Name: hyperpolarized xenon for nmr and mri applications
Uploaded: 2012-09-06T13:00:00
Description: Watch this Scientific Journal Video about Hyperpolarized Xenon for NMR and MRI Applications at JoVE.com

This research project has received funding from the European Research Council under the European Community's Seventh Framework Programme (FP7/2007-2013) / ERC grant agreement n &deg; 242710 and was additionally supported by the Human Frontier Science Program and the Emmy Noether Program of the German Research Foundation (SCHR 995/2-1).

1. Preparation of the SEOP Setup
Rubidium must be brought into the optical pumping cell, to facilitate the transfer of polarization from the laser light to xenon. Due to its high reactivity this process must occur without the Rb coming into contact with oxygen or water, otherwise it will become oxidized and won't polarize Xe. Extra caution should be taken as Rb reacts violently with water.
<ol>
 <li>If the optical cell has previously been used it will be coated with a layer of Rb and Rb oxid...

<ol>
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Critical aspects in the preparation of hyperpolarized xenon are oxygen impurities in the gas manifold including the pumping cell and sufficient illumination of the cell with circularly polarized light. The above mentioned light bulb test is a simple way to detect deleterious oxygen concentrations while transferring rubidium. The alkali metal might loose its shiny surface by the time the cell is installed in the polarizer. However, sufficient vaporization of non-oxidized Rb can be monitored by reduced laser transmission (...

Hyperpolarized agents are gaining increasing attention for NMR/MRI applications since they can solve the sensitivity problem under certain circumstances 2. Three major approaches are currently used (dynamic nuclear polarization, DNP; para-hydrogen induced polarization, PHIP; and spin exchange optical pumping, SEOP) that all prepare an artificially increased spin population difference outside an NMR magnet prior to the actual spectroscopy or imaging experiment. Here we describe the function and operation of a SEOP setup that has been optimized for production of hyperpolarized129Xe used in solution state experiments.
An essential component is an intense light source emitting infrared photons at 795 nm. Laser diode arrays (LDA) are convenient devices that provide high power output &gt; 100 W at reasonable cost. In many setups, the LDA is emitting into an optical fiber that more or less retains the polarization of the laser light. To guarantee a sufficient SEOP process this elliptical polarization must be converted into circular polarization of high purity. Major components of the polarization optics are shown in Figures 1 and 2 and setting up the system is explained schematically in supplementary movie 1.
To circularly polarize the light we first attach the fiber end to a primary beam expansion optics (e.g., a fiber collimator) for reducing power density. The light then passes through a polarizing beam splitter cube, generating linearly polarized light. By rotating this cube we can determine the preferred axis of the remaining polarization with a power meter. Maximum transmission corresponds to the situation where the fast axis of the cube is aligned with the principal light polarization axis. Cubes with high extinction coefficients (100,000 : 1 or better) yield a good separation of polarization components. This can be tested using a second beam splitter cube as an analyzer that is rotated while the first one is aligned for maximum transmission of the extra-ordinary beam.
Once the linear polarization of the transmitted light has been confirmed, a &lambda;/4 wave plate designed for 795 nm is introduced into the extra-ordinary beam to convert linear into circular polarization. For this purpose, the fast axis of the wave plate is rotated by 45 &deg; relative to the beam splitter cube fast axis. (If desired, circular polarization of the reflected ordinary beam with its linear polarization axis perpendicular to the extra-ordinary beam can be achieved in a similar manner.)
The quality of the circular polarization can be tested with a second beam splitter cube that should yield constant transmission upon rotation. A secondary beam expansion optics (e.g. two lenses in a Galilean telescope configuration) then increases the beam diameter to completely illuminate the glass cell for the pumping process inside an oven box. Absorption of the laser light by Rb vapor in the cell is monitored through a pin hole behind the pumping cell at the end of the box: a collimator collects an attenuated IR beam to be analyzed with an optical spectrometer (see Figure 3 for pumping cell setup).
A heating mechanism outside the pumping cell partially vaporizes a Rb droplet sitting inside the cell (Figure 4a) and therefore causes laser light absorption. Density of the vapor can be adjusted via the heating set point of the respective PID controller. High temperatures (ca. 190 &deg;C) are good for compact setups where the xenon has a limited amount of time to build up polarization. The gas mixture containing Xe, N2 and He flows through the pumping cell opposite to the laser beam direction (Figure 3). An external magnetic field aligned with the laser beam ensures that the IR photons are only pumping one Rb transition. Relaxation of the electron states is fast and must be non-radiative to avoid emission of IR photons with 'wrong' polarization. Here, the N2 comes into play as a quench gas. Eventually, the Rb system builds up an overpopulation of one of the ground state sublevels while the other one is continuously depleted by the laser (Figure 5). Xenon getting in close contact to the Rb atoms experiences spin-spin interactions and the electron spin polarization is transferred onto Xe nuclei in flip-flop processes.
The hyperpolarized gas flowing out of the pumping cell contains trace amounts of Rb vapor that condensate on the tubing wall within a few cm of the outlet due to the low temperature (similar to Figure 4b). In vivo applications, however, would require additional elimination of the alkali metal (e.g. through a cold trap) whereas in vitro experiments can be performed safely with the gas as it leaves the hyperpolarizer. Teflon tubing connects the polarizer outlet with the inlet of a glass apparatus to perform NMR experiments on test solutions. Mass flow controllers are used to adjust the amount of Xe flowing into the NMR setup. They are triggered by commands in the NMR pulse sequence. After checking the achieved polarization enhancement, the gas can be used as an NMR/MRI contrast agent in solution state experiments.
Xe has a certain solubility in water (4.5 mM/atm) and other solvents. It therefore can already serve on its own as a contrast agent to display the distribution of some liquids. However, it is also possible to link the NMR-active nuclei to certain molecules in order to acquire molecular-specific information through the otherwise inert gas. By providing a molecular host for the dissolved Xe, it is possible to confer molecular specificity to the Xe NMR signal. This provides the opportunity to design functionalized contrast agents - also called biosensors - when such a host structure is coupled to a targeting unit that binds to specific analytes of biomedical interest (Figure 6).
Further sensitivity enhancement is required when the biosensor should be detected at concentrations that are low for MR contrast agents (&lt; 100 &mu;M). This can be achieved by chemical exchange saturation transfer (CEST). This method detects the biosensor indirectly by destroying the magnetization of the caged Xe and observing the signal change of free Xe in solution. Since the hyperpolarized nuclei are continuously replaced after some 10 ms, many 100 to 1000 nuclei transfer the information onto the detected pool and amplify the signal ca. 103-fold (see movie 2).

<table border="1">
<tbody>
 <tr>
 <td>Name of the reagent</td>
 <td>Company</td>
 <td>Catalogue number</td>
 <td>Comments (optional)</td>
 </tr>
 <tr>
 <td>Rb ingot</td>
 <td>Sigma-Aldrich</td>
 <td>276332-1G</td>
 <td></td>
 </tr>
 <tr>
 <td>P4O10</td>
 <td>Sigma-Aldrich</td>
 <td>79610-500G</td>
 <td></td>
 </tr>
 <tr>
 <td>Ar</td>
 <td>Praxair</td>
 <td></td>
 <td></td>
 </tr>
 <tr>
 <td>Xe</td>
 <td>Sigma-Aldrich</td>
 <td>00472-1EA</td>
 <td></td>
 </tr>
 <tr>
 <td>O2</td>
 <td>Sigma-Aldrich</td>
 <td>00476-1EA</td>
 <td></td>
 </tr>
 <tr>
 <td>Laser system</td>
 <td>QPC Lasers/Laser Operations</td>
 <td>Brightlock 50</td>
 <td></td>
 </tr>
 <tr>
 <td>Vacuum system</td>
 <td>Pfeiffer</td>
 <td>HiCube</td>
 <td></td>
 </tr>
 <tr>
 <td>Thermocouples</td>
 <td>Newport Omega</td>
 <td>SA2F-KI-3M</td>
 <td></td>
 </tr>
 <tr>
 <td>Silicon heater</td>
 <td>Newport Omega</td>
 <td>FMA5514</td>
 <td></td>
 </tr>
 <tr>
 <td>Pressure transducer</td>
 <td>Newport Omega</td>
 <td>PR 33X-V-10</td>
 <td></td>
 </tr>
 <tr>
 <td>Process meter</td>
 <td>Newport Omega</td>
 <td>INFCP-100B</td>
 <td></td>
 </tr>
 <tr>
 <td>Mass flow controllers</td>
 <td>Newport Omega</td>
 <td>MFC</td>
 <td></td>
 </tr>
 <tr>
 <td>PID regulators</td>
 <td>Newport Omega</td>
 <td>CN7800</td>
 <td></td>
 </tr>
 <tr>
 <td>Control Software</td>
 <td>Newport Omega</td>
 <td>DasyLab</td>
 <td></td>
 </tr>
 <tr>
 <td>Data acquisition</td>
 <td>Newport Omega</td>
 <td>Daqboard 3000</td>
 <td></td>
 </tr>
 <tr>
 <td>Vacuum sensor</td>
 <td>Oerlikon</td>
 <td>TTR91</td>
 <td></td>
 </tr>
 <tr>
 <td>Vacuum controller</td>
 <td>Vacom</td>
 <td>MVC-3</td>
 <td></td>
 </tr>
 <tr>
 <td>Beam collimator</td>
 <td>Thorlabs</td>
 <td>F810SMA-780</td>
 <td></td>
 </tr>
 <tr>
 <td>Polarizing beam splitter cube</td>
 <td>Thorlabs</td>
 <td>GL15-B</td>
 <td></td>
 </tr>
 <tr>
 <td>&lambda;/4 wave plate</td>
 <td>Thorlabs</td>
 <td>WPQ10M-780</td>
 <td></td>
 </tr>
 <tr>
 <td>Beam expansion lenses</td>
 <td>Thorlabs</td>
 <td></td>
 <td></td>
 </tr>
 <tr>
 <td>Optical spectrometer</td>
 <td>Ocean Optics</td>
 <td>HR4000</td>
 <td></td>
 </tr>
 <tr>
 <td>Optical fiber</td>
 <td>Ocean Optics</td>
 <td></td>
 <td></td>
 </tr>
 <tr>
 <td>Low pressure NMR tube</td>
 <td>Wilmad</td>
 <td>513-7LPV-7</td>
 <td></td>
 </tr>
 <tr>
 <td>5mm NMR tube</td>
 <td>Sigma-Aldrich</td>
 <td>HX58.1</td>
 <td></td>
 </tr>
 <tr>
 <td>Helmholtz coils</td>
 <td>Phywe</td>
 <td>06960-00</td>
 <td></td>
 </tr>
 <tr>
 <td>Fused silica capillaries</td>
 <td>Polymicro</td>
 <td>TSG 250350</td>
 <td></td>
 </tr>
 </tbody>
</table>

hyperpolarized xenon for nmr and mri applications

Nuclear magnetic resonance (NMR) spectroscopy and imaging (MRI) suffer from intrinsic low sensitivity because even strong external magnetic fields of ~10 T generate only a small detectable net-magnetization of the sample at room temperature 1. Hence, most NMR and MRI applications rely on the detection of molecules at relative high concentration (e.g., water for imaging of biological tissue) or require excessive acquisition times. This limits our ability to exploit the very useful molecular specificity of NMR signals for many biochemical and medical applications. However, novel approaches have emerged in the past few years: Manipulation of the detected spin species prior to detection inside the NMR/MRI magnet can dramatically increase the magnetization and therefore allows detection of molecules at much lower concentration 2.
Here, we present a method for polarization of a xenon gas mixture (2-5% Xe, 10% N2, He balance) in a compact setup with a ca. 16000-fold signal enhancement. Modern line-narrowed diode lasers allow efficient polarization 7 and immediate use of gas mixture even if the noble gas is not separated from the other components. The SEOP apparatus is explained and determination of the achieved spin polarization is demonstrated for performance control of the method.
The hyperpolarized gas can be used for void space imaging, including gas flow imaging or diffusion studies at the interfaces with other materials 8,9. Moreover, the Xe NMR signal is extremely sensitive to its molecular environment 6. This enables the option to use it as an NMR/MRI contrast agent when dissolved in aqueous solution with functionalized molecular hosts that temporarily trap the gas 10,11. Direct detection and high-sensitivity indirect detection of such constructs is demonstrated in both spectroscopic and imaging mode.

Watch this Scientific Journal Video about Hyperpolarized Xenon for NMR and MRI Applications at JoVE.com

Hyperpolarized Xenon for NMR and MRI Applications

The production of hyperpolarized xenon by means of spin exchange optical pumping (SEOP) is described. This method yields a ~10000-fold enhancement of the nuclear spin polarization of Xe-129 and has applications in nuclear magnetic resonance spectroscopy and imaging. Examples of gas phase and solution state experiments are given.

Nuclear magnetic resonance (NMR) spectroscopy and imaging (MRI) suffer from intrinsic low sensitivity because even strong external magnetic fields of ~10 ...

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