Biomedical Engineering Reference
In-Depth Information
These four clinical studies show that iron oxide labels appear to be safe and that
clinical detection of the labelled cells is possible. To achieve the goal of clinical
cellular MRI, more off-label use of clinically approved contrast agents, such as
ferumoxide or ferucarbotran, in cellular therapy trials is needed. Currently, the FDA
requires preclinical studies to be performed in experimental models of diseases
using labelled and unlabelled cells along with sham controls to assess the toxicity and
any alteration in morbidity and mortality (Arbab and Frank 2008 ). Serum chemistry
analysis, histology correlation and experimentation in a clinical grade manufacturing
practice (CGMP) facility are foreseeable requirements in the future.
7
Challenges of Cellular MRI
Cellular MRI faces several challenges in the pursuit of a cell marking method that
can be translated to clinical use. Being non-phagocytic, stem cells do not internalise
sufficient quantities of clinically-available SPIO by simple incubation. We have
reviewed the optimization of uptake through particle design, labelling conditions
and the use of transfection agents or electroporation while ensuring that cellular
functions are retained. The other challenges of this technique are the dilution of
label, false positivity, cellular quantification and positive contrast generation.
7.1
Label Dilution
A drawback of using exogenous particles is the dilution of labels as cells undergo
division in vivo . The cellular labels are split among the two daughter cells, resulting
in approximately halving of the iron quantity per cell after each division (Fig. 2 ).
Although the dilution of label will affect the visibility of cell grafts that undergo
rapid division, it is an acceptable limitation to cell types, such as MSC, that generally
do not proliferate extensively post-transplantation.
7.2
Label Transfer
In spite of sufficient cellular iron loading, the route and timing of cellular delivery
may have significant effects on cell survival and engraftment. Cellular graft destru-
ction by hostile host immune responses may result in transfer of labels to the host
immune cells. When cells are tagged with exogenous fluorescent labels such as
5-bromo-2-deoxyuridine (BrdU) and bis benzamide (BBZ) prior to transplantation,
label transfer to host macrophages can potentially cause erroneous diagnoses of
cellular engraftment or differentiation (Pawelczyk et al. 2006 ; Burns et al. 2006 ;
Coyne et al. 2006 ). Iron oxide MRI labels face the same problem. Hence, secondary
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