The goal of this project is to develop a new three-dimensional imaging technique, using magnetic nanoparticle tracers, to observe and study biological processes at the cellular and sub-cellular level in live organisms, tissue and cell cultures.
Intellectual Merit: Advances in optical microscopy and imaging have transformed biology. However, the penetration depth of optical microscopy is limited due to the scattering and absorption of light within tissue. Thus, interrogating tissue and 3D cell cultures beyond (0.5 to 0.8) mm with high resolution and minimal photodamage from the required high-intensity illumination has been challenging. Magnetic fields, in contrast, penetrate biological samples without scattering or harm to the cells, providing the opportunity for a new imaging modality from magnetic nanoparticle microscopy as proposed here. Cells and cellular organelles may be labeled with magnetic nanoparticle tracers, which can then be imaged with high contrast and resolution. Magnetic nanoparticle microscopy is based on the principles of magnetic particle imaging (MPI). Briefly, a magnetic field distribution is established such that tracer particles everywhere within the sample except a small field free point are magnetically saturated. As a result, when an ac excitation field is applied, a response is elicited only from nanoparticles within the field free point. A 3D image of the nanoparticle concentration is constructed by scanning the field free point within the sample to spatially select the nanoparticles and measure their response inductively. Research on MPI has focused on the development of millimeter-scale resolution scanners with a field of view encompassing the whole human or small animal body. The proposed research seeks instead to scale magnetic particle imaging for sub cellular resolution. The experimental goal is to demonstrate 25 µm in a relevant biological specimen. A magnet field assembly will be implemented to provide the high field gradient needed for nearly two orders of magnitude finer resolution. The system hardware will be designed with low noise electronics to ensure maximal signal-to-noise ratio. Further, nanoparticle tracers of custom size and biocompatible coatings will be precision engineered with to meet the imaging requirements. A modular synthetic approach will allow the core and biocompatible coatings to be independently and systematically tailored, with exquisite control. Imaging capabilities will be demonstrated in embryonic zebrafish and verified via concurrent optical microscopy. Experiments proposed to qualify magnetic nanoparticle imaging will also advance ongoing research in identifying physical and chemical properties of nanoparticles that influence their uptake and thereby provide insight to their toxicity.
Broader Impact: This project forges an interdisciplinary and inter-institutional collaboration, bridging engineering, chemistry and biology, to meet the need for an imaging technology to explore new scientific frontiers in microbiology and medicine. The successful demonstration of cellular and sub cellular resolution will establish a new means of microscopy, using magnetic nanoparticle tracers, to investigate cell behavior in optically opaque, living tissue. Beyond fundamental biology, this effort will advance synthesis techniques for precisely engineered nanoparticles and bring new insight to nanoparticle interactions with living systems. Further, it will lay the foundation for applications envisioned in medical imaging of clinical skin and breast cancer screening. The PIs will involve 2 graduate and 4 undergraduate students in research. The participating students will gain a well -rounded technical education acquiring not only expertise in their respective areas of specialization but also knowledge of methods and materials in complementary areas of research. Suitable sub-topics within the project will be integrated in to cross disciplinary and discipline-specific courses taught by the PIs. The research findings will be published in relevant high-impact journals and presented at regional, national and international technical meetings. In addition, as discussed in the data management plan, final data will be archived and made available to the public. The PIs will serve K-12 education by developing grade-level appropriate instruction materials in collaboration with elementary, middle and high school science teachers. The PIs will also participate in Science Pubs, an informal science education program to engage the public in discussion on the synthesis, applications and implications of nanoparticles in medicine and biology.
