Musculoskeletal Imaging Research Program

Musculoskeletal diseases represent a leading cause of pain, physical disability, and health-care utilization in Canada. A recent report on arthritis by the Public Health Agency of Canada states that the economic burden of musculoskeletal diseases was the highest of any group of diseases, with a total annual cost of over $20 billion in Canada. Musculoskeletal imaging is emerging as a research area of great importance, fueled by recent advances in pharmacological and surgical therapies for arthritis. The Arthritis Imaging program within BIRC involves all aspects of bone and joint imaging, from animal studies (using micro-CT and micro-MRI in rodent models), to clinical imaging of early joint disease and monitoring of patients following total joint replacement. This program is strengthened by collaborations with leading biologists, engineers, and physicians at Western University and associated hospitals.

Radiographic Assessment of Joint Replacements

Total joint replacement (TJR) is a cost-effective method of alleviating joint pain and restoring function; however, many of them must be revised before the expected maximum lifetime of the patient. Many studies have revealed that the long-term clinical stability of TJR can be predicted by careful measurements of small motions between the implant and surrounding bone. It is important to make these measurements with great care, because the amount of motion needed to be detected over one year may be equivalent to the thickness of a sheet of paper! The group is fortunate to have one of North America’s only dedicated stereo digital X-ray imaging systems for assessing implant stability in patients following joint replacement surgery. With support from the CIHR, the group is now working to extend these techniques to include dynamic imaging, which will allow observation of the function of replacement components in the hip and knee, eventually leading to the development of improved joint replacements.

In the initial stages of research, utilizing a small animal model, such as the rat would be ideal for testing novel implant surfaces as this would contribute to increased cost-effectiveness, reduced variability, higher statistical throughput, more repeatable experiments and better access to pre-clinical imaging compared to traditional large animal models. However, functional implants do not commonly exist in sizes required for testing in rats because they are difficult to manufacture via traditional methods. Fortunately, recent advances in additive manufacturing, 3D selective laser melting, have made it possible to rapidly create precise, functional prototypes of components small enough to be implanted and tested in a rat. Furthermore, image data from micro-CT can be used to guide the design of custom components for orthopaedic applications. Thus our goal is to design and fabricate custom, functional metal-alloy orthopaedic implants for use in a rodent model of osseointegration.

A miniature hip component at two stages of manufacture, pre and post-polishing. The device shown is certainly the first of its kind in the world. Image courtesy of Adam Paish, Hristo Nikolov and David Holdsworth.

Bone and Joint Imaging in Research Animals 

Osteoporosis is a bone degenerative disease that often results in fractures which affects millions of Canadians each year. One of the potential non-pharmacological ways of reversing osteoporosis is by applying a small external mechanical force to the body. This is due to the fact that bones of human and animal are sensitive to any mechanical changes. One such method of introducing mechanical force to the body is called the whole body vibration. However, currently there is lack of knowledge of how much vibration is actually transmitted to bone, since soft tissues surround the bone.

The group at Robarts uses small animal model and novel imaging technique to quantify in vivo vibration. The result will help better understand what vibration frequency and intensity would produce the optimal effect in reversing osteoporosis.

We are very interested in understanding the underlying mechanism(s) that may be responsible for the initiation and progression of osteoarthritis (OA). We have developed a novel exogenous contrast agent (image), and in conjunction with dual-energy micro-computed tomography, will allow us to study the changes in vascular supply, which are responsible for the maintenance, to bones and joints. This will provide more information into the initiation and progression of OA.

Working with colleagues in Skeletal Biology, they have developed a rat model of arthritis and optimized micro-CT and micro-MRI imaging techniques to observe changes to the joint over a few months. Robarts provides access to state-of-the-art 9.4-Tesla MR imaging and high-resolution computed tomography. This program is now being extended to include nuclear medicine imaging, using one of Canada’s few micro-SPECT imaging systems, which provides sub-millimeter imaging of bone metabolic activity in rodents.

High-field MRI of Bone and Cartilage

Conventional radiographic techniques (X-ray radiography and trans-axial CT) do not provide sufficient sensitivity and specificity to detect OA at its earliest stages, or to monitor cartilage response to therapy. The need for improved non-invasive imaging will increase in the next decade as the population ages and new pharmacological therapies become available. As part of the Arthritis Imaging Program, the team is developing new techniques to image cartilage and bone in patients using high-field (3-Tesla) MRI. The state-of-the-art facilities at Robarts provide access to 3-Tesla MRI systems from two major vendors (GE and Siemens), allowing the team to develop new imaging techniques that can be implemented at many other sites. The MRI facilities are also integrated with the digital X-ray system, allowing comparison of X-ray and MRI images.

The development of new arthritis imaging techniques has taken on renewed priority in recent years, due to the development of new drugs and surgical techniques that promise to reduce the impact of arthritis. The musculoskeletal imaging research team is developing the next generation of X-ray, CT, and MRI techniques for use in animal studies and clinical trials. Over the next decade, imaging will play a pivotal role in the development of effective new treatments for arthritis.

Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder that affects 1 in 3500 boys, and is characterized by muscle degeneration. Patients are confined to a wheelchair when young and succumb to the disease in their 2nd to 3rd decade of life, and effective treatment is currently lacking. Stem cell therapy is a good candidate for treatment since healthy myogenic (muscle-forming) cells can be transplanted into damaged muscle, but this is limited by the poor ability of transplanted cells to migrate and engraft within damaged muscle. The Duchenne Research Initiative at Lawson is developing methods to address this issue, in both skeletal and cardiac muscle tissues. One such approach is, for the first time, to adapt a Bioelectromagnetics model to help overcome a great limitation in DMD research and translation; in brief, to use specific magnetic fields to direct the migration of cells following transplant into damaged muscle.

This group has the ability to track myogenic cells as they differentiate in vivo. Specifically, these investigators have generated a transgenic mouse line that harbours a PET reporter gene, sr39tk, under the control of a well-characterized, muscle-specific myogenin promoter. The promoter is activated only upon the differentiation of activated muscle satellite stem cells (SCs). SCs harvested from these mice have been implanted into the calf muscle of a dystrophic (mdx) mouse model of DMD. Four weeks post-implant, the presence of tk-expressing myoblasts can be detected in the mouse. This group also has developed in vivo functional imaging techniques using dynamic contrast enhanced computed tomography (DCE-CT), PET-FDG scanning and high frequency 3D ultrasound (HFU) to assess changes over time in muscle perfusion, metabolism and morphology, respectively, in 2 mouse models of DMD. These studies clearly demonstrate that non-invasive imaging of biomarkers correlates well with conventional histological analyses of DMD, accurately reflects the severity of the disease state, and can be potentially translated to the clinic as an alternative to invasive procedures. These imaging techniques will now be used to assess the regenerative capacity of transgenic SCs following transplant into dystrophic mice.

(A) Composite image of vasculature (in red) and bone (in white) to demonstrate their interaction. (B) Larger view of the green box with a plane running through the bone, demonstrating the perfused vasculature within the tibia and femur of this rat. The green arrows demonstrates the nutrient artery that extends along the length of the bone. Also not the abundant perfused vasculature that is found in the subchondral bone. Image courtesy of Justin Tse from Dr. David Holdsworth Lab.

Assessing the efficacy of therapy for DMD is hampered by an inability of current methods (invasive muscle biopsies) to assess cell survival, differentiation and function over time. Reporter gene imaging represents a powerful approach to study the physiology and biology of transplanted cells in vivo. The group’s strategy is to use cells harvested from a transgenic mouse line that harbours a unified fusion reporter gene composed of different genes, whose expression can be imaged with different imaging modalities, in both individual cells and living subjects.

This approach allows the merging of PET and optical imaging techniques for applications in a single living subject, and should facilitate rapid translation of approaches developed in cells to preclinical models and to clinical applications. PET is particularly well-suited for translational research, and thus forms the basis of our future research.

Investigators
Rob Bartha, PhD, MRI and MRS Imaging
Frank Beier, PhD,  Osteoarthritis
Robert Bourne, MD, Joint Replacement Surgery
Savita Dhanvantari, PhD, Molecular Imaging, DMD/Diabetes
S. Jeffrey Dixon, DDS, PhD, Skeletal Development
David Hill, D Phil, Stem Cell Therapy, Diabetes
Lisa Hoffman, PhD, Molecular Imaging, DMD
David Holdsworth, PhD, Musculoskeletal Imaging
Michael Kovacs, PhD, PET Radiochemistry, DMD
Ting-Yim Lee, PhD, PET/CT, DMD
Charles McKenzie, PhD, MRI and Spectroscopy
Douglas Naudie, MD, Joint Replacement Surgery
Terry Peters, PhD, Image-guided interventions
Frank Prato, PhD, Bioelectromagnetics, DMD
Alex Thomas, PhD, Bioelectromagnetics, DMD
Terry Thompson, PhD, MR Spectroscopy