Small Animal Micro-Imaging Research

Multi-modality micro-imaging is an established research focus within BIRC and includes micro-CT, micro-MR, micro-PET, micro-SPECT, micro- ultrasound, and high-field MRI facilities dedicated to the development and application of micro-imaging in basic and applied science. There are two central concepts that characterize this research. First and foremost is the use of an array of imaging tests, each of which provides unique information to characterize tissues in vivo. The second concept is to establish the imaging tests as in vivo surrogates for specific pathologic, cellular, and molecular events.

The non-invasive nature of in vivo micro-imaging systems allows investigators to study models of disease and the effects of therapies using living research animal models, such as mice and rats, including serial studies of the same animal. Well-characterized rodent models have been developed for a wide range of diseases to facilitate a more complete understanding of the diseases and to provide appropriate vehicles for drug validation. The mouse has become a key animal model system to study human disease, and the genetically engineered rat promises to be an equally important participant in many areas of medical research.

Many important small animal disease models are being actively investigated by our scientists. The new in vivo micro imaging techniques being developed will be used to visualize structural and functional aspects of disease and disease progression in these models to allow the monitoring of treatment effectiveness over time. The Multi-Modality In Vivo Microscopy Research Facility promotes collaborative medical research in 7 major programs, and includes collaboration between BIRC groups.

The 9.4 Tesla MRI scanner is one of only two in Canada that operate at this high magnetic field strength, allowing the acquisition of high signal to noise ratio and high resolution images and spectra more rapidly compared to lower field strength systems.  The 9.4 T laboratory at Robarts Research Institute was constructed to operate as a level 2 facility and includes an integrated wet lab and surgical area.  The MRI scanner can be operated from either a “clean” side or a “dirty” side.  All MR systems have a full range of MRI compatible physiological monitoring instrumentation to maintain the well-being of the subjects.

The Preclinical Imaging Research Centre (PIRC), a core facility of Robarts Research Institute, houses three micro-CT systems, two high-frequency ultrasound systems, and a micro-SPECT/CT scanner as well as a dedicated animal surgery and preparation room. These scanners are employed for collaborative research using small-animal models of cancer, cardiovascular, musculoskeletal, and respiratory diseases as well as preclinical research in radiotherapy and image-guided interventions.

Cellular and Molecular Imaging

Cellular and Molecular Imaging is a newly emerging field that combines micro-imaging technologies with the use of sensitive and specific cell labelling agents for the direct imaging of cells and molecules. Cellular and molecular imaging research at BIRC is focused in five main areas: Cancer Cell Tracking, Inflammation, Transplantation, Technology Development, and Imaging Probe Development and Validation.

The group is developing broadly applicable tools for validating new cellular and molecularly targeted probes. This single coordinated facility allows thorough characterization of probes, spanning the entire range from first production of the probe to in vivo imaging studies. Physical characterization can be performed using a range of techniques including dynamic light scattering for nanoparticle size determination, transmission electron microscopy, optical fluorescence, gel electrophoresis, and iron and gadolinium concentration determination by inductively-coupled mass spectrometry.

Hyperpolarized MRI probes are another area of development in molecular imaging of small animals. Dynamic nuclear polarization (DNP) and spin exchange optical pumping (SEOP) facilities permit increases in signal of more than 10,000 times for 13C and 129Xe. Following injection or inhalation, these nuclei (and molecules to which they are conjugated) can then be visualized with extremely high sensitivity in the organs (e.g. brain, liver, kidney, lung and heart) as well as tumours to provide functional and metabolic information to complement conventional anatomical MRI. For example, hyperpolarized [1-13C]pyruvate is currently being used to measure anaerobic glycolysis associated with brain gliomas, lung inflammation and to study fatty liver disease.

NMR characterization of probes is by measurements of T1 and T2 relaxivity at the common imaging field strengths of 0.5T, 1.5T, 3T, 7T, 9.4T. Cell viability, function and other characteristics are measured with standardized methods, including MTT assay, and flow cytometry.  Preliminary assessment of probe effectiveness is performed in vitro using solutions/suspensions, tissue extracts or cell-based preparations. Standardized methods for sparse cell suspension in gel (both 2D and 3D) are used to measure single cell response/sensitivity and to correlate results between MRI and optical imaging.  In vivo probe validation can be tested in a variety of in-house animal model systems with our customized imaging tools to support high resolution, high sensitivity imaging.

Digital Histology

The digital histology group has developed the capability of using expert-assessed digital histopathology images of excised tissue as an appropriate gold standard for validation. The optimal use of digital histopathology as a gold standard requires an accurate, non-rigid, fine-scale spatial registration (alignment) of quantities (e.g. appearance, 3D shape, functional characteristics) derived from in vivo images, to anatomically homologous locations in the space of digital histopathology images. Due to differential shrinkage and deformation of tissue during imaging, fixation, and histological processing, this registration problem poses a significant challenge. The team has developed novel hardware and software techniques that render this registration problem tractable and yield useful anatomic concordance between in vivo imaging and digital histopathology.

Large Animal Imaging

To aid investigators in translating research findings to the clinic, the group at Lawson has invested extensively in animal imaging technology. Biomedical Imaging can provide anatomical, functional, biochemical and/or molecular information for mechanistic studies, to chart the progression of disease, and to predict and monitor the effectiveness of novel therapeutics. A significant advantage of non-invasive in vivo imaging is that repeated measurements can be acquired over time in the same animal (longitudinal studies) and can reduce the total number of animals required.

Large animal imaging is performed on clinical platforms, facilitating translation of new medical imaging techniques to humans. Imaging equipment is strategically located with on-site support facilities including animal housing and a veterinary clinic. All animal procedures are carried out according to the guidelines of the Canadian Council on Animal Care and approved by the Animal Use Subcommittee of Western University.

Investigators
Robert Bartha, PhD, MR Physics, Alzheimer Disease
Ann Chambers, MD, Oncology
Blaine Chronik, PhD, MicroPET/MRI
Savita Dhanvantari, PhD, Molecular Imaging
Maria Drangova, PhD, Cardiac Imaging
Aaron Fenster, PhD, 3D Ultrasound Physics
Paula Foster, PhD, Molecular and Micro-imaging
Donna Goldhawk, PhD, Reporter Gene Expression
Beth Gillies, PhD, Nanotechnology
Lisa Hoffman, PhD, MicroPET
David Holdsworth, PhD, CT Imaging Physics
Steve Karlik, PhD, Multiple Sclerosis
Michael Kovacs, PhD, PET Radiochemistry
James Lacefield, PhD, High-frequency Ultrasound
Ting-Yim Lee, PhD, MicroPET, MicroSPECT/CT
Len Luyt, PhD, Probe Development
Charles McKenzie, PhD, MRI and Spectroscopy
Ravi Menon, PhD, fMRI
Grace Parraga, PhD, Respiratory Imaging
Frank Prato, PhD, MRI, SPECT/CT, CT, PET
Giles Santyr, PhD, Respiratory Imaging
Tim Scholl, PhD, MRS Imaging Probes
Robert Stodilka, PhD, SPECT/CT, MRI
Eugene Wong, MD, Radiation Oncology Physics

Collaborators 
Greg Dekaban, PhD, Microbiology
Arthur Brown, PhD, Neurological Disease
David Hess, PhD, Stem Cell Biology
John Lewis, PhD (LRCP), Multivalent Nanoparticles
Brian Rutt, PhD (Stanford)
QingPing Feng, PhD, Cellular and Molecular Biology
David Cechetto, PhD, Neuroinflammation
Jim Koropatnick, MD, (LRCP) Molecular Oncology
Ruud Veldhuizen, PhD, Lung Mechanical Ventilation
James Lewis, MD, Pulmonary Surfactant/Lung Injury
Ian Welch, DVM, Neuroinflammation
Subrata Chakrabarti, MD, Pathology
Kevin Shoemaker, PhD, Kinesiology
Wei-Ping Min, MD, Immunopathology
Tianqing Peng, PhD, Molecular Biology
Shaun Salisbury, PhD