The Integration of Positron Emission Tomography With Magnetic Resonance Imaging

A number of laboratories and companies are currently exploring the development of integrated imaging systems for magnetic resonance imaging (MRI) and positron emission tomography (PET). Scanners for both preclinical and human research applications are being pursued. In contrast to the widely distributed and now quite mature PET/computed tomography technology, most PET/MRI designs allow for simultaneous rather than sequential acquisition of PET and MRI data. While this offers the possibility of novel imaging strategies, it also creates considerable challenges for acquiring artifact-free images from both modalities. This paper discusses the motivation for developing combined PET/MRI technology, outlines the obstacles in realizing such an integrated instrument, and presents recent progress in the development of both the instrumentation and of novel imaging agents for combined PET/MRI studies. The performance of the first-generation PET/MRI systems is described. Finally, a range of possible biomedical applications for PET/MRI are outlined

Contrast enhanced spectroscopic optical coherence tomography

A method of forming an image of a sample includes performing SOCT on a sample. The sample may include a contrast agent, which may include an absorbing agent and/or a scattering agent. A method of forming an image of tissue may include selecting a contrast agent, delivering the contrast agent to the tissue, acquiring SOCT data from the tissue, and converting the SOCT data into an image. The contributions to the SOCT data of an absorbing agent and a scattering agent in a sample may be quantified separately

New MRI Techniques for Nanoparticle Based Functional and Molecular Imaging

Although in clinical use for several decades, magnetic resonance imaging: MRI) is undergoing a transition from a qualitative anatomical imaging tool to a quantitative technique for evaluating myriad diseases. Furthermore, MRI has made great strides as a potential tool for molecular imaging of cellular and tissue biomarkers. Of the candidate contrast agents for molecular MRI, the excellent bio-compatibility and adaptability of perfluorocarbon nanoparticles: PFC NP) has established these agents as a potent targeted imaging agent and as a functional platform for non-invasive oxygen tension sensing. Direct readout and quantification of PFC NP can be achieved with fluorine: 19F) MRI because of the unique 19F signal emanating from the core PFC molecules. However, the signal is usually limited by the modest accumulated concentrations as well as several special NMR considerations for PFC NP, which renders 19F MRI technically challenging in terms of detection sensitivity, scan time, and image reconstruction. In the present dissertation, some of the pertinent NMR properties of PFC NP are investigated and new 19F MRI techniques developed to enhance their performance and expand the biomedical applications of 19F MRI with PFC NP. With the use of both theoretical and experimental methods, we evaluated J-coupling modulation, chemical shift and paramagnetic relaxation enhancement of PFC molecules in PFC NP. Our unique contribution to the technical improvement of 19F MRI of small animal involves:: 1) development of general strategies for RF 1H/19F coil design;: 2) design of novel MR pulse sequences for 19F T1 quantification; and: 3) optimization of imaging protocols for distinguishing and visualizing multiple PFC components: multi-chromatic 19F MRI). The first pre-clinical application of our novel 19F MRI techniques is blood vessel imaging and rapid blood oxygen tension measurement in vivo. Blood vessel anatomy and blood oxygen tension provide pivotal physiological information for routine diagnosis of cardiovascular disease. Using our novel Blood: flow)-Enhanced-Saturation-Recovery: BESR) sequence, we successfully visualized reduced flow caused by thrombosis in carotid arteries and jugular veins, and we quantified the oxygen tension in the cardiac ventricles of the mouse. The BESR sequence depicted the expected oxygenation difference between arterial and venous blood and accurately registered the response of blood oxygen tension to high oxygen concentration in 100% oxygen gas. This study demonstrated the potential application of PFC NP as a blood oxygen tension sensor and blood pool MR contrast agent for angiography. Another pre-clinical application investigated was functional kidney imaging with 19F MRI of circulating PFC NP. Conventional functional kidney imaging typically calls for the injection of small molecule contrast agents that may be nephrotoxic, which raises concerns for their clinical applications in patients with renal insufficiency. We demonstrated that our 19F MRI technique offers a promising alternative functional renal imaging approach that generates quantitative measurement of renal blood volume and intrarenal oxygenation. We successfully mapped the expected heterogeneous distribution of renal blood volume and confirmed the presence of an oxygenation gradient in healthy kidneys. We validated the diagnostic capability of 19F MRI in a mouse model of acute ischemia/reperfusion kidney injury. We also employed 19F MRI as a tool to test the therapeutic efficacy of a new nanoparticle-based drug, i. e. PPACK: D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone) PFC NP, which was postulated to inhibit microvascular coagulation during acute kidney injury. Based on our preliminary 19F MRI findings, we observed that PPACK PFC NP effectively reduced coagulation in our animal model, as evidenced by lesser accumulation of particles trapped by the clotting process. This finding suggests the potential for 19F MRI to be used as a drug monitoring tool as well in common medical emergencies such as acute kidney failure

Photoacoustic imaging using nanoclusters

Advances in novel imaging techniques and molecular probes are now extending the opportunity of visualizing molecular targets of disease. Molecular imaging provides anatomic as well as functional and pathological information to sense the expression of molecular biological events. In general, molecular imaging aims to target a specific cell type or tissue and visualize biological events in vivo at the molecular or cellular levels through specific probes. Molecular imaging is usually performed in conjunction with probes for specific targets. The objective of this dissertation is to explore molecular imaging by providing highly efficient photoacoustic nanocluster contrast agents to further validate in vivo molecular imaging, improve the therapeutic procedure, and study fundamental photoacoustic signal processes from cluster of nanoparticles. Initially, a photothermal stimuli-responsive photoacoustic nanocluster was designed and synthesized to provide highly sensitive dynamic contrast within tissue samples. The photoacoustic signal enhancement from clustering of nanoparticles was demonstrated by characterizing the photoacoustic signal from photothermal stimuli-responsive nanoclusters. After characterization, photothermal stimuli-responsive nanoclusters were injected into a mouse tissue and the dynamic photoacoustic response from the nanoclusters activated by an external laser source was observed. This activation can be repeatedly turned on by modulating input laser signals, suggesting a new route for dynamic photoacoustic contrast imaging that will further improve the imaging contrast and more accurately guide the drug release process. Despite tremendous advantages of using these nanoparticles, their safety in a biological environment could be a major hurdle for their in vivo utilization. In order to avoid accumulation and long-term toxicity of nanoparticles, biodegradable nanoclusters consisting of sub-5 nm primary gold particles stabilized by a weakly adsorbed biodegradable polymer were introduced. The photoacoustic signal from biodegradable nanoclusters was quantitatively characterized. In addition, photothermal stability of different sizes of biodegradable nanoclusters was investigated. These nanoclusters were then intravenously injected into mice and biodistribution of nanoparticles was observed. Finally, in vivo spectroscopic photoacoustic imaging was performed on tumor-bearing mice with antibody conjugated biodegradable nanoclusters. This research may provide a new opportunity for molecular imaging to help diagnose tumors at an early stage and promote clinical translation of these techniques.Electrical and Computer Engineerin

Raman spectroscopy for medical diagnostics - From in-vitro biofluid assays to in-vivo cancer detection

This is the final version of the article. Available from the publisher via the DOI in this record.Raman spectroscopy is an optical technique based on inelastic scattering of light by vibrating molecules and can provide chemical fingerprints of cells, tissues or biofluids. The high chemical specificity, minimal or lack of sample preparation and the ability to use advanced optical technologies in the visible or near-infrared spectral range (lasers, microscopes, fibre-optics) have recently led to an increase in medical diagnostic applications of Raman spectroscopy. The key hypothesis underpinning this field is that molecular changes in cells, tissues or biofluids, that are either the cause or the effect of diseases, can be detected and quantified by Raman spectroscopy. Furthermore, multivariate calibration and classification models based on Raman spectra can be developed on large "training" datasets and used subsequently on samples from new patients to obtain quantitative and objective diagnosis. Historically, spontaneous Raman spectroscopy has been known as a low signal technique requiring relatively long acquisition times. Nevertheless, new strategies have been developed recently to overcome these issues: non-linear optical effects and metallic nanoparticles can be used to enhance the Raman signals, optimised fibre-optic Raman probes can be used for real-time in-vivo single-point measurements, while multimodal integration with other optical techniques can guide the Raman measurements to increase the acquisition speed and spatial accuracy of diagnosis. These recent efforts have advanced Raman spectroscopy to the point where the diagnostic accuracy and speed are compatible with clinical use. This paper reviews the main Raman spectroscopy techniques used in medical diagnostics and provides an overview of various applications

Recent progress in photoacoustic molecular imaging

By acoustically detecting the optical absorption contrast, photoacoustic (PA) tomography (PAT) has broken the penetration limits of traditional high-resolution optical imaging. Through spectroscopic analysis of the target's optical absorption, PAT can identify a wealth of endogenous and exogenous molecules and thus is inherently capable of molecular imaging with high sensitivity. PAT's molecular sensitivity is uniquely accompanied by non-ionizing radiation, high spatial resolution, and deep penetration in biological tissues, which other optical imaging modalities cannot achieve yet. In this concise review, we summarize the most recent technological advancements in PA molecular imaging and highlight the novel molecular probes specifically made for PAT in deep tissues. We conclude with a brief discussion of the opportunities for future advancements

Recent progress in photoacoustic molecular imaging

By acoustically detecting the optical absorption contrast, photoacoustic (PA) tomography (PAT) has broken the penetration limits of traditional high-resolution optical imaging. Through spectroscopic analysis of the target's optical absorption, PAT can identify a wealth of endogenous and exogenous molecules and thus is inherently capable of molecular imaging with high sensitivity. PAT's molecular sensitivity is uniquely accompanied by non-ionizing radiation, high spatial resolution, and deep penetration in biological tissues, which other optical imaging modalities cannot achieve yet. In this concise review, we summarize the most recent technological advancements in PA molecular imaging and highlight the novel molecular probes specifically made for PAT in deep tissues. We conclude with a brief discussion of the opportunities for future advancements

Surface-Enhanced Coherent Raman scattering (SE-CRS) with Noble Metal Nanoparticles

Early cancer detection remains challenging due to numerous complex tempo-spatial metabolic changes in cell physiology. Based on their ability to recognise molecular structures and pathological changes at molecular levels, spectroscopic have recently emerged as promising non-invasive, non-ionising, and cost-efficient tools to help detect cancer, and other human pathologies. Raman spectroscopy is a valuable technique that provides information regarding the chemical properties of materials. Nevertheless, it has limitations due to the limited amount of Raman light scattered. Strategies for cancer diagnostics and therapies are based on the hypothesis that nanoparticles (NPs) can be precisely tailored to target cancer cells. However, the tools required to image NPs at cellular levels remain scarce in the literature. The work outlined in this thesis, for the first time, utilises noble metal NPs and Raman reporters, with the mechanisms of surface enhanced Raman scattering (SERS) and coherent anti-Stokes Raman scattering (CARS), in cancer cells and tumour spheroids to address the demerits of low spatial resolution, signal-to-noise ratio, and chemical specificity. SERS and CARS have broadly been explored in this regard. To increase the effectiveness of Raman scattering, a variety of techniques have been devised to boost its intensity. Primarily, I studied four techniques to increase Raman scattering intensity with the ultimate objective of improving sensitivity and assessing limits of various Raman methods: SERS, surface-enhanced coherent anti-Stokes Raman scattering (SE-CARS), surface-enhanced stimulated Raman scattering (SE-SRS), and broadband coherent anti-Stokes Raman scattering (BCARS). Coherent Raman scattering (CRS) is utilised to enhance weak Raman bands. The signal is enhanced by nonlinear interaction of the excitation lasers within the sample. Despite the advantages offered over Raman, CRS has been relatively unexploited for image Raman tagged NPs. This challenge has recently been addressed using surface plasmon enhancement, which gives significantly enhanced inelastic scattering signals as well as reduced signal-to-noise ratio. Surface-enhanced coherent Raman scattering (SE-CRS) has been characterised by using a variety of techniques such as SERS, CARS, and SE-CARS. This work provides a step forward to develop plasmon enhanced SRS and CARS in addressing critical biological questions using nonlinear bio-photonics. In the first part of this thesis, I developed a reproducible substrate that mimics gold nanoparticles (AuNPs) and allows forward detection which is critical for CRS. I investigated the effects of annealing on gold films deposited on glass substrates with thicknesses from 3 nm to 15 nm as described in depth in chapter 5. In addition to this, it provides an explanation of the work that was performed to explore the interaction between Raman tags BPT (biphenyl-4-thiol), BPE trans-1,2-bis(4-pyridyl) ethylene, and IR 820 (new indocyanine green) on gold films substrates using 785 nm laser excitation. In the second part of this thesis, I investigated the interactions between Raman tags of BPT on gold films substrates using CRS and broadband CARS techniques. These experiments also offer the SE-CRS enhancement signal. The research done to examine gold thin film substrates and to offer SE-SRS and SE-CARS enhancement signals in the fingerprint region as described in chapter 6. Using CRS microscopy, the investigations in this chapter study these interactions. In the third part of this thesis, I developed a novel imaging methodology for the visualisation of AuNPs inside cellular structures and spheroids, with the intention of acquiring distinct spectroscopic fingerprints. Consequently, I undertook the task of devising protocols for visualising AuNPs and Raman reporter molecules within cancer cell models, spheroids, and animal tissues as described in chapter 7. The aim was to attain distinctive spectroscopic profiles by employing the SE-CRS technique, achieved by illuminating AuNPs along with Raman reporter molecules (BPT, BPE, IR 820) using low intensity infrared light, with both the pump and Stokes beams operating at intensities below 0.2 mW. In summary, this thesis sheds light on the development of surface plasmon resonance phenomena based on metallic nanostructures for use in nonlinear inelastic scattering systems, including surface-enhanced Raman scattering (SERS), coherent Raman scattering (CRS), and surface-enhanced coherent Raman scattering (SE- CRS). The primary focus is to use this system for disease diagnostics, rooted in SERS, reflects a commitment to advancing cancer diagnostics, based on SERS thereby enhancing the precision and discrimination of molecular signals, making a significant stride towards more effective and nuanced cancer diagnostics

Optical and X-Ray Technology Synergies Enabling Diagnostic and Therapeutic Applications in Medicine

X-ray and optical technologies are the two central pillars for human imaging and therapy. The strengths of x-rays are deep tissue penetration, effective cytotoxicity, and the ability to image with robust projection and computed-tomography methods. The major limitations of x-ray use are the lack of molecular specificity and the carcinogenic risk. In comparison, optical interactions with tissue are strongly scatter dominated, leading to limited tissue penetration, making imaging and therapy largely restricted to superficial or endoscopically directed tissues. However, optical photon energies are comparable with molecular energy levels, thereby providing the strength of intrinsic molecular specificity. Additionally, optical technologies are highly advanced and diversified, being ubiquitously used throughout medicine as the single largest technology sector. Both have dominant spatial localization value, achieved with optical surface scanning or x-ray internal visualization, where one often is used with the other. Therapeutic delivery can also be enhanced by their synergy, where radio-optical and optical-radio interactions can inform about dose or amplify the clinical therapeutic value. An emerging trend is the integration of nanoparticles to serve as molecular intermediates or energy transducers for imaging and therapy, requiring careful design for the interaction either by scintillation or Cherenkov light, and the nanoscale design is impacted by the choices of optical interaction mechanism. The enhancement of optical molecular sensing or sensitization of tissue using x-rays as the energy source is an important emerging field combining x-ray tissue penetration in radiation oncology with the molecular specificity and packaging of optical probes or molecular localization. The ways in which x-rays can enable optical procedures, or optics can enable x-ray procedures, provide a range of new opportunities in both diagnostic and therapeutic medicine. Taken together, these two technologies form the basis for the vast majority of diagnostics and therapeutics in use in clinical medicine