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 cell that can improve function of damaged organs. None of the current methods to track stem cells will be useful for tracking stem cells through a living human. MRI is too insensitive and expensive. While optical imaging methods (fluorescence and luminescence) are useful for cell studies under a microscope, they all fail deeper than about 1 cm. Nuclear imaging methods involve radiation and offer poor 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 has 200x better sensitivity compared to MRI and it will be significantly (50x) less expensive; and will require no expert operator. Only developed in the last year, Magnetic Particle Imaging scanners are not available commercially. Our expected resolution is 100 um with scan times of seconds per imaging slice. Initial in-vitro tests show promise that single cell detection is quite feasible. The method employs FDA approved superparamagnetic nanoparticles (e.g., Resovist or Ferumoxtran) for Magnetic Particle Imaging. The specific aims are to (1) construct a Magnetic Particle Scanner for mice; (2) test the MPI scanner against histology; and (3) validate the MPI scanner against MRI in a cardiac infarct mouse model. An inexpensive ($40,000) high-resolution, simple stem cell scanner is absolutely critical for the field of stem cell therapy to progress to humans. Research on mESC is funded heavily by the NIH, but this research is motivated principally to track hESCs in humans and, hence, is very unlikely to be funded by the Federal Government.
Statement of Benefit to California:
Stem cell therapy has enormous promise to become a viable therapy for a range of illnesses, including cardiac 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 Medicaid costs for the State. The diseases mentioned above are the leading cost illnesses as measured in lost productivity, lost wages, and extended care of the disabled. A study of the 1987 National Medicaid Expenditure Survey and the 2000 Medical Expenditure Panel Survey showed the 15 most costly medical conditions are (1) heart 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. Unfortunately 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 Berkeley and Stanford. We also have formed a key collaboration with Dr. Nick Van Bruggen of the Bioimaging Group at Genentech Corporation, which is very interested in this research for their own business. Hence, we are very excited to begin this research so the basic technology will be in place once the complex biology of stem cells is worked out.
SYNOPSIS: This is an application is to develop a highly sensitive imaging device, the Magnetic Particle Imager, to permit in vivo tracking of stem cells. The new scanner will be 100x more sensitive than current MRIs and is being worked out on mES cells. With collaborators Conboy and Healy they will be investigating hES cells in a mouse model and then subsequently an infarct model with cardiologists at Stanford. SIGNIFICANCE AND INNOVATION: The novelty and innovation is related to the technology of magnetic particle imaging and the new instrumentation that is under development. The ability to image stem cells in-vivo, and the stated significance of imaging stem cell delivery, adherence, survival, differentiation and ability to enhance function, will be an important addition to current techniques for assessing the biology of stem cells within a host. STRENGTHS: The strength of the proposal lies in the new instrumentation under development. The PI and group have expertise and a track record in related work. WEAKNESSES: The principal weakness relates to the highly contrived nature of this application with regard to use of hES cells; this project does not pertain to stem cells per se. The development of the instrumentation, initial assessment and validation can best be accomplished in a much simpler model system (i.e., with mES cells). The group already has numerous grants to develop imaging technology and it is not clear how they will add value to ongoing work as it relates to stem cell research. hES cells appear to be part of this proposal principally to gain access to the CIRM grant mechanism; thus, the justification for use of hES cells (as opposed to their current plans for use of mES cells) and for funding this work in the current RFA is weak. Once the instrumentation is developed and initially tested with mES cells, the PI should then plan experiments that will be insightful with hES cells. While the technology is innovative and significant for cell tracking, the scientific portion does not adequately address how the studies of cell fate and function will be accomplished. The proposal will involve imaging the location of the stem cells but will not elucidate their fate much more than existing technology. 100 micron resolution is not a big leap from existing MRI technology, although in some instances it can conceivably provide higher information content (the case is not laid out here). Pitfalls and alternate methods are not discussed in a meaningful way. A detailed accounting of work involving positive contrast MRI is provided and is not very germane. If resubmitted for possible future funding opportunities, perhaps the proposal can be written with greater care. Figures are mislabeled, incorrectly numbered and out of order. More care in writing the proposal would instill confidence in the group's commitment to the project and the care that will be given to its execution. Some detail on how magnetic particle imaging will deal with physiological motion also would be beneficial. DISCUSSION: There was no discussion following the reviewers' comments.