In-vivo magnetic resonance imaging of hyperpolarized silicon particles

Silicon-based micro and nanoparticles have gained popularity in a wide range of biomedical applications due to their biocompatibility and biodegradability in-vivo, as well as a flexible surface chemistry, which allows drug loading, functionalization and targeting. Here we report direct in-vivo imaging of hyperpolarized 29Si nuclei in silicon microparticles by MRI. Natural physical properties of silicon provide surface electronic states for dynamic nuclear polarization (DNP), extremely long depolarization times, insensitivity to the in-vivo environment or particle tumbling, and surfaces favorable for functionalization. Potential applications to gastrointestinal, intravascular, and tumor perfusion imaging at sub-picomolar concentrations are presented. These results demonstrate a new background-free imaging modality applicable to a range of inexpensive, readily available, and biocompatible Si particles.Comment: Supplemental Material include

Quantitative Mapping of Lung Ventilation Using Hyperpolarized Gas Magnetic Resonance Imaging

The main objective of this project was to develop and implement techniques for high-resolution quantitative imaging of ventilation in lungs using hyperpolarized gas magnetic resonance imaging (MRI). Pulmonary ventilation is an important aspect of lung function and is frequently compromised through several different mechanisms and at varying degrees in presence of certain lung conditions, such as chronic obstructive pulmonary diseases. The primary focus of this development is on large mammalian species as a steppingstone towards translation to human subjects. The key deliverables of this project are a device for real-time mixing and delivery of hyperpolarized gases such as 3He and 129Xe in combination with O2, an MRI acquisition scheme for practical imaging of ventilation signal build-up in the lungs, and a robust mathematical model for estimation of regional fractional ventilation values at a high resolution. A theoretical framework for fractional gas replacement in the lungs is presented to describe MRI signal dynamics during continuous breathing of a mixture of hyperpolarized gases in presence of several depolarization mechanisms. A hybrid ventilation and imaging acquisition scheme is proposed to acquire a series of images during short end-inspiratory breath-holds over several breaths. The sensitivity of the estimation algorithm is assessed with respect to noise, model uncertainty and acquisition parameters, and subsequently an optimal set of acquisition parameters is proposed to minimize the fractional ventilation estimation error. This framework is then augmented by an undersampled parallel MRI scheme to accelerate image acquisition to enable fractional ventilation imaging over the entire lung volume in a single pass. The image undersampling was also leveraged to minimize the coupling associated with signal buildup in the airways and the irreversible effect of RF pulses. The proposed technique was successfully implemented in pigs under mechanical ventilation, and preliminary measurements were performed in an adult human subject under voluntary breathing

Dissolved hyperpolarized xenon‐129 MRI in human kidneys

Purpose To assess the feasibility of using dissolved hyperpolarized xenon‐129 (129Xe) MRI to study renal physiology in humans at 3 T. Methods Using a flexible transceiver RF coil, dynamic and spatially resolved 129Xe spectroscopy was performed in the abdomen after inhalation of hyperpolarized 129Xe gas with 3 healthy male volunteers. A transmit‐only receive‐only RF coil array was purpose‐built to focus RF excitation and enhance sensitivity for dynamic imaging of 129Xe uptake in the kidneys using spoiled gradient echo and balanced steady‐state sequences. Results Using spatially resolved spectroscopy, different magnitudes of signal from 129Xe dissolved in red blood cells and tissue/plasma could be identified in the kidneys and the aorta. The spectra from both kidneys showed peaks with similar amplitudes and chemical shift values. Imaging with the purpose‐built coil array was shown to provide more than a 3‐fold higher SNR in the kidneys when compared with surrounding tissues, while further physiological information from the dissolved 129Xe in the lungs and in transit to the kidneys was provided with the transceiver coil. The signal of dissolved hyperpolarized 129Xe could be imaged with both tested sequences for about 40 seconds after inhalation. Conclusion The uptake of 129Xe dissolved in the human kidneys was measured with spectroscopic and imaging experiments, demonstrating the potential of hyperpolarized 129Xe MR as a novel, noninvasive technique to image human kidney tissue perfusion

The medical applications of hyperpolarized Xe and nonproton magnetic resonance imaging

Hyperpolarized 129Xe (HP 129Xe) magnetic resonance imaging (MRI) is a relatively young field which is experiencing significant advancements each year. Conventional proton MRI is widely used in clinical practice as an anatomical medical imaging due to its superb soft tissue contrast. HP 129Xe MRI, on the other hand, may provide valuable information about internal organs functions and structure. HP 129Xe MRI has been recently clinically approved for lung imaging in the United Kingdom and the United States. It allows quantitative assessment of the lung function in addition to structural imaging. HP 129Xe has unique properties of anaesthetic, and may transfer to the blood stream and be further carried to the highly perfused organs. This gives the opportunity to assess brain perfusion with HP 129Xe and perform molecular imaging. However, the further progression of the HP 129Xe utilization for brain perfusion quantification and molecular imaging implementation is limited by the absence of certain crucial milestones. This thesis focused on providing important stepping stones for the further development of HP 129Xe molecular imaging and brain imaging. The effect of glycation on the spectroscopic characteristics of HP 129Xe was studied in whole sheep blood with magnetic resonance spectroscopy. An additional peak of HP 129Xe bound to glycated hemoglobin was observed. This finding should be implemented in the spectroscopic HP 129Xe studies in patients with diabetes. [...

Medical applications of fluorine-19 and hyperpolarized xenon129 magnetic resonance imaging

Multinuclear magnetic resonance imaging (MRI) is currently under extensive development. Although conventional proton MRI is mostly known as an anatomical medical imaging modality with an excellent soft tissue contrast, multinuclear MRI proves that MRI can provide researchers and clinicians with information about the internal organs function. This class of MRI techniques relies on imaging different nuclei than protons. A large part of multinuclear MRI includes fluorine-19 (19F) and hyperpolarized (HP) xenon-129 (129Xe) MRI. 19F MRI is used for functional imaging of the lungs, molecular imaging of fluorinated biosensors, cell labeling, and drug metabolism investigation. On the other hand, HP 129Xe can be used for functional brain imaging along with perfusion imaging of the brain and kidneys. This thesis is focused on the development of HP 129Xe Time-of-Flight (TOF) perfusion imaging technique, functional lung imaging using octafluorocyclobutane (OFCB), and colorectal adenocarcinoma resistivity detection to 5-fluorouracil (5-FU) using 19F MRI. HP 129Xe TOF pulse sequence is capable to map and measure perfusion quantitively was developed and evaluated in phantoms and healthy volunteers. As a representative application, HP 129Xe TOF perfusion imaging was used to detect hemodynamic response to motor and visual stimuli in healthy brains. The performance of OFCB as a contrast agent has been evaluated in vitro and in vivo and compared to perfluoropropane, which is the most commonly used inhalation agent for 19F lung MRI. Theoretical comparison between both gases was conducted as well. Finally, resistivity detection of human colorectal adenocarcinoma to 5-FU was performed using 19F chemical shift imaging to access chemotherapy retention in the colorectal cancer. This work expands the arsenal of multinuclear MRI techniques with completely new approaches that can be readily applied for the current needs of neurology, pulmonology, and oncology

Hyperpolarized Carbon-13 Magnetic Resonance Imaging As A Tool For Assessing Lung Transplantation Outcomes

Lung transplantation is the established treatment for patients with chronic, end-stage lung diseases such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and cystic fibrosis (CF). However, its utility remains limited by the chronic shortage of donor lungs, limited lung preservation strategies and post-transplant complications leading to graft failure. Although efforts have been made to expand the limited pool of viable donor lungs via novel preservation strategies such as ex vivo lung perfusion (EVLP), our limited understanding of the mechanism and progression of donor lung injury continues to inhibit our ability to fully exploit these advances to improve lung transplant outcomes. Furthermore, the clinical standard for post-transplant assessment is limited to whole lung measurement such as pulmonary functional tests (PFTs) and structural imaging via radiography or HRCT, both of which lack the necessary sensitivity to detect lung rejection early. Given these limitations of currently available pre- and post-transplant lung assessment tools, a novel metabolic biomarker may provide higher sensitivity for determining the viability of donated lungs, as well as for assessing the onset of rejection before permanent structural changes in the lungs become apparent. We proposed that hyperpolarized (HP) [1-13C]pyruvate magnetic resonance imaging (MRI)—which provides real-time metabolic assessment of tissue based on the conversion of [1-13C] pyruvate to [1-13C]lactate via glycolysis, or to 13C bicarbonate via oxidative phosphorylation—may be an effective tool for assessing the health of donated lungs and may also serve as an early biomarker for detecting pulmonary graft dysfunction (PGD)-associated inflammation or acute lung rejection. In a rat model, we demonstrated the feasibility of using HP [1-13C]pyruvate nuclear magnetic resonance (NMR) spectroscopy to assess the viability of ex vivo perfused lungs. We further showed that our technique can be used to measure the improved viability of those lungs after treatment with ascorbic acid. Finally, translating our previously developed technique to in vivo HP [1-13C]pyruvate imaging of an inflamed rat lung, we not only demonstrated its utility for detecting lung transplantation rejection, but found that the HP lactate-to-pyruvate ratio is a better predictor of acute lung rejection in a rat model than computed tomography

19F Magnetic Resonance Imaging of Lung Ventilation Dynamics and Cell Tracking

The Fluorine isotope 19F has great potential in the use of magnetic resonance imaging (MRI) for clinical applications. 19F is inert, naturally abundant, has a close resonance frequency to proton (1H) (allowing most modern MRI scanners to work with the addition of a tuned coil), has negligible presence in the mammalian body (allowing background signal free acquisitions), and the high gyromagnetic ratio provides sufficient magnetic resonance signal to be visible without hyperpolarization. Uses for 19F MRI includes functional lung imaging, diffusion imaging, cell tracking, and oxygenation sensing among others. Although not widely used in the clinical setting at the time of writing this dissertation. The potential improvements 19F MRI could bring to healthcare are vast. 19F lung imaging has been studied in animal and human models, and has shown to be capable of producing sensitive markers for lung diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) by providing spatially localized functional information. In cell tracking, 19F has shown potential in drug delivery monitoring, inflammation imaging, immune cell tracking, and oxygenation measurement with the potential of spatial localization and cell quantification. This dissertation presents my work on human in-vivo multi-breath wash-in/out 19F lung imaging, and the processing of biomarkers more sensitive to CF disease progression over the current gold standard (spirometry). 19F lung MRI was compared to hyperpolarized (HP) Xenon (129Xe) ventilation defect percentage (VDP) analysis. The feasibility of free-breathing 19F lung imaging was explored using a combination of spiral acquisition and denoising. The last two chapters present preliminary work on sequence programming for diffusion imaging and cell tracking at high magnetic fields (9.4T). Preliminary work on oxygen sensing at 9.4T is also explored.Doctor of Philosoph

Biomarkers in preclinical cancer imaging

In view of the trend towards personalized treatment strategies for (cancer) patients, there is an increasing need to noninvasively determine individual patient characteristics. Such information enables physicians to administer to patients accurate therapy with appropriate timing. For the noninvasive visualization of disease-related features, imaging biomarkers are expected to play a crucial role. Next to the chemical development of imaging probes, this requires preclinical studies in animal tumour models. These studies provide proof-of-concept of imaging biomarkers and help determine the pharmacokinetics and target specificity of relevant imaging probes, features that provide the fundamentals for translation to the clinic. In this review we describe biological processes derived from the “hallmarks of cancer” that may serve as imaging biomarkers for diagnostic, prognostic and treatment response monitoring that are currently being studied in the preclinical setting. A number of these biomarkers are also being used for the initial preclinical assessment of new intervention strategies. Uniquely, noninvasive imaging approaches allow longitudinal assessment of changes in biological processes, providing information on the safety, pharmacokinetic profiles and target specificity of new drugs, and on the antitumour effectiveness of therapeutic interventions. Preclinical biomarker imaging can help guide translation to optimize clinical biomarker imaging and personalize (combination) therapies

Biomedical applications of the dynamic nuclear polarization and parahydrogen induced polarization techniques for hyperpolarized 13C MR imaging

Since the first pioneering report of hyperpolarized [1-13C]pyruvate magnetic resonance imaging (MRI) of the Warburg effect in prostate cancer patients, clinical dissemination of the technique has been rapid; close to 10 sites worldwide now possess a polarizer fit for the clinic, and more than 30 clinical trials, predominantly for oncological applications, are already registered on the US and European clinical trials databases. Hyperpolarized 13C probes to study pathophysiological processes beyond the Warburg effect, including tricarboxylic acid cycle metabolism, intra-cellular pH and cellular necrosis have also been demonstrated in the preclinical arena and are pending clinical translation, and the simultaneous injection of multiple co-polarized agents is opening the door to high-sensitivity, multi-functional molecular MRI with a single dose. Here, we review the biomedical applications to date of the two polarization methods that have been used for in vivo hyperpolarized 13C molecular MRI; namely, dissolution dynamic nuclear polarization and parahydrogen-induced polarization. The basic concept of hyperpolarization and the fundamental theory underpinning these two key 13C hyperpolarization methods, along with recent technological advances that have facilitated biomedical realization, are also covered

Cerebral Blood Flow Measurement Using MRI: Mathematical Regularization and Phantom Evaluation.

Strokes have been the third most prevalent cause of death in developed countries and the second most prevalent cause of mortality worldwide. Ischemic strokes are by far the most common type of strokes. Verifying the extent and severity of brain damage may be the most challenging problem in the diagnosis and treatment of stroke. Magnetic resonance imaging provides important indicators, such as cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transition time (MTT), for tissues at the risk for acute strokes. These perfusion-related parameters can be estimated using MR techniques, specifically as dynamic susceptibility contrast (DSC). The DSC technique measures the change in MR signal during the passage of a non-diffusible tracer through the brain tissue. The signal change can be related to the blood flow through a mathematical convolution model, originally suggested by Meier and Zierler, based on indicator-dilution theory. There have been many attempts to find a deconvolution algorithm that overcomes the many limitations, especially, the instability issue of this ill-posed problem. We have suggested a new approach based on the framework of Tikhonov regularization which we will refer to that as "Generalized Tikhonov". Using computer simulations, this method proved promising for blood flow estimation in the presence of the major sources of error: noise, tracer delay and dispersion. In comparison to the standard Tikhonov regularization, our method showed less sensitivity to the changes in regularization parameters that determine the extent of the regularization. To investigate the model we have designed a perfusion phantom which is very similar to actual tissues in terms of perfusion-related parameters such as blood volume, blood flow and the flow transition time. The signal to noise ratio, due to the similarity of the flow volume, is similar to that in actual perfusion measurements. The phantom has the capability of including or excluding the tracer delay and dispersion depending on the desired nature of experiments. Flow at every point of the phantom can be calculated using finite element methods. The perfusion phantom was used to verify the accuracy of the Generalized Tikhonov method and to compare it to the conventional methods.Ph.D.Biomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/61616/4/Ebrahimi.pd