23for clinical use as liver-specific contrast agents—however, the production of both
has since been ceased due to commercial reasons. SPIOs have an iron- oxide core
(usually of magnetite or maghemite), a coating layer (often dextran or carboxydex-
tran, chitosan, silica or gelatin) that stabilizes the magnetic core, and finally surface
functional groups (such as polyethylene glycol and polystyrene) that provide hydro-
philicity and stability, and prevent nanoparticle aggregation (Fig. 2.3). SPIOs act as
good T-2 contrast agents in MRI, enhancing the contrast between tissues [ 16 ].
There has been marked variety in the composition of SPIOs including different
types of iron cores, different coating layers, different transfection agents (peptides
helping SPIO incorporation into the cell), and significantly differing dosing strate-
gies across published studies, precluding robust conclusions about their usage in
stem cell applications thus far. However, mesenchymal stem cells, adipose-derived
stem cells and neural progenitor cells have been labeled and tracked with SPIOs
in vivo in a rabbit [ 41 ] and a rat [ 42 ], in diseases such as cardiovascular disease,
skeletal tissue injury, traumatic brain injury, stroke, spinal cord injury, and multiple
sclerosis [ 43 – 49 ]. Beyond tracking transplanted stem cells, SPIOs have also been
utilized in identifying and labeling endogenous stem cells in vivo [ 50 ]. Most of
these studies report that more than 90% of cells contained enough iron to allow for
their detection without significant alterations in cell viability and differentiation,
however reports do exist of decreased cell proliferation and migration, as well as
signs of inflammation [ 51 ].
In clinical trials involving bone marrow derived stem cells and hematopoietic
stem cells that are used in patients within 24 h after their isolation, the labeling of
stem cells with SPIO nanoparticles should be performed in less than one day. A
rapid method to label stem cells has been reported based in the electroporation of
cells (“magnetoelectroporation”) [ 52 ]. This technique involves low-voltage pulses
to induce endocytosis of contrast agents in a matter of minutes. In addition to the
advantage of rapid labeling of cells, this technique does not require transfection
agents for the internalization of SPIO nanoparticles, which simplifies the regulatory
pathway required for approval by regulatory agencies.
A number of factors affect the MRI detection threshold of SPIOs-labeled cells,
such as the SPIO concentration per cell, and intrinsic MRI parameters, such as field
strength, signal-to noise ratio, pulse sequence, and acquisition parameters. In most
Fig. 2.3 Silica-coated iron
oxide nanoparticle.
Reprinted with open-
access permission from
Bohmer et al. [ 40 ]
2 Nanotechnology-Based Stem Cell Applications and Imaging