Читать книгу Magnetic Resonance Microscopy - Группа авторов - Страница 26

Micro-NMR detectors feature a sensitivity advantage for mass-limited samples, yet still suffer in terms of absolute sensitivity as dictated by the total number of signal-contributing spins in the sample. Hyperpolarization methods successfully circumvent this limitation and have proven extremely fruitful under “standard” NMR measurement conditions. Extending these capabilities to the microfluidic NMR domain was inevitable, yet progress has not been as dramatic as in macro-scale NMR.¹ This observation can be explained by considering first, the microfluidic NMR community is certainly small compared with the NMR community as a whole; and second, several technical challenges must be addressed to bring hyperpolarization to the micro-scale (material interfaces, scaling effects, integration, etc.). Nevertheless, all versions of NMR hyperpolarization have been explored at small scales.

Hyperpolarized gases offer profiling of both physical structures and chemical space. Using a remote sensing approach, both Xe and H₂ gases with enhanced polarization levels were used together with microfluidic systems to characterize on-chip gas flow profiles [64] and chemical micro-reactor systems [65]. Production of Xe at polarization levels approaching 10% at the micro-scale using microfabricated hyperpolarization cells significantly enhances portability together with local production for microfluidic applications [66,67]. To access the chemical space, the hyperpolarized gas must typically be brought into solution. At the macro-scale this can be achieved by bubbling a sample and pressuring the tube with the gas prior to the NMR experiment. Under microfluidic conditions a bubbling procedure is somewhat disastrous – bubbles easily disrupt microfluidic flow and destroy NMR spectral resolution and thus must be either managed by fluidic design, or preferably avoided altogether. This has been addressed by using membrane contacting systems (high-field examples in Figure 1.12), enabling bubble-free parahydrogen transport from the gas to solution phase. This has been leveraged for flow chemistry using both hydrogenative [52] and nonhydrogenative [51,53] PHiP experiments, with picomole sensitivities achieved under high-magnetic-field conditions.

Figure 1.12 Membrane-contacting devices for high-field microfluidic parahydrogen-induced polarization (PHiP). (A) Drawing of the contact chip (top), and overview of the assembly (bottom). The region of the sample chamber slides into a micro-stripline detector. (B) Photograph of the gas contacting and NMR detector assembly (left) and schematic of the exploded assembly (right). The fluidic insert is compatible with a micro Helmholtz detector, with liquid lines in blue and gas lines in orange. [51] Lorenzo Bordonali et al. (2019), figure 01[p.03]/with permission from Royal Society of Chemistry.

DNP has made enormous advances in academic spectroscopy and imaging research, even to the point of commercialization and clinical studies [68]. Leveraging this potential for microfluidic-compatible MR microscopy has only begun, first taking root primarily in metabolic monitoring. Jeong et al. [69] used the relatively long-lived ¹³C enhanced state of pyruvate and lactate to monitor cancer cell metabolism. The hyperpolarized pyruvate was added to a microcoil accommodating 2 µl of sample and subsequently moved to a 1.05-T NMR magnet for measurement. Metabolic flux was measured for a population of only 104 cells, three orders of magnitude better than what was typically required. Mompéan et al. [70] used the photo-inducible version of DNP (photo-chemically induced DNP, photo-CIDNP) on a micro-NMR flow device to enable sub-picomole sensitivity of a 1-µl sample at 9.4 T. Uberrück et al. [71] demonstrated liquid-state Overhauser DNP (ODNP) at 0.342 T, while Kiss [72] performed ODNP at 0.5 T using a fully integrated microsystem approach (Figure 1.13). A key challenge to be faced with microfluidic-compatible DNP-based hyperpolarization at high magnetic fields is handling high-frequency microwaves for electron excitation. This is alleviated in the case of photo-CIDNP where microwaves are not necessary, at the cost of limited applicability. This challenge is general, and is a focus for the entire high-field DNP community.

Figure 1.13 Photograph of a fully integrated Overhauser dynamic nuclear polarization (ODNP) probe head, designed to operate in a palm-held 0.5-T permanent magnet. [72] Sebastian Kiss (2019)/figure 05.26 [p.125]/with permission from University of Freiburg.