Page 79 - Cellular Imaging in Regenerative Medicine, Cancer and Osteoarthritis
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                                Introduction
In vivo cell tracking is a very promising technique to visualize cells of interest inside the body. It allows tracking of motile therapeutic cells like immune cells, stem cells, and endothelial progenitor cells to sites of inflammation, cancer, or ischemia [1-5]. Additionally, this technique can be used to track tumor cells [6], tumor vasculature [7, 8], or endothelial cells in tissue engineered valves [9] and vascular grafts [10].
After labeling the cells of interest with an imaging probe, they can be tracked by an imaging modality. Magnetic resonance imaging (MRI) is interesting for cell tracking because it is precise, harmless, and thus well suited for longitudinal studies. Moreover, single cell tracking is possible by MRI. However, in vivo cell labeling with an MRI contrast agent is challenging [6, 11-16]. For cell labeling, the T2 and T2*-shortening MRI contrast agent superparamagnetic iron oxide nanoparticles (SPIO) of 80–180 nm in size [17] are often used [18, 19]. They are relatively safe compounds [19-22], but most of in vitro cell labeling techniques for SPIO are not applicable in vivo, because of the high toxicity and broad systemic effects of transfection agents [23]. Therefore, there has been growing interest in safe, site-specific cell labeling techniques. One potential method involves using ultrasound contrast agent, which are comprised of microbubbles. The microbubbles have a low diffusible gas core (for example C4F10), vary in diameter from 1–10 μm, and are encapsulated by a coating material (for example phospholipids). When ultrasound is applied, the microbubbles oscillate due to sequential compression and expansion caused by pressure variations in the surrounding medium. The oscillation of microbubbles has been shown to deliver therapeutic materials into cells and interstitial tissue [24-27]. Up till now there is no consensus on the mechanism of the enhanced uptake. One of the uptake routes is a phenomenon called sonoporation, when reversible or non-reversible cell membrane pores are generated upon microbubble oscillations or violent collapse. Other uptake routes include enhanced endocytosis and opening of cell-cell contacts [25, 26, 28]. It has been reported that the efficacy of cellular uptake of therapeutic agents can be improved up to 7.7-fold in vitro [29] and up to fivefold in vivo [30] by using targeted microbubbles (tMB) instead of non-targeted microbubbles (non-
SPIO cell labeling using ultrasound
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