Tools and Technologies I
Stem Cell Use:
Embryonic Stem Cell
We aim to develop, test and validate a new, sensitive and affordable scanner for tracking the location of injected cells in humans and animals. This new scanning method, called Magnetic Particle Imaging, will ultimately be used to track the location and viability of stem cells within the human body. It could solve one of the greatest obstacles to human hESC therapy---the ability to track stem cells and see if the cells are thriving and becoming a fully differentiated cell that can improve function of damaged organs. All of the current imaging methods used to track stem cells have significant problems when tracking stem cells through a living mouse or human. MRI is too insensitive and expensive. Optical imaging methods (fluorescence and luminescence) are useful for cell studies under a microscope, but they cannot produce high resolution images when the labeled cells are deeper than about 1 cm. Nuclear imaging methods involve radiation and offer poor spatial resolution. Ultrasound has many obstructions and the gas bubble stem cell tags do not persist very long. Hence, we wish to develop a new imaging method tailored for tracking stem cells in the human body---Magnetic Particle Imaging. Magnetic Particle Imaging should be 200x better sensitivity compared to MRI and it is simpler and significantly less expensive. Only developed in the last 3 years, Magnetic Particle Imaging scanners are not available commercially. The method uses FDA-approved contrast agents that are nanometer-scale magnetic cell tags. Our initial tests show great promise since we were able to create 1 mm resolution images with 100 nanogram detection limits. We plan to improve that detection limit to 100 picograms, which would translate to detecting just 10 cells anywhere within a mouse. Ultimately, we believe that single cell detection will be feasible with Magnetic Particle Imaging.
Statement of Benefit to California:
Stem cell therapy has enormous promise to become a viable therapy for a range of illnesses, including cardiovascular disease, diabetes, stroke, and Alzheimer’s. If we could expedite the development of these therapies, it would be of enormous benefit to both the citizens of the State of California, since they and their relatives would enjoy far less disability. Moreover it would greatly reduce the Medical costs for the State. The diseases mentioned above are the leading cost illnesses as measured in lostproductivity, lost wages, and extended care of the disabled. In fact, a study of the 1987 National Medicaid Expenditure Survey and the 2000 Medical Expenditure Panel Survey showed these diseases featured prominently in the top 15 most costly medical conditions: (1) cardiovascular disease (8%); (4) cancer (5%); (5) hypertension (4%); (7) cerebrovascular disease (3.5%) (9) diabetes (2.5%). A key obstacle to stem cell therapy is the inability to track stem cells through a human body. This means that there is no way (other than measuring organ function) to determine how well the therapy works. Considering the number of delivery methods and the number of challenges to getting stem cells in place, and then coaxing them to differentiate and improve organ function, it will be impossible to optimize the entire process without intermediate imaging feedback to optimize each step independently. Unforunately there is no acceptable method now for tracking stem cells throughout the human body. The new method, called Magnetic Particle Imaging, to be developed in this research does offer a way to track stem cells. Moreover, it will be inexpensive and quite simple to operate. The research requires a collaboration between imaging bioengineers, stem cell biologists, and cardiologists. Fortunately, we have been able to form such a team between [REDACTED] and [REDACTED]. Hence, we are very excited to begin this research so the basic imaging tool will be available to expedite the complex stem cell therapy research so critical for the State of California and its citizens.
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.