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#15 - A novel MRI contrast agent to improve the visibility of internal body structures during MR imaging
Long Title: Color MRI Contrast Agents Using Magnetic Microstructures
NIH Reference No.: E-081-2008; E-309-2009
Executive Summary
General Description
Magnetic Resonance Imaging (MRI) is a widespread tool commonly used for both research and medical diagnostics. It allows for live imaging of deep tissues, but chemical image-enhancing (contrast) agents are often required to achieve good image quality. Currently available MRI contrast agents provide monotone signal which is uniform and disperse. While optical fluorescence microscopy allows for multi-color capability to track different color fluorescent tags, dyes, or quantum dots, it cannot penetrate deep into tissues. These microfabricated particles provide a method to generate MRI contrast agents with the ‘color’ properties that used to only be associated with optical fluorescence microscopy.
Top--down microfabrication was used to produce magnetic particles of specified dimensions and sizes. Since the resonance frequency shift depends on the particle structure, as well as its ability to be penetrated by surrounding water, particles resembling two parallel discs separated by a non-magnetic spacer were produced by a series of micromachining processes (metal evaporation and electroplating followed by lithographically defined ion-milling and selective wet etching). By changing the diameter of the discs, as well as the distance separating them, their spectral shift (analogous to the color of emitted light) can be engineered to suit different detection needs. The water diffusion into the particle further provides signal enhancement, which allows for use at much lower concentration in comparison to currently utilized agents (e.g. order of magnitude lower than clinical gadolinium). The utility of the micro-fabricated particles has been expanded through the development of an ellipsoidal microcavity, with a unique capability of generating uniform local electromagnetic fields, demonstrating that different shapes result in different MRI properties.
These new micro-fabricated structures are designed by magnetic geometry rather than chemical structure and are engineered to exploit diffusion, thus increasing sensitivity by orders of magnitude compared to currently used contrast agents for MRI. As RFID tags, they are engineered at sub-cellular size, far smaller than existing tags. Based on the ability of these particles to shift electromagnetic spectra by a defined value, they can be utilized as microscopic RFID-tags in applications where traditional, macroscopic electronic devices would be unsuitable.
Scientific Progress
A method for microfabrication of microscopic magnetic geometric structures that can be individually detected by MRI due to their unique spectral shift capabilities has been developed. Resonance spectra originating from differently engineered particles can be clearly distinguished from both each other and from background water proton signal. Water diffusion into “open” particles leads to strong signal enhancement as opposed to “closed” (filled) particles where water cannot penetrate.
Future Direction
Strengths
Weaknesses
Patent Status
US Application No. 12/753,689 filed April 3, 2010
US Application No. 12/937,843 filed Apr 20,2009
PCT Application No. PCT/US2009/041142 filed Apr 18, 2009
Relevant Publications
G Zabow et al. Ellipsoidal microcavities: electromagnetic properties, fabrication, and use as multispectral MRI agents. Small 2014 May;10(10):1902-7. doi: 10.1002/smll.201303045 PubMed:24623519
G Zabow et al. Micro-engineered local field control for high-sensitivity multispectral MRI. Nature 2008 Jun 19;453(7198):1058-1063. PubMed: 18563157
KA Hinds et al. Highly efficient endosomal labeling of progenitor and stem cells with large magnetic particles allows magnetic resonance imaging of single cells. Blood 2003 Aug 1;102(3):867-872. PubMed: 12676779
Inventor Bio
Gary Zabow, Ph.D.
Dr. Zabow is a senior research fellow at the National Institutes of Health (NIH), where he works within the National Institute of Neurological Disorders and Stroke (NINDS). He also holds a concurrent guest researcher position at the National Institute of Standards and Technology (NIST) in Boulder, Colorado. His interests range widely, including atomic physics, microfluidics, magnetic resonance imaging (MRI), and micro- and nanofabrication technology. His current research focuses on novel microfabrication techniques and on leveraging such techniques for bio-related applications including enhancing magnetic resonance imaging and sensing functionalities. He holds a PhD in physics from Harvard University.
Alan P. Koretsky, Ph.D.
Dr. Koretsky received his B.S. degree from the Massachusetts Institute of Technology and Ph.D. from the University of California at Berkeley. He performed postdoctoral work in the NHLBI at NIH studying regulation of mitochondrial metabolism using optical and NMR techniques. Dr. Koretsky spent twelve years on the faculty in the Department of Biological Sciences at Carnegie Mellon University where he was the Eberly Professor of Structural Biology and Chemistry. In summer 1999, he moved to NINDS as Chief of the Laboratory of Functional and Molecular Imaging and Director of the NIH MRI Research Facility. Dr. Koretsky's laboratory is interested in two main areas. They are actively developing novel imaging techniques to visualize brain function and study the regulation of cellular energy metabolism combining molecular genetics with non-invasive imaging tools.
NIH Reference No.: E-081-2008; E-309-2009
Executive Summary
- Invention Type: Device, MRI Contrast Agent
- Patent Status: US patents pending (12/937,843 and 12/753,689); PCT/US2009/04112 and PCT/US2010/29839 (pending in EU, CA, AU)
- LINK: http://www.ott.nih.gov/technology/e-081-20080
- NIH Reference Number: E-081-2008
- NIH Institute or Center: National Institute of Neurological Disorders and Stroke (NINDS) and National Institute of Standards and Technology (NIST)
- Basis of Invention: MRI Imaging/RFID System
- How it works: Micro-fabricated structures that specifically shift magnetic resonance spectrum providing the ability to take on different “colors” in an MRI system rather than just grey-scale and the ability to track multiple different types of cells simultaneously
- Lead Inventors: Gary Zabow (NINDS/NIST), Alan Koretsky (NINDS), Stephen Dodd (NINDS), and John Moreland (NIST)
- Development Stage: Pre-clinical; particles have been thoroughly characterized
- Novelty: Powerful multichannel imaging for MRI, Structure composition can be from same (FDA approved) materials used in regular contrast agents
- Clinical Application: MRI contrast agents, diagnostic markers for MRI detection of cells or proteins associated with a specific disease state (infection, toxin, inflammation, tumor, etc.), stent applications, RFID-based microfluidics, flow cytometry, MEMS technology, MRI calibration
General Description
Magnetic Resonance Imaging (MRI) is a widespread tool commonly used for both research and medical diagnostics. It allows for live imaging of deep tissues, but chemical image-enhancing (contrast) agents are often required to achieve good image quality. Currently available MRI contrast agents provide monotone signal which is uniform and disperse. While optical fluorescence microscopy allows for multi-color capability to track different color fluorescent tags, dyes, or quantum dots, it cannot penetrate deep into tissues. These microfabricated particles provide a method to generate MRI contrast agents with the ‘color’ properties that used to only be associated with optical fluorescence microscopy.
Top--down microfabrication was used to produce magnetic particles of specified dimensions and sizes. Since the resonance frequency shift depends on the particle structure, as well as its ability to be penetrated by surrounding water, particles resembling two parallel discs separated by a non-magnetic spacer were produced by a series of micromachining processes (metal evaporation and electroplating followed by lithographically defined ion-milling and selective wet etching). By changing the diameter of the discs, as well as the distance separating them, their spectral shift (analogous to the color of emitted light) can be engineered to suit different detection needs. The water diffusion into the particle further provides signal enhancement, which allows for use at much lower concentration in comparison to currently utilized agents (e.g. order of magnitude lower than clinical gadolinium). The utility of the micro-fabricated particles has been expanded through the development of an ellipsoidal microcavity, with a unique capability of generating uniform local electromagnetic fields, demonstrating that different shapes result in different MRI properties.
These new micro-fabricated structures are designed by magnetic geometry rather than chemical structure and are engineered to exploit diffusion, thus increasing sensitivity by orders of magnitude compared to currently used contrast agents for MRI. As RFID tags, they are engineered at sub-cellular size, far smaller than existing tags. Based on the ability of these particles to shift electromagnetic spectra by a defined value, they can be utilized as microscopic RFID-tags in applications where traditional, macroscopic electronic devices would be unsuitable.
Scientific Progress
A method for microfabrication of microscopic magnetic geometric structures that can be individually detected by MRI due to their unique spectral shift capabilities has been developed. Resonance spectra originating from differently engineered particles can be clearly distinguished from both each other and from background water proton signal. Water diffusion into “open” particles leads to strong signal enhancement as opposed to “closed” (filled) particles where water cannot penetrate.
Future Direction
- Development of additional particles with improved signal and smaller dimensions
- Development of “switchable” particles, where water penetration can be controlled by enzymatically activated gate, molecular binding, or pH change (change in resonance response due to detection of biological condition)
- Optimization and simplification of particle manufacturing
Strengths
- Ability to identify and track different targets by MRI using particles of different resonance shift
- Capability of self-orientation and self-assembly in response to magnetic field
- Signal enhancement in response to water diffusion, possibly allowing for design of “switchable” markers
- RFID-tags that can be used on a microscopic scale or packed in a very small volume
Weaknesses
- Penetration through blood-brain barrier has not been proven and clearance of particles in vivo is still unknown
- Require high skill and specialized equipment for microfabrication
Patent Status
US Application No. 12/753,689 filed April 3, 2010
US Application No. 12/937,843 filed Apr 20,2009
PCT Application No. PCT/US2009/041142 filed Apr 18, 2009
Relevant Publications
G Zabow et al. Ellipsoidal microcavities: electromagnetic properties, fabrication, and use as multispectral MRI agents. Small 2014 May;10(10):1902-7. doi: 10.1002/smll.201303045 PubMed:24623519
G Zabow et al. Micro-engineered local field control for high-sensitivity multispectral MRI. Nature 2008 Jun 19;453(7198):1058-1063. PubMed: 18563157
KA Hinds et al. Highly efficient endosomal labeling of progenitor and stem cells with large magnetic particles allows magnetic resonance imaging of single cells. Blood 2003 Aug 1;102(3):867-872. PubMed: 12676779
Inventor Bio
Gary Zabow, Ph.D.
Dr. Zabow is a senior research fellow at the National Institutes of Health (NIH), where he works within the National Institute of Neurological Disorders and Stroke (NINDS). He also holds a concurrent guest researcher position at the National Institute of Standards and Technology (NIST) in Boulder, Colorado. His interests range widely, including atomic physics, microfluidics, magnetic resonance imaging (MRI), and micro- and nanofabrication technology. His current research focuses on novel microfabrication techniques and on leveraging such techniques for bio-related applications including enhancing magnetic resonance imaging and sensing functionalities. He holds a PhD in physics from Harvard University.
Alan P. Koretsky, Ph.D.
Dr. Koretsky received his B.S. degree from the Massachusetts Institute of Technology and Ph.D. from the University of California at Berkeley. He performed postdoctoral work in the NHLBI at NIH studying regulation of mitochondrial metabolism using optical and NMR techniques. Dr. Koretsky spent twelve years on the faculty in the Department of Biological Sciences at Carnegie Mellon University where he was the Eberly Professor of Structural Biology and Chemistry. In summer 1999, he moved to NINDS as Chief of the Laboratory of Functional and Molecular Imaging and Director of the NIH MRI Research Facility. Dr. Koretsky's laboratory is interested in two main areas. They are actively developing novel imaging techniques to visualize brain function and study the regulation of cellular energy metabolism combining molecular genetics with non-invasive imaging tools.
