Scalable NMR spectroscopy with semiconductor chips

1 Scalable NMR spectroscopy with semiconductor chipsDongwan Haa, Jeffrey Paulsenb, Nan Sunc, Yi-Qiao Songb, and Donhee Hama,1aSchool of Engineering and Applied Sciences,Harvard University, Cambridge, MA 02138;bSchlumberger-Doll Research Center, Cambridge, MA 02139;andcElectrical and Computer Engineering, The University of Texas at Austin, Austin, TX 78712 Edited by Adriaan Bax, National Institutes of Health, Bethesda, MD, and approved July 8, 2014 (received for review February 1, 2014)State-of-the-art NMR spectrometers using superconducting magnetshave enabled, with their ultrafine spectral resolution, the determi-nation of the structure of large molecules such as proteins, which isone of the most profound applications of modern NMR spectros-copy. Many chemical and biotechnological applications, however,involve only small-to-medium size molecules, for which the ultrafineresolution of the bulky, expensive, and high-maintenance NMRspectrometers is not required.

2 For these applications, there is acritical need for portable, affordable, and low-maintenance NMRspectrometers to enable in-field, on-demand, or online applications( , quality control, chemical reaction monitoring) and co-use ofNMR with other analytical methods ( , chromatography, electro-phoresis). As a critical step toward NMR spectrometer miniaturiza-tion, small permanent magnets with high field homogeneity havebeen developed. In contrast, NMR spectrometer electronics capableof modern multidimensional spectroscopy have thus far remainedbulky. Complementing the magnet miniaturization, here we in-tegrate the NMR spectrometer electronics into 4-mm2silicon , we perform various multidimensional NMR spectros-copies by operating these spectrometer electronics chips togetherwith a compact permanent magnet. This combination of the spec-trometer-electronics-on-a- chip with a permanent magnet representsa useful step toward miniaturization of the overall NMR spectrom-eter into a portable spectroscopy has been celebrated for its ability to probemolecular structures and dynamics with the atomic resolu-tion (1 9).

3 State-of-the-art NMR spectrometers use large super-conducting magnets, whose high and uniform magnetic fields leadto the fine spectral resolution necessary for interrogating largemolecules such as proteins. In fact, the structural study of largemolecules is one of the most profound applications of modernNMR , the spectral resolution of the bulky, expensive, andhigh-maintenance NMR spectrometers is not necessary for abroad array of studies involving small-to-medium size moleculesin chemistry, chemical engineering, and biotechnology (10, 11).In this case, portable, affordable, and low-maintenance NMRspectrometers built with a permanent magnet can make thebenefits of NMR spectroscopy more broadly available and en-able new applications. Bulky superconducting systems have to bepermanently placed in dedicated laboratories, but portable sys-tems can enable in-field, on-demand, or online applications suchas quality control and chemical reaction monitoring (4), and cangreatly facilitate co-use of NMR spectroscopy with other ana-lytical methods such as liquid chromatography (12) and capillaryelectrophoresis (13).

4 Thus, much effort has been devoted tominiaturizing NMR spectrometers, leading to the critical de-velopment of small permanent magnets with high field homo-geneity (10, 14, 15).Complementing this advance in magnet miniaturization, here weintegrate the spectrometer electronics which is another essential,and traditionally bulky, component of the NMR spectrometer into a 4-mm2silicon chip (Fig. 1). Moreover, to demonstrate theoverall system miniaturization for portability, we operate thesechips with a compact permanent magnet (Fig. 1), per-forming various two-dimensional (2D) spectroscopies correlationspectroscopy (COSY),J-resolved spectroscopy , and heteronuclearsingle/multiple-quantum coherence (HSQC/HMQC) spectroscopy as well as one-dimensional (1D) spectroscopy and organic, biological, and drug compound molecules areused as demonstrational semiconductor technology and NMR science haveremained largely orthogonal, a few foundational works reportedsilicon chips realizing some aspects of NMR electronics beforethe present study (16 20).

5 Despite the vision and tour de forcedesign, however, none of these earlier chips explored modernmultidimensional spectroscopy . In refs. 16, 17, the chip designfocus was not on spectroscopy , but on relaxometry, with a dedi-cated integrated Carr Purcell Meiboom Gill (CPMG) pulsesequencer to achieve overall relaxometry system miniaturizationwith permanent magnets. The chips in refs. 18 20 performedspectroscopy but limited to 1D and with external pulse sequencers(and with external transmitters in refs. 18, 19), and they wereoperated with superconducting magnets, and thus were far fromportable. Significantly building upon these prior works, we in-tegrate at a large scale a radio-frequency (RF) transmitter, an RFreceiver, and an arbitrary pulse sequencer into our spectrometerelectronics chip so that it can perform a far more diverse set ofNMR experiments, including 2D spectroscopy , in an integratedmanner.

6 In addition, our overall system is the first portable NMRspectroscopy platform to our knowledge that combines permanentmagnets and spectrometer electronics chips . In view of this, thepresent work is a step forward in utilizing semiconductor tech-nology for portable NMR addition to these main contributions, our portable systemincorporates two other features to cope with ambient temperaturevariations, which are relevant to portable applications. First, thespectrometer electronics chips are designed to operate over a widetemperature range (room temperature to 165 C). Second, a signal-processing method based on statistical estimation/inference whichSignificanceThe strong application-driven need for portable NMR spec-trometers has led to development of spectroscopy -grade per-manent magnets. In contrast, NMR spectrometer electronicscapable of modern multidimensional spectroscopy remain , we report on 4-mm2silicon spectrometer electronics chips ,and perform various multidimensional NMR spectroscopies byusing these chips with a permanent magnet.

7 This combination ofsemiconductor technology and advanced permanent magnettechnology is a step toward portable NMR spectrometers, whichcan enable in-field, on-demand, or online applications and fa-cilitate co-use of NMR with other analytical methods. Besides theportable application, the spectrometer electronics chips withtheir cost/size economy can improve other NMR technologies whether with permanent or superconducting magnet such asmulti-channel spectroscopy , phased-array imaging, microfluidicmicroscopy, and parallel, high-throughput contributions: D. Ha, , and D. Ham designed research; D. Ha, , , ,and D. Ham performed research; D. Ha, , , , and D. Ham analyzed data; D. Hadesigned integrated circuits; D. Ham oversaw research; and D. Ha and D. Ham wrotethe authors declare no conflict of article is a PNAS Direct whom correspondence should be addressed. Email: article contains supporting information online |August 19, 2014|vol.

8 111|no. 33|11955 11960 CHEMISTRYD ownloaded by guest on August 12, 2021 does not require isolated reference peaks as in the referencedeconvolution technique (21) calibrates out the effect of thepermanent magnet s field drift caused by environmental tem-perature fluctuations. This software-domain method, as an ad-dition to the arsenal of various magnetic field fluctuationcalibration techniques, may help reduce the need for physicalthermal regulation that adds power consumption and extrahardware, the avoidance of which, if possible, is desired forportable and spectroscopy experiments in this work (seeFigs. 3 6) use a solenoidal coil (axial length: 1 mm) around acapillary sample tube ( : 1 mm) with an effective sample volumeof L, and a compact NdFeB permanent magnet witha field inhomogeneity achieved with a six-directionelectrical shimming (Materials and Methods).

9 The inductanceLcand resistanceRcof the coil are 173 nH and , Larmor frequency,f0, is MHz with the magnet, andthe quality factor of the coil atf0isQ=2 f0Lc/Rc Spectrometer Electronics integrated spectrometerelectronics chip consists of three main parts, an RF receiver, anRF transmitter, and an arbitrary pulse sequencer (Fig. 2). TheRF receiver amplifies the voltage signal across the coil inducedby nuclear spin precessions using a front-end low-noise amplifier(SI Appendix, section S1), and down converts the amplified signalinto two phase-sensitive audio-frequency signals using mixersdriven by quadrature local oscillators. Spectral information isextracted by taking the Fourier transform of these audio-fre-quency signals. The overall receiver voltage gain is tunable from34 to 100 the inherently weak spin precession signal is furtherreduced to 1 V in our case due to the small sample and lowmagnetic field, maximizing receiver sensitivity , minimizingthe degradation of the signal-to-noise ratio (SNR) by receivernoise is a critical task.

10 First, we minimize the input-referrednoise of the receiver to a measured value ofNr2= (nV)2/Hzat 300 K (Fig. 2 BandSI Appendix, section S1), which translatesto an effective noise resistance ofRr= . However, this stepalone, albeit crucial, is not sufficient, because the source noiseNc2= (nV)2/Hz inside the coil due toRc= is still farsmaller thanNr2and thus, the SNR would be greatly degraded bythe dominant receiver noise. Hence our second step is to add anoff- chip tuning capacitorCcin parallel to the coil so thatLcandCcresonate atf0(Fig. 2); the resonator quality factor is stillQ= , as the capacitor loss is negligible. Due to this resonance, theeffective coil voltage (for both noise and signal) seen by the receiverat frequencyf0is approximatelyQtimeslargerthantheactualvo ltage inside the coil; thus the effective coil noise,Q2Nc2,is 18times larger than the receiver noise,Nr2(or, the effective coil noiseresistanceQ2Rc=744 is 18timeslargerthanRr= ).