Ions in models of articular cartilage : The importance of electrostatic interactions for transport and equilibrium distribution

Sammanfattning: Osteoarthritis (OA) is a degenerative disease that affects articular cartilage, which covers the surfaces of the bones in synovial joints. At later stages the disease can result in major loss of articular cartilage and thus lead to major disability. In order to allow for an early detection and treatment of OA, it is necessary to better understand the rather subtle biochemical changes in the cartilage that occurs at the initial stages of the disease.An important example of a molecular-level change, that is associated with OA is a decrease in the concentration of glycosaminoglycans (GAGs), which are polysaccharides carrying a high density of negative charges. The loss of GAGs can be monitored by, for instance, magnetic resonance imaging (MRI) or computed tomography (CT) in combination with the administration of charged contrast agents. Because of electrostatic interactions between the GAGs, and the charged contrast agent, the concentration of contrast agent in cartilage will depend on the concentration of GAGs and it is found that the partitioning can be described according to the principle of Donnan equilibrium. In the interpretation of MRI data on cartilage, the concentration of contrast agent is commonly related to the concentration of GAGs by the application of ideal Donnan theory, where non-idealities of the involved ions are neglected. Although this assumption is sometimes appropriate, it has been found that analyses of MRI data on cartilage involving ideal Donnan theory in the dGEMRIC method can lead to substantial errors in the estimated GAG concentration. The origin of the discrepancy is debated, but one possibility is that the error arises from the neglect of nonidealities.In the work underlying this thesis, the impact of non-idealities due to electrostatic interactions on the transport and equilibrium distribution of charged species in synovial fluid and articular cartilage has been investigated. To this end, systematic studies were performed on well-defined theoretical and experimental model systems, which were designed to capture the most important ionic features of articular cartilage and the synovial fluid, using a combination of μMRI experiments, Monte Carlo simulations, andfinite element method (FEM) simulations.It was found that the non-idealities arising from electrostatic interactions can, depending on the character of the solute considered, have a substantial influence on the partitioning of a charged solute between cartilage and synovial fluid and, thus, on the applicability of ideal Donnan theory for estimation of the GAG concentration. Importantly, the results from the model systems investigated in this work show good consistency with data on real cartilage found in the literature. Furthermore, non-idealities can also be important to take into account when predicting the rate of transport of a charged solute into cartilage. The results from this thesis are valuable for work towards improving the interpretation of MRI data on cartilage. Since the same mechanisms that control the partitioning of contrast agents are involved in the partitioning of potential drugs, the results are also valuable in the development of drugs to treat OA.