Biomedical Engineering Reference
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result of its dextran coat (Sharma et al. 1999 ; Jung and Jacobs 1995 ). A preclinical
particle of similar size to USPIO is the monocrystalline iron oxide nanocompound
(MION) developed by Massachusetts General Hospital (Shen et al. 1993 ). Each
particle has a single 4-5 nm core coated with dextran, resulting in a hydrated
diameter of 20 nm. Two other ultra-small preclinical particles that are coated with
monomers are the citrate-coated very small superparamagnetic iron oxide particles
(VSOP, 5 nm core, 8 nm hydrated diameter) (Taupitz et al. 2000 ) and the
dimercaptosuccinic acid-coated anionic magnetic nanoparticle (AMNP, 8 nm core,
30 nm hydrated diameter) (Wilhelm and Gazeau 2008 ).
MRI of inflammatory processes is feasible using the ability of macrophages to take
up iron oxide particles in vivo . Macrophages involved in atherosclerotic plaques have
been imaged following an intravenous injection of SPIO (Ruehm et al. 2001 ; von
Zur Muhlen et al. 2007 ). After USPIO injection, particle uptake was predominantly
in ruptured and rupture-prone atherosclerotic lesions, differentiating such lesions from
intact ones (Kooi et al. 2003 ). Iron oxide particles can also be used for assessing
neuroinflammation following ischemic stroke, by differentiating infiltrating macro-
phages from resident ones. By intravenously (IV) injecting rodents with SPIO 24 h
prior to imaging, MR images showed darkened stroke periphery at day 6 or darkened
stroke core at day 8 post-stroke. The specific darkening was due to iron-laden macro-
phages infiltrating the stroke site (Kleinschnitz et al. 2003 ). Interestingly, when
SPIO/USPIO were delivered IV 2-5 h post-stroke, the stroke periphery darkened as
well but this was due to focal accumulation of SPIO/USPIO in the occluded vessels
(Kleinschnitz et al. 2005 ; Wiart et al. 2007 ). Therefore, IV administration of SPIO/
USPIO can monitor both ischemic development and the infiltration of macrophages
into the stroke site in animal models (Bendszus et al. 2007 ), leading to clinical
phase II trials of the particles in neuroinflammatory imaging (Saleh et al. 2004 ).
4
Cellular Labelling with Iron Oxide Particles
Another method of MR cell tracking, first reported two decades ago, is through the
ex vivo labelling of cells with iron oxide particles prior to their transplantation
(Ghosh et al. 1990 ). Particles were introduced into the culture medium of cells and
incubated for hours to encourage particle uptake by endocytosis into intracellular
compartments. Labelled cells appeared as hypo-intense regions on MR, similar to
those that have taken up intravenously-injected SPIO. In the early 1990s, neural
tissues (Norman et al. 1992 ) and T cells (Yeh et al. 1993 ) were labelled with iron
oxide particles and transplanted into healthy animals, demonstrating that labelled
cells can be visualized in vivo . The signal void created by iron oxide labelling extends
well beyond the cell membrane, making it easier to identify the cells in the image
(Pintaskeet et al. 2006 ).
Since its early successes, more cell types have been labelled with iron oxide
particles, including monocytes, glioma cells, oligodendrocytes progenitors (Bulte
and Kraitchman 2004 ), macrophages, mesenchymal stem cells (Wang et al. 2010 )
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