Show simple item record

dc.contributor.advisorNewby, D.E.
dc.contributor.advisorGarden, James
dc.contributor.authorRichards, Jennifer Margaret Jane
dc.date.accessioned2013-11-07T16:24:20Z
dc.date.available2013-11-07T16:24:20Z
dc.date.issued2013-07-06
dc.identifier.urihttp://hdl.handle.net/1842/8079
dc.description.abstractBackground Superparamagnetic particles of iron oxide (SPIO) are part of a novel and exciting class of ‘smart’ magnetic resonance imaging (MRI) contrast agents that are taken up by inflammatory cells. Ultrasmall SPIO (USPIO; ~30 nm diameter) can be used to assess cellular tissue inflammation and SPIO (80-150 nm) have the potential to be used to label cells ex vivo for in vivo cell tracking studies. Objectives The aims of the thesis were therefore (i) to develop and validate quantitative MRI methodology for assessing SPIO uptake within tissues, (ii) to demonstrate USPIO accumulation within the aortic wall and its implications in patients with abdominal aortic aneurysms (AAA), and (iii) to develop and apply a Good Manufacturing Practice (GMP) compliant method of SPIO cell labelling in healthy volunteers. Methods Patients with asymptomatic AAA >4.0 cm in diameter were recruited. Imaging sequences were optimised in eight patients using a 3 tesla MRI scanner. Data were analysed using the decay constant for multi echo T2* weighted (T2*W) sequences (T2*) or its inverse (R2*) and the repeatability of these measurements was established. A further twenty-nine patients underwent MRI scanning before and 24- 36 hours after administration of USPIO. T2 and multi echo T2*W sequences were performed and ultrasound-based growth rate data were collected. Operative aortic wall tissue samples were obtained from patients undergoing open surgical aneurysm repair. A GMP compliant protocol was developed for labelling cells with SPIO for clinical cell tracking studies. The effects of SPIO-labelling on cell viability and function were assessed in vitro. A phased-dosing protocol was used to establish the safety of intravenous administration of SPIO-labelled cells in healthy volunteers. The feasibility of imaging cells at a target site in vivo following local or systemic administration was assessed. Tracking of SPIO-labelled cells to a target site was investigated by inducing an iatrogenic inflammatory focus in the skin of the anterior thigh of healthy volunteers, following which autologous SPIO-labelled cells were administered and their accumulation was assessed using MRI scanning and histology of skin biopsies. Results Robust and semi-quantitative data acquisition and image analysis methodology was developed for the assessment of SPIO accumulation in tissues. In patients with AAA, histological analysis of aortic wall tissue samples confirmed USPIO accumulation in areas of cellular inflammation. USPIO-enhanced MRI detected aortic wall inflammation and mural USPIO uptake was associated with a 3-fold higher aneurysm expansion rate. Human mononuclear cells were labelled with SPIO under GMP compliant conditions without affecting cell viability or function. Both local and intravenous administration of SPIO-labelled cells was safe and cells were detectable in vitro and in vivo using a clinical MRI scanner. SPIO-labelled cells tracked to a focal iatrogenic inflammatory focus following intravenous administration in humans and were detectable on MRI scanning and histological examination of skin biopsies. Conclusions SPIO contrast agents have an extensive range of potential clinical applications. USPIO uptake in the wall of AAA appears to identify cellular inflammation and predict accelerated aneurysm expansion. This is therefore a promising investigative tool for stratifying the risk of disease progression in patients with AAA, and may also be considered as a biomarker for response to novel pharmacological agents. The ability to label cells for non-invasive cell tracking studies would facilitate the further development of novel cell-based therapies and would enable assessment of dynamic inflammatory processes through inflammatory cell tracking.en_US
dc.contributor.sponsorBritish Heart Foundationen_US
dc.language.isoenen_US
dc.publisherThe University of Edinburghen_US
dc.relation.hasversionAbdominal aortic aneurysm growth predicted by uptake of ultrasmall superparamagnetic particles of iron oxide: a pilot study Jennifer M.J. Richards, Scott I. Semple, Thomas J. MacGillivray, Calum Gray, Jeremy P. Langrish, Michelle Williams, Marc Dweck, William Wallace, Graham McKillop, Roderick T.A. Chalmers, O. James Garden and David E. Newby Circ Cardiovasc Imaging 2011; 4:274-281en_US
dc.relation.hasversionIn Vivo Mononuclear Cell Tracking Using Superparamagnetic Particles of Iron Oxide: Feasibility and Safety in Humans Jennifer M.J. Richards, Catherine A. Shaw, Ninian N. Lang, Michelle C. Williams, Scott I.K. Semple, Thomas J. MacGillivray, Calum Gray, Julie H. Crawford, Shirjel R. Alam, Anne P.M. Atkinson, Elaine K. Forrest, Carol Bienek , Nicholas L. Mills, Anne Burdess, Kev Dhaliwal, A. John Simpson, William A. Wallace, Adam T. Hill, P. Huw Roddie, Graham McKillop, Thomas A. Connolly, Giora Z. Feuerstein, G. Robin Barclay, Marc L. Turner, David E. Newby Circ Cardiovasc Imaging 2012; 5:509-517en_US
dc.subjectmagnetic resonance imagingen_US
dc.subjectMRIen_US
dc.subjectaortic aneurysmsen_US
dc.titleMagnetic resonance imaging in cardiovascular diseaseen_US
dc.typeThesis or Dissertationen_US
dc.type.qualificationlevelDoctoralen_US
dc.type.qualificationnamePhD Doctor of Philosophyen_US


Files in this item

This item appears in the following Collection(s)

Show simple item record