Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Medical Biophysics

Supervisor

Drangova, Maria

2nd Supervisor

Gillies, Elizabeth R.

Joint Supervisor

Abstract

Dual energy (DE) computed tomography (CT) has the capability to influence medicine and pre-clinical research by providing quantitative information that can detect nascent lesions, identify perfusion restoration or inhomogeneities within tissues, and recognize the presence of calcium deposits. A wide variety of instrumentation techniques and scan protocols have been developed for DE CT, with a common goal of acquiring a pair of images that reports the attenuation of a given volume to two different x-ray distributions. While DE image acquisition has benefitted from technical advancements in CT, the contrast agents that are used are still predominantly composed of iodinated small molecules, which first appeared in the 1970s. Recent work has demonstrated that lanthanide-based contrast agents have optimized properties for DE decomposition, specifically when using in vivo micro-CT scanners. By adopting nanoparticle design strategies that were developed for disease therapeutics and diagnosis, this thesis takes advantage of existing technical advancements in nanotechnology and polymer science to develop a long-circulating contrast agent that can be used for in vivo micro‑CT and DE micro‑CT imaging of the mouse vasculature. The contrast agents that were developed provided a high loading of 100 mg/mL of lanthanide for intravenous injections of mice, and introduced CT contrast enhancements of at least 245 HU. The contrast was maintained for at least 30 minutes, and for as long as one hour, which exceeds the in vivo micro-CT scan time requirements. Furthermore, although the synthesis techniques and in vivo scans were demonstrated using model lanthanides such as gadolinium and erbium, they can easily be substituted by any other lanthanide. By using a fast-filter switcher to obtain interleaved scans, the feasibility of an in vivo DE CT technique that produces decomposed quantitative images of soft tissue, bone and gadolinium-enhanced vessels was demonstrated, which can be used with any pre-clinical, gantry-based micro-CT scanner. When used in combination with the DE CT technique presented, the long-circulating lanthanide contrast agents that were developed in this thesis have the potential to become powerful tools for pre-clinical research on the microvasculature.

Summary for Lay Audience

Cardiovascular disease is studied in mouse models so that treatment and prevention methods can be developed for humans. To study the heart and vessels, 3D images of the mouse body can be obtained using computed tomography (CT). CT uses x-rays, and results into greyscale 3D images that represent the density of the volume being captured. For instance, low density organs like the lungs may appear black or dark grey, and high-density tissue like bone appears white. Since vessels have comparable densities as other soft tissues, they result in similar greyscale values, unless a dye containing a high-density material is injected into the blood. However, dyed vessels appear like bone in CT images and become difficult to distinguish when they are inside or near bone. A technique called Dual Energy CT allows us to discriminate between soft tissue, bone, and dyed vessels. Two chapters of this thesis feature the development of a dye that can be used in living mice so that vessels can be mapped by Dual Energy CT without the need for surgery. The physical properties of the dyes that were developed were modeled after existing pharmaceutical drugs composed of nanoparticles within polymers. Nanoparticles are materials sized in the nanometer range, and polymers are large molecules with repeated subunits. The dye was composed of a type of metal called a lanthanide, which can successfully map mouse vessels post-mortem by Dual Energy CT. A chapter of this thesis demonstrates that the lanthanide dye – when used in combination with Dual Energy CT – gives researchers the ability to distinguish between soft tissue, bone, and dyed vessels in living mice. The presented Dual Energy CT technique and dye design can allow researchers to track anatomical changes in the same mice over time, which can provide new information and further understanding of vascular diseases.

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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