Technology Research & Development
Current technology research and development (TRD) is focused on improving and developing novel cellular MRI technologies. Cells are the fundamental building blocks of the immune system and any organ system. Non-invasive imaging of the dynamic trafficking patterns of immune cells can play a key role in elucidating the basic pathogenesis of major diseases such as cancer and autoimmune disorders. Other cells of interest, such as tumor or stem cells, can be tracked using MRI giving insight into metastatic processes, cell engraftment and differentiation, and tissue renewal. The NMR Center has several multidisciplinary TRD programs in key areas of MRI-based cell tracking spanning the fields of chemistry, cell biology, spin-physics, and image processing. The current TRD projects at the Center include:
Leader Eric Ahrens
Ahrens’ lab develops 19F-based cell tracking methods. This TRD addresses current limitations of MRI cell tracking using nanoparticle probes – there inability to report on cellular activity or cell viability in vivo. Towards these goals, this TRD project explores the utility of real-time monitoring of intracellular oximetry in vivo using perfluorocarbon emulsion imaging probes.
Leader Chien Ho
Dr. Ho is a leader in the use of iron-oxide nanoparticles for cell tracking by MRI, and his early pioneering work help launch the field of MRI cell tracking. Dr. Ho’s work continues to focus on the development and application of novel iron-oxide-based MRI contrast agents and imaging methods, with particular emphasis on the use of cellular MRI to detect organ transplant rejection.
Leader Alan Waggoner
This TRD’s focus is developing novel bio-sensing, fluorine and iron-oxide based agents for optical and MRI imaging. The project is developing a new paradigm for the synthesis of imaging probes for cell tracking that will result in at least a 5-fold sensitivity improvement and enable multispectral imaging of multiple cell populations in vivo.
Leader Zhi-Pei Liang
This TRD is developing unique pulse sequences and image reconstruction algorithms that are tailored for quantitative in vivo cell tracking. These methods will be used for both SPIO- and 19F-based cell tracking.
Over the years, the Pittsburgh NMR Center for Biomedical Research has made a significant impact to many areas of biological MRI, such as the invention of arterial-spin labeling (ASL) techniques for quantitative perfusion imaging (Williams et al., 1992; Detre et al., 1992 & 1994), fast imaging methods (Zha and Lowe, 1995; Silva et al., 1998; Madio and Lowe, 1995), the invention of functional neuroimaging using manganese ions (Lin and Koretsky, 1997; Pautler et al., 1998), pioneering early work in cell tracking using iron oxide nanoparticles (Yeh et al., 1993 & 1995; Dodd et al., 1999; Zhang et al., 2000; Kanno et al., 2001; Wu et al., 2006; Ye et al., 2008; Wu et al., 2009; Foley, et al., 2009), the development of novel cell tracking agents and methods using perfluorocarbons and fluorine-19 MRI (Ahrens et al., 2005; Srinivas et al., 2007; Janjic et al., 2008; Hitchens et al., 2011), and the development of DNA-based MR reporters (Koretsky et al., 1990; Genove et al., 2005; Iordanova et al., 2012).
Ahrens ET, Flores R, Xu HY, Morel PA. "In Vivo Imaging Platform for Tracking Immunotherapeutic Cells", Nature Biotechnology 23, 983-987 (2005).
Detre JA, Leigh JS, Williams DS, and Koretsky AP. "Perfusion Imaging," Magnetic Resonance in Medicine 23, 37-45 (1992).
Detre JA, Zhang W, Roberts DA, Silva AC, Williams DS, Grandis DJ, Koretsky AP, and Leigh JS. "Tissue Specific Perfusion Imaging Using Arterial Spin Labeling", NMR in Biomedicine, 7, 75-82 (1994).
Foley LM, Hitchens TK, Ho C, Janesko-Feldman KL, Melick JA, Bayir H, Kochanek PM. "Magnetic Resonance Imaging Assessment of Macrophage Accumulation in Mouse Brain after Experimental Traumatic Brain Injury," Journal of Neurotrauma, 26:1509-1519 (2009).
Genove G, DeMarco U, Xu H, Goins WF, and Ahrens ET. "A New Transgene Reporter for In Vivo Magnetic Resonance Imaging," Nature Medicine 11, 450-454 (2005).
Hitchens TK, Ye Q, Eytan D, Janjic JM, Ahrens ET, Ho C. "19F MRI Detection of Acute Allograft Rejection with In vivo Perfluorocarbon Labeling of Immune Cells," Magnetic Resonance in Medicine, 65(4): 145-1154 (2011).
Iordanova B, Ahrens ET. "In Vivo Magnetic Resonance Imaging of Ferritin-Based Reporter Visualizes Native Neuroblast Migration," Neuroimage, 59:1004-1012 (2012).
Janjic JM, Srinivas M, Kadayakkara DK, Ahrens ET. "Self-Delivering Nanoemulsions for Dual Fluorine-19 MRI and Fluorescence Detection," J Am Chem Soc, 130(9):2832-2841 (2008).
Kanno S, Wu YJL, Lee PC, Billiar TR, and Ho C. "Angiotensin-Converting Enzyme Inhibitor Preserves p21 and Endothelial Nitric Oxide Synthase Expression in Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats", Circulation 104, 945-950 (2001).
Koretsky AP, Brosnan MJ, Chen LH, Chen JD, and Van Dyke TA. "NMR Detection of Creatine Kinase Expressed in Liver of Transgenic Mice: Determination of Free ADP Levels," Proceedings of the National Academy of Sciences, U.S.A. 87, 3112-3116 (1990).
Lin YJ and Koretsky AP. "Manganese Ion Enhances T1-Weighted MRI During Brain Activation: An Approach to Direct Imaging of Brain Function", Magnetic Resonance in Medicine, (1997).
Madio DP, and Lowe IJ. "Ultra-Fast Imaging Using Low Flip-Angles and FID's", Magnetic Resonance in Medicine, 34, 525-529, (1995).
Pautler RG, Silva AC, Koretsky AP. In vivo neuronal tract tracing using manganese-enhanced magnetic resonance imaging. Magn Reson Med. 1998 40(5):740-8.
Silva AC, Barbier EL, Lowe IJ, Koretsky AP. Radial echo-planar imaging. J Magn Reson. 1998 135(1):242-7.
Srinivas M, Morel PA, Ernst LA, Laidlaw DH, Ahrens ET. "Fluorine-19 MRI for Visualization and Quantification of Cell Migration in a Diabetes Model," Magn Reson Med, 58(4): 725-34 (2007).
Williams DS, Detre JA, Leigh, Jr, JS, and Koretsky AP. "Magnetic Resonance Imaging of Perfusion using Spin Inversion of Arterial Water," Proceedings of the National Academy of Sciences, U.S.A. 89, 212-216 (1992).
Wu YJL, Ye Q, Foley LM, Hitchens TK, Sato K, Williams JB, and Ho C. (2006), "In Situ Labeling of Immune Cells with Iron Oxide Particles: An Approach to Detect Organ Rejection by Cellular MRI“, Proc Natl Acad Sci 103(6), 1852-1857.
Wu YL, Ye Q, Sato K, Foley LM, Hitchens TK, Ho C. "Non-Invasive Evaluation of Cardiac Allograft Rejection by Cellular and Functional MRI," Journal of American Cardiology: Cardiovascular Imaging, 2(6): 731-741 (2009).
Ye Q, Wu YJ, Foley LM, Hitchens TK, Eytan EF, Shirwan H, Ho C. "Longitudinal Tracking of Recipient Macrophages in a Rat Chronic Cardiac Allograft Rejection Model with Noninvasive Magnetic Resonance Imaging Using Micrometer-Sized Paramagnetic Iron Oxide Particles," Circulation, 118:149-156 (2008).
Yeh TC, Zhang W, Ildstad ST, and Ho C. "In Vivo Dynamic MRI Tracking of Rat T-Cells Labeled with Superparamagnetic Iron-oxide Particles", Magn. Reson. Med., 33, 200-208 (1995).
Yeh TC, Zhang W, Ildstad ST, and Ho C. "Intracellular Labelling of T-Cells with Superparamagnetic Contrast Agents," Magnetic Resonance in Medicine 30, 617-625 (1993).
Zha L, and Lowe IJ. "Optimized Ultra-Fast Imaging Sequence (OUFIS)", Magn. Reson. Med., 33, 377-395 (1995).
Zhang, Y. Dodd, S.J., Hendrich, K.S., Williams, M. and Ho, C. "MRI Detection of Rat Renal Transplant Rejection by Monitoring Macrophage Infiltration", Kidney International 58, 1300-1312 (2000).