Nicholas Whiting

Near-unity nuclear polarization with an open-source 129Xe hyperpolarizer for NMR and MRI

Significance Lung diseases comprise the third leading cause of death in the United States and could benefit from new imaging modalities. “Hyperpolarized” xenon-129 can overcome the ordinarily weak MRI signals from low-density species in lung space or dissolved in tissue; however, clinical progress has been slowed by the difficulty in preparing large amounts of hyperpolarized xenon with high magnetization, as well as the cost and limited availability of xenon hyperpolarization devices. We describe a unique low-cost “open-source” xenon “hyperpolarizer,” characterize its ability to produce xenon-129 with high magnetization, and demonstrate its utility for human lung imaging. The exquisite NMR spectral sensitivity and negligible reactivity of hyperpolarized xenon-129 (HP129Xe) make it attractive for a number of magnetic resonance applications; moreover, HP129Xe embodies an alternative to rare and nonrenewable 3He. However, the ability to reliably and inexpensively produce large quantities of HP129Xe with sufficiently high 129Xe nuclear spin polarization (PXe) remains a significant challenge—particularly at high Xe densities. We present results from our “open-source” large-scale (∼1 L/h) 129Xe polarizer for clinical, preclinical, and materials NMR and MRI research. Automated and composed mostly of off-the-shelf components, this “hyperpolarizer” is designed to be readily implementable in other laboratories. The device runs with high resonant photon flux (up to 200 W at the Rb D1 line) in the xenon-rich regime (up to 1,800 torr Xe in 500 cc) in either single-batch or stopped-flow mode, negating in part the usual requirement of Xe cryocollection. Excellent agreement is observed among four independent methods used to measure spin polarization. In-cell PXe values of ∼90%, ∼57%, ∼50%, and ∼30% have been measured for Xe loadings of ∼300, ∼500, ∼760, and ∼1,570 torr, respectively. PXe values of ∼41% and ∼28% (with ∼760 and ∼1,545 torr Xe loadings) have been measured after transfer to Tedlar bags and transport to a clinical 3 T scanner for MR imaging, including demonstration of lung MRI with a healthy human subject. Long “in-bag” 129Xe polarization decay times have been measured (T1 ∼38 min and ∼5.9 h at ∼1.5 mT and 3 T, respectively)—more than sufficient for a variety of applications.

Generation of laser-polarized xenon using fiber-coupled laser-diode arrays narrowed with integrated volume holographic gratings

Volume holographic gratings (VHGs) can be exploited to narrow the spectral output of high-power laser-diode arrays (LDAs) by nearly an order of magnitude, permitting more efficient generation of laser-polarized noble gases for various applications. A approximately 3-fold improvement in (129)Xe nuclear spin polarization, P(Xe), (compared to a conventional LDA) was achieved with the VHG-LDAs center wavelength tuned to a wing of the Rb D(1) line. Additionally, an anomalous dependence of P(Xe) on the xenon density within the OP cell is reported-including high P(Xe) values (>10%) at high xenon partial pressures (approximately 1000 torr).

Interdependence of in-cell xenon density and temperature during Rb/129Xe spin-exchange optical pumping using VHG-narrowed laser diode arrays.

The (129)Xe nuclear spin polarization (P(Xe)) that can be achieved via spin-exchange optical pumping (SEOP) is typically limited at high in-cell xenon densities ([Xe](cell)), due primarily to corresponding reductions in the alkali metal electron spin polarization (e.g. P(Rb)) caused by increased non-spin-conserving Rb-Xe collisions. While demonstrating the utility of volume holographic grating (VHG)-narrowed lasers for Rb/(129)Xe SEOP, we recently reported [P. Nikolaou et al., JMR 197 (2009) 249] an anomalous dependence of the observed P(Xe) on the in-cell xenon partial pressure (p(Xe)), wherein P(Xe) values were abnormally low at decreased p(Xe), peaked at moderate p(Xe) (~300 torr), and remained surprisingly elevated at relatively high p(Xe) values (>1000 torr). Using in situ low-field (129)Xe NMR, it is shown that the above effects result from an unexpected, inverse relationship between the xenon partial pressure and the optimal cell temperature (T(OPT)) for Rb/(129)Xe SEOP. This interdependence appears to result directly from changes in the efficiency of one or more components of the Rb/(129)Xe SEOP process, and can be exploited to achieve improved P(Xe) with relatively high xenon densities measured at high field (including averaged P(Xe) values of ~52%, ~31%, ~22%, and ~11% at 50, 300, 500, and 2000 torr, respectively).

Developing hyperpolarized silicon particles for in vivo MRI targeting of ovarian cancer

Abstract. Silicon-based nanoparticles are ideally suited for use as biomedical imaging agents due to their biocompatibility, biodegradability, and simple surface chemistry that facilitates drug loading and targeting. A method of hyperpolarizing silicon particles using dynamic nuclear polarization, which increases magnetic resonance imaging signals by several orders-of-magnitude through enhanced nuclear spin alignment, has recently been developed to allow silicon particles to function as contrast agents for in vivo magnetic resonance imaging. The enhanced spin polarization of silicon lasts significantly longer than other hyperpolarized agents (tens of minutes, whereas <1  min for other species at room temperature), allowing a wide range of potential applications. We report our recent characterizations of hyperpolarized silicon particles, with the ultimate goal of targeted, noninvasive, and nonradioactive molecular imaging of various cancer systems. A variety of particle sizes (20 nm to 2  μm) were found to have hyperpolarized relaxation times ranging from ∼10 to 50 min. The addition of various functional groups to the particle surface had no effect on the hyperpolarization buildup or decay rates and allowed in vivo imaging over long time scales. Additional in vivo studies examined a variety of particle administration routes in mice, including intraperitoneal injection, rectal enema, and oral gavage.

Real-Time MRI-Guided Catheter Tracking Using Hyperpolarized Silicon Particles

Visualizing the movement of angiocatheters during endovascular interventions is typically accomplished using x-ray fluoroscopy. There are many potential advantages to developing magnetic resonance imaging-based approaches that will allow three-dimensional imaging of the tissue/vasculature interface while monitoring other physiologically-relevant criteria, without exposing the patient or clinician team to ionizing radiation. Here we introduce a proof-of-concept development of a magnetic resonance imaging-guided catheter tracking method that utilizes hyperpolarized silicon particles. The increased signal of the silicon particles is generated via low-temperature, solid-state dynamic nuclear polarization, and the particles retain their enhanced signal for ≥40 minutes—allowing imaging experiments over extended time durations. The particles are affixed to the tip of standard medical-grade catheters and are used to track passage under set distal and temporal points in phantoms and live mouse models. With continued development, this method has the potential to supplement x-ray fluoroscopy and other MRI-guided catheter tracking methods as a zero-background, positive contrast agent that does not require ionizing radiation.

Hyperpolarized Porous Silicon Nanoparticles: Potential Theragnostic Material for 29Si Magnetic Resonance Imaging

Porous silicon nanoparticles have recently garnered attention as potentially-promising biomedical platforms for drug delivery and medical diagnostics. Here, we demonstrate porous silicon nanoparticles as contrast agents for 29 Si magnetic resonance imaging. Size-controlled porous silicon nanoparticles were synthesized by magnesiothermic reduction of silica nanoparticles and were surface activated for further functionalization. Particles were hyperpolarized via dynamic nuclear polarization to enhance their 29 Si MR signals; the particles demonstrated long 29 Si spin-lattice relaxation (T1 ) times (∼25 mins), which suggests potential applicability for medical imaging. Furthermore, 29 Si hyperpolarization levels were sufficient to allow 29 Si MRI in phantoms. These results underscore the potential of porous silicon nanoparticles that, when combined with hyperpolarized magnetic resonance imaging, can be a powerful theragnostic deep tissue imaging platform to interrogate various biomolecular processes in vivo.

Using Raman Spectroscopy to Improve Hyperpolarized Noble Gas Production for Clinical Lung Imaging Techniques

Spin-exchange optical pumping (SEOP) can be used to “hyperpolarize” Xe for human lung MRI. SEOP involves transfer of angular momentum from light to an alkali metal (Rb) vapor, and then onto Xe nuclear spins during collisions; collisions between excited Rb and N2 ensure that incident optical energy is nonradiatively converted into heat. However, because variables that govern SEOP are temperature-dependent, the excess heat can complicate efforts to maximize spin polarization—particularly at high laser fluxes and xenon densities. Ultra-low frequency Raman spectroscopy may be used to perform in situ gas temperature measurements to investigate the interplay of energy thermalization and SEOP dynamics. Experimental configurations include an “orthogonal” pump-and-probe design and a newer “inline” design (with source and detector on the same axis) that has provided a >20-fold improvement in SNR. The relationship between Xe polarization and the spatiotemporal distribution of N2 rotational temperatures has been investigated as a function of incident laser flux, exterior cell temperature, and gas composition. Significantly elevated gas temperatures have been observed —hundreds of degrees hotter than exterior cell surfaces—and variances with position and time can indicate underlying energy transport, convection, and Rb mass-transport processes that, if not controlled, can negatively impact Xe hyperpolarization.