Obtaining High-Quality Hyperpolarized Xenon-129 Magnetic Resonance Images

<ol>
	<li>Pellegrino, R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Interpretative+strategies+for+lung+function+tests.">Interpretative strategies for lung function tests.</a> European Respiratory Journal. 26 (5), 948-968 (2005).</li><li>Ebner, L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Hyperpolarized+129Xenon+MRI+to+quantify+regional+ventilation+differences+in+mild+to+moderate+asthma:+A+prospective+comparison+between+semi-automated+ventilation+defect+percentage+calculation+and+pulmonary+function+tests.">Hyperpolarized 129Xenon MRI to quantify regional ventilation differences in mild to moderate asthma: A prospective comparison between semi-automated ventilation defect percentage calculation and pulmonary function tests.</a> Investigative Radiology. 52 (2), 120-127 (2017).</li><li>Abuelhia, E., Alghamdi, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Evaluation+of+arising+exposure+of+ionizing+radiation+from+computed+tomography+and+the+associated+health+concerns.">Evaluation of arising exposure of ionizing radiation from computed tomography and the associated health concerns.</a> Journal of Radiation Research and Applied Sciences. 13 (1), 295-300 (2020).</li><li>Kern, A. L., Vogel-Claussen, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Hyperpolarized+gas+MRI+in+pulmonology.">Hyperpolarized gas MRI in pulmonology.</a> The British Journal of Radiology. 91 (1084), 20170647 (2018).</li><li>M&#246;ller, H. E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=MRI+of+the+lungs+using+hyperpolarized+noble+gases.">MRI of the lungs using hyperpolarized noble gases.</a> Magnetic Resonance in Medicine. 47 (6), 1029-1051 (2002).</li><li>Salerno, M., Altes, T. A., Mugler, J. P., Nakatsu, M., Hatabu, H., de Lange, E. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Hyperpolarized+noble+gas+MR+imaging+of+the+lung:+Potential+clinical+applications.">Hyperpolarized noble gas MR imaging of the lung: Potential clinical applications.</a> European Journal of Radiology. 40 (1), 33-44 (2001).</li><li>. New Drug Therapy Approvals at 2022 Available from: <a target="_blank" href="https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/new-drug-therapy-approvals-2022">https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/new-drug-therapy-approvals-2022</a> (2023)</li><li>Nikolaou, P., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Near-unity+nuclear+polarization+with+an+open-source+129Xe+hyperpolarizer+for+NMR+and+MRI.">Near-unity nuclear polarization with an open-source 129Xe hyperpolarizer for NMR and MRI.</a> Proceedings of the National Academy of Sciences. 110 (35), 14150-14155 (2013).</li><li>Birchall, J. R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=XeUS:+A+second-generation+automated+open-source+batch-mode+clinical-scale+hyperpolarizer.">XeUS: A second-generation automated open-source batch-mode clinical-scale hyperpolarizer.</a> Journal of Magnetic Resonance. 319, 106813 (2020).</li><li>He, M., Zha, W., Tan, F., Rankine, L., Fain, S., Driehuys, B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+comparison+of+two+hyperpolarized+129Xe+MRI+ventilation+quantification+pipelines:+The+effect+of+signal+to+noise+ratio.">A comparison of two hyperpolarized 129Xe MRI ventilation quantification pipelines: The effect of signal to noise ratio.</a> Academic Radiology. 26 (7), 949-959 (2019).</li><li>Niedbalski, P. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Protocols+for+multi-site+trials+using+hyperpolarized+129+Xe+MRI+for+imaging+of+ventilation,+alveolar-airspace+size,+and+gas+exchange:+A+position+paper+from+the+129+Xe+MRI+clinical+trials+consortium.">Protocols for multi-site trials using hyperpolarized 129 Xe MRI for imaging of ventilation, alveolar-airspace size, and gas exchange: A position paper from the 129 Xe MRI clinical trials consortium.</a> Magnetic Resonance in Medicine. 86 (6), 2966-2986 (2021).</li><li>M&#246;ller, H. E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=MRI+of+the+lungs+using+hyperpolarized+noble+gases.">MRI of the lungs using hyperpolarized noble gases.</a> Magnetic Resonance in Medicine. 47 (6), 1029-1051 (2002).</li><li>Bier, E. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+thermally+polarized+129Xe+phantom+for+quality+assurance+in+multi-center+hyperpolarized+gas+MRI+studies.">A thermally polarized 129Xe phantom for quality assurance in multi-center hyperpolarized gas MRI studies.</a> Magnetic Resonance in Medicine. 82 (5), 1961-1968 (2019).</li><li>Wild, J. M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Comparison+between+2D+and+3D+gradient-echo+sequences+for+MRI+of+human+lung+ventilation+with+hyperpolarized+3He.">Comparison between 2D and 3D gradient-echo sequences for MRI of human lung ventilation with hyperpolarized 3He.</a> Magnetic Resonance in Medicine. 52 (3), 673-678 (2004).</li><li>Garrison, W. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Lung+volume+dependence+and+repeatability+of+hyperpolarized+129Xe+MRI+gas+uptake+metrics+in+healthy+volunteers+and+participants+with+COPD.">Lung volume dependence and repeatability of hyperpolarized 129Xe MRI gas uptake metrics in healthy volunteers and participants with COPD.</a> Radiology: Cardiothoracic Imaging. 5 (3), e220096 (2023).</li><li>Ni, W., Qi, J., Liu, L., Li, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+pulse+signal+preprocessing+method+based+on+the+Chauvenet+criterion.">A pulse signal preprocessing method based on the Chauvenet criterion.</a> Computational and Mathematical Methods in Medicine. 2019, 2067196 (2019).</li><li>. Available from: <a target="_blank" href="https://www.129xectc.org">https://www.129xectc.org</a> (2023)</li></ol>

Robert Thomen has provided consulting to Polarean, LLC.

The ability to troubleshoot 129Xe MRI issues is a necessary skill and may help mitigate problems in real time. Until a hyperpolarized gas infrastructure can be purchased from a single party and garner support from scanner manufacturers, these quality control tasks are the sole responsibility of the individual laboratories. The goal of this manuscript is to provide the reader with helpful practices and suggestions for the inevitable event of poor data acquisition. While we attempt to address as many potential i...

For over a century, lung function assessment has primarily relied on global measurements from spirometry and body plethysmography. However, these traditional pulmonary function tests (PFTs) are limited in their ability to capture early-stage disease&#39;s regional nuances and subtle changes in lung tissue1. Nuclear medicine with inhaled radiotracers has been used widely for the assessment of ventilation/perfusion mismatches commonly associated with pulmonary emboli, but this involves ionizing radiation and yields lower resolution. In contrast, computed tomography (CT) has emerged as the gold standard for lung imaging, offering exceptional spatial and temporal clarity compared to nuclear imaging2. While low-dose CT scans can mitigate radiation exposure, potential radiation risk should still be considered3,4. Proton MRI of the lung is uncommon due to low tissue density of the lung and rapid signal decay from lung tissue, although recent advances offer functional information despite potential low signal. On the other hand, hyperpolarized xenon magnetic resonance imaging (HP 129Xe MRI) is a non-invasive modality that allows for imaging of lung function with regional specificity5,6. It produces a high nonequilibrium nuclear magnetization of the gas in liter quantities. The inert gas is then inhaled by a subject inside the MR scanner for a single breath and is directly imaged by the scanner. Thus, the inhaled gas is directly imaged as opposed to the tissue itself. This technique has been used to assess lung ventilation across many diseases, including asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, idiopathic pulmonary fibrosis, coronavirus disease 2019 (COVID-19), and many others3. In December 2022, HP 129Xe MRI was approved by the United States FDA as an MRI ventilation contrast agent to be used in the United States of America (USA) in adults and pediatric patients aged 12 years and older7. Physicians can now use 129Xe MRI to better care for patients with improved/personalized treatment plans.
Historically, clinical MRI focuses exclusively on imaging hydrogen nuclei (protons) which are abundant in nearly all human viscera. The MRI scanners, sequences, and quality control are generally maintained by the scanner manufacturer as part of the site license and warranty. However, 129Xe requires a multinuclear capable MR scanner and has required a dedicated research team to operationalize the hyperpolarizer, custom-built radiofrequency (RF) coils, dedicated pulse sequences, and offline reconstruction/analysis software. Each of these components can be supplied by third-party vendors or developed in-house. Thus, the burden of quality control generally rests on the 129Xe research team as opposed to the scanner manufacturer or individual third party. Consistent acquisition of high-quality 129Xe data is therefore uniquely challenging as each component of the 129Xe MRI process introduces the potential for error, which must be closely monitored by the 129Xe team. Not only can these situations be extremely frustrating as researchers have to troubleshoot and investigate possible causes for any challenges that may have arisen, but they can be very costly as this slows down patient imaging and subject recruitment. Some costs associated with troubleshooting involve MRI time costs, the hyperpolarization of 129Xe, which involves the consumption of different gases, and the use of materials. Additionally, with the recent FDA approval and growth in 129Xe imaging, providing a standardized protocol for quality control is necessary to avoid common issues and setbacks in 129Xe operation8,9.
Here, we present some of the more commonly encountered issues in 129Xe MRI, including RF coil failures, the emergence of various noise profiles that lead to low signal-to-noise ratio (SNR), and poor quality images10. We aim to provide some concise quality control (QC) guidelines and protocols to ensure the acquisition of high-quality image data and troubleshoot some of the more common issues that can arise in 129Xe MRI. The insights provided here are also relevant for hyperpolarized helium-3 troubleshooting.

<table><tbody><tr><td>Polarization measurement station&amp;nbsp;</td><td>Polerean</td><td>42881</td><td>https://polarean.com/</td></tr><tr><td>Pressure vessele with plunger valve</td><td>Ace glass</td><td>8648-85</td><td>https://www.aceglass.com/html/3dissues/Pressure_Vessels/offline/download.pdf</td></tr><tr><td>Tedlar bag</td><td>Jensen inert</td><td>GST381S-0707TJO&amp;nbsp;&amp;nbsp;</td><td>http://www.jenseninert.com/</td></tr><tr><td>Xenon Hyperpolarizer 9820</td><td>Polerean</td><td>49820</td><td>https://polarean.com/</td></tr><tr><td>Xenon loop coil</td><td>Clinical MR Solutions</td><td>Custom device</td><td>https://www.sbir.gov/sbc/clinical-mr-solutions-llc</td></tr><tr><td>Xenon vest coil</td><td>Clinical MR Solutions</td><td>Custom device</td><td>https://www.sbir.gov/sbc/clinical-mr-solutions-llc</td></tr></tbody></table>

troubleshooting and quality assurance in hyperpolarized xenon magnetic resonance imaging: tools for high-quality image acquisition

Hyperpolarized (HP) xenon magnetic resonance imaging (129Xe MRI) is a recently federal drug administration (FDA)-approved imaging modality that produces high-resolution images of an inhaled breath of xenon gas for investigation of lung function. However, implementing 129Xe MRI is uniquely challenging as it requires specialized hardware and equipment for hyperpolarization, procurement of xenon imaging coils and coil software, development and compilation of multinuclear MR imaging sequences, and reconstruction/analysis of acquired data. Without proper expertise, these tasks can be daunting, and failure to acquire high-quality images can be&#160;frustrating, and expensive. Here, we present some quality control (QC) protocols, troubleshooting practices, and helpful tools for129Xe MRI sites, which may aid in the acquisition of optimized, high-quality data and accurate results. The discussion will begin with an overview of the process for implementing HP 129Xe MRI, including requirements for a hyperpolarizer lab, the combination of 129Xe MRI coil hardware/software, data acquisition and sequence considerations, data structures, k-space and image properties, and measured signal and noise characteristics. Within each of these necessary steps lies opportunities for errors, challenges, and unfavorable occurrences leading to poor image quality or failed imaging, and this presentation aims to address some of the more commonly encountered issues. In particular, identification and characterization of anomalous noise patterns in acquired data are necessary to avoid image artifacts and low-quality images; examples will be given, and mitigation strategies will be discussed. We aim to make the 129Xe MRI implementation process easier for new sites while providing some guidelines and strategies for real-time troubleshooting.

Figure 4&#160;depicts the results of the noise characterization analysis performed on the noise scan. The plot demonstrates the impact of both regular and irregular noise on the k-space, where the deviation from the ideal y=x reference line is observed. Regular noise leads to a continuous pattern in the k-space, while irregular noise results in high-value outliers in the QQ plot.
Moving on to Figure 5, a series of lung images acquired...

Watch this Scientific Journal Video about Using Hyperpolarized Xenon-129 MRI to Study Lung Diseases at JoVE.com

Author Spotlight: Using Hyperpolarized Xenon-129 MRI to Study Lung Diseases 

Here, we present a protocol for obtaining high-quality hyperpolarized xenon-129 magnetic resonance images, covering hardware, software, data acquisition, sequence selection, data management, k-space utilization, and noise analysis.

Troubleshooting and Quality Assurance in Hyperpolarized Xenon Magnetic Resonance Imaging: Tools for High-Quality Image Acquisition

Hyperpolarized (HP) xenon magnetic resonance imaging (129Xe MRI) is a recently federal drug administration (FDA)-approved imaging modality that produces ...

troubleshooting-quality-assurance-hyperpolarized-xenon-magnetic

Research

JoVE Journal

Bioengineering

1.1K Views.  University of Missouri. Here, we present a protocol for obtaining high-quality hyperpolarized xenon-129 magnetic resonance images, covering hardware, software, data acquisition, sequence selection, data management, k-space utilization, and noise analysis.

Video: Author Spotlight: Using Hyperpolarized Xenon-129 MRI to Study Lung Diseases 

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.

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 ...

Engineering

Visualizing Proteins and Macromolecular Complexes by Negative Stain EM: from Grid Preparation to Image Acquisition

Single particle electron microscopy (EM), of both negative stained or frozen hydrated biological samples, has become a versatile tool in structural biology 1. In recent years, this method has achieved great success in studying structures of proteins and macromolecular complexes 2, 3. Compared with electron cryomicroscopy (cryoEM), in which frozen hydrated protein samples are embedded in a thin layer of vitreous ice 4, negative staining is a simpler sample preparation method in which protein samples are embedded in a thin layer of dried heavy metal salt to increase specimen contrast 5. The enhanced contrast of negative stain EM allows examination of relatively small biological samples. In addition to determining three-dimensional (3D) structure of purified proteins or protein complexes 6, this method can be used for much broader purposes. For example, negative stain EM can be easily used to visualize purified protein samples, obtaining information such as homogeneity/heterogeneity of the sample, formation of protein complexes or large assemblies, or simply to evaluate the quality of a protein preparation.
In this video article, we present a complete protocol for using an EM to observe negatively stained protein sample, from preparing carbon coated grids for negative stain EM to acquiring images of negatively stained sample in an electron microscope operated at 120kV accelerating voltage. These protocols have been used in our laboratory routinely and can be easily followed by novice users.

Visualizing protein samples by negative stain electron microscopy (EM) has become a popular structural analysis method. It is useful for quantitative structural analysis, such as calculating a 3D reconstruction of the molecules being studied, and also for qualitative examination of the quality of protein preparations. In this article we present detailed protocols for preparing the EM grids, staining the sample and visualizing the sample in an electron microscope. Novice users can follow these protocols easily and to utilize negative stain EM as a routine assay, in addition to other biochemical assays, for evaluating their protein samples.

Single particle electron microscopy (EM), of both negative stained or frozen hydrated biological samples, has become a versatile tool in structural ...

Magnetic Resonance Elastography Methodology for the Evaluation of Tissue Engineered Construct Growth

Traditional mechanical testing often results in the destruction of the sample, and in the case of long term tissue engineered construct studies, the use of destructive assessment is not acceptable. A proposed alternative is the use of an imaging process called magnetic resonance elastography. Elastography is a nondestructive method for determining the engineered outcome by measuring local mechanical property values (i.e., complex shear modulus), which are essential markers for identifying the structure and functionality of a tissue. As a noninvasive means for evaluation, the monitoring of engineered constructs with imaging modalities such as magnetic resonance imaging (MRI) has seen increasing interest in the past decade1. For example, the magnetic resonance (MR) techniques of diffusion and relaxometry have been able to characterize the changes in chemical and physical properties during engineered tissue development2. The method proposed in the following protocol uses microscopic magnetic resonance elastography (&mu;MRE) as a noninvasive MR based technique for measuring the mechanical properties of small soft tissues3. MRE is achieved by coupling a sonic mechanical actuator with the tissue of interest and recording the shear wave propagation with an MR scanner4. Recently, &mu;MRE has been applied in tissue engineering to acquire essential growth information that is traditionally measured using destructive mechanical macroscopic techniques5. In the following procedure, elastography is achieved through the imaging of engineered constructs with a modified Hahn spin-echo sequence coupled with a mechanical actuator. As shown in Figure 1, the modified sequence synchronizes image acquisition with the transmission of external shear waves; subsequently, the motion is sensitized through the use of oscillating bipolar pairs. Following collection of images with positive and negative motion sensitization, complex division of the data produce a shear wave image. Then, the image is assessed using an inversion algorithm to generate a shear stiffness map6. The resulting measurements at each voxel have been shown to strongly correlate (R2&gt;0.9914) with data collected using dynamic mechanical analysis7. In this study, elastography is integrated into the tissue development process for monitoring human mesenchymal stem cell (hMSC) differentiation into adipogenic and osteogenic constructs as shown in Figure 2.

The procedure demonstrates the methodology of magnetic resonance elastography for monitoring the engineered outcome of adipose and osteogenic tissue engineered constructs through noninvasive local assessment of the mechanical properties using microscopic magnetic resonance elastography (&mu;MRE).

Traditional mechanical testing often results in the destruction of the sample, and in the case of long term tissue engineered construct studies, the use ...

Magnetically-Assisted Remote Controlled Microcatheter Tip Deflection under Magnetic Resonance Imaging

X-ray fluoroscopy-guided endovascular procedures have several significant limitations, including difficult catheter navigation and use of ionizing radiation, which can potentially be overcome using a magnetically steerable catheter under MR guidance.
	The main goal of this work is to develop a microcatheter whose tip can be remotely controlled using the magnetic field of the MR scanner. This protocol aims to describe the procedures for applying current to the microcoil-tipped microcatheter to produce consistent and controllable deflections.
	A microcoil was fabricated using laser lathe lithography onto a polyimide-tipped endovascular catheter. In vitro testing was performed in a waterbath and vessel phantom under the guidance of a 1.5-T MR system using steady-state free precession (SSFP) sequencing. Various amounts of current were applied to the coils of the microcatheter to produce measureable tip deflections and navigate in vascular phantoms.
	The development of this device provides a platform for future testing and opportunity to revolutionize the endovascular interventional MRI environment.

Current applied to an endovascular microcatheter with microcoil tip made by laser lathe lithography can achieve controllable deflections under magnetic resonance (MR) guidance, which may improve speed and efficacy of navigation of vasculature during various endovascular procedures.

X-ray fluoroscopy-guided  endovascular procedures have several significant limitations, including  difficult catheter navigation and use of ionizing ...

Construction of a Preclinical Multimodality Phantom Using Tissue-mimicking Materials for Quality Assurance in Tumor Size Measurement

World Health Organization (WHO) and the Response Evaluation Criteria in Solid Tumors (RECIST) working groups advocated standardized criteria for radiologic assessment of solid tumors in response to anti-tumor drug therapy in the 1980s and 1990s, respectively. WHO criteria measure solid tumors in two-dimensions, whereas RECIST measurements use only one-dimension which is considered to be more reproducible 1, 2, 3,4,5. These criteria have been widely used as the only imaging biomarker approved by the United States Food and Drug Administration (FDA) 6. In order to measure tumor response to anti-tumor drugs on images with accuracy, therefore, a robust quality assurance (QA) procedures and corresponding QA phantom are needed.
To address this need, the authors constructed a preclinical multimodality (for ultrasound (US), computed tomography (CT) and magnetic resonance imaging (MRI)) phantom using tissue-mimicking (TM) materials based on the limited number of target lesions required by RECIST by revising a Gammex US commercial phantom 7. The Appendix in Lee et al. demonstrates the procedures of phantom fabrication 7. In this article, all protocols are introduced in a step-by-step fashion beginning with procedures for preparing the silicone molds for casting tumor-simulating test objects in the phantom, followed by preparation of TM materials for multimodality imaging, and finally construction of the preclinical multimodality QA phantom. The primary purpose of this paper is to provide the protocols to allow anyone interested in independently constructing a phantom for their own projects. QA procedures for tumor size measurement, and RECIST, WHO and volume measurement results of test objects made at multiple institutions using this QA phantom are shown in detail in Lee et al. 8.

This paper describes in-house procedures of constructing a preclinical multimodality phantom made of tissue-mimicking (TM) materials for quality assurance (QA) of tumor size measurement in animal imaging modalities such as ultrasound (US), computed tomography (CT) and magnetic resonance imaging (MRI).

World Health Organization (WHO) and the Response Evaluation Criteria in Solid Tumors (RECIST) working groups advocated standardized criteria for ...

Hybrid &#181;CT-FMT imaging and image analysis

Fluorescence-mediated tomography (FMT) enables longitudinal and quantitative determination of the fluorescence distribution in vivo and can be used to assess the biodistribution of novel probes and to assess disease progression using established molecular probes or reporter genes. The combination with an anatomical modality, e.g., micro computed tomography (&#181;CT), is beneficial for image analysis and for fluorescence reconstruction. We describe a protocol for multimodal &#181;CT-FMT imaging including the image processing steps necessary to extract quantitative measurements. After preparing the mice and performing the imaging, the multimodal data sets are registered. Subsequently, an improved fluorescence reconstruction is performed, which takes into account the shape of the mouse. For quantitative analysis, organ segmentations are generated based on the anatomical data using our interactive segmentation tool. Finally, the biodistribution curves are generated using a batch-processing feature. We show the applicability of the method by assessing the biodistribution of a well-known probe that binds to bones and joints.

Hybrid  &#181;CT-FMT imaging and image analysis

We describe a protocol for hybrid imaging, combining fluorescence-mediated tomography (FMT) with micro computed tomography (&#181;CT). After fusion and reconstruction, we perform interactive organ segmentation to extract quantitative measurements of the fluorescence distribution.

Fluorescence-mediated tomography (FMT) enables longitudinal and quantitative determination of the fluorescence distribution in vivo and can be used to ...

Custom-designed Laser-based Heating Apparatus for Triggered Release of Cisplatin from Thermosensitive Liposomes with Magnetic Resonance Image Guidance

Liposomes have been employed as drug delivery systems to target solid tumors through exploitation of the enhanced permeability and retention (EPR) effect resulting in significant reductions in systemic toxicity. Nonetheless, insufficient release of encapsulated drug from liposomes has limited their clinical efficacy. Temperature-sensitive liposomes have been engineered to provide site-specific release of drug in order to overcome the problem of limited tumor drug bioavailability. Our lab has designed and developed a heat-activated thermosensitive liposome formulation of cisplatin (CDDP), known as HTLC, to provide triggered release of CDDP at solid tumors. Heat-activated delivery in vivo was achieved in murine models using a custom-built laser-based heating apparatus that provides a conformal heating pattern at the tumor site as confirmed by MR thermometry (MRT). A fiber optic temperature monitoring device was used to measure the temperature in real-time during the entire heating period with online adjustment of heat delivery by alternating the laser power. Drug delivery was optimized under magnetic resonance (MR) image guidance by co-encapsulation of an MR contrast agent (i.e.,&#160;gadoteridol) along with CDDP into the thermosensitive liposomes as a means to validate the heating protocol and to assess tumor accumulation. The heating protocol consisted of a preheating period of 5 min prior to administration of HTLC and 20 min heating post-injection. This heating protocol resulted in effective release of the encapsulated agents with the highest MR signal change observed in the heated tumor in comparison to the unheated tumor and muscle. This study demonstrated the successful application of the laser-based heating apparatus for preclinical thermosensitive liposome development and the importance of MR-guided validation of the heating protocol for optimization of drug delivery.

AN MRI-compatible&#160;custom-designed laser-based heating apparatus has been developed to provide local heating of subcutaneous tumors in order to activate release of agents from thermosensitive liposomes specifically at the tumor region.

Liposomes have been employed as drug delivery systems to target solid tumors through exploitation of the enhanced permeability and retention (EPR) effect ...

Hyperpolarized 129Xe Lung MRI and Spectroscopy in Mechanically Ventilated Mice

Hyperpolarized (HP) xenon-129 (129Xe) is an inhaled magnetic resonance imaging (MRI) contrast agent with unique spectral and physical properties that can be exploited to quantify pulmonary physiology, including ventilation, restricted diffusion (alveolar-airspace size), and gas exchange. In humans, it has been used to evaluate disease severity and progression in a variety of pulmonary disorders and is approved for clinical use in the United States and United Kingdom. Beyond its clinical applications, the ability of 129Xe MRI to noninvasively assess pulmonary pathophysiology and provide spatially resolved information is valuable for preclinical research. Among animal models, mice are the most widely used due to the accessibility of genetically modified disease models. Here, 129Xe MRI is promising as a minimally invasive, radiation-free, and sensitive technique to longitudinally monitor lung disease progression and therapy response (e.g., in drug discovery). This technique can extend to preclinical applications by incorporating an MRI-triggered, free-breathing apparatus or mechanical ventilator to deliver gas. Here, we describe the steps and provide checklists to ensure robust data collection and analysis, including creating a thermally polarized xenon gas phantom for quality control, optimizing polarization, animal handling (sedation, intubation, ventilation, and care for mice), and protocols for ventilation, restricted diffusion, and gas exchange data. While preclinical 129Xe MRI can be applied in various animal models (e.g., rats, pigs, sheep), this protocol focuses on mice due to the challenges posed by their small anatomy, which are balanced by their affordability and the availability of many disease models.

Hyperpolarized xenon MRI can quantify regional lung microstructure (air-space dimensions) and physiology (ventilation and gas exchange) in translational research and clinical care. Although challenging, it can provide comparable pulmonary insights in preclinical studies. This protocol describes the infrastructure and procedures needed to perform routine xenon lung MRI in mice.

Hyperpolarized (HP) xenon-129 (129Xe) is an inhaled magnetic resonance imaging (MRI) contrast agent with unique spectral and physical properties that can ...

Assessing Lung Function with Hyperpolarized Xenon-129 MRI

Quantitative Measure of Lung Structure and Function Obtained from Hyperpolarized Xenon Spectroscopy

Hyperpolarized Xenon-129 (HXe) magnetic resonance imaging (MRI) provides tools for obtaining 2- or 3-dimensional maps of lung ventilation patterns, gas diffusion, Xenon uptake by lung parenchyma, and other lung function metrics. However, by trading spatial for temporal resolution, it also enables tracing of pulmonary Xenon gas exchange on a ms timescale. This article describes one such technique, chemical shift saturation recovery (CSSR) MR spectroscopy. It illustrates how it can be used to assess capillary blood volume, septal wall thickness, and the surface-to-volume ratio in the alveoli. The flip angle of the applied radiofrequency pulses (RF) was carefully calibrated. Single-dose breath-hold and multi-dose free-breathing protocols were employed for administering the gas to the subject. Once the inhaled Xenon gas reached the alveoli, a series of 90&#176; RF pulses was applied to ensure maximum saturation of the accumulated Xenon magnetization in the lung parenchyma. Following a variable delay time, spectra were acquired to quantify the regrowth of the Xenon signal due to gas exchange between the alveolar gas volume and the tissue compartments of the lung. These spectra were then analyzed by fitting complex pseudo-Voigt functions to the three dominant peaks. Finally, the delay time-dependent peak amplitudes were fitted to a one-dimensional analytical gas-exchange model to extract physiological parameters.

Author Spotlight: Advancing Lung Disease Research with Free-Breathing Hyperpolarized Xenon-129 MRI

The manuscript presents a detailed protocol for using hyperpolarized Xenon-129 chemical shift saturation recovery (CSSR) to trace pulmonary gas exchange, assess the apparent alveolar septal wall thickness, and measure the surface-to-volume ratio. The method has the potential to diagnose and monitor lung diseases.

Hyperpolarized Xenon-129 (HXe) magnetic resonance imaging (MRI) provides tools for obtaining 2- or 3-dimensional maps of lung ventilation patterns, gas ...

Medicine

A Standardized Workflow for Hyperpolarized 129Xe MRI to Study Pulmonary Function

Acquiring Hyperpolarized 129Xe Magnetic Resonance Images of Lung Ventilation

Hyperpolarized 129Xe MRI comprises a unique array of structural and functional lung imaging techniques. Technique standardization across sites is increasingly important given the recent FDA approval of 129Xe as an MR contrast agent and as interest in 129Xe MRI increases among research and clinical institutions. Members of the 129Xe MRI Clinical Trials Consortium (Xe MRI CTC) have agreed upon best practices for each of the key aspects of the 129Xe MRI workflow, and these recommendations are summarized in a recent publication. This work provides practical information to develop an end-to-end workflow for collecting 129Xe MR images of lung ventilation according to the Xe MRI CTC recommendations. Preparation and administration of 129Xe for MR studies will be discussed and demonstrated, with specific topics including choice of appropriate gas volumes for entire studies and for individual MR scans, preparation&#160;and delivery of individual 129Xe doses, and best practices for monitoring subject safety and 129Xe tolerability during studies. Key MR technical considerations will also be covered, including pulse sequence types and optimized parameters, calibration of 129Xe flip angle and center frequency, and 129Xe MRI ventilation image analysis.

Author Spotlight: Standardization and Best Practices for Advancing Lung Imaging Using 129Xe MRI

Hyperpolarized 129Xe magnetic resonance imaging (MRI) is a method for studying regionally resolved aspects of pulmonary function. This work presents an end-to-end standardized workflow for hyperpolarized 129Xe MRI of lung ventilation, with specific attention to pulse sequence design, 129Xe dose preparation, scan workflow, and best practices for subject safety monitoring.

Troubleshooting and Quality Assurance in Hyperpolarized Xenon Magnetic Resonance Imaging: Tools for High-Quality Image Acquisition

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