SBIR-STTR Award

The NIH Division of Cell Biology and Biophysics supports studies of the biological macromolecules that affect the function and structure of living cells, and often play a role in disease. Within the realm of biophysics, one of the most important tools to study the structure and interactions of these molecules is nuclear magnetic resonance (NMR). For example, NMR has been used to study the oligomeric forms of amyloid-? that are that are critical to understanding the development of Alzheimer's disease. Also, NMR allows study of the structure of membrane proteins for use as potential pharmaceutical targets. Cleary, NMR is an extremely powerful scientific tool, however, the technique is not simple and the measurements can be expensive and time consuming. This is primarily because the NMR signal is weak and requires sensitive receivers and long integration times for reliable detection. Within the field of NMR, dynamic nuclear polarization (DNP) is a well-known technique to greatly increase the signal strength. Most DNP systems rely on a Gyrotron to generate the required microwave power. Although Gyrotrons generate sufficient power, they are incapable of generating the short pulses and modulated signals desired for advanced DNP systems. Also, their cost is prohibitive for all but the most well-funded laboratories. The key focus of this project is to advance solid-state (SS) source technology to the point where it can begin to replace the Gyrotrons for a significant proportion of DNP-NMR measurements, thereby lowering the barriers to entry into this field and accelerating the pace of scientific discovery. The Phase I effort is focused on demonstrating that recent technological innovations can be used to significantly increase the power and functionality of the SS sources for DNP. The first objective is to demonstrate an innovative frequency doubler design that is expected to generate greater than 200 mW at 263 GHz. This is a significant milestone not only because it will increase the range of measurements possible with a SS source, but also because it is sufficient to fully pump the emerging traveling wave tube (TWT) amplifiers, which can increase the power to the several watts. The second objective is to generate short pulses and complex waveforms with accurate phase and frequency modulation. This is an important milestone because such control of the microwave signal can significantly increase the NMR signal without requiring increased power. The final Phase I objective is to develop the general research plan for Phase II that will lead to watt level power at 263 GHz, extension of the technology to other frequencies of interest, and the implementation of the pulse and modulation controls into a system optimized for DNP- NMR research.

Public Health Relevance Statement:
VDI Project Narrative:  The purpose of this research is to develop a solid?state source technology that will enable  advanced DNP?NMR and pulsed EPR systems with higher operating frequencies and improved  modulation schemes, while also reducing the cost and complexity of the systems. Pulsed EPR  and DNP?NMR systems are being used to gain greater knowledge of the atomic?level structural  detail of biological molecules, and particularly proteins, at a speed that has not previously been  possible. Thus, this effort will facilitate the mission of the Division of Cell Biology and Biophysics  to “better understand the basic structures and processes in living cells ... and lay the foundation  for ways to prevent, treat and cure diseases that result from disturbed or abnormal cellular  activity.”  

Project Terms:
Affect; Alzheimer's Disease; Amplifiers; Amyloid beta-Protein; Biological; Biophysics; Cell division; Cells; Cellular biology; cold temperature; Complex; cost; Coupled; Coupling; cryostat; design; Detection; Development; digital; Disease; experimental study; Foundations; Frequencies; Funding; Generations; Goals; improved; Industry; innovation; interest; Knowledge; Laboratories; Laboratory Research; macromolecule; Measurement; Membrane; Membrane Proteins; meter; microwave electromagnetic radiation; Mission; Nuclear; Nuclear Magnetic Resonance; operation; Pharmacologic Substance; Phase; Physiologic pulse; Play; Power Sources; prevent; Process; Proteins; Pump; Research; Role; Sampling; Scheme; Signal Transduction; solid state; Source; Speed; Structure; System; Techniques; technological innovation; Technology; Time; tool; Travel; Tube; United States National Institutes of Health; Weight

Powerful Solid-State Sources to Enable Advanced EPR and DNP-NMR Measurements NIH SBIR Phase II Proposal VDI Project Summary/Abstract: DNP-NMR and EPR are important scientific tools that are of interest to the NIGMS Division of Cell Biology and Biophysics. They both rely on a high frequency microwave source to increase the polarization of electrons in the samples under test. In the past, progress in DNP-NMR and EPR has been hindered by the difficulty of generating sufficient power levels at the desired frequencies, which now extend well above 100 GHz. Typical systems rely on a Gyrotron oscillator that generates tens of watts of power. However, these systems are expensive to purchase and install, and even the operating and maintenance costs can be prohibitive. The key focus of this project is to advance solid-state (SS) source technology to the point where it can begin to replace the Gyrotrons for a significant proportion of DNP-NMR and pulsed-EPR measurements, thereby lowering the barriers to entry into this field and accelerating the pace of scientific discovery. The solid-state sources will also enable advanced modulation schemes that greatly improve the performance of EPR systems, and can potentially have a similar impact on DNP-NMR. The Phase I research achieved all of the proposal goals, including the demonstration of a more powerful 263 GHz source that was demonstrated to achieve significant DNP signal enhancement. The Phase II effort will build on this success in three ways; (i) the power level of the 263 GHz source will be further increased to facilitate a greater range of measurements, (ii) the technology will be extended to other frequencies of importance for EPR and DNP, specifically 395 and 527 GHz, (ii) the new sources will incorporate fast pulse capability as well as frequency and phase modulation, and (iv) the 263 GHz source will be developed to ensure easier operation by researchers who are not experts in millimeter wave technology; thereby accelerating the path to Phase III commercialization of this important technology.

Public Health Relevance Statement:
Powerful Solid-State Sources to Enable Advanced EPR and DNP-NMR Measurements NIH SBIR Phase II Proposal VDI

Project narrative:
The purpose of this research is to develop a solid?state source technology that will enable advanced DNP?NMR and pulsed?EPR systems with higher operating frequencies and improved modulation schemes, while also reducing the cost and complexity of the systems. Pulsed EPR and DNP?NMR systems are being used to gain greater knowledge of the atomic?level structural detail of biological molecules, and particularly proteins, at a speed that has not previously been possible. Thus, this effort will facilitate the mission of the Division of Cell Biology and Biophysics to “better understand the basic structures and processes in living cells ... and lay the foundation for ways to prevent, treat and cure diseases that result from disturbed or abnormal cellular activity.”

Project Terms:
2,4-Dinitrophenol; Advanced Development; Amplifiers; Area; Biological; Biophysics; Cell division; Cells; Cellular biology; cold temperature; commercialization; Communication; cost; cryogenics; design; digital; Disease; Electron Spin Resonance Spectroscopy; Electrons; Ensure; experience; experimental study; falls; Foundations; Frequencies; Generations; Goals; improved; Industry; interest; Knowledge; Laboratories; Laboratory Research; macromolecule; Maintenance; Measurement; microwave electromagnetic radiation; millimeter; Mission; nanosecond; National Institute of General Medical Sciences; Nuclear; Nuclear Magnetic Resonance; operation; Output; Performance; Phase; Physiologic pulse; prevent; Process; Proteins; Pump; Reporting; Research; research and development; Research Personnel; Sampling; Scheme; Signal Transduction; Small Business Innovation Research Grant; solid state; Source; Speed; Structure; success; System; Technology; Testing; Time; tool; United States National Institutes of Health; Virginia; Weight