Magnetic Particle Imaging: A Novel Ultra-sensitive Imaging Scanner for Tracking Stem Cells In Vivo

Cardiovascular disease and diabetes are two very common disorders that can be fatal. Stem cell therapy holds great promise for repairing these organs inside a living human. And stem cell biologists have invented hundreds of competing methods to deliver stem cells to the diseased organ, and hundreds of methods to promote those cells to differentiate into cardiac cells or pancreatic cells. However, current treatments have not been fully debugged yet, and stem cell biologists need to know if the deliver or scaffold or differentiation steps failed. To do this, they need to be able to "see" the cells inside a live animal. This allows them to see where stem cells go inside the body, what happens to them when they settle within an organ, and if they successfully restore function to diseased organs. But there is no imaging modality now that does this reliably; this is one of the great obstacles today for stem cell therapy. Animals and humans are almost completely opaque to light so standard microscopy tools just cannot tell us if the cells are in the spleen or in the liver or in the targeted organ. Knowing if the cells got to the target organ allows stem cell biologists to know which of several candidate techniques is the best to target cells specifically to, say, a diseased heart or to a diseased pancreas. Seeing inside small animals and the human body has been the job of diagnostic imaging methods such as CT, X-ray, Ultrasound, Nuclear Medicine, and MRI. Each of these standard medical imaging modalities has been modified (usually with a contrast agent) to attempt to track stem cells inside the body. However, each has significant limitations, and stem cell biologists are left with inadequate information to optimize stem cell therapies. Because there is no ideal imaging modality, most stem cell biologists resort to serial studies on large numbers of mice and resort to microscopy at the time the animal is sacrificed. No dynamic data can be gathered this way and this process is slow and cumbersome, often requiring weeks for a single data point. Stem cell therapies require a faster, real-time stem cell tracking modality since each target organ is likely to need its own particular delivery, targeting and differentiation methods. We are the only research group in the USA developing Magnetic Particle Imaging small animal imaging scanner technology for stem cell tracking. The MPI method is still in its early days, similar to where MRI was in the early 1980's. However, our preliminary images are already much better than preliminary MRI scans of that era. The reason is that MPI has several fundamental physics advantages: we are imaging the magnetization on a contrast agent (called a Super-paramagnetic Iron Oxide or SPIO) that is 1 million times more magnetic than the magnetism used to create MRI scans of humans. Still, this SPIO contrast agent is completely safe, and is already FDA approved for other applications. SPIO's have been safely used to treat anemia in humans for decades. One cannot make an MPI image within an MRI scanner or within any medical imaging scanner. No company sells MPI mouse scanners. Hence, we spent the first year designing and building the world's first Magnetic Particle Imaging scanner suitable for tracking stem cell therapies in a mouse model. We also are developing a theoretical breakthrough on the basic imaging method (called X-space Analysis) that offers enormous advantages in image clarity and spatial resolution. Progress on our research has been outstanding, with one journal publication, two other journal articles submitted, one patent application, and ten conference publications. As a biomedical instrumentation research group, we recognize the critical importance of collaborating with stem cell biologists and clinician-scientists who are looking for life-saving therapies with stem cells. Hence, we are collaborating on this state-of-the-art molecular imaging technology with Prof. David Schaffer's stem cell research group at UC Berkeley. And we work closely with my long-time cardiology collaborators at Stanford Medical Center, Michael McConnell, MD, MSEE and Philip Yang, MD.

Stem cell therapy has enormous potential to heal damaged organs, including the diabetic pancreas, the damaged myocardium after a heart attack, and the brain of Parkinson’s patients. However, stem cell scientists currently lack an adequate in vivo imaging method to ensure that stem cells arrive at and remain in these target organs. This would be essential for clinical adoption of stem cell therapies. Robust stem cell imaging would enable optimizing in vivo protocols to deliver, sustain, or promote differentiation of stem cells at the affected organ since each step can be validated without sacrificing the animal or using invasive tests. We need this to work well in humans, too, because a robust stem cell imaging method would enable proof of stem cell destination and fate, both of which are crucial for eventual regulatory approval as well as for clinical effectiveness. Comparing existing imaging modalities for tracking stem cells in vivo, x-ray, CT, ultrasound, and Magnetic Resonance Imaging techniques do not provide adequate contrast, sensitivity, and spatial resolution at depth. All optical imaging methods suffer from attenuation. A brand new imaging method, called Magnetic Particle Imaging (MPI), was invented just 6 years ago. My lab at UC Berkeley is one of the pioneers of this technology. MPI physics is fundamentally a better match to stem cell tracking than these traditional imaging methods, and it has the requisite contrast, sensitivity and safety for both human and small animal applications. Critically, we expect no attenuation with the magnetic reporting of stem cells deep within tissue. The fundamental physics offers far greater sensitivity than other imaging methods. Hence, stem cell scientists will greatly benefit from the technical development of stem cell imaging with MPI. My research group at UC Berkeley has designed and built all four of the MPI mouse scanners that now exist in the USA. This year we have made several breakthroughs in MPI technology, including demonstrating the world’s first x-space MPI scans and the world’s first projection MPI scan. Specific to stem cell tracking applications, we have experimentally confirmed all of our key MPI physical hypotheses: the MPI signal is positive, linear and quantitative with stem cell count; the MPI signal is not attenuated when the cells are deep within tissue; and we also confirmed that MPI is very sensitive to labeled stem cells. And we are rapidly improving the one remaining significant weakness of MPI, spatial resolution, in collaboration with UW Prof. Kannan Krishnan. Beyond these research accomplishments and publications, the CIRM Phase I grant has made possible the training of some of the finest graduate students in the world. My engineering students are excited about startup possibilities to translate our research results into genuine products so that all stem cell scientists can benefit from this cutting-edge UC Berkeley research effort. We greatly appreciate the grant support of the CIRM Phase I Tools & Technology program, which allowed us to build, debug and radically improve MPI imaging instrumentation that will soon become an essential tool for all stem cell scientists. CIRM I support was critical for us to secure Phase II CIRM Tools and Technology support, UC Discovery grant support and NIH R01 MPI grant support.