Periodic Reporting for period 2 - MagSense (Hyperpolarized NMR made simple)
Reporting period: 2024-04-01 to 2025-03-31
Nuclear magnetic resonance (NMR) is the gold standard analytical technique for non-invasive analysis of bulk materials, such as chemical compounds, industrial products, and biological and medical samples. Users often turn to NMR for the wealth of information and specificity it provides, but in a growing number of applications run into limits of sensitivity that require combined use with other chemical analytical techniques. In the present project, we use quantum-based parahydrogen induced hyperpolarization (PHIP) to make NMR spectrometers significantly more sensitive (>150 times for benchtop spectrometers) using our hyperpolarization system. The quantum nature of our technology allows us to provide an efficient, fast, and easy-to-use system as an add-on to standard NMR spectrometers. This increased sensitivity can be leveraged for new NMR capabilities such as detecting transient effects (e.g. chemical reactions) and enabling breakthrough point-of-service applications (e.g. point-of-care diagnostics) with portable NMR spectrometers. MAGSENSE is targeting a market of more than 5,000 NMR users, as well as a sizable new user base for point-of-service applications. After the project ends, we will deploy working prototypes to key opinion leaders and will be prepared for the commercialization of the technology.
The principal scientific achievements of the MAGSENSE project include the hyperpolarization of a source molecule (labeled dimethyl maleate) to achieve a high degree of polarization (30%) at a high concentration of 1M, as published in Dagys, L., et al., [arXiv:2401.07243 (2024)]. This magnetization was successfully transferred to a mixture of small molecules via the intermolecular Nuclear Overhauser Effect, resulting in enhancements 22-fold greater than thermal polarization at a 400MHz NMR spectrometer. Projecting these results onto an 80MHz Benchtop System, we anticipate enhancements exceeding 100-fold relative to the corresponding thermal signal. However, the exceptionally high magnetization of the source molecule can trigger effects such as negative or positive feedback from the detection coil ( known as radiation damping for negative feedback or rasing for positive feedback). To facilitate standard NMR spectroscopic analysis of the enhanced target molecules without overwhelming background interference, we developed following methodologies through several scientific collaborations. Initially, we developed a strategy to suppress the source molecule signal during measurement of the enhanced target molecule signal [De Biaso et al., in preparation], and demonstrated NOE-based hyperpolarized, ultrafast 2D NMR spectroscopy [Parker, A. J., et al., Angewandte Chemie, 135, no. 50 (2023): e202312302; follow-up article including PHIPNOESYS in preparation].
To achieve these scientific breakthroughs, two distinct systems were developed. The first is a lab demonstrator designed for proof-of-concept experiments to push beyond current scientific limits. This system integrates a 400MHz Bruker NMR Spectrometer with a PHIP-Polarization add-on, connected via a mechanical shuttling system. The second is a portable, user-friendly system adaptable to various benchtop-NMR systems, aimed at point-of-service applications for instance contamination monitoring in wastewater treatment facilities or early drug discovery labs in pharmaceutical companies.
To meet increasing demand, we have developed a scalable chemical synthesis process capable of producing tens of grams of deuterated and isotopically labeled source molecules with high purity. Additionally, we have established a strategy for a global supply chain of highly-enriched parahydrogen.
To achieve these scientific breakthroughs, two distinct systems were developed. The first is a lab demonstrator designed for proof-of-concept experiments to push beyond current scientific limits. This system integrates a 400MHz Bruker NMR Spectrometer with a PHIP-Polarization add-on, connected via a mechanical shuttling system. The second is a portable, user-friendly system adaptable to various benchtop-NMR systems, aimed at point-of-service applications for instance contamination monitoring in wastewater treatment facilities or early drug discovery labs in pharmaceutical companies.
To meet increasing demand, we have developed a scalable chemical synthesis process capable of producing tens of grams of deuterated and isotopically labeled source molecules with high purity. Additionally, we have established a strategy for a global supply chain of highly-enriched parahydrogen.
In the Magsense project, we achieved several groundbreaking results that advance the state of the art in NMR spectroscopy. Notably, we successfully hyperpolarized a source molecule in high concentration and to high polarization levels through Parahydrogen Induced Polarization (PHIP). To our knowledge, achieving such levels of magnetization via PHIP, which requires a transition from singlet order to order in a magnetized state, have never before been achieved. This is because doing so required the understanding we developed during this project of how to perform polarization transfer when the dipolar field from the magnetized source becomes a dominant interaction during the transfer process. Effects of highly magnetized samples had been studied in the 1980s and 1990s but for samples with often less than 100x the magnetization produced during our hyperpolarization process. Not only did our technology require the development of hardware for producing and studying highly concentrated and highly polarized materials, but also solutions for observing the resulting hyperpolarized target species in terms of new NMR pulse sequences [Parker et al., Angew. Chem., 2023, De Biaso et al., in preparation], data analysis [Eichhorn, T. et al., JACS 2022], and locking techniques. Our strategy so far has been to expand upon the capabilities of our hyperpolarization technique, step-by-step, for the user to be able to apply it and still have access to the essential parts of the NMR toolkit that make it such a vital technique for chemical analysis. Our efforts thus far demonstrate the leveraging and building upon previous scientific research to advance well beyond the state of the art or what was previously achieved.