Cardiovascular Disease (CVD) is the leading cause of death in the United States. CVD is

caused by a buildup of plaque in the blood vessels of the heart and brain. CVD is comorbid

with Peripheral Vascular Disease (PVD), which is a buildup of plaque in the extremities

and organs below the stomach. Medical imaging is a clinically indispensable tool for diagnosing CVD and PVD, as well as guiding real-time interventional procedures. Currently,

the two main procedures for diagnosing CVD and PVD are X-Ray and CT angiography,

both of which rely on injection of iodinated contrast agents. However, about 25% of patient

undergoing these procedures suer from Chronic Kidney Disease (CKD). For this patient

subpopulation, iodinated contrast agents are risky and can lead to complete kidney failure.

Physicians risk damaging patients' kidneys in order to alleviate the more imminent threat of

death from a heart attack. Hence, an open challenge remains to develop a safer diagnostic

angiography method that could match current methods in resolution, contrast, and speed.

Here we introduce and develop two new imaging methods for imaging patients with CKD.

The rst method is MR Saline Angiography, an alternative Magnetic Resonance (MR) based

angiographic method for coronary imaging. In combination with the inherent resolution and

speed of traditional MR methods, MR Saline Angiography has the advantage of utilizing

saline as a safe contrast agent. This approach is an improvement upon the commonly used

Gadolinium-based contrast agent that is also toxic to patients with CKD. Using a novel

electromagnetically shielded catheter and a tailored pulse sequence, we have demonstrated

that MR Saline Angiography is a feasible alternative for imaging coronary arteries. The second method is Magnetic Particle Imaging (MPI), a tracer imaging modality, which images

Superparamagnetic Iron Oxide nanoparticles. MPI is an emerging imaging technique with

possible applications in angiography as well as targeted and non-targeted tumor imaging,

hyperthermia, perufsion, cell tracking and targeted drug delivery. Here we study the feasibility

of MPI as an angiographic imaging method by looking at short-term biodistribution

and long-term iron clearance for two most common MPI tracers.

Magnetic Particle Imaging (MPI) is an emergent medical imaging technology that directly images the intense magnetization of clinically safe superparamagnetic iron oxide (SPIO) nanoparticles. Because biological tissues do not produce signals detectable in MPI scanners, MPI images have extremely high image contrast and sensitivity for SPIO tracers, akin to nuclear medicine imaging techniques. The MPI signal is also linearly proportional to SPIO tracer concentrations in the imaging volume, making it a truly quantitative imaging technique. Hence, because of its high image contrast, sensitivity, quantitativeness, and tracer safety, MPI may be useful in applications ranging from coronary angiography to stem cell therapy tracking and is extremely promising for translation to the clinic.

The physical basis behind signal generation in MPI is unlike that of any other imaging modality, giving MPI the potential to be one of the most sensitive medical imaging modalities. However, several limitations have prevented existing MPI scanners from reaching the physical limits of detection sensitivity. These limitations include direct feedthrough interference from the MPI transmitter to the receiver, which can obscure the desired SPIO magnetization signal and limit SNR. In Chapter 2 of this dissertation, I aim to determine the sources of interference generation in MPI scanners and to develop engineering solutions to attenuate the feedthrough interference in the detected signal spectrum. My results indicate that feedthrough interference can arise from high-power passive components used to generate the MPI drive fields, as well as from the interaction between the MPI drive field and the magnets used to generate the MPI magnetic field gradient. To remove these interfering signals for improved detection sensitivity, I designed an actively-controlled magnetic interference cancellation system using a Cartesian feedback controller. Data from this active cancellation system has shown the ability to suppress interfering MPI signals by over 55 dB.

Another limitation in the sensitivity of existing MPI scanners is the use of non-optimized electronics in the MPI detector chain, which can add substantial noise beyond the noise mechanisms generated in the patient and in the detector coil. In Chapter 3 of this dissertation, I investigate the sources of electronic noise in MPI and describe three methods to reduce noise from the MPI detector preamplifier to below the noise generated by the MPI detector coil. Using these noise-matching techniques, I then describe the design and implementation of a custom transformer-coupled MPI preamplifier. Finally, using a 7 T/m preclinical MPI scanner, I demonstrate that the custom MPI preamplifier can achieve an 11-fold improvement in the signal-noise ratio (SNR) of MPI scanners over a commercially available low-noise preamplifier.

Building upon these improvements in the sensitivity and SNR of our preclinical MPI scanners, I then perform the first two in vivo experiments to track implanted stem cell therapies in rodent models. In Chapter 4, we show that MPI can be used to sensitively and quantitatively track stereotactically implanted neural progenitor cell xenografts over an 87- day period. In Chapter 5, we show the first use of MPI to systemically monitor intravenously implanted therapeutic cells. MPI was able to visualize the entrapment of large mesenchymal stem cells in lung vasculature during circulation and quantify the gradual clearance of these cells through the liver over a period of 12 days. Importantly, these experiments demonstrate the ability of MPI to sensitively trace small quantities of SPIOs in the body, potentially enabling new clinical approaches to metastatic cancer detection and the diagnosis of other systemic diseases.

Magnetic particle imaging (MPI) is an emerging tracer imaging modality. In this work, we develop novel scanning strategies to improve the imaging performance of MPI and explore novel methods to use MPI for theranostic applications. A major focus is inventing and exploring different scanning strategies to overcome or leverage the magnetic relaxation dynamics associated with the tracers used in MPI in order to find optimal trade-offs in imaging performance metrics such as spatial resolution, SNR and scanning time. In the first part of this thesis, we perform an experimental study to underscore the significant discrepancy between experimental performance of large core size tracers and their theoretical performance, and demonstrate that this is a major obstacle to improving MPI performance. Subsequently, we describe the hardware design and construction of a frequency-flexible, arbitrary waveform tabletop scanner to enable the investigation of novel scanning strategies to help address this issue. Conventional MPI uses a single frequency excitation wave around 20 kHz. With this new device, we show the first study of non-sinusoidal excitation waveforms such as square, trapezoidal, triangle waveforms, and based on this, we design a novel approach to scanning and signal encoding in MPI which we name pulsed MPI (pMPI). Subsequently, we show that pMPI unlocks the potential of large core size nanoparticles by suppressing deleterious relaxation-based blurring effects. This enabled the first viable use of these nanoparticles which previously have been unusable in MPI. We also exploit the frequency-flexibility to optimize parameters for continuous (sinusoidal) wave MPI and elucidate an optimal waveform that achieves both good resolution and SNR where previous work has suboptimally traded-off one for another.

In the second part, we perform extensive preclinical studies as the first in vivo proof-of-concept of theranostic MPI. We show that MPI is unique as a theranostic modality due to many key advantages such as precise localization of therapy in vivo, an ability to receive measure and predict dosage based on image-guidance, and finally elucidate an approach for future development of real-time feedback for fine control and definite quantification of dosage. Our in vivo proof-of-concept results show robust localization of the heating dose deposited as well as therapeutic outcomes in a dual tumor xenograft rodent model. Importantly, we prove that this localization method can address one key challenge in Magnetic Hyperthermia, which is to avoid collateral damage to off-target organs such as the liver which tends to accumulate magnetic nanoparticles and is prone to unintended heat damage. Furthermore, we investigate aerosolized magnetic nanoparticles as a method to image the lungs with MPI. We demonstrate that MPI lung imaging with magnetic aerosol can be a viable alternative to clinically established radioaerosol procedures. This lays important groundwork for use of magnetic aerosols and MPI for safer lung imaging and lung theranostics in combination with the abovementioned work.

Magnetic Particle Imaging (MPI) is a noninvasive imaging modality that exploits the saturation properties of superparamagnetic iron oxide particles (SPIOs). A major thrust of MPI research aims to sharpen the magnetic resolution of biocompatible SPIOs, which will be crucial for affordable and safe clinical translation. We recently reported on a new class of MPI tracers —called superferromagnetic iron oxide nanoparticles (SFMIOs) — which offer much sharper magnetic saturation curves. SFMIOs experimentally demonstrate 5-13x improvement in both resolution and sensitivity. However, superferromagnetism is a relatively unexplored branch of physics and the nanoscale physics and dynamics of SFMIOs remain a mystery. Here we show experimentally that chaining of SPIOs can explain SFMIO’s boost in SNR and resolution. We show how concentration, viscosity, transmit amplitude, and prepolarization time can all affect SPIO chain formation and SFMIO behavior. These experiments will inform strategies on SFMIO chemical synthesis as well as SFMIO data acquisition pulse sequences.

Magnetic Particle Imaging (MPI) is an emerging imaging modality with potential clinical applications in rapid angiography, cell therapy tracking, cancer imaging, and inflammation imaging. While still in its infancy, MPI already has excellent contrast, safety, depth penetration, and sensitivity without the serious health risks posed by current modalities such as ionizing radiation and iodinated contrast agents.

With any tracer imaging modality, high sensitivity is necessary to improve safety and enable new clinical applications. The first Magnetic Computed Tomography (MCT) system and experimental images were created in this work with the goal of improving sensitivity in MPI. MCT uses projection reconstruction algorithms similar to those in X-ray computed tomography to reconstruct 3D images from a projection MPI sytem. Analytical derivation and experimental evidence demonstrate that MCT has an order-of-magnitude higher SNR than previous 3D MPI methods for the same scan time as well as a 40% resolution improvement. The MCT experimental system acquisition speed was improved from initial work to acquire images twenty-fold faster at less than two minutes per 3D image.

Critical to any medical imaging technology is the reliability and accuracy of image reconstruction. Unfortunately, prior approaches to x-space MPI reconstruction suffer from image artifacts such as banding and haze. In this work, a priori knowledge of image continuity and non-negativity are introduced into a new optimization formulation to reduce these non-physical artifacts in 2D and 3D reconstructions.

Magnetic particle imaging (MPI) is a novel medical imaging modality that spatially detects a tracer of superparamagnetic iron oxide nanoparticles (SPIOs) with high sensitivity, contrast, and no tissue penetration limitations. MPI has great potential for safer angiography, in vivo cell tracking, and cancer detection, among other applications. Current MPI theoretical descriptions and reconstruction techniques make an adiabatic assumption that the SPIO tracer instantaneously follows the applied magnetic fields of the MPI scanner. This assumption is not strictly true, and we refer to SPIO magnetization delays as relaxation effects.

We begin by extending the x-space theory of MPI to include relaxation effects. We choose this MPI theory because it directly converts the temporal MPI signal to the image (spatial) domain, lending itself well to investigating how relaxation time delays translate into spatial effects. Using the non-adiabatic x-space theory and experimentally-measured data, we demonstrate that relaxation blurs the x-space image in the scanning direction.

Next, we study how we may design MPI scanning sequences to minimize relaxation-induced blurring. From the non-adiabatic x-space theory we derive a mathematical description of how this blur can vary with scanning parameters for a given relaxation time. We compare theoretical predictions to experimental data by measuring relaxation times and spatial resolution under various scanning conditions. Despite increased relaxation time delays with slower scanning conditions, we observe that relaxation-induced blurring can be minimized when scanning slower.

Finally, we derive a magnetic field-driven relaxation mechanism called magneto-viscous relaxation. This mechanism describes how the applied magnetic field creates a magnetic torque on the SPIO, inducing physical rotation of the SPIO to align with the field; however viscous resistance of the carrier liquid hinders this movement. We compare predicted relaxation times to measured values for a range of SPIO characteristics and scanning conditions.

In this dissertation, we show how relaxation can have deleterious effects on the MPI signal and image. We explore how relaxation-induced blurring and relaxation times may be minimized through improved SPIO characteristics and MPI scanning sequence design. In addition to improving MPI image quality, this important area of research can lead to future clinical applications. Using this knowledge and specially-designed MPI pulse sequences, we can exploit variations in relaxation behavior as a source of contrast, which will increase the diagnostic potential of MPI.

Magnetic particle imaging (MPI) is a sensitive, high contrast tracer modality that directly images superparamagnetic iron oxide nanoparticles (SPIOs), enabling radiation-free theranostic imaging. With zero tissue signal, persistent biosafe tracers, and no ionizing radiation, MPI has shown great promise for cell tracking, vascular imaging, and imaging applications. Indeed, its capability for multi-month studies and exquisite contrast position itself uniquely for immune-cell based diagnoses and extended monitoring of immunotherapies. However, MPI resolution is currently limited by scanner and particle constraints. Recent tracers have experimentally shown 10x resolution and signal improvements, with dramatically sharper M-H curves. Experiments suggest that this results from interparticle interactions, conforming to literature definitions of superferromagnetism. We thus call our tracers superferromagnetic iron oxide nanoparticles (SFMIOs). While SFMIOs provide excellent signal and resolution, they exhibit hysteresis, with non-negligible remanence and coercivity. In my dissertation I provide the first report on MPI scanning with remanence and coercivity, including the first quantitative measurements of SFMIO remanence decay and reformation using a novel multi-echo pulse sequence. We also describe an SNR-optimized pulse sequence for SFMIOs under human electromagnetic safety limitations. I separately investigate ex vivo and in situ labeling neutrophils and macrophages and tracking to inflammation and immune activity with XY Zhou and P Chandrasekharan. I demonstrate the first antibody MPI (Ab-MPI) images using antibody-conjugated SPIOs (Ab-SPIOs), showing bone marrow and sites of lipopolysaccharide-induced myositis. Through bioluminescent imaging, electron microscopy, flow cytometry and histopathology, I confirm labeling and tracking of neutrophils and macrophages. Excitingly, our images are able to differentiate between the acute inflammation response from neutrophils, and the chronic response from macrophages. With the resolution improvements from SFMIOs, which could be used to reduce hardware costs by 100x, and the demonstrated applications of Ab-SPIOs, MPI demonstrates incredible potential for clinical diagnosis and immunotherapy monitoring.

Magnetic particle imaging (MPI) is an emerging tracer imaging modality with high sensitivity and ideal image contrast. MPI uses low-frequency magnetic fields to image the spatial distribution of superparamagnetic iron oxide (SPIO) tracers. There is ideal image contrast because background tissue (bone, muscle, blood, fat) produces no MPI signal. Moreover, there is zero depth attenuation of low-frequency magnetic fields in tissue, allowing for quantitative imaging. In this dissertation, I describe several new preclinical imaging applications which take advantage of the unique physics of MPI: lung perfusion imaging, white blood cell tracking, and enzyme-responsive nanocarriers.

Pulmonary embolism (PE), a blood clot in the lung, is usually diagnosed with CT pulmonary angiography. However, patients with poor renal function are not able to tolerate the high iodine dose. The MPI tracer is kidney-safe because it clears through the liver and spleen instead of the kidneys. Moreover, imaging around air-tissue interfaces such as those in the lung do not result in imaging artifacts (unlike in magnetic resonance imaging) because of the comparably low gradient homogeneity needed. Hence, MPI has ideal properties for a kidney-safe alternative lung perfusion imaging method. In Chapter 2, I show fabrication and optimization of the first MPI lung perfusion imaging agent, MAA-SPIO, and \textit{in vivo} lung perfusion images in a rat. I quantitatively track the biodistribution and clearance of the tracer over time. Additionally, I show that the lung perfusion imaging method can be paired with a method for lung ventilation imaging using aerosolized SPIOs. This allows for imaging of both the lung capillaries and lung airways.

In Chapter 3, I discuss MPI white blood cell imaging. This technique is of particular interest for tracking autologous cell-based immunotherapies, such as chimeric antigen receptor T cells (CAR-T). Moreover, the natural homing abilities of the WBCs can localize difficult-to-find infections, such as osteomyelitis, and a similar technique is used in nuclear medicine. However, MPI allows for effective long-term cell tracking because no radionuclide tag is used. I demonstrate dynamic imaging of MPI tracer-tagged white blood cells (WBC) administered to \textit{in vivo} mice, and initial work on tracking these WBCs in a mouse model of inflammation.

In Chapter 4, I demonstrate proof-of-concept work on a concept for enzyme-responsive nanocarriers. Tracers that can visualize and respond to the function of biological and cellular processes would allow for more specific disease diagnoses. I show that aggregated SPIOs have a quenched MPI signal as compared to stably-dispersed SPIOs, and that SPIOs can be encapsulated in a liposomal formulation. In the platform described, the enzyme hydrolyzes the SPIO-containing liposomes, and MPI signal quenching is observed. These projects represent novel work in diverse categories of MPI applications research, showcasing the strengths of the unique physics of MPI.