Temporal and Noninvasive Monitoring of Inflammatory-Cell Infiltration to Myocardial Infarction Sites Using Micrometer-Sized Iron Oxide Particles Yidong Yang, 1,2 Yuhui Yang, 1 Nathan Yanasak, 1 Autumn Schumacher, 1 and Tom C.-C. Hu 1,2 * Micrometer-sized iron oxide particles (MPIO) are a more sen- sitive MRI contrast agent for tracking cell migration compared to ultrasmall iron oxide particles. This study investigated the temporal relationship between inflammation and tissue remodeling due to myocardial infarction (MI) using MPIO- enhanced MRI. C57Bl/6 mice received an intravenous MPIO injection for cell labeling, followed by a surgically induced MI seven days later (n 5 7). For controls, two groups underwent either sham-operated surgery without inducing an MI post- MPIO injection (n 5 7) or MI surgery without MPIO injection (n 5 6). The MRIs performed post-MI showed significant signal attenuation around the MI site for the mice that received an intravenous MPIO injection for cell labeling, followed by a sur- gically induced MI seven days later, compared to the two con- trol groups (P < 0.01). The findings suggested that the prelabeled inflammatory cells mobilized and infiltrated into the MI site. Furthermore, the linear regression of contrast-to- noise ratio at the MI site and left ventricular ejection function suggested a positive correlation between the labeled inflam- matory cell infiltration and cardiac function attenuation during post-MI remodeling (r 2 5 0.98). In conclusion, this study dem- onstrated an MRI technique for noninvasively and temporally monitoring inflammatory cell migration into the myocardium while potentially providing additional insight concerning the pathologic progression of a myocardial infarction. Magn Reson Med 63:33–40, 2010. V C 2009 Wiley-Liss, Inc. Key words: cardiac remodeling; cardiac MRI; myocardial infarction; imaging; inflammation; MPIO contrast agent; prelabeling The potential of MRI as a noninvasive tool to detect con- trast agent-labeled cells has been investigated recently, with the advent of novel contrast agents and cell labeling techniques (1,2). As a negative enhancement contrast agent, iron oxide particles cause signal attenuation in T 2 *- and T 2 -weighted images, which makes them useful in a variety of animal models for cellular imaging (3). Sized large to small, iron oxide particles are categorized as micrometer-sized iron oxide particles (MPIOs), small iron oxide particles, or ultrasmall iron oxide particles, respectively (4). The majority of iron oxide particles accumulate in the liver, spleen, bone marrow, and lym- phatic node tissue after injection (3,5,6). The physico- chemical characteristics of iron oxide particles determine their MRI efficacy, blood pool kinetics, biodistribution, and metabolism within the imaged subjects (7,8). Iron oxide contrast has been used to detect liver tumors (9,10) and lymph node metastases (11,12), and also for tracking stem cells (13) and monitoring various diseases associated with high macrophage activity (14,15). Recently, MPIO were shown to significantly improve cellular imaging when single cells loaded with single MPIO were detected via MRI (16). In contrast, accumu- lation of a considerable number of ultrasmall iron oxide particles in one cell was required to achieve sufficient image contrast. Furthermore, the dilution effect caused by cell division more readily renders loss of cell track- ing in ultrasmall iron oxide particle cell labeling than in MPIO cell labeling. Inflammatory cells, in particular macrophages, are ca- pable of taking up iron oxide particles (17). Conse- quently, the labeled inflammatory cells can be detected using T 2 *-weighted MRI during the inflammation pro- cess. In this manner, the iron oxide particles have been used to detect brain inflammation (18,19), macro- phage-rich atherosclerosis (20,21), and acute cardiac graft rejection (22). Several pathways have been pro- posed for transporting iron oxide particles to macro- phages (3). For example, iron oxide particles could be endocytosed by activated blood monocytes migrating into affected tissue, or they could be transcytosed across the endothelium via progressive endocytosis by in situ macrophages. Both mechanisms may take place simultaneously when iron oxide particles are trans- ported into the affected tissue via the inflammatory neovasculature. Recently, iron oxide particles have been used to label inflammatory cells involved with myocardial infarction (MI)–induced cardiac tissue inflammation. Furthermore, Sosnovik et al. (23) demonstrated that inflammatory cells could be labeled by intravenous injection of iron oxide particles after the MI. In this manner, both circulating and resident inflammatory cells will engulf iron oxide particles and contribute to the signal attenuation around the MI site. Although inflammatory cells such as macro- phages could also be labeled in vitro and then trans- planted into the infarcted heart (24), the transplantation delivery is usually limited by a low engraftment. There- fore, this study demonstrates a new cell labeling method 1 Small Animal Imaging, Department of Radiology, Medical College of Georgia, Augusta, Georgia, USA. 2 Nuclear and Radiological Engineering/Medical Physics Programs, George W. Woodruff School, Georgia Institute of Technology, Atlanta, Georgia, USA. *Correspondence to: Tom C.-C. Hu, Ph.D., M.B.A., 1410 Laney Walker Blvd CN-3155, Medical College of Georgia, Augusta, GA 30912. E-mail: tom.cc. hu@gmail.com Received 7 April 2009; revised 1 July 2009; accepted 23 July 2009. DOI 10.1002/mrm.22175 Published online 1 December 2009 in Wiley InterScience (www.interscience. wiley.com). Magnetic Resonance in Medicine 63:33–40 (2010) V C 2009 Wiley-Liss, Inc. 33