Tools and Technologies II
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 cannot produce high resolution images deeper than a few mm. 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, it will be significantly more affordable, and will require no expert operator. Only developed in the last year, Magnetic Particle Imaging scanners are not available commercially. Our expected resolution is 200 um with scan times of seconds per imaging slice. Initial in-vitro tests show promise that 200 cell detection is feasible. In fact, with industrial efforts on electronics and contrast agents, single cell detection may be feasible. The method employs FDA approved superparamagnetic nanoparticles (e.g., Resovist or Ferumoxtran) for Magnetic Particle Imaging. Our specific aims are to (1) construct a Magnetic Particle Scanner for mice; (2) Optimize the MPI nanoparticle contrast agent for spatial resolution and sensitivity; (3) Validate the MPI scanner against histology with [REDACTED]; and (4) disseminate our designs to the stem cell community. An affordable high-resolution, and quantitative 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 our 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 Parkinson's. If we could expedite the development of these therapies, it would be of enormous benefit to the citizens 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%; and (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 quantitative imaging feedback to optimize each step. Unfortunately there is no acceptable method now for quantitative tracking of stem cells throughout the human body. Our new method, called Magnetic Particle Imaging, looks very promising for track stem cells in vivo. Moreover, it will be affordable and quite simple to operate. This research requires a collaboration between imaging instrument engineers, stem cell biologists, nanoparticle experts, and physicians. Fortunately, we have been able to form such a team between [REDACTED]. We also have formed a key collaboration with [REDACTED]. [REDACTED] is very excited by this bold research, which could open up an entirely new branch of diagnostic imaging technology for many medical applications. Hence, we are very excited to begin this research so the basic technology will be in place to help stem cell biologists work out the ideal protocols for stem cell therapies.
This application describes the development of a magnetic particle imaging (MPI) device that can be utilized to enhance the visualization and tracking of stem cells in vivo. The applicant identifies accurate and sensitive tracking of cell therapy products as a critical bottleneck to preclinical and clinical use of these products. Current technologies, including magnetic resonance imaging (MRI), do not have sufficient detection sensitivity, imaging resolution, and/or do not penetrate the necessary tissue depth for in vivo cell tracking. MPI is an imaging technology that uses nanoparticles as contrast agents to deliver better spatial resolution than MRI at lower costs and increased ease of operation. The applicants suggest this technology has the potential to address many of the sensitivity, resolution, and tissue depth issues that currently limit tracking of stem cell products in vivo. In this proposal, the applicant first plans to construct and optimize two MPI scanners for use in mice. Next, the applicant will characterize and optimize nanoparticles to gain the targeted MPI resolution and sensitivity. Once these two aims are completed, the applicant will then test the in vivo spatial resolution and sensitivity of the MPI scanner and test the ability of the MPI signal to indicate cell viability. Lastly, the applicant plans to disseminate the design for the MPI scanner to the research community. The reviewers agreed that if successfully constructed and validated, the MPI scanner would represent a significant advance in detecting small numbers of stem cells in vivo and would positively impact the regenerative medicine field. The engineering described is innovative, several new algorithms for data sampling are included, and the proposed MPI scanner is a clever alternative to MRI. However, reviewers noted that competing industry products are in development, and the applicant did not adequately delineate how their product compares and would ultimately fit into commercialization approaches for this type of device. Reviewers praised the research plan, the preliminary data, and the applicants’ previous work, which sets up the theoretical basis to achieve the proposed device resolution and sensitivity. The ample preliminary data demonstrates a high sensitivity of detection and supports the ability of the applicant to execute construction of the proposed scanner. While the research plan is solid, the reviewers would have appreciated a better-developed discussion of alternative plans. For example, the applicants do not address alternate strategies if either the MPI scanner design cannot meet resolution levels or the new nanoparticles cannot meet the proposed diameter. Further, the applicants do not fully discuss nor plan to appropriately explore how the stem cells will tolerate and respond to the nanoparticles. Reviewers also expressed concern that the applicant’s plan to detect the viability of the stem cells by MPI might be not sound since label dilution, cell division, and clearance of dead cells by macrophages will interfere with the accuracy of assessment. The reviewers suggested that incorporation of reporter genes and/or bioluminescent imaging to validate viability would be more useful for this purpose. Finally, it was noted that while the application contained a solid and reasonable research plan with quantitative goals, it seemed under-ambitious since some of the tasks should not take as long as planned. Despite these concerns, the reviewers remained highly enthusiastic that this application could open a completely new arena for in vivo stem cell tracking. The Principal Investigator (PI) is a world-renowned scientist in his area of expertise and has a solid publication and patent record. The PI is ideally suited to lead this project and has assembled an appropriate team to conduct the proposed research. A strong point in the team is the inclusion of a junior team member who has been instrumental to previous successes by this PI. There was some concern that this critical junior team member might not remain in the lab of the PI throughout the life of the project; thus, a reviewer suggested that a full-time postdoctoral fellow with expertise complementary to the junior member might benefit the project. Reviewers considered the collaborations with industry representatives as a major benefit to the proposal. In summary, though some concerns with the research plan were raised, the reviewers were enthusiastic about the proposal’s innovative engineering, the significant potential impact, and the track record of the PI and research team, and recommended this application for funding.
- A motion was made to move this application into Tier 1, Recommended for Funding. Reviewers commented that though some other groups are attempting to commercialize this work, this is a strong team with a proven track record, and they are the only California-based group developing this technology. The motion carried.