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Magnetically Targeted Endothelial Cell Localization in Stented Vessels

Sorin V. Pislaru, MD, PhD^_*, Adriana Harbuzariu, MD^_*, Rajiv Gulati, MD, PhD^_*, Tyra Witt^_*, Nicole P. Sandhu, MD, PhD, Robert D. Simari, MD, FACC^_* and Gurpreet S. Sandhu, MD, PhD, FACC^_*,_*

^_* Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, Rochester, Minnesota
Division of General Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota

View larger version (20K): [in this window] [in a new window] [Download PPT slide]   Figure 1 Escalating superparamagnetic microsphere dose inhibits cell proliferation. Exposure of endothelial outgrowth cell (EOC) to escalating doses of superparamagnetic microsphere (SPM) results in a small but significant decrease in bromo-deoxyuridine (BrdU) incorporation at high, but not at low doses. * p < 0.05 versus no SPM.

View larger version (139K): [in this window] [in a new window] [Download PPT slide]   Figure 2 Apoptosis and secretory profiles are stable with low-dose SPM. (A and B) Terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) assays: composite confocal images. Green fluorescence is given by SPM whereas red fluorescence represents TUNEL-positive apoptotic cells. Exposure to SPM at a 500:1 ratio results in minimal apoptosis (A) , whereas significantly increased presence of apoptotic cells is evident at a higher SPM to EOC ratio (B , 4,000:1 ratio). (C and D) Cytokine array studies. EOC secretory profile was very similar for untreated cells (C) and cells exposed to SPM at a 500:1 ratio (D) . The top four left dots and bottom two right dots are built-in positive controls of the array. All other dots represent an individual cytokine (72 in total). With these studies, secretion of interleukins (IL)-8 and IL-10; growth factors EGF, HGF, and GDNF; and metalloproteinase inhibitors TIMP-1 and TIMP-2 and MIP-1b were identified. Other abbreviations as in Figure 1 .

View larger version (69K): [in this window] [in a new window] [Download PPT slide]   Figure 3 SPM-labeled EOCs: interactions with magnetic fields. (A and B) Stacked confocal images obtained along the z-axis (100x magnification). EOCs are labeled with CM-DiI (red) and SPM (green) . Exposure of SPM-loaded EOCs to a degaussed stainless steel loop does not result in significant cell attraction (A) . On the contrary, in the presence of a magnetized stainless steel loop, SPM-loaded cells are rapidly cleared from the suspension and accumulate predominantly on the loop bend (B) . A green reflection from the stainless-steel loop is evident. (C and D) Nickel coating of a commercially available stent results in multiple, small, uniformly distributed magnetic domains, as shown in ferrofluid studies (C) . Presence of numerous magnetic microdomains is evident (arrows) . This translated into a more uniform coverage of the stent surface (D) . Endothelial outgrowth cells are labeled with SPM (green) . (E and F) Transmission electronic microscopy confirms uniform cytoplasmic capture of SPM microspheres (E) . Scanning electron microscopy shows early accumulation of rounded cells to the metal surface (F) . (G and H) Representative en face fluorescent microscopy images (200x magnification) from explanted coronary arteries. Local delivery of CM-DiI (red) –labeled EOCs to a non-magnetized stent containing arterial segment results in retention of cells in small numbers (G) . Local delivery is greatly enhanced in the segment that received a nickel-coated, magnetized stent before EOC delivery. Note presence of CM-diI–labeled cells along a stent strut (H) . Abbreviations as in Figure 1 .

View larger version (39K): [in this window] [in a new window] [Download PPT slide]   Figure 4 Arteries retain more EOCs in the presence of magnetized stents. (A) Cell retention in vivo was significantly higher on magnetized (solid bars) versus non-magnetized control stents (open bars) for both femoral and coronary position. *p < 0.05 for magnetized versus non-magnetized stent. (B) Overlapping, composite, low-power microscopic images of the luminal surface of a porcine coronary artery showing distribution of labeled cells along stent tines and the adjacent denuded endothelium. Abbreviations as in Figure 1 .