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

Algotsson, Jenny LU (2017)
Abstract (Swedish)
Artros är en vanligt förekommande ledsjukdom som kan leda till stelhet och
smärta i den drabbade leden. Sjukdomen innebär att det sker en nedbrytning av det brosk som fungerar som smörjmedel och skyddande lager runt benändarna i leden. Nedbrytningen av brosket sker gradvis under flera år och oftast upptäcker man sjukdomen först i ett sent stadium när man börjar känna smärta eller få problem med rörligheten.

I tidiga stadier av artros sker förändringar i brosket på molekylnivå. För att
kunna behandla sjukdomen i ett tidigt skede, och för att på ett effektivt sätt
kunna utveckla botemedel, måste man kunna upptäcka och studera dessa molekylära förändringar i brosket. På senare år har metoder utvecklats som gör detta... (More)
Artros är en vanligt förekommande ledsjukdom som kan leda till stelhet och
smärta i den drabbade leden. Sjukdomen innebär att det sker en nedbrytning av det brosk som fungerar som smörjmedel och skyddande lager runt benändarna i leden. Nedbrytningen av brosket sker gradvis under flera år och oftast upptäcker man sjukdomen först i ett sent stadium när man börjar känna smärta eller få problem med rörligheten.

I tidiga stadier av artros sker förändringar i brosket på molekylnivå. För att
kunna behandla sjukdomen i ett tidigt skede, och för att på ett effektivt sätt
kunna utveckla botemedel, måste man kunna upptäcka och studera dessa molekylära förändringar i brosket. På senare år har metoder utvecklats som gör detta möjligt. I flera av dessa metoder använder man sig av kontrastmedel som tas upp i brosket i en mängd som beror på graden av artros. Det är dock inte
helt klarlagt hur mängden upptaget kontrastmedel ska ”översättas” till graden
av molekylära förändringar i brosket. Uppbyggandet av en grundläggande
förståelse för vad som styr upptaget av kontrastmedel försvåras av att brosk
har en komplicerad sammansättning och struktur.

Detta doktorandarbete har handlat om att öka förståelsen för hur vissa faktorer
styr upptaget av kontrastmedel och andra substanser i brosk. För att kunna studera detta på ett systematiskt sätt har förenklade system som efterliknar brosk konstruerats, där man har god kontroll över sammansättningen. Dessa system har sedan studerats både experimentellt och med matematiska modeller. Ett viktigt resultat från arbetet är att kontrastmedlet växelverkar med omgivningen annorlunda i brosket än i ledvätskan runt brosket, vilket har en stor inverkan på vilken mängd av kontrastmedlet som tas upp. Detta är oftast något som oftast förbises eftersom skillnaderna i växelverkan är svåra att bestämma i riktigt brosk. Med de metoder som utvecklats i detta arbete är det möjligt att systematiskt undersöka hur olika beståndsdelar i brosk påverkar upptaget, vilket kan vara till hjälp för att dra rätt slutsatser från undersökningar med kontrastmedel. Dessutom är samma mekanismer som styr upptaget av kontrastmedel inblandade i upptag av läkemedel i brosk. Resultaten från detta arbete kan därför också vara värdefulla vid utveckling av läkemedel mot artros. (Less)
Abstract
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... (More)
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, and
finite 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. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Dr. Nissi, Mikko J., University of Eastern Finland, Kuopio, Finland
organization
publishing date
type
Thesis
publication status
published
subject
keywords
articular cartilage, Donnan equilibrium, diffusion, MRI, Monte Carlo simulations, dGEMRIC
publisher
Lund University, Faculty of Science, Department of Chemistry, Division of Physical Chemistry
defense location
Lecture hall C, Center for chemistry and chemical engineering, Naturvetarvägen 14, Lund
defense date
2017-02-17 09:30
ISBN
978-91-7422-499-3
978-91-7422-498-6
language
English
LU publication?
yes
id
d9eedb0f-9aa4-4e70-9e91-cc3e833653c0
date added to LUP
2017-01-20 17:02:07
date last changed
2017-02-03 16:01:16
@phdthesis{d9eedb0f-9aa4-4e70-9e91-cc3e833653c0,
  abstract     = {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.<br/><br/>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.<br/><br/>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, and<br/>finite element method (FEM) simulations.<br/><br/>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.},
  author       = {Algotsson, Jenny},
  isbn         = {978-91-7422-499-3},
  keyword      = {articular cartilage,Donnan equilibrium,diffusion,MRI,Monte Carlo simulations,dGEMRIC},
  language     = {eng},
  publisher    = {Lund University, Faculty of Science, Department of Chemistry, Division of Physical Chemistry},
  school       = {Lund University},
  title        = {Ions in models of articular cartilage : The importance of electrostatic interactions for transport and equilibrium distribution},
  year         = {2017},
}