Applying NMR methods to systems in which the spin density is low has been the major challenge precluding its more widespread use in applications on the micro-length scale where sample volumes are in the nanoliter or even picoliter range. In this project, new applications of NMR and MRI are developed for assaying small-volume samples of biological or synthetic origin. A central aspect towards this goal is the use of microcoil NMR, using microfluidics on a chip [1,2]. This approach ultimately aims at integration into a complete microfluidic chip system, where for example on-chip mixing and separation techniques can be applied in combination with magnetic resonance detection.
In itself, microcoil NMR already yields impressive improvements in sensitivity per mass unit for small samples [3,4]. However, in this case the interest is not primarily to record spectra of highly concentrated solutions but also to enable detection of specific molecules at low concentration or imaging with very high resolution. Two parallel approaches to overcome the low sensitivity barriers inherent in NMR have been applied. The first utilizes hyperpolarized xenon gas which can be polarized through an optical pumping scheme to several orders of magnitude above the thermal polarization achievable even with the highest magnetic fields used for NMR spectroscopy. The second approach applies a method developed in the Pines lab to enhance the sensitivity of an NMR or MRI experiment by physically separating the encoding and detection steps in space and time so that each can be separately optimized. In the case of microfluidics this is particularly advantageous in that it allows the very low spin density across the large chip to be concentrated into a very small microcoil with orders of magnitude better sensitivity. In tandem these techniques allow gas flow to be visualized or high resolution spectra to be recorded in a way not possible with direct methods. [5] Furthermore, the approach, because it is based on detection of nuclear spins requires neither optical access to the sample or foreign markers, making it a completely noninvasive method to tag and monitor the processes inside the microfluidic device. Current work is focused on monitoring flow of liquids inside the chip and using the chemical shift of protons in different chemical environments to visualize the dynamics of mixing when two channels of different species converge.
Recent work demonstrated this by monitoring the fluid mixing of different liquids inside a simple T-chip, using the chemical shift of protons in different chemical environments to differentiate each species in a single experiment [6]. This has important implications, for example, in monitoring the kinetics of ligand-protein binding events and fast chemical reactions.
[1] Webb, A.G. (1997) Prog. NMR Spectrosc. 31, 1-42.
[2] Wolters, A.M., Jayawickrama, D.A. and Sweedler, J.V. (2002) Curr. Opin. Chem. Biol. 6, 711-716.
[3] Massin, C., Vincent, F., Homsy, A., Ehrmann, K., Boero, G., Besse, P.A., Daridon, A., Verpoorte, E., de Rooij, N.F. and Popovic, R.S. (2003) J. Magn. Reson. 164, 242-255.
[4] McDonnell, E.E., Han S.I., Hilty C., Pierce K.L., Pines, A. (2005) Anal. Chem., 77, 8109-8114.
[5] Hilty, C., McDonnell, E.E., Granwehr, J., Pierce, K.L., Han, S.I., Pines, A. (2005) PNAS 102, 14960-14963
[6] Harel, E., Hilty, C., Koen, K., McDonnell, E. E., Pines, A., Phys. Rev. Lett. 98, 017601 (2007)