and different meniscus pathologies can lead to osteoarthritis (OA) .Younger more active patients and athletes with sport injuries will also require special treatments to prevent them from the development of delayed joint degeneration. Presently sophisticate orthopaedic surgical techniques are available to treat meniscus pathologies and ligament tears, also cartilage repair surgery has constantly improved and new cell based repair techniques had been developed so far. All of these techniques require high quality follow up which provide as much information on the state of the knee joint as possible. Magnetic resonance imaging allows in comparison to arthroscopy a non-invasive assessment of tissue repair which in case of cartilage repair is not limited on the tissue-surface. Compared to arthroscopy a more frequent examination can be tolerated which will improve diagnostic over a longer time period to get more information on the optimal time point of several treatment options. It will also improve the quality of clinical studies needed to design new treatments.Finally we can summarize that our findings will be implemented into future investigative protocols as high field musculoskeletal MRI moves towards clinical application. Our multi-parametric approach has significantly improved our ability to analyse morphological and biochemical properties of the whole knee joint by developing and improving MRI methods and validated them by using gold standard histology. The methods developed so far will support early diagnosis of degenerative joint diseases which will have a significant socio-economic impact by reducing treatment costs and improving the life quality of patients.