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Introduction: Proper placental development is crucial to fetal health but is challenging to functionally assess non-invasively and is thus poorly characterized in populations. Body mass index (BMI) has been linked with adverse outcomes, but the causative mechanism is uncertain. Velocity-selective arterial spin labeling (VS-ASL) MRI provides a method to non-invasively measure placental perfusion with robustness to confounding transit time delays. In this study, we report on the measurement of perfusion in the human placenta in early pregnancy using velocity-selective arterial spin labeling (VS-ASL) MRI, comparing non-obese and obese participants., Methods: Participants (N = 97) undergoing routine prenatal care were recruited and imaged with structural and VS-ASL perfusion MRI at 15 and 21 weeks gestation. Resulting perfusion images were analyzed with respect to obesity based on BMI, gestational age, and the presence of adverse outcomes., Results: At 15 weeks gestation BMI was not associated with placental perfusion or perfusion heterogeneity. However, at 21 weeks gestation BMI was associated with higher placental perfusion (p < 0.01) and a decrease in perfusion heterogeneity (p < 0.05). In alignment with past studies, perfusion values were also higher at 21 weeks compared to 15 weeks gestation. In a small cohort of participants with adverse outcomes, at 21 weeks lower perfusion was observed compared to participants with uncomplicated pregnancies., Discussion: These results suggest low placental perfusion in the early second trimester may not be the culpable factor driving associations of obesity with adverse outcomes., Competing Interests: Declaration of competing interest The University of Wisconsin – Madison receives research support in support of the general MRI program from GE Healthcare., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Magnetic resonance imaging (MRI) is a routine diagnostic modality in oncology that produces excellent imaging resolution and tumor contrast without the use of ionizing radiation. However, improved contrast agents are still needed to further increase detection sensitivity and avoid toxicity/allergic reactions associated with paramagnetic metal contrast agents, which may be seen in a small percentage of the human population. Fluorine-19 ( 19 F)-MRI is at the forefront of the developing MRI methodologies due to near-zero background signal, high natural abundance of 100%, and unambiguous signal specificity. In this study, we have developed a colloidal nanoemulsion (NE) formulation that can encapsulate high volumes of the fluorous MRI tracer, perfluoro-[15-crown-5]-ether (PFCE) (35% v/v). These nanoparticles exhibit long-term (at least 100 days) stability and high PFCE loading capacity in formulation with our semifluorinated triblock copolymer, M2F8H18. With sizes of approximately 200 nm, these NEs enable in vivo delivery and passive targeting to tumors. Our diagnostic formulation, M2F8H18/PFCE NE, yielded in vivo 19 F-MR images with a high signal-to-noise ratio up to 100 in a tumor-bearing mouse model at clinically relevant scan times. M2F8H18/PFCE NE circulated stably in the vasculature, accumulated in high concentration of an estimated 4-9 × 10 17 19 F spins/voxel at the tumor site, and cleared from most organs over the span of 2 weeks. Uptake by the mononuclear phagocyte system to the liver and spleen was also observed, most likely due to particle size. These promising results suggest that M2F8H18/PFCE NE is a favorable 19 F-MR diagnostic tracer for further development in oncological studies and potential clinical translation., (© 2024 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Current clinical MRI of patients with juvenile osteochondritis dissecans (JOCD) is limited by the low reproducibility of lesion instability evaluation and inability to predict which lesions will heal after nonoperative treatment and which will later require surgery. The aim of this study is to verify the ability of apparent diffusion coefficient (ADC) to detect differences in lesion microstructure between different JOCD stages, treatment groups, and healthy, unaffected contralateral knees. Pediatric patients with JOCD received quantitative diffusion MRI between January 2016 and September 2020 in this prospective research study. A disease stage (I-IV) and stability of each JOCD lesion was evaluated. ADCs were calculated in progeny lesion, interface, parent bone, cartilage overlying lesion, control bone, and control cartilage regions. ADC differences were evaluated using linear mixed models with Bonferroni correction. Evaluated were 30 patients (mean age, 13 years; 21 males), with 40 JOCD-affected and 12 healthy knees. Nine patients received surgical treatment after MRI. Negative Spearman rank correlations were found between ADCs and JOCD stage in the progeny lesion (ρ = -0.572; p < 0.001), interface (ρ = -0.324; p = 0.041), and parent bone (ρ = -0.610; p < 0.001), demonstrating the sensitivity of ADC to microstructural differences in lesions at different JOCD stages. We observed a significant increase in the interface ADCs (p = 0.007) between operative (mean [95% CI] = 1.79 [1.56-2.01] × 10 -3  mm 2 /s) and nonoperative group (1.27 [0.98-1.57] × 10 -3  mm 2 /s). Quantitative diffusion MRI detects microstructural differences in lesions at different stages of JOCD progression towards healing and reveals differences between patients assigned for operative versus nonoperative treatment., (© 2022 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Identification of placental dysfunction in early pregnancy with noninvasive imaging could be a valuable tool for assessing maternal and fetal risk. Dynamic contrast enhanced (DCE) magnetic resonance imaging (MRI) can be a powerful tool for interrogating placenta health. After inoculation with Zika virus or sham inoculation at gestation age (GA) 45 or 55 days, animals were imaged up to three times at GA65, GA100, and GA145. DCE MRI images were acquired at all imaging sessions using ferumoxytol, an iron nanoparticle-based contrast agent, and analyzed for placental intervillous blood flow, number of perfusion domains, and perfusion domain volume. Cesarean section was performed at GA155, and the placenta was photographed and dissected for histopathology. Photographs were used to align cotyledons with estimated perfusion domains from MRI, allowing comparison of estimated cotyledon volume to pathology. Monkeys were separated into high and low pathology groups based on the average number of pathologies present in the placenta. Perfusion domain flow, volume, and number increased through gestation, and total blood flow increased with gestation for both low pathology and high pathology groups. A statistically significant decrease in perfusion domain volume associated with pathology was detected at all gestational ages. Individual perfusion domain flow comparisons demonstrated a statistically significant decrease with pathology at GA100 and GA145, but not GA65. Since ferumoxytol is currently used to treat anemia during human pregnancy and as an off-label MRI contrast agent, future transition of this work to human pregnancy may be possible., (© The Author(s) 2022. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Juvenile osteochondritis dissecans (JOCD) lesions contain cartilaginous, fibrous and osseous tissues which are difficult to distinguish with clinical, morphological magnetic resonance imaging (MRI). Quantitative T 2 * mapping has earlier been used to evaluate microstructure and composition of all aforementioned tissues as well as bone mineral density. However, the ability of T 2 * mapping to detect changes in tissue composition between different JOCD lesion regions, different disease stages, and between stable and unstable lesions has not been demonstrated. This study analyzed morphological and T 2 * MRI data from 25 patients (median age, 12.1 years) with 34 JOCD-affected and 13 healthy knees. Each lesion was assigned a stage reflecting the natural history of JOCD, with stages I and IV representing early and healed lesion, respectively. T 2 * values were evaluated within the progeny lesion, interface and parent bone of each lesion and in the control bone region. T 2 * was negatively correlated with JOCD stage in progeny lesion (ρ = -0.871; p < 0.001) and interface regions (ρ = -0.649; p < 0.001). Stage IV progeny showed significantly lower T 2 * than control bone (p = 0.028). T 2 * was significantly lower in parent bone than in control bone of patients with stable lesions (p = 0.009), but not in patients with unstable lesions (p = 0.14). Clinical significance: T 2 * mapping enables differentiation between different stages of JOCD and quantitative measurement of the ossification degree in progeny lesion and interface. The observed T 2 * decrease in healed and stable lesions may indicate increased bone density as a result of the active repair process. T 2 * mapping provides quantitative information about JOCD lesion composition., (© 2021 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Natural killer (NK) cell therapies are being increasingly used as an adoptive cell therapy for cancer because they can recognize tumor cells in an antigen-independent manner. While promising, the understanding of NK cell persistence, particularly within a harsh tumor microenvironment, is limited. Fluorine-19 ( 19 F) MRI is a noninvasive imaging modality that has shown promise in longitudinally tracking cell populations in vivo; however, it has not been studied on murine NK cells. In this study, the impact of 19 F labeling on murine NK cell viability and function was assessed in vitro and then used to quantify NK cell persistence in vivo. While there was no noticeable impact on viability, labeling NK cells with 19 F did attenuate cytotoxicity against lymphoma cells in vitro. Fluorescent microscopy verified 19 F labeling in both the cytoplasm and nucleus of NK cells. Lymphoma-bearing mice were given intratumoral injections of 19 F-labeled NK cells in which signal was detectable across the 6 day observation period via 19 F MRI. Quantification from the composite images detected 78-94% of the initially injected NK cells across 6 days, with a significant decrease between Days 3 and 6. Postmortem flow cytometry demonstrated retention of 19 F intracellularly within adoptively transferred NK cells with less than 1% of 19 F-containing cells identified as tumor-associated macrophages that presumably ingested nonviable NK cells. This work demonstrates that 19 F MRI offers a specific imaging platform to track and quantify murine NK cells within tumors noninvasively., (© 2021 John Wiley & Sons, Ltd.)

Objective: Evaluate articular cartilage by magnetic resonance imaging (MRI) T2∗ mapping within the distal femur and proximal tibia in adolescents with juvenile osteochondritis dissecans (JOCD)., Design: JOCD imaging studies acquired between August 2011 and February 2019 with clinical and T2∗ mapping MRI knee images were retrospectively collected and analyzed for 31 participants (9F/22M, 15.0 ± 3.8 years old) with JOCD lesions in the medial femoral condyle (MFC). In total, N = 32 knees with JOCD lesions and N = 14 control knees were assessed. Mean T2∗ values in four articular cartilage regions-of-interest (MFC, lateral femoral condyle (LFC), medial tibia (MT), and lateral tibia (LT)) and lesion volume were measured and analyzed using Wilcoxon-rank-sum tests and Spearman correlation coefficients (R)., Results: Mean ± standard error T2∗ differences observed between the lesion-sided MFC and the LFC in JOCD-affected knees (28.5 ± 0.9 95% confidence interval [26.8, 30.3] vs 26.3 ± 0.7 [24.8, 27.7] ms, P = 0.088) and between the affected- and control-knee MFC (28.5 ± 0.9 [26.8, 30.3] vs 28.5 ± 0.6 [27.1, 29.9] ms, P = 0.719) were nonsignificant. T2∗ was significantly increased in the lesion-sided MT vs the LT for the JOCD-affected knees (21.5 ± 0.7 [20.1, 22.9] vs 18.0 ± 0.7 [16.5, 19.5] ms, P = 0.002), but this same difference was also observed between the MT and LT in control knees (21.0 ± 0.6 [19.7, 22.3] vs 18.1 ± 1.1 [15.8, 20.4] ms, P = 0.037). There was no significant T2∗ difference between the affected- and control-knee MT (21.5 ± 0.7 [20.1, 22.9] vs 21.0 ± 0.6 [19.7, 22.3] ms, P = 0.905). T2∗ within the lesion-sided MFC was not correlated with patient age (R = 0.20, P = 0.28) or lesion volume (R = 0.06, P = 0.75). T2∗ values were slightly increased near lesions in later-stage JOCD subjects but without statistical significance., Conclusions: T2∗ relaxations times were not significantly different from control sites in the articular cartilage overlying JOCD lesions in the MFC or adjacent MT cartilage in early-stage JOCD., (Copyright © 2020. Published by Elsevier Ltd.)

Ferumoxytol is a superparamagnetic iron oxide nanoparticle used off-label as an intravascular magnetic resonance imaging (MRI) contrast agent. Additionally, ferumoxytol-uptake by macrophages facilitates detection of inflammatory sites by MRI through ferumoxytol-induced image contrast changes. Therefore, ferumoxytol-enhanced MRI holds great potential for assessing vascular function and inflammatory response, critical to determine placental health in pregnancy. This study sought to assess the fetoplacental unit and selected maternal tissues, pregnancy outcomes, and fetal well-being after ferumoxytol administration. In initial developmental studies, seven pregnant rhesus macaques were imaged with or without ferumoxytol administration. Pregnancies went to term with vaginal delivery and infants showed normal growth rates compared to control animals born the same year that did not undergo MRI. To determine the impact of ferumoxytol on the maternal-fetal interface (MFI), fetal well-being, and pregnancy outcome, four pregnant rhesus macaques at ~100 gestational day underwent MRI before and after ferumoxytol administration. Collection of the fetoplacental unit and selected maternal tissues was performed 2-3 days following ferumoxytol administration. A control group that did not receive ferumoxytol or MRI was used for comparison. Iron levels in fetal and MFI tissues did not differ between groups, and there was no significant difference in tissue histopathology with or without exposure to ferumoxytol, and no effect on placental hormone secretion. Together, these results suggest that the use of ferumoxytol and MRI in pregnant rhesus macaques does not negatively impact the MFI and can be a valuable experimental tool in research with this important animal model., (© The Author(s) 2019. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We introduce a quantitative measure of epiphyseal cartilage vascularity and examine vessel networks during human skeletal maturation. Understanding early morphological changes in the distal femoral condyle is expected to provide information on the pathogenesis of developmental diseases such as juvenile osteochondritis dissecans., Methods: Twenty-two cadaveric knees from donors ranging from 1 month to 10 years of age were included in the study. Images of bone, cartilage, and vascularity were acquired simultaneously with a 3-dimensional gradient-recalled-echo magnetic resonance imaging (MRI) sequence. The secondary ossification center volume and total epiphysis cartilage volume ratio and articular-epiphyseal cartilage complex and epiphyseal cartilage widths were measured. Epiphyseal cartilage vascularity was visualized for 9 data sets with quantitative susceptibility mapping and vessel filtering, resulting in 3-dimensional data to inform vessel network segmentation and to calculate vascular density., Results: Three distinct, non-anastomosing vascular networks (2 peripheral and 1 central) supply the distal femoral epiphyseal cartilage. The central network begins regression as early as 3 months and is absent by 4 years. From 1 month to 3 years, the ratio of central to peripheral vascular area density decreased from 1.0 to 0.5, and the ratio of central to peripheral vascular skeletal density decreased from 0.9 to 0.6. A narrow, peripheral vascular rim was present at 8 years but had disappeared by 10 years. The secondary ossification center progressively acquires the shape of the articular-epiphyseal cartilage complex by 8 years of age, and the central areas of the medial and lateral femoral condyles are the last to ossify., Conclusions: Using cadaveric pediatric knees, we provide quantitative, 3-dimensional measures of epiphyseal cartilage vascular regression during skeletal development using vessel image features. Central areas with both early vascular regression and delayed ossification correspond to predilection sites of juvenile osteochondritis dissecans in this limited case series. Our findings highlight specific vascular vulnerabilities that may lead to improved understanding of the pathogenesis and better-informed clinical management decisions in developmental skeletal diseases., Clinical Relevance: This paradigm shift in understanding of juvenile osteochondritis dissecans etiology and disease progression may critically impact future patient management. Our findings highlight specific vascular vulnerabilities during skeletal maturation in a group of active young patients seen primarily by orthopaedic surgeons and sports medicine professionals., (Copyright © 2019 The Authors. Published by The Journal of Bone and Joint Surgery, Incorporated. All rights reserved.)

Juvenile osteochondritis dissecans (JOCD) is a developmental disease characterized by formation of intra-articular (osteo)chondral flaps or fragments. Evidence-based treatment guidelines for JOCD are currently lacking. An animal model would facilitate study of JOCD and evaluation of diagnostic and treatment approaches. The purpose of this study was to assess the suitability of miniature pigs as a model of JOCD at the distal femur. First, stifle (knee) joints harvested from three juvenile miniature pigs underwent magnetic resonance imaging (MRI) to establish the vascular architecture of the distal femoral epiphyseal cartilage. Second, vessels supplying the axial or abaxial aspects of the medial femoral condyle were surgically interrupted in four additional juvenile miniature pigs, and the developing epiphyseal cartilage lesions were monitored using three consecutive MRI examinations over nine weeks. The miniature pigs were then euthanized, and their distal femora were harvested for histological evaluation. Vascular architecture of the distal femoral epiphyseal cartilage in the miniature pigs was found to be nearly identical to that of juvenile human subjects, characterized by separate vascular beds supplying the axial and abaxial aspects of the condyles. Surgical interruption of the vascular supply to the abaxial aspect of the medial femoral condyle resulted in ischemic cartilage necrosis (a precursor lesion of JOCD) in 75% (3/4) of the miniature pigs. Cartilage lesions were identified during the first MRI performed 3 weeks post-operatively. No clinically apparent JOCD-like lesions developed. In conclusion, miniature pigs are suitable for modeling JOCD precursor lesions. Further investigation of the model is warranted to assess induction of clinically apparent JOCD lesions. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2130-2137, 2019., (© 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Purpose: Fluorescence lifetime imaging microscopy (FLIM) of endogenous fluorescent metabolites permits the measurement of cellular metabolism in cell, tissue and animal models. In parallel, magnetic resonance spectroscopy (MRS) of dynamic nuclear (hyper)polarized (DNP) 13 C-pyruvate enables measurement of metabolism at larger in vivo scales. Presented here are the design and initial application of a bioreactor that connects these 2 metabolic imaging modalities in vitro, using 3D cell cultures., Methods: The model fitting for FLIM data analysis and the theory behind a model for the diffusion of pyruvate into a collagen gel are detailed. The device is MRI-compatible, including an optical window, a temperature control system and an injection port for the introduction of contrast agents. Three-dimensional printing, computer numerical control machining and laser cutting were used to fabricate custom parts., Results: Performance of the bioreactor is demonstrated for 4 T1 murine breast cancer cells under glucose deprivation. Mean nicotinamide adenine dinucleotide (NADH) fluorescence lifetimes were 10% longer and hyperpolarized 13 C lactate:pyruvate (Lac:Pyr) ratios were 60% lower for glucose-deprived 4 T1 cells compared to 4 T1 cells in normal medium. Looking at the individual components of the NADH fluorescent lifetime, τ 1 (free NADH) showed no significant change, while τ 2 (bound NADH) showed a significant increase, suggesting that the increase in mean lifetime was due to a change in bound NADH., Conclusion: A novel bioreactor that is compatible with, and can exploit the benefits of, both FLIM and 13 C MRS in 3D cell cultures for studies of cell metabolism has been designed and applied., (© 2019 International Society for Magnetic Resonance in Medicine.)

Purpose: To investigate the correspondence between arterial spin labeling (ASL) flow-sensitive alternating inversion recovery (FAIR) and ferumoxytol DCE MRI for the assessment of placental intervillous perfusion., Methods: Ten pregnant macaques in late second trimester were imaged at 3 T using a 2D ASL FAIR, with and without outer-volume saturation pulses used to control the bolus width, and a 3D ferumoxytol DCE-MRI acquisition. The ASL tagged/control pairs were averaged, subtracted, and normalized to create perfusion ratio maps. Contrast arrival time and uptake slope were estimated by fitting the DCE data to a sigmoid function. Macaques (N = 4) received interleukin-1β to induce inflammation and disrupt perfusion., Results: The FAIR tag modification with outer-volume saturation reduced the median ASL ratio percentage compared with conventional FAIR (0.64% ± 1.42% versus 0.71% ± 2.00%; P < .05). Extended ferumoxytol arrival times (34 ± 25 seconds) were observed across the placenta. No significant DCE signal change was measured in fetal tissue ( - 0.6% ± 3.0%; P = .52) or amniotic fluid (1.9% ± 8.8%; P = .59). High ASL ratio was significantly correlated with early arrival time and high uptake slope (P < .05), but ASL signal was not above noise in late-DCE-enhancing regions. No significant differences were observed in perfusion measurements between the interleukin-1β and controls (P > .05)., Conclusion: The ASL-FAIR and ferumoxytol DCE-MRI methods are feasible to detect early blood delivery to the macaque placenta. Outer volume saturation reduced the high macrovascular ASL signal. Interleukin-1β exposure did not alter placental intervillous perfusion. An endogenous-labeling perfusion technique is limited due to extended transit times for flow within the placenta beyond the immediate vicinity of the maternal spiral arteries., (© 2018 International Society for Magnetic Resonance in Medicine.)

Purpose: To develop a chemical shift encoding (CSE) approach for fluorine-19 MRI of perfluorocarbons in the presence of multiple known fluorinated chemical species., Theory and Methods: A multi-echo CSE technique is applied for spectral separation of the perfluorocarbon perfluoro-15-crown-5-ether (PFCE) and isoflurane (ISO) based on their chemical shifts at 4.7 T. Cramér-Rao lower bound analysis is used to identify echo combinations with optimal signal-to-noise performance. Signal contributions are fit with a multispectral fluorine signal model using a non-linear least squares estimation reconstruction directly from k-space data. This CSE approach is tested in fluorine-19 phantoms and in a mouse with a 2D and 3D spoiled gradient-echo acquisition using multiple echo times determined from Cramér-Rao lower bound analysis., Results: Cramér-Rao lower bound analysis for PFCE and ISO separation shows signal-to-noise performance is maximized with a 0.33 ms echo separation. A linear behavior (R 2  = 0.987) between PFCE signal and known relative PFCE volume is observed in CSE reconstructed images using a mixed PFCE/ISO phantom. Effective spatial and spectral separation of PFCE and ISO is shown in phantoms and in vivo., Conclusion: Feasibility of a gradient-echo CSE acquisition and image reconstruction approach with optimized noise performance is demonstrated through fluorine-19 MRI of PFCE with effective removal of ISO signal contributions. Magn Reson Med 79:2183-2189, 2018. © 2017 International Society for Magnetic Resonance in Medicine., (© 2017 International Society for Magnetic Resonance in Medicine.)

In medical imaging, clinicians, researchers and technicians have begun to use 3D printing to create specialized phantoms to replace commercial ones due to their customizable and iterative nature. Presented here is the design of a 3D printed open source, reusable magnetic resonance imaging (MRI) phantom, capable of flood-filling, with removable samples for measurements of contrast agent solutions and reference standards, and for use in evaluating acquisition techniques and image reconstruction performance. The phantom was designed using SolidWorks, a computer-aided design software package. The phantom consists of custom and off-the-shelf parts and incorporates an air hole and Luer Lock system to aid in flood filling, a marker for orientation of samples in the filled mode and bolt and tube holes for assembly. The cost of construction for all materials is under $90. All design files are open-source and available for download. To demonstrate utility, B 0 field mapping was performed using a series of gadolinium concentrations in both the unfilled and flood-filled mode. An excellent linear agreement (R 2 >0.998) was observed between measured relaxation rates (R 1 /R 2 ) and gadolinium concentration. The phantom provides a reliable setup to test data acquisition and reconstruction methods and verify physical alignment in alternative nuclei MRI techniques (e.g. carbon-13 and fluorine-19 MRI). A cost-effective, open-source MRI phantom design for repeated quantitative measurement of contrast agents and reference standards in preclinical research is presented. Specifically, the work is an example of how the emerging technology of 3D printing improves flexibility and access for custom phantom design., Competing Interests: The authors have no relevant conflicts of interest to disclose.

In the past decade, hyperpolarized (HP) contrast agents have been under active development for MRI applications to address the twin challenges of functional and quantitative imaging. Both HP helium ( 3 He) and xenon ( 129 Xe) gases have reached the stage where they are under study in clinical research. HP 129 Xe, in particular, is poised for larger scale clinical research to investigate asthma, chronic obstructive pulmonary disease, and fibrotic lung diseases. With advances in polarizer technology and unique capabilities for imaging of 129 Xe gas exchange into lung tissue and blood, HP 129 Xe MRI is attracting new attention. In parallel, HP 13 C and 15 N MRI methods have steadily advanced in a wide range of pre-clinical research applications for imaging metabolism in various cancers and cardiac disease. The HP [1- 13 C] pyruvate MRI technique, in particular, has undergone phase I trials in prostate cancer and is poised for investigational new drug trials at multiple institutions in cancer and cardiac applications. This review treats the methodology behind both HP gases and HP 13 C and 15 N liquid state agents. Gas and liquid phase HP agents share similar technologies for achieving non-equilibrium polarization outside the field of the MRI scanner, strategies for image data acquisition, and translational challenges in moving from pre-clinical to clinical research. To cover the wide array of methods and applications, this review is organized by numerical section into (1) a brief introduction, (2) the physical and biological properties of the most common polarized agents with a brief summary of applications and methods of polarization, (3) methods for image acquisition and reconstruction specific to improving data acquisition efficiency for HP MRI, (4) the main physical properties that enable unique measures of physiology or metabolic pathways, followed by a more detailed review of the literature describing the use of HP agents to study: (5) metabolic pathways in cancer and cardiac disease and (6) lung function in both pre-clinical and clinical research studies, concluding with (7) some future directions and challenges, and (8) an overall summary.

The availability of clinical-grade cytokines and artificial antigen-presenting cells has accelerated interest in using natural killer (NK) cells as adoptive cellular therapy (ACT) for cancer. One of the technological shortcomings of translating therapies from animal models to clinical application is the inability to effectively and non-invasively track these cells after infusion in patients. We have optimized the nonradioactive isotope fluorine-19 ((19)F) as a means to label and track NK cells in preclinical models using magnetic resonance imaging (MRI). Human NK cells were expanded with interleukin (IL)-2 and labeled in vitro with increasing concentrations of (19)F. Doses as low as 2 mg/mL (19)F were detected by MRI. NK cell viability was only decreased at 8 mg/mL (19)F. No effects on NK cell cytotoxicity against K562 leukemia cells were observed with 2, 4 or 8 mg/mL (19)F. Higher doses of (19)F, 4 mg/mL and 8 mg/mL, led to an improved (19)F signal by MRI with 3 × 10(11) (19)F atoms per NK cell. The 4 mg/mL (19)F labeling had no effect on NK cell function via secretion of granzyme B or interferon gamma (IFNγ), compared to NK cells exposed to vehicle alone. (19)F-labeled NK cells were detectable immediately by MRI after intratumoral injection in NSG mice and up to day 8. When (19)F-labeled NK cells were injected subcutaneously, we observed a loss of signal through time at the site of injection suggesting NK cell migration to distant organs. The (19)F perfluorocarbon is a safe and effective reagent for monitoring the persistence and trafficking of NK cell infusions in vivo, and may have potential for developing novel imaging techniques to monitor ACT for cancer.

Real-time imaging of (13)C metabolism in vivo has been enabled by recent advances in hyperpolarization. As a result of the inherently low natural abundance of endogenous (13)C nuclei, hyperpolarized (13)C images lack structural information that could be used to aid in motion detection and anatomical registration. Motion before or during the (13)C acquisition can therefore result in artifacts and misregistration that may obscure measures of metabolism. In this work, we demonstrate a method to simultaneously image both (1)H and (13)C nuclei using a dual-nucleus spectral-spatial radiofrequency excitation and a fully coincident readout for rapid multinuclear spectroscopic imaging. With the appropriate multinuclear hardware, and the means to simultaneously excite and receive on both channels, this technique is straightforward to implement requiring little to no increase in scan time. Phantom and in vivo experiments were performed with both Cartesian and spiral trajectories to validate and illustrate the utility of simultaneous acquisitions. Motion compensation of dynamic metabolic measurements acquired during free breathing was demonstrated using motion tracking derived from (1)H data. Simultaneous multinuclear imaging provides structural (1)H and metabolic (13)C images that are correlated both spatially and temporally, and are therefore amenable to joint (1)H and (13)C analysis and correction of structure-function images., (Copyright © 2015 John Wiley & Sons, Ltd.)