Magnetic Particle Imaging for Highly Sensitive, Quantitative, and Safe in Vivo Gut Bleed Detection in a Murine Model.

Gastrointestinal (GI) bleeding causes more than 300 000 hospitalizations per year in the United States. Imaging plays a crucial role in accurately locating the source of the bleed for timely intervention. Magnetic particle imaging (MPI) is an emerging clinically translatable imaging modality that images superparamagnetic iron-oxide (SPIO) tracers with extraordinary contrast and sensitivity. This linearly quantitative modality has zero background tissue signal and zero signal depth attenuation. MPI is also safe: there is zero ionizing radiation exposure to the patient and clinically approved tracers can be used with MPI. In this study, we demonstrate the use of MPI along with long-circulating, PEG-stabilized SPIOs for rapid in vivo detection and quantification of GI bleed. A mouse model genetically predisposed to GI polyp development (ApcMin/+) was used for this study, and heparin was used as an anticoagulant to induce acute GI bleeding. We then injected MPI-tailored, long-circulating SPIOs through the tail vein, and tracked the tracer biodistribution over time using our custom-built high resolution field-free line (FFL) MPI scanner. Dynamic MPI projection images captured tracer accumulation in the lower GI tract with excellent contrast. Quantitative analysis of the MPI images show that the mice experienced GI bleed rates between 1 and 5 μL/min. Although there are currently no human scale MPI systems, and MPI-tailored SPIOs need to undergo further development and evaluation, clinical translation of the technique is achievable. The robust contrast, sensitivity, safety, ability to image anywhere in the body, along with long-circulating SPIOs lends MPI outstanding promise as a clinical diagnostic tool for GI bleeding.

[1]  R. Weissleder,et al.  Experimental gastrointestinal hemorrhage: detection with contrast-enhanced MR imaging and scintigraphy. , 1995, Radiology.

[2]  Sanjiv S Gambhir,et al.  A molecular imaging primer: modalities, imaging agents, and applications. , 2012, Physiological reviews.

[3]  M. Rodallec,et al.  Multidetector CT angiography in acute gastrointestinal bleeding: why, when, and how. , 2011, Radiographics : a review publication of the Radiological Society of North America, Inc.

[4]  Kannan M. Krishnan,et al.  Tuning Surface Coatings of Optimized Magnetite Nanoparticle Tracers for In Vivo Magnetic Particle Imaging , 2015, IEEE Transactions on Magnetics.

[5]  Hyung Won Choi,et al.  Role of interventional radiology in the management of acute gastrointestinal bleeding. , 2014, World journal of radiology.

[6]  Roy W. Chantrell,et al.  Measurements of particle size distribution parameters in ferrofluids , 1978 .

[7]  Jian-Rong Xu,et al.  Usefulness of CT angiography in diagnosing acute gastrointestinal bleeding: a meta-analysis. , 2010, World journal of gastroenterology.

[8]  Zhi Wei Tay,et al.  The relaxation wall: experimental limits to improving MPI spatial resolution by increasing nanoparticle core size , 2017, Biomedical physics & engineering express.

[9]  L. Fass Imaging and cancer: A review , 2008, Molecular oncology.

[10]  Frank G Shellock,et al.  Regarding the value reported for the term "spatial gradient magnetic field" and how this information is applied to labeling of medical implants and devices. , 2011, AJR. American journal of roentgenology.

[11]  M. Magnani,et al.  New Strategies to Prolong the In Vivo Life Span of Iron-Based Contrast Agents for MRI , 2013, PloS one.

[12]  Di Xiao,et al.  Optimal Broadband Noise Matching to Inductive Sensors: Application to Magnetic Particle Imaging , 2017, IEEE Transactions on Biomedical Circuits and Systems.

[13]  Kevin R Minard,et al.  Optimizing magnetite nanoparticles for mass sensitivity in magnetic particle imaging. , 2011, Medical physics.

[14]  P. Reimer,et al.  Ferucarbotran (Resovist): a new clinically approved RES-specific contrast agent for contrast-enhanced MRI of the liver: properties, clinical development, and applications , 2003, European Radiology.

[15]  L. Holder Radionuclide imaging in the evaluation of acute gastrointestinal bleeding. , 2000, Radiographics : a review publication of the Radiological Society of North America, Inc.

[16]  Yi-Xiang J. Wang Superparamagnetic iron oxide based MRI contrast agents: Current status of clinical application. , 2011, Quantitative imaging in medicine and surgery.

[17]  L. S. Friedman,et al.  Review article: the management of lower gastrointestinal bleeding , 2005, Alimentary pharmacology & therapeutics.

[18]  Jenny J. Choi,et al.  Noninvasive evaluation of active lower gastrointestinal bleeding: comparison between contrast-enhanced MDCT and 99mTc-labeled RBC scintigraphy. , 2008, AJR. American journal of roentgenology.

[19]  Kannan M. Krishnan,et al.  Fundamentals and Applications of Magnetic Materials , 2016 .

[20]  Kannan M. Krishnan,et al.  In vivo Delivery, Pharmacokinetics, Biodistribution and Toxicity of Iron Oxide Nanoparticles , 2016 .

[21]  Bernhard Gleich,et al.  Tomographic imaging using the nonlinear response of magnetic particles , 2005, Nature.

[22]  H. Jadvar,et al.  Pharmacologic interventions in nuclear radiology: indications, imaging protocols, and clinical results. , 2002, Radiographics : a review publication of the Radiological Society of North America, Inc.

[23]  J. Laberge,et al.  Differential diagnosis of gastrointestinal bleeding. , 2004, Techniques in vascular and interventional radiology.

[24]  P. Lauterbur,et al.  The sensitivity of the zeugmatographic experiment involving human samples , 1979 .

[25]  K. Krishnan,et al.  Monodisperse magnetite nanoparticles with nearly ideal saturation magnetization , 2016 .

[26]  W. Dyck,et al.  The accuracy of technetium-99m-labeled red cell scintigraphy in localizing gastrointestinal bleeding. , 1994, The American journal of gastroenterology.

[27]  Bo Zheng,et al.  Quantitative Magnetic Particle Imaging Monitors the Transplantation, Biodistribution, and Clearance of Stem Cells In Vivo , 2016, Theranostics.

[28]  David Saloner,et al.  Vascular Imaging With Ferumoxytol as a Contrast Agent. , 2015, AJR. American journal of roentgenology.

[29]  Patrick W. Goodwill,et al.  The X-Space Formulation of the Magnetic Particle Imaging Process: 1-D Signal, Resolution, Bandwidth, SNR, SAR, and Magnetostimulation , 2010, IEEE Transactions on Medical Imaging.

[30]  H. Pitot,et al.  A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. , 1990, Science.

[31]  S. Gong,et al.  Diagnosis of lower gastrointestinal bleeding by multi-slice CT angiography: A meta-analysis. , 2017, European journal of radiology.

[32]  Emine U Saritas,et al.  Effects of pulse duration on magnetostimulation thresholds. , 2015, Medical physics.

[33]  Justin J. Konkle,et al.  Magnetic Particle Imaging With Tailored Iron Oxide Nanoparticle Tracers , 2015, IEEE Transactions on Medical Imaging.

[34]  H. Kiat,et al.  Scintigraphic Evaluation of Acute Lower Gastrointestinal Hemorrhage: Current Status and Future Directions , 2011, Journal of clinical gastroenterology.

[35]  C S Patlak,et al.  Graphical Evaluation of Blood-to-Brain Transfer Constants from Multiple-Time Uptake Data , 1983, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[36]  Bo Zheng,et al.  Magnetic particle imaging (MPI) for NMR and MRI researchers. , 2013, Journal of magnetic resonance.

[37]  E. Saritas,et al.  Effects of Duty Cycle on Magnetostimulation Thresholds in MPI , 2017 .

[38]  R. Pazdur,et al.  FDA report: Ferumoxytol for intravenous iron therapy in adult patients with chronic kidney disease , 2010, American journal of hematology.

[39]  L. Friedman,et al.  Lower gastrointestinal bleeding. , 2007, Gastrointestinal endoscopy clinics of North America.

[40]  K. M. Krishnan,et al.  Evaluation of PEG-coated iron oxide nanoparticles as blood pool tracers for preclinical magnetic particle imaging. , 2017, Nanoscale.

[41]  Lawrence L. Wald,et al.  Design analysis of an MPI human functional brain scanner , 2017, International journal on magnetic particle imaging.

[42]  H. Ziessman,et al.  Gastrointestinal bleeding scintigraphy , 2016, Applied Radiology.

[43]  K. Mckusick,et al.  99mTc red blood cells for detection of gastrointestinal bleeding: experience with 80 patients. , 1981, AJR. American journal of roentgenology.

[44]  Ondrej Hovorka,et al.  Tailoring the magnetic and pharmacokinetic properties of iron oxide magnetic particle imaging tracers , 2013, Biomedizinische Technik. Biomedical engineering.

[45]  B Gleich,et al.  Three-dimensional real-time in vivo magnetic particle imaging , 2009, Physics in medicine and biology.

[46]  M. Chintala,et al.  A novel approach to assess the spontaneous gastrointestinal bleeding risk of antithrombotic agents using Apc min/+ mice , 2014, Thrombosis and Haemostasis.

[47]  James E Bear,et al.  PEGylated PRINT nanoparticles: the impact of PEG density on protein binding, macrophage association, biodistribution, and pharmacokinetics. , 2012, Nano letters.

[48]  A. Vernava,et al.  Lower gastrointestinal bleeding , 1997, Diseases of the colon and rectum.

[49]  Mark A Griswold,et al.  Magnetic Particle Imaging Tracers: State-of-the-Art and Future Directions. , 2015, The journal of physical chemistry letters.

[50]  Patrick W. Goodwill,et al.  Magnetic Particle Imaging: A Novel in Vivo Imaging Platform for Cancer Detection. , 2017, Nano letters.

[51]  J. Welch,et al.  The 99mTc-labeled RBC scan. A diagnostic method for lower gastrointestinal bleeding. , 1984, Diseases of the colon and rectum.

[52]  S. Srivastava,et al.  Radionuclide-labeled red blood cells: current status and future prospects. , 1984, Seminars in nuclear medicine.

[53]  Patrick W. Goodwill,et al.  Multidimensional X-Space Magnetic Particle Imaging , 2011, IEEE Transactions on Medical Imaging.

[54]  J. Samra,et al.  Diagnosis of gastrointestinal bleeding: A practical guide for clinicians. , 2014, World journal of gastrointestinal pathophysiology.

[55]  Yixiang Wang Current status of superparamagnetic iron oxide contrast agents for liver magnetic resonance imaging. , 2015, World journal of gastroenterology.

[56]  Patrick W. Goodwill,et al.  Magnetic Particle Imaging tracks the long-term fate of in vivo neural cell implants with high image contrast , 2015, Scientific Reports.

[57]  Bo Zheng,et al.  Projection X-Space Magnetic Particle Imaging , 2012, IEEE Transactions on Medical Imaging.

[58]  Kim-Lien Nguyen,et al.  Safety and technique of ferumoxytol administration for MRI , 2016, Magnetic resonance in medicine.

[59]  Erin Grady Gastrointestinal Bleeding Scintigraphy in the Early 21st Century , 2016, The Journal of Nuclear Medicine.

[60]  Justin J. Konkle,et al.  Projection Reconstruction Magnetic Particle Imaging , 2013, IEEE Transactions on Medical Imaging.

[61]  M. Lindstrom,et al.  ApcMin, a mutation in the murine Apc gene, predisposes to mammary carcinomas and focal alveolar hyperplasias. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[62]  Kannan M. Krishnan,et al.  Monodisperse magnetite nanoparticle tracers for in vivo magnetic particle imaging. , 2013, Biomaterials.

[63]  Emine Ulku Saritas,et al.  Twenty-fold acceleration of 3D projection reconstruction MPI , 2013, Biomedizinische Technik. Biomedical engineering.

[64]  Paul Keselman,et al.  Tracking short-term biodistribution and long-term clearance of SPIO tracers in magnetic particle imaging , 2017, Physics in medicine and biology.