Transplanted stem cells suffer from poor viability, migration, and misguided delivery and thus improved imaging techniques are needed to increase the effectiveness of stem cell therapy. Here, we combined real-time acoustic imaging techniques with magnetic particle imaging (MPI) that offers zero background imaging for high contrast data sets. We used PLGA/iron oxide hybrid nanoparticles (diameter = 185 ± 2 nm) labeled with DiR as a trimodal contrast agent. The PLGA coating facilitated ultrasound backscatter, the DiR enhanced the photoacoustic signal, and the iron oxide generated the MPI signal. The in vitro limit of detection of the contrast media was 120 μg/mL for ultrasound, 24 μg/mL for photoacoustic, and 60 μg/mL for magnetic particle imaging. ICP-OES measurements determined that there were 1,043, 1,402, 4,542, 9,069,11,070, and 11,218 iron oxide particles in cells treated with concentrations of 2.4, 24, 60, 120,180, and 240 μg/ml nanobubbles respectively for 6 hrs. The human mesenchymal stem cells differentiated into adipogenic and osteogenic cell lines with no major morphological differences from non-treated cells. The nanoparticle-labeled stem cells were injected intracardially into live mice for real-time imaging. The ultrasound signal was 3.8-fold higher, the photoacoustic signal was 10.2 times higher (imaged at 730 nm), and the MPI signal was 20-fold higher in these stem cell-injected animals than in the control animals injected with PBS. The limit of detection was 10,461 cells for ultrasound and 996 cells for photoacoustics. This technique is advantageous over MRI techniques due to the ability to image stem cell injections in real-time combined with the very high signal-to-background of MPI.
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