Scalable NMR spectroscopy with semiconductor chips

Abstract

State-of-the-art NMR spectrometers using superconducting magnets have enabled, with their ultrafine spectral resolution, the determination of the structure of large molecules such as proteins, which is one of the most profound applications of modern NMR spectroscopy. Many chemical and biotechnological applications, however, involve only small-to-medium size molecules, for which the ultrafine resolution of the bulky, expensive, and high-maintenance NMR spectrometers is not required. For these applications, there is a critical need for portable, affordable, and low-maintenance NMR spectrometers to enable in-field, on-demand, or online applications (e.g., quality control, chemical reaction monitoring) and co-use of NMR with other analytical methods (e.g., chromatography, electrophoresis). As a critical step toward NMR spectrometer miniaturization, small permanent magnets with high field homogeneity have been developed. In contrast, NMR spectrometer electronics capable of modern multidimensional spectroscopy have thus far remained bulky. Complementing the magnet miniaturization, here we integrate the NMR spectrometer electronics into 4-mm 2 silicon chips. Furthermore, we perform various multidimensional NMR spectroscopies by operating these spectrometer electronics chips together with a compact permanent magnet. This combination of the spectrometer-electronics-on-a-chip with a permanent magnet represents a useful step toward miniaturization of the overall NMR spectrometer into a portable platform. N MR spectroscopy has been celebrated for its ability to probe molecular structures and dynamics with the atomic resolution (1-9). State-of-the-art NMR spectrometers use large superconducting magnets, whose high and uniform magnetic fields lead to the fine spectral resolution necessary for interrogating large molecules such as proteins. In fact, the structural study of large molecules is one of the most profound applications of modern NMR spectroscopy.However, the spectral resolution of the bulky, expensive, and high-maintenance NMR spectrometers is not necessary for a broad array of studies involving small-to-medium size molecules in chemistry, chemical engineering, and biotechnology (10, 11). In this case, portable, affordable, and low-maintenance NMR spectrometers built with a permanent magnet can make the benefits of NMR spectroscopy more broadly available and enable new applications. Bulky superconducting systems have to be permanently placed in dedicated laboratories, but portable systems can enable in-field, on-demand, or online applications such as quality control and chemical reaction monitoring (4), and can greatly facilitate co-use of NMR spectroscopy with other analytical methods such as liquid chromatography (12) and capillary electrophoresis (13). Thus, much effort has been devoted to miniaturizing NMR spectrometers, leading to the critical development of small permanent magnets with high field homogeneity (10,14,15).Complementing this advance in magnet miniaturization, here we integrate the spectrometer elec...

A broadband single-chip transceiver for multi-nuclear NMR probes

“…14,15 NMR systems also require relatively complex RF electronics for resonance excitation and signal detection. The design of electronic micro-chips for NMR purposes has the aim to shrink the size of electronics for low-cost NMR spectrometers [16][17][18][19] and to combine microcoils with integrated receivers in order to achieve probes parallelization and high spin sensitivity. [20][21][22][23] The first integrated probe was proposed for magnetometry purposes and employed integrated pick-up-coils coupled to receivers, with the excitation operated by a second inductively decoupled coil.…”

“…24 Receiver-only chips, with the whole electronics buried below integrated microcoils, were proposed a) marco.grisi@epfl.ch as optimal choice for micro-imaging, 23 parallel imaging arrays, 20 and probes for surgical guidance. 22 The realization of integrated transceivers for NMR purposes, of which there are only a few examples, [16][17][18] also included integrated pulse sequencers aiming at miniaturizing the size and abating the costs of the overall electronics needed to build spectrometers.…”

In vivo online magnetic resonance quantification of absolute metabolite concentrations in microdialysate

“…Micro-structured NMR/MRS probes have been fabricated in a variety of different geometries1516171819202122232425262728 and have partly been applied to continuous flow investigations2930 with solenoidal coils being the most sensitive to date1516. Utilizing this fact with the goal of online detection of metabolites at physiological concentrations for in vivo studies, we have constructed two different microprobes with solenoidal geometry: a 1 H-optimized probe tuned at 300 MHz and a 13 C-optimized probe with unprecedented sensitivity tuned at 50 MHz.…”

A Handheld High-Sensitivity Micro-NMR CMOS Platform With B-Field Stabilization for Multi-Type Biological/Chemical Assays

“…Yet, due to the large sensing coil, the implementation of microarray for multiplex sensing is unfeasible. In addition, limited by the homogeneity of the magnet, NMR spectroscopy, as demonstrated by Ha et al [22], is not supported by this platform. Still, the NMR relaxometry applications demonstrated here render this platform as a promising candidate for PoU tool.…”

“…As such, fL of the nuclei shifts together with B0, imposing that calibration is essential to safeguard the system against environmental changes. Conventional frequency stabilization techniques are based on the measured NMR signals [22], [26], [27]. However, if the magnetic field fluctuates large enough such that the excitation pulses cannot excite the nucleus effectively, those calibration schemes may not work properly.…”