Dissertations / Theses on the topic 'X-ray contrast agent'

Computed Tomography is one of the most important image modalities in medical imaging nowadays. Recent developments have led to a new acquisition technique called 'dual-energy', where images are taken with different x-ray spectra. This enables for the first time spectral information in the CT dataset. Our approach was to use an energy resolving detector (Medipix) and investigate its potential in the medical imaging domain. Images are taken in different energy bins. For acquisition of the data, a CT scanner called 'Medipix All Resolution System' (MARS) scanner was constructed. It was upgraded to achieve better image quality as well as faster scan time and a stable operation. In medical imaging, it is important to achieve a high contrast and a good detail recognition at a low dose. Therefore, it is common practice to use contrast agents to highlight certain regions of the body like e.g. the vascular system. But with a broad spectrum acquisition, it is often impossible to distinguish highly absorbing body elements like bones from the contrast agent. We target this problem by a contrast agent study using different energy bins. This so called spectral contrast agent study has been conducted with small animals using the MARS scanner. The data has been processed to create an optimal CT reconstruction. The image enhancement techniques consist of corrections for noisy pixels, intensity fluctuations and eliminating streaks in the sinograms to reduce ring artifacts. In order to evaluate the data, we used two methods of material identification. The material reconstruction method works on projection data and uses a maximum-likelihood estimation to reconstruct images of base materials. The second method, the principal component analysis (PCA), identifies the relevant information from the spectral dataset in a few derived variables that account for most of the variance in the dataset. This resulted in images with enhanced contrast and removed redundancies. It is possible to combine these images in one colour image where anatomical structures are shown in good detail and certain materials show up in different colors. Based on this new information from spectral data, we could show that it is possible to distinguish the spinal bone from contrast agent.

The author discusses the difficulties that arise with the determination of the concentration of the iodinated contrast agents in the blood stream via the traditional gray-scale computer tomography and searches for the new imaging modalities that would provide for better sensitivity. The topic of the energy-discriminative color CT is discussed as a potential solution and its suitability is evaluated by performing the experiments on the contrast materials phantom and the phantom containing the iohexol solutions of varying concentrations on the original CT system assembled by the author. A method of the effective atomic number mapping is discussed as a viable alternative to the traditional attenuation-based tomography. The dependency of the effective atomic number of the compound on the energy of the x-ray beam is a phenomenon well recorded in the literature, yet no formal study exists to correctly predict the effective atomic number for a given compound. An extensive physical model is developed based on the previously presented models and adaptations unique to the task in order to determine the effective atomic numbers for exact energies experimentally. The method is tested on different materials. The resultant effective atomic numbers for the water, oil, and iohexol-water solutions of varying concentrations are presented in the study. The effects of the k-edge on both the linear attenuation curve and the effective atomic number curve are discussed. The possible future venues of the research are presented in the final part of the thesis.
Master of Science

During the PhD course my research projects focused mainly on the effectiveness, safety and optimisation of contrast agents in computed tomography (CT) and magnetic resonance imaging (MRI), subdivided into different studies. This doctoral thesis aims at explore the possible optimisation of contrast medium administration protocols in different clinical contexts. In the first section of my thesis, we proposed two studies focused on the optimisation of the practice of iodinated contrast medium (ICM) injection in CT. First, we tried to verify the conditions for a change in the dose calculation to be administered in patients undergoing an abdominal CT. Since decades, it is an established practice to inject a dose of ICM calculated on the patient total body weight (TBW). However, this approach does not consider the different volume of biodistribution among patients with different body mass index (BMI). Indeed, it was demonstrated that the ICM poorly distributes in adipose tissue and obese patients may receive a higher dose than that really needed. We have hypothesized that dosing ICM as based on the lean body weight (LBW) would be a more appropriate approach. We firstly retrospectively calculated an ICM dose based on LBW that was equivalent to the dose based on TBW in terms of liver contrast enhancement (LCE). We found that the injected ICM dose was highly variable, with underweight patients receiving a higher dose than obese patients, as a radiologist-driven compensation effect. Starting from the results obtained from the retrospective study, we conducted a randomized controlled trial based on the dose equivalent between the ICM based on patient TBW and the dose calculated using LBW. The Ethics Committee approved the single-center, double-blinded randomized controlled trial (trial registration NCT03384979). Patients were randomized to LBW-based ICM dose (0.61 gI/kg of lean body weight), or TBW-based ICM dose (0.44 gI/kg of TBW) and these equivalent doses derived from the retrospective study. In conclusion, LBW- and TBW-based ICM doses lead to a similar LCE with no significantly different variation for the LBW group, negating the study hypothesis and highlighting the knowledge gap about factors affecting LCE. The last part of the section I aimed to systematically review contrast-enhanced spectral mammography (CESM) studies, focusing on adopted CESM technique, ICM issues and adverse reactions ICM related. Of 120 retrieved articles, 84 were included, totalling 14,012 patients. Contrast type and concentration was reported in 79/84 studies (94%), with Iohexol 350 mgI/mL mostly used (25/79, 32%), dose and flow rate in 72/84 (86%), with 1.5 mL/kg dose at 3 mL/s in 62/72 studies (86%). Thirty adverse reactions were reported by 14/84 (17%) studies (26 mild, 3 moderate, 1 severe non-fatal) with a pooled rate of 0.82%. Factory-set kVp, contrast 1.5-mL/kg at 3 mL/s, and 120-s acquisition delay were mostly used and only 1 severe adverse reaction was reported. In the second PhD thesis section, I focused on gadolinium-based contrast agent (GBCA) protocol issues. A systematic review was conducted in collaboration with the University College Dublin (Dublin, Ireland) during the six months fellowship and it was regarding GBCA administration protocols used for cardiothoracic applications of time-resolved (TR) magnetic resonance angiography (MRA) sequences. A search of the literature was performed to identify articles utilising TR-MRA sequences, focusing on type of sequence, adopted technical parameters, GBCA issues and acquisition workflow. Of 117 retrieved articles, 16 matched the inclusion criteria and study population ranged from 5 to 185 patients, for a total of 506 patients who underwent cardiothoracic TR-MRA. The administered GBCA was gadobutrol (Gadovist) in 6/16 (38%) articles, gadopentetate dimeglumine (Magnevist) in 5/16 (31%), gadobenate dimeglumine (Multihance) in 2/16 (13%), gadodiamide (Omniscan) in 2/16 (13%), gadofosveset trisodium (AblavarTM) in 1/16 (6%). GBCA showed highly variable doses among studies: fixed amount or based on patient body weight (0.02–0.2 mmol/kg). In conclusions, a consensus on technique for cardiothoracic applications of TR-MRA is still far from reached, mostly due to differences regarding contrast agent type and dose. Further studies are warranted to provide a common standardised acquisition protocol.

L’imagerie biomédicale est aujourd’hui un outil essentiel pour établir un diagnostic grâce à l’observation des tissus et des fluides biologiques. L’usage d’instruments à imagerie combinée avec des produits de contraste est la clé pour réussir à distinguer précisément un tissu ciblé via l’accumulation de produit de contraste dans le tissu. Les deux principaux appareils à imagerie utilisés sont le scanner à rayons X et l’imagerie à résonance magnétique (IRM). Ils sont fréquemment employés en complément de l’un et l’autre. Typiquement, de petites molécules iodées hydrophiles sont utilisées comme produit de contraste pour la radiographie à rayons X tandis que l’IRM implique des matériaux magnétiques tels que des nanoparticules d’oxyde de fer. Dans le cadre de ce projet doctoral, nous avons donc proposé deux nouveaux produits de contraste dont le premier visait à constituer une alternative aux produits iodés dont la rapide élimination et la toxicité rénale forment deux problèmes récurrents et un second produit, cette fois-ci bimodale, afin de faciliter les procédures d’imagerie bimodale. Pour le premier point, des nanoparticules de polymères iodés pour l’imagerie à rayons X ont été formulées et ce, par une technique de nanoprécipitation. Les paramètres de formulation ont été élucidés de telle sorte que les nanoparticules possédaient une distribution de taille adaptée pour l’administration par voie intraveineuse et une teneur en iode suffisante en iode pour contraster sous rayons X. Une étude in vivo a révélé le potentiel du produit de contraste à visualiser distinctement le foie et la rate et ce, tout en ne présentant pas les principaux problèmes des produits iodés commerciaux. La seconde étude a eu pour but de formuler des nano-véhicules lipidiques capables de générer un contraste pour l’imagerie à rayons X et l’IRM de par l’incorporation d’huile iodée et de nanoparticules d’oxyde de fer dans le coeur de nano-émulsions. Ceci avait pour objectif de fournir une plateforme nanoparticulaire bimodale pour réaliser efficacement et rapidement des procédures d’imagerie multimodale. Nous avons réussi à produire un efficace agent de contraste bimodal permettant d’observer distinctement le foie et les reins par IRM et le foie et la rate par imagerie à rayons X. La pharmacocinétique de la substance administrée a ainsi pu être mise en avant grâce à la bimodalité de l’agent. Employer l’IRM a permis de montrer qu’une fraction de la dose injectée était éliminée par voie rénale tandis que l’imagerie à rayons X a confirmé que les deux tissus, foie et rate,étaient passivement ciblés par l’agent de contraste. Ces deux études ont donc fournies de potentielles solutions pour répondre aux besoins en produits pour l’imagerie à rayons X et en formulations facilitant l’imagerie bimodale des tissus mous
Biomedical imaging is nowadays an essential tool to establish a diagnosis by means of observation of tissues and biological fluids. Combination of imaging instrument with contrast enhancers is a key to obtain clear delineation of a desired tissue by accumulation of a contrast agent into this specific target. The two main imagers are the X-ray scanner and the magnetic resonance imaging (MRI).These imagers are frequently used in conjuncture. Typically, small hydrosoluble iodinated molecules are used as contrasting material for radiography whereas MRI involves magnetic materials like iron oxide nanoparticles. In this work, we proposed two novel contrast agents, the first one was aiming to form an alternative to iodinated contrast agents suffering from fast excretion and causing renal toxicity whereas the second one was aiming at providing bimodal contrasting ability to facilitate access to bimodal imaging procedure in clinics. In the first case, iodinated polymeric nanoparticles, serving for preclinical X-ray imaging were formulated by nanoprecipitation technique. Parameters of formulation were elucidated to provide nanoparticles with size distribution suitable for in vivo administration and high iodine content for contrast enhancement. In vivo study revealed the efficacy of our nanoparticles to clearly visualize liver and spleen and limiting current issues associated with marketed radiopaque contrast agents. The second work achieved was aiming at formulating bimodal lipids-based nanocarriers capable of yielding contrast enhancement for X-ray imaging and MRI by combining iodinated oil and iron oxide nanoparticles within a nano-emulsion core. This would provide bimodal nanoparticulate platform to carry out fast and efficient dual modal imaging procedures. In this context we succeeded to generate efficient dual modal contrast agent yielding clear visualization of liver and kidney by MRI and liver and spleen by X-ray imaging. Pharmacokinetic profile was so determined thanks to bimodal imaging. Using MRI allowed to show that kidneys eliminated a fraction of the dose whereas X-ray imaging confirmed that both tissues, liver and spleen, were passively targeted. These two studies proposed solutions limiting current issues of radiopaque contrast agents and novel formulations to facilitate bimodal imaging for soft tissues imaging

La micro-tomodensitométrie à rayons X (dite micro-CT, CT = Computed Tomography), est une technique d’imagerie de haute résolution qui consiste d’une part à mesurer l’absorption des rayons X par les tissus, et d’autre part de reconstruire les images et les structures anatomiques en 3 dimensions par traitement informatique. L’agent de contraste est une substance capable d’améliorer la visibilité des structures d’un organe ou d’un liquide organique in vivo. Ce travail de thèse a eu pour objectif le développement d’agents de contraste iodés sous formes de nano-émulsions pour des applications précliniques en imagerie biomédicale. Nous nous sommes proposés d’étudier d’une part des nano-émulsions iodées afin d’avoir une longue rémanence vasculaire in vivo, une meilleure biocompatibilité et d’autre part de mettre au point une synthèse et une formulation plus simples que celles des agents de contraste nanoparticulaires commercialisés. Trois différentes huiles iodées ont été synthétisées et utilisées comme partie contrastante dans les nano-émulsions. Enfin, les nano-émulsions de l’α-tocophérol iodé nous ont permis d’atteindre l’objectif de cette thèse. Ces nano-émulsions iodées ont montré une très bonne biocompatibilité et combinent à la fois les propriétés d’un agent de contraste à longue rémanence vasculaire et un agent de contraste spécifique du foie
The X-ray microtomography (called mico-CT, CT = Computed Tomography) is a high-resolution X-ray tomography, uses X-rays to create cross-sections of a 3D-object that later can be used to recreate a virtual model without destroying the original model. The contrast agent is a substance used to enhance the contrast of structures or fluids within the body in medical imaging. The purposes of the thesis were the development of iodine-containing nano-emulsion based contrast for preclinical applications in biomedical imaging. We proposed to study blood pool contrast agents based on iodine-containing nano-emulsions and to develop simpler procedure for the preparation of these iodine-containing nano-emulsions. Three different iodinated oils were synthesized and used as the contrasting part in the nano-emulsions. Finally, nano-emulsions of iodinated α-tocopherol have been enabled us to achieve the purpose of the thesis. These iodinated nano-emulsions demonstrated very good biocompatibility and showed prolonged and significant contrast enhancement in both bloodstream and liver tissues

Bismuth based nanomaterials have recently attracted attention as heavy element X-ray contrast agents because of the high atomic number and predicted biological compatibility of bismuth. Nanoparticle X-ray contrast agents may enable a number of novel medical imaging applications, including blood pool and site-directed imaging. However these hypothetical applications are hindered by lack of suitable synthetic methods for production of imaging agents. This dissertation describes synthesis of a novel class of bismuth nanoparticles that are aqueously stabilized using poly and monosaccharides. These particles are synthesized using highly biologically compatible reagents and are oxidatively stable in water and in moderately basic buffered solutions. Bismuth nanoparticles stabilized by the polysaccharide dextran have a large hydrodynamic radius and a relatively small bismuth nanocrystal core (4% bismuth by volume.) Glucose-capped particles have a much higher ratio of bismuth by volume (>60%), and experimental CT scans of these particle solutions demonstrate higher X-ray contrast versus a current clinically used radiocontrast agent. Additional syntheses of hydrophobic organoamine-capped bismuth nanoparticles by reduction of an iodobismuth cluster, and development of other X-ray contrast materials, such as a radiopaque surgical sponge marker and ink, using bismuth micoparticles produced by a top-down ball milling method, are also described.

Gold nanoparticles (Au NPs) always fascinated the scientific community, demonstrating several applications in nano-medicine, due to the peculiar properties of this metal at the nano-metric scale. First of all, gold is characterized by a strong inert nature, resisting to the air oxidation and corrosion. This chemical non-reactivity is correlated to a bio-inert nature of the metal that makes it an outstanding candidate for the development of in vitro and in vivo devices. Despite this great inertness, Au can form stable bonds with sulphur containing compounds, like thiols or disulfides. Exploiting this kind of chemistry is possible to easy and robustly functionalize Au NPs with different types of polymers, bio-molecules or targeting moieties. Moreover, Au NPs possess fascinating optical properties like localized surface plasmon resonance (LSPR), photoluminescence, enhancement of Raman signals and elevated X-rays attenuation. By tuning the Au NPs size, shape, coating, labelling and active targeting it is possible to obtain designed platforms acting as therapeutic, diagnostic or theranostic agents. In the present thesis are investigated three fundamental aspects correlated with the employment of gold nanoparticles in biomedicine. Au NPs, thanks to the high density and atomic number, present an elevated X-ray absorption coefficient. These NPs, if properly functionalized, can act as effective CT contrast agent and can be easily visualized by mean of in vivo micro-CT analysis. Here in is reported a methodology for the synthesis of highly stable and functionalized Au. The presented method allowed us to tune the surface coatings and the morphology of the Au NPs, designing a “one-pot” synthesis of engineered isotropic and anisotropic nanoparticles. The present study is devoted to elucidate the major factors involved in the in vivo biodistribution of PEGylated Au NPs. The effects of NPs structural parameters (eg. charge, shape and dimension) on the circulation time in the blood pool were analysed. From this study, we derived interesting information, generally applicable to the design of different types nano-structured contrast agents. Furthermore, other two fundamental topics involved in the design of effective nano-structured contrast agents has been investigate: the nanoparticles renal clearance and the active targeting toward inflamed tissues. Moreover, in the present thesis is investigated the interaction of surface functionalized Au NPs with the biological matter. When nanoparticles come in contact with biological materials, bio-molecules are adsorbed on their surface. This phenomenon causes a modification the identity of the systems and an uncontrolled aggregation of the NPs. The investigation of this phenomenon is fundamental to understand both the intracellular dynamics and the physiological behaviour of the nanoparticles. It is essential to consider these factors in the design of nano-systems effectively applicable in the biomedical field. In particular, in the present study, Fluorescence Correlation Spectroscopy (FCS) has been exploited to acquire information on the diffusion times of surface functionalized Au NPs, both in protein solution and in living cells. In the last chapter is investigated a more technical issue, related to the nanoparticles synthesis. In order to think to a reliable application of the nanotechnologies in the biomedical field, innovative synthetic procedure needs to be identified, to ensure a scale up and higher reproducibility of the production. A fluidic manufacturing method for the production of structurally controlled Au NPs was developed. Fluidic chemistry is a promising technology that can address to the scale up and reproducibility issues that affect the nano-materials production. The presented manufacturing method demonstrated to be strongly versatile, allowing the one-pot production of nano-materials with controlled shape, and engineered surface, readily applicable in a vast number of fields.

L’objectif de cette thèse est de réaliser un agent de contraste vasculaire pour tomodensitométrie utilisable en préclinique. En collaboration avec le laboratoire de biogalénique de Strasbourg, ce travail a permis d’obtenir des nano-émulsions iodées produites par diffusion spontanée de surfactif et des nanoparticules iodées produites par ”émulsion - diffusion de solvant”, comme agent de contraste vasculaire. Ces émulsions et particules polymériques présentent en effet, un temps de rémanence vasculaire de plusieurs heures, un pouvoir contrastant suffisant pour un usage en tomodensitométrie (compris entre 170 et 400 HU), la possibilité de les administrer par intraveineuse et une stabilité de plusieurs mois. Les nano-émulsions, notamment celles produites à partir de Lipiodol®, sont les plus prometteuses comme agents de contraste vasculaire de par leur forte radiopacité (475 ± 30 HU) et leur rémanence vasculaire (T1/2 of 4.1 ± 1.10 h). Les nanoparticules iodées à base de PCL présentent un pouvoir contrastant inférieur (168 ± 13 HU) mais elles sont connus pour leur capacité à modifier la libération du principe actif encapsulé. De ce fait même si les agents de contraste de nature lipidique ou ceux inorganiques sont plus performant, elles restent intéressantes pour une visualisation rapide de la distribution du principe actif dans l’organisme. Cette thèse par ailleurs, apporte plusieurs éléments pour la compréhension de la formulation des nano-émulsions obtenues par diffusion spontanée de surfactif et celle des nanoparticules produites par ”émulsion - diffusion de solvant”. Concernant les nano-émulsions, l’influence de l’iodation des huiles et du surfactif a été étudiée autant sur le plan pharmacotechnique que ceux toxicologique et pharmacocinétique. Concernant les nanoparticules à base de PCL, nous avons montré que l’impact du type d’huile et de l’iodation, des polymères PCL et PCL-mPEG et de diverses méthodes de concentration sur la formulation
The aim of this thesis is to formulate a blood pool contrast agent for preclinical X-ray imaging application. In collaboration with the galenic laboratory of Strasbourg, this work has allowed to obtain iodinated nano-emulsions produced by spontaneous diffusion of surfactant and nano-particles produced by iodine ”emulsion - solvent diffusion” as blood pool contrast agent. These emulsions and polymer particles present indeed a vascular persistence of several hours, a sufficient contrast to be use in computed tomography (between 170 and 400 HU), the ability to be administered intravenous and stability of several months. Nano-emulsions, including those produced from Lipiodol®, are the most promising as blood pool contrast media by their high radiopacity (475 ± 30 HU) and vascular persistence (T1/2 of 4.1 ± 1.10 h). Iodinated nano-particles of PCL have a lower X-ray attenuation (168 ± 13 HU), but they are known for their control release of the encapsulated substances. Therefore even if inorganic or lipidic contrast agents show a better contrast, they remain attractive for rapid visualization of the co-encapsulated substance distribution in the body. This thesis also introduced several features for understanding the formulation of nano-emulsions obtained by spontaneous diffusion of surfactant and the nano-particles produced by ”emulsion - solvent diffusion.”

The work in this thesis involves the development of a protected transesterification route for the production of novel cyanoacrylate monomers. As well as the modification of iodinated contrast agents to increase their solubility in cyanoacrylate, to enable monitoring of the adhesive within the body for possible use in the treatment of brain aneurysms. Chapter 1 provides an introduction to biological adhesives, in particular alky 2-cyanoacrylates and how they degrade to release formaldehyde. Details into iodinated X-ray contrast agents, their structure, uses and synthesis, as well as the current treatments for brain aneurysms. Chapter 2 focuses on the modification of several iodinated contrast agents in order to increase solubility in ethyl cyanoacrylate. Three existing contrast agents were protected using a variety of different protecting groups and tested for solubility in ethyl cyanoacrylate. Partition coefficients were calculated for the successfully modified compounds. Chapter 3 outlines the development of the anthracene protected route for the synthesis of cyanoacrylate monomers, utilising the Diels- Alder and retro-Diels-Alder reactions of anthracene. This route was subsequently used to synthesis a range of cyanoacrylate monomers. Polymerisation of these monomers gave a range of polymers which were tested to determine their rate of degradation through formaldehyde detection. Chapter 4 further details the first and final step of the anthracene protected route developed in chapter 3. It involved 1H NMR experiments to determine how substitution at the 9 and 10 position of anthracene affects the rate of reaction of the forward and retro-Diels-Alder reaction.

Zero-dimensional graphene (carbon) quantum dots have been drawing attention in bio-related applications since their discovery, especially for their optical properties, chemical stability, and easily modifiable surface.  This thesis focuses on the green synthesis of nitrogen-doped graphene quantum dots (GQDs) for dual-mode bioimaging with X-ray fluorescence (XRF) and optical fluorescence. Both conventional and microwave- (MW-)assisted solvothermal methods were followed to investigate the precursors’ effect on the synthesized GQDs. The MW-assisted method permitted the synthesis of uniform GQDs with an excitation-independent behavior, due to highly controllable reaction conditions. It was demonstrated that the molecular structure of the precursors influenced the optical fluorescence properties of the GQDs. Thus, both blue- (BQDs) and red-emitting (RQDs) GQDs were obtained by selecting specific precursors, leading to emission maxima at 438 and 605 nm under the excitation wavelengths of 390 and 585 nm, respectively.  Amine-functionalized Rh nanoparticles (NPs) were chosen as the X-ray fluorescence (XRF) active core, synthesized via MW-assisted hydrothermal method with a custom designed sugar ligand as the reducing agent. These NPs were conjugated with BQDs using EDC-NHS treatment. The hybrid Rh-GQDs NPs exhibited green emission (520 nm) under 490 nm excitation and led to a reduced cytotoxicity with respect to bare Rh NPs, highlighting the passivation role of the GQDs via the real-time cell analysis (RTCA) assay. The hybrid complex constituted a multimodal bioimaging contrastagent, tested with confocal microscopy (in vitro) and XRF phantom experiments.
Sedan deras upptäckt har nolldimensionella kvantprickar av grafen (kol) uppmärksammats inom biorelaterade applikationer, särskilt för deras optiska egenskaper, kemiska stabilitet och enkelt modifierbara yta. Denna avhandling fokuserar på en grön syntesmetod av kvävedopade grafen-kvantprickar för bimodal bioavbildning med röntgenfluorescens och optisk fluorescens. Både konventionella och mikrovågs-assisterade solvotermiska syntesmetoder användes för att undersöka metodernas effekt på de syntetiserade kvantprickarna. Den mikrovågs-assisterade metoden möjliggjorde syntes av uniforma kvantprickar med exciteringsoberoende egenskaper på grund av mycket kontrollerbara reaktionsförhållanden. Det demonstrerades att den molekylära strukturen hos prekursorerna påverkade de optiska fluorescensegenskaperna hos grafen-kvantprickarna. Genom att välja specifika prekursorer erhölls kvantprickar som emitterar i både blått och rött ljus, motsvarande emissionsmaxima vid 438 respektive 605 nm under excitering vid 390 respektive 585 nm. Amin-funktionaliserade Rh-nanopartiklar valdes som en aktiv kärna för röntgenfluorescens, syntetiserad genom en mikrovågs-assisterad hydrotermisk metod med en specialdesignad sockerligand som reduktionsmedel. Dessa nanopartiklar konjugerades med blåemitterande kvantprickar genom EDC-NHS-behandling. De hybrida nanopartiklarna uppvisade grön emission (520 nm) under 490 nm excitation och ledde till en minskad cytotoxicitet uppmätt genom cellanalys i realtid (RTCA) jämfört med endast Rh-nanopartiklar, vilket framhävde passiveringsrollen som kvantprickarna spelar. Hybridkomplexet utgjorde ett multimodalt kontrastmedel för bioavbildning, vilket demonstrerades med konfokalmikroskopi (in vitro) och fantomexperiment med röntgenfluorescens.

¨This thesis focuses on evaluating the dual-modal Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) capabilities of contrast agents. For such purposes a gadolinium based contrast agent is of high interest, due to its paramagnetic properties, which while present inside a magnetic field will hence interact with the protons spins of water (in tissue and fat) and shorten their the T1 relaxation time, thereby creating a positive image contrast in MRI. Furthermore, the X-ray Mass Attenuation Coefficient (MAC) of gadolinium is relatively high, thus suggesting its potential use, also as a CT contrast agent. Gadolinium nanoparticles (GdNPs) can be loaded into cells, such as macrophages, which offers the possibility to track cells inside entire organisms. In the first step the uptake of GdNPs inside cells was investigated, together with a test for toxicity. To show the potential of using GdNP loaded macrophages for functional imaging of inflammation, an acute allergic airway inflammation mouse model (mimicking asthma in humans) was used and analyzed by in-situ synchrotron phase contrast CT. In the first step this approach was evaluated using macrophages loaded with a clinical contrast agent containing barium sulphate (BaSO4), since this agent is known to provide high contrast in CT. In the ultimate step a combination of both BaSO4 and GdNP loaded macrophages was used in the same asthmatic mouse model and analyzed by dual modal Synchrotron phase contrast CT and Micro Magnetic Resonance Imaging (μ-MRI). Complementary results in terms of the biodistribution of injected macrophages could only be obtained by the combination of both synchrotron phase contrast CT and μ-MRI, where the first modality allows a detailed localization of clustered BaSO4 loaded macrophages, but fails to detect single macrophages, which could instead be indirectly observed by μ-MRI as an increase of the T1-contrast, coming from the soft tissue of mice injected with GdNP loaded macrophages.

The first fullerene-based X-ray contrast agent (CA) has been designed, synthesized, and characterized. The new CA is an externally functionalized derivative of C60 that is conceptually based on contemporary X-ray CA, all of which use iodine as the X-ray attenuating vehicle and are built on the 2,4,6-triiodinated-benzene-ring substructure. Aqueous solutions of the agents are injected intravenously via catheter into patients followed by X-ray imaging. The CA is then eliminated rapidly through the kidneys. A modified Bingel-type reaction (nucleophilic cyclopropanation) was developed in which 6 iodine atoms can be appended to C60 (per addend) to form a cyclopropane ring exclusively across one of the [6,6] double bonds of C60. Each addend contains two 2,4,6-triiodinated-benzene-ring moieties attached to a malonodiamide functionality through a nitrogen in the 5 ring position, with water-solubilizing 1,3-diol-containing serinol-benzamide substituents in the remaining ring positions (1 and 3). When the malonodiamide is reacted with C60 in excess (≥3 molar excess), however, only the fullerene monoadduct forms in good yield, with only small amounts of the diadduct detected. A general method for producing highly water-soluble, non-ionic fullerene materials was simultaneously developed. The synthetic approach also utilizes the new malonodiamide addend methodology to form multiple Bingel adducts with C60 to give C60[C(COSer)2]n (n = 4, 5, 6, Ser = 2-amino-1,3-propanediol). The compound is the most water soluble fullerene material reported to date (>240 mg C 60 mL-1). In addition, the aqueous solubility has no notable pH dependence. Due to the lack of water solubility of the amphiphilic iodinated C 60 monoadduct, the water-solubilization methodology was combined with the iodination methodology to prepare a "hybrid" material that contains both the water-solubilizing groups and the iodine containing groups. The resulting fullerene-based X-ray CA is a fully water-soluble, non-ionic pentaadduct with one hexaiodinated addend containing 8 hydroxy groups and four additional addends each containing 4 hydroxy groups. The new, first generation fullerene-based CA contains 24% iodine by weight. The ideological development of the new CA, the successful (and some of the unsuccessful) synthetic pathways and the spectral characterization of the new products is presented and discussed.

Contrast agents are often crucial in medical imaging for disease diagnosis. Novel contrast agents, such as gold nanoparticles (AuNPs) and lanthanides, are being ex- plored for a variety of clinical applications. Preclinical testing of these contrast agents is necessary before being approved for use in humans, which requires the use of small animal imaging techniques. Small animal imaging demands the detection of these contrast agents in trace amounts at acceptable imaging time and radiation dose. Two such imaging techniques include x-ray fluorescence computed tomography (XFCT) and photon-counting CT (PCCT). XFCT combines the principles of CT with x-ray fluorescence by detecting fluorescent x-rays from contrast agents at various projections to reconstruct contrast agent maps. XFCT can image trace amounts of AuNPs but is limited to small animal imaging due to fluorescent x-ray attenuation and scatter. PCCT uses photon-counting detectors that separate the CT data into energy bins. This enables contrast agent detection by recognizing the energy dependence of x-ray attenuation in different materials, independent of AuNP depth, and can provide anatomical information that XFCT cannot. To achieve the best of both worlds, we modeled and built a table-top x-ray imaging system capable of simultaneous XFCT and PCCT imaging. We used Monte Carlo simulation software for the following work in XFCT imaging of AuNPs. We simulated XFCT induced by x-ray, electron, and proton beams scanning a small animal-sized object (phantom) containing AuNPs with Monte Carlo techniques. XFCT induced by x-rays resulted in the best image quality of AuNPs, however high-energy electron and medium-energy proton XFCT may be feasible for on-board x-ray fluorescence techniques during radiation therapy. We then simulated a scan of a phantom containing AuNPs on a table-top system to optimize the detector arrangement, size, and data acquisition strategy based on the resulting XFCT image quality and available detector equipment. To enable faster XFCT data acquisition, we separately simulated another AuNP phantom and determined the best collimator geometry for Au fluorescent x-ray detection. We also performed experiments on our table-top x-ray imaging system in the lab. Phantoms containing multiples of three lanthanide contrast agents were scanned on our tabletop x-ray imaging system using a photon-counting detector capable of sustaining high x-ray fluxes that enabled PCCT. We used a novel subtraction algorithm for reconstructing separate contrast agent maps; all lanthanides were distinct at low concentrations including gadolinium and holmium that are close in atomic number. Finally, we performed the first simultaneous XFCT and PCCT scan of a phantom and mice containing both gadolinium and gold based on the optimized parameters from our simulations. This dissertation outlines the development of our tabletop x-ray imaging system and the optimization of the complex parameters necessary to obtain XFCT and PCCT images of multiple contrast agents at biologically-relevant concentrations.
Graduate

Lanthanide-based nanoparticles are of interest for optical displays, catalysis, telecommunication, bio-imaging, magnetic resonance imaging, multimodal imaging, etc. These applications are possible partly because the preparation of lanthanide-based nanoparticles has made tremendous progress. Now, nanoparticles are routinely being made with a good control over size, crystal phase and even shape. Despite the achievements, little attention is given to the fundamental physical chemistry aspects, such as crystal structure, architecture, cation exchange, etc. The results of the study on the crystal structures of LnF3 nanoparticles show that the middle GdF3 and EuF3 nanoparticles have two crystal phases, which has then been tuned by doping with La3+ ions. However, the required doping level is very different from the bulk. While the results for the bulk are well explained by thermodynamic calculations, kinetics is actually responsible for the results of the undoped and doped GdF3 and EuF3 nanoparticles. The attempt to make LnF3 core-shell nanoparticles led to the finding of cation exchange, a phenomenon that upon exposure of LnF3 nanoparticles to an aqueous solution containing Ln3+ ions, the Ln3+ ions in the nanoparticles are replaced by the Ln3+ ions in the solution. The consequence of the cation exchange is that LnF3 core-shell nanoparticles are unlikely to form in aqueous media using a core-shell synthesis procedure. It has also been verified that nanoparticles synthesized using an alloy procedure do not always have an alloy structure. This means that the core-shell and alloy structure of nanoparticles in the literature may not be true. The investigation of the architecture of nanoparticles synthesized in aqueous media is extended to those synthesized in organic media. The dopant ion distribution in NaGdF4 nanoparticles has been examined. It has been found that they don’t have the generally assumed statistical dopant distribution. Instead, they have a gradient structure with one type of Ln3+ ions more concentrated towards the center and the other type more concentrated towards the surface of the nanoparticles. With the understanding of these physical insights, lanthanide-based core-shell nanoparticles are prepared using the cation exchange. These core-shell nanoparticles containing a photoluminscent core and a paramagnetic shell are promising candidates for multimodal imaging.
Graduate

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Osteoarthritis (OA) is a painful, chronic, non-inflammatory disease affecting 140 million people worldwide that alters synovial joint structure and function. OA progressively breaks down hyaline cartilage, the hydrated tissue that provides a smooth, nearly frictionless surface and distributes loads applied to articulating joint surfaces. The loss of glycosaminoglycans (GAGs) from the extracellular matrix of cartilage is an early marker of OA. Therefore, imaging methods that quantify the GAG content of cartilage are of interest. This work investigates the synthesis and development of three cationic contrast agents (CAs) for imaging articular cartilage (AC): CA4+, an iodinated small molecule, and tantalum oxide nanoparticles (Ta2O5 NPs) for x-ray Computed Tomography (CT) imaging; and Gadopentetate-dilysine (Gd(DTPA)Lys2), a gadolinium small molecule for Magnetic Resonance (MR) imaging. These cationic contrast agents are attracted to the strong negative fixed charge of extracellular GAG and, therefore, infiltrate cartilage. This work begins with an overview of CT and MR imaging basic principles, current clinical CAs and contrast enhanced imaging of AC. First, the large-scale (50 g) synthesis of CA4+ is described and the partitioning over time of CA4+ into ex vivo AC is correlated to GAG content and cartilage mechanical properties. Similar partitioning studies are applied to anionic, neutral and cationic Ta2O5 NPs, where the cationic NP exhibited substantially greater affinity for AC. Moreover, by maintaining the positive charge on the NP surface and introducing a polyethylene glycol coating, a NP formulation is described for successful in vivo cartilage imaging. Next described is the MRI CA, Gd(DTPA)Lys2, which affords an equivalent T1 signal in cartilage at 1/10th the effective dosage of anionic gadopentetate. Finally, the equilibrium partitioning of the small molecule CT and MRI CAs is directly compared to GAG content and mechanical properties in human finger AC. In summary, results show cationic CAs strongly correlate to both GAG and mechanical properties and distribute in direct proportion to GAG unlike anionic CAs. The use of cationic CAs to quantify the biochemical and mechanical changes of AC may aid drug discovery and improve clinical assessment and intervention of OA for future patients.
2017-11-03T00:00:00Z

La tomodensitométrie par rayons-X (CT) est une modalité d’imagerie produisant une carte tridimensionnelle du coefficient d’atténuation des rayons-X d’un objet. En radiothérapie, le CT fournit de l’information anatomique et quantitative sur le patient afin de permettre la planification du traitement et le calcul de la dose de radiation à livrer. Le CT a plusieurs problèmes, notamment (1) une limitation au niveau de l’exactitude des paramètres physiques quantitatifs extraits du patient, et (2) une sensibilité aux biais causés par des artéfacts de durcissement du faisceau. Enfin, (3) dans le cas où le CT est fait en présence d’un agent de contraste pour améliorer la planification du traitement, il est nécessaire d’effectuer un deuxième CT sans agent de contraste à des fins de calcul de dose, ce qui augmente la dose au patient. Ces trois problèmes limitent l’efficacité du CT pour certaines modalités de traitement qui sont plus sensibles aux incertitudes comme la protonthérapie. Le CT spectral regroupe un ensemble de méthodes pour produire plusieurs cartes d’atténuation des rayons-X moyennées sur différentes plages énergétiques. L’information supplémentaire, pondérée en énergie qui est obtenue permet une meilleure caractérisation des matériaux analysés. Le potentiel de l’une de ces modalités spectrales, le CT bi-énergie (DECT), est déjà bien démontré en radiothérapie, alors qu’une approche en plein essor, le CT spectral à comptage de photons (SPCCT), promet davantage d’information spectrale à l’aide de détecteurs discriminateurs en énergie. Par contre, le SPCCT souffre d’un bruit plus important et d’un conditionnement réduit. Cette thèse investigue la question suivante : y a-t-il un bénéfice à utiliser plus d’information résolue en énergie, mais de qualité réduite pour la radiothérapie ? La question est étudiée dans le contexte des trois problèmes ci-haut. Tout d’abord, un estimateur maximum a posteriori (MAP) est introduit au niveau de la caractérisation des tissus post-reconstruction afin de débruiter les données du CT spectral. L’approche est validée expérimentalement sur un DECT. Le niveau de bruit du pouvoir d’arrêt des protons diminue en moyenne d’un facteur 3.2 à l’aide de l’estimateur MAP. Celui-ci permet également de conserver généralement le caractère quantitatif des paramètres physiques estimés, le pouvoir d’arrêt variant en moyenne de 0.9% par rapport à l’approche conventionnelle. Ensuite, l’estimateur MAP est adapté au contexte de l’imagerie avec agent de contraste. Les résultats numériques démontrent un bénéfice clair à utiliser le SPCCT pour l’imagerie virtuellement sans contraste par rapport au DECT, avec une réduction de l’erreur RMS sur le pouvoir d’arrêt des protons de 2.7 à 1.4%. Troisièmement, les outils développés ci-haut sont validés expérimentalement sur un micro-SPCCT de la compagnie MARS Bioimaging, dont le détecteur à comptage de photons est le Medipix 3, qui est utilisé pour le suivi de particules au CERN. De légers bénéfices au niveau de l’estimation des propriétés physiques à l’aide du SPCCT par rapport au DECT sont obtenus pour des matériaux substituts à des tissus humains. Finalement, une nouvelle paramétrisation du coefficient d’atténuation pour l’imagerie pré-reconstruction est proposée, dans le but ultime de corriger les artéfacts de durcissement du faisceau. La paramétrisation proposée élimine les biais au niveau de l’exactitude de la caractérisation des tissus humains par rapport aux paramétrisations existantes. Cependant, aucun avantage n’a été obtenu à l’aide du SPCCT par rapport au DECT, ce qui suggère qu’il est nécessaire d’incorporer l’estimation MAP dans l’imagerie pré-reconstruction via une approche de reconstruction itérative.
X-ray computed tomography (CT) is an imaging modality that produces a tridimensional map of the attenuation of X-rays by the scanned object. In radiation therapy, CT provides anatomical and quantitative information on the patient that is required for treatment planning. However, CT has some issues, notably (1) a limited accuracy in the estimation of quantitative physical parameters of the patient, and (2) a sensitivity to biases caused by beam hardening artifacts. Finally, (3) in the case where contrast-enhanced CT is performed to help treatment planning, a second scan with no contrast agent is required for dose calculation purposes, which increases the overall dose to the patient. Those 3 problems limit the efficiency of CT for some treatment modalities more sensitive to uncertainties, such as proton therapy. Spectral CT regroups a set of methods that allows the production of multiple X-ray attenuation maps evaluated over various energy windows. The additional energy-weighted information that is obtained allows better material characterization. The potential of one spectral CT modality, dual-energy CT (DECT), is already well demonstrated for radiation therapy, while an upcoming method, spectral photon counting CT (SPCCT), promises more spectral information with the help of energy discriminating detectors. Unfortunately, SPCCT suffers from increased noise and poor conditioning. This thesis thus investigates the following question: is there a benefit to using more, but lower quality energy-resolved information for radiotherapy? The question is studied in the context of the three problems discussed earlier. First, a maximum a posteriori (MAP) estimator is introduced for post-reconstruction tissue characterization for denoising purposes in spectral CT. The estimator is validated experimentally using a commercial DECT. The noise level on the proton stopping power is reduced, on average, by a factor of 3.2 with the MAP estimator. The estimator also generally con- serves the quantitative accuracy of estimated physical parameters. For instance, the stopping power varies on average by 0.9% with respect to the conventional approach. Then, the MAP estimation framework is adapted to the context of contrast-enhanced imaging. Numerical results show clear benefits when using SPCCT for virtual non-contrast imaging compared to DECT, with a reduction of the RMS error on the proton stopping power from 2.7 to 1.4%. Third, the developed tools are validated experimentally on a micro-SPCCT from MARS Bioimaging, which uses the Medipix 3 chip as a photon counting detector. Small benefits in the accuracy of physical parameters of tissue substitutes materials are obtained. Finally, a new parametrization of the attenuation coefficient for pre-reconstruction imaging is pro- posed, whose ultimate aim is to correct beam hardening artifacts. In a simulation study, the proposed parametrization eliminates all biases in the estimated physical parameters of human tissues, which is an improvement upon existing parametrizations. However, no ad- vantage has been obtained with SPCCT compared to DECT, which suggests the need to incorporate MAP estimation in the pre-reconstruction framework using an iterative reconstruction approach.