This thesis compares theoretical models of ultrasound contrast agents to the acoustic response from single Microbubbles(MBs). The acoustic response was compared using a range of driving parameters. A rigid shelled contrast agent and a lipid shelled contrast agent were used in the comparison. While attempts to model the behaviour of some contrast agents at low mechanical index (MI) have been successful at higher MI the behaviour of MBs is still not well understood. Understanding and predicting the response ofMBs to medical ultrasound can lead to improvements in the clinical use of MBs through improved contrast agent design or improved signal processing. Numerical models were developed to compare to three specific cases; 1) Rigid shelled contrast agents 2) Lipid shelled contrast agents 3) Responses from lipid shelled contrast agents that are hit by subsequent driving pulses. Three models were used to compare to the responses from single rigid shelled contrast agents. Two of these models have been used before and the third was developed based on the optical observations of the responses of these rigid shelled agents at these MI. Two shelled models were used to compare to the response of single lipid shelled MBs. Using statistical methods the parameters defining the shell properties were found. The parameters that gave best agreement with the lipid shelled data was then used with a model to account for the molecular diffusion of gas from a MB and a new model to account for the optically observed shedding of the shell from a MB to compare to the multiple response from single MBs. While the theoretical prediction of an acoustic response of a suspension of MBs or the radial oscillation of single MBs has been compared before to experimental data, the successful comparison of the acoustic response of single MBs to the theoretical prediction is the first of it’s kind known to the author. The new theoretical model of the rigid shelled MB that was developed in this thesis gave better agreement with the experimental data than the other previously used models. The shell parameters of the lipid shelled MB were determined for the lowest driving amplitude and were in agreement with those measured previously from optical observations. Finally, the model for the shedding of the shell was shown to give quantitative agreement with the multiple acoustic responses from single MBs. When shedding of the shell was included the choice of constitutive equation for the shell was shown to strongly affect subsequent responses from the MB.

Multi-modality imaging is a possible solution for overcoming individual modality limitations. With the use of modality specific contrast agents, contrast-enhanced multi-modality imaging may provide a more comprehensive evaluation of tumour characteristics. This may be possible by combining ultrasound and magnetic resonance imaging, whose contrast agents behave differently within the microvasculature. A novel, microvascular, and leaky phantom is presented that permits ultrasound contrast agents to remain entirely within the mimicking vascular compartment while the magnetic resonance contrast agents may freely diffuse between the mimicking vasculature and tissue compartments. The results show that the phantom is a useful tool for investigating the combination of contrast-enhanced ultrasound and magnetic resonance imaging. This work motivates further combined contrast-enhanced imaging studies, with future work to incorporate additional modalities.

Multi-modality imaging is a possible solution for overcoming individual modality limitations. With the use of modality specific contrast agents, contrast-enhanced multi-modality imaging may provide a more comprehensive evaluation of tumour characteristics. This may be possible by combining ultrasound and magnetic resonance imaging, whose contrast agents behave differently within the microvasculature. A novel, microvascular, and leaky phantom is presented that permits ultrasound contrast agents to remain entirely within the mimicking vascular compartment while the magnetic resonance contrast agents may freely diffuse between the mimicking vasculature and tissue compartments. The results show that the phantom is a useful tool for investigating the combination of contrast-enhanced ultrasound and magnetic resonance imaging. This work motivates further combined contrast-enhanced imaging studies, with future work to incorporate additional modalities.

Medical ultrasound imaging is ubiquitous in clinics due to its safety, low cost, portability, and imaging depth. The development of technologies to assist ultrasound in the diagnosis of diseases thus have a potentially broad clinical impact. More recently, photoacoustics has emerged as a complementary, high contrast modality for imaging optical absorption. Injectable dyes and nanoparticles locally amplify ultrasound and photoacoustic signal, helping to identify disease markers and track its progression. We have constructed a dual ultrasound and photoacoustic contrast agent that can be activated using an external optical trigger. In response to pulsed laser irradiation, the particle undergoes a liquid to gas phase change, or vaporization, which emits a strong acoustic wave and results in an echogenic microbubble, simultaneously enhancing contrast for both modalities. We designed and developed several iterations of particles, altering parameters to optimize biocompatibility, cost, and image contrast enhancement, and we then characterized key traits of the particles. Next, we imaged the contrast agents in phantom, ex vivo, and in vivo models to validate the image enhancement, developing image process algorithms to maximize image quality. These optically triggered contrast agents are a valuable tool for minimally invasive, highly specific, early identification of cancer. / text

In these days, nanomaterials are applied in a variety of biomedical applications including magnetic resonance imaging (MRI), cell imaging, drug delivery, and cell separation. Most MRI contrast agents affect the longitudinal relaxation time (T1) and transverse relaxation time (T2) of water protons in the tissue and result in increased positive or negative contrast. Here, we report the optimization of r1 (1/T1) or r2 (1/T2) relaxivity dynamics with diameter controlled gadolinium oxide nanocrystals (2~22 nm) and iron based magnetic nanocrystals (4 ~33 nm). The r1 and r2 MR relaxivity values of hydrated nanocrystals were optimized and examined depending on their core diameter, surface coating, and compositions; the high r1 value of gadolinium oxide was 40-60 S-1mM-1, which is 10-15 fold higher than that of commercial Gd (III) chelates (4.3~4.6 S-1mM-1). Moreover, in vitro toxicological studies revealed that polymer coated nanocrystals suspensions had no significant effect on human dermal fibroblast (HDF) cells even at high concentration. Towards multimodal imaging or multifunctional ability, we developed the iron oxide/QDs complexes, which consist of cores of iron oxide that act as nucleation sites for fluorescent QDs. The choice of variable QDs helped to visualize and remove large iron oxide materials in a magnetic separation. Additionally, diluted materials concentrated on the magnet could be fluorescently detected even at very low concentration. The designed MRI or multifunctional nanomaterials will give great and powerful uses in biomedical applications.

The use of multimodal imaging as a tool to assess the in vivo pharmacokinetics and biodistribution of nanoparticles is important in drug development and imaging-guided therapy. The current study reports the use of combined micro-CT and optical imaging FMT to quantitatively assess the whole body and intratumoural distribution of a nano-sized liposome-based CT/optical imaging probe carrying iohexol and Cy5.5. Micro-CT was used to guide the FMT tumour delineation and signal correction. This investigation demonstrates the critical role micro-CT can play in guiding FMT-based quantification of distribution. As well the combination of CT and optical imaging enable visualization of the liposomes at the whole body, tumor and cellular levels with high sensitivity and excellent anatomical background. Such non-invasive assessment of therapeutic distribution at the macro and micro scale is necessary for implementation of personalized medicine including image-guided patient stratification and real-time adjustment of therapeutic dose.

The use of multimodal imaging as a tool to assess the in vivo pharmacokinetics and biodistribution of nanoparticles is important in drug development and imaging-guided therapy. The current study reports the use of combined micro-CT and optical imaging FMT to quantitatively assess the whole body and intratumoural distribution of a nano-sized liposome-based CT/optical imaging probe carrying iohexol and Cy5.5. Micro-CT was used to guide the FMT tumour delineation and signal correction. This investigation demonstrates the critical role micro-CT can play in guiding FMT-based quantification of distribution. As well the combination of CT and optical imaging enable visualization of the liposomes at the whole body, tumor and cellular levels with high sensitivity and excellent anatomical background. Such non-invasive assessment of therapeutic distribution at the macro and micro scale is necessary for implementation of personalized medicine including image-guided patient stratification and real-time adjustment of therapeutic dose.

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Ultrasound-mediated drug delivery has been proposed as a safe and non-invasive method to achieve localized drug release. Drug-loaded microbubbles are injected in the vascular system and ultrasound waves are then used to localize and burst the microbubbles at a specific targeted area. The relatively large size of microbubbles however limits both their lifetime and their reach in the human body. Phase-change liquid droplets can extend the use of ultrasound contrast agents for localized drug delivery. Their smaller size provides several advantages. The droplets can reach smaller capillaries, such as those in tumors vasculature. Their lifetime is also considerably prolonged. Through the phenomenon of Acoustic Droplet Vaporization (ADV), triggered by ultrasound stimulation, the liquid-filled droplets experience a phase change and are converted into gas-filled microbubbles. The newly created microbubbles can then be disrupted by further stimulation and release their drug load in the tumor tissue. In this project, a protocol to image and burst perfluoropentane-based micro-sized droplets using a single transducer is developed using the Verasonics Ultrasound System. The pulse sequences are developed to allow close monitoring of the drug delivery by capturing a series of images before and after the vaporization or destruction of the droplets. The droplets response was assessed for different pulse voltages and durations. Mean pixel value was calculated for the regions of interest, using the images captured before and after delivery of the ultrasound pulse. Vaporization of the droplets can be achieved with low voltage (10V), whereas high voltage (50V) triggers their destruction. Combined with high voltage, pulse duration affects the rate at which droplets can be destructed.

The harmonic generation due to the nonlinear behavior of Ultrasound Contrast Agents (UCAs) must be exploited for improved efficiency when imaging vascular targets in the neighborhood of highly echogenic tissue. One may even further improve the efficiency by focusing on the subharmonic generation of the UCAs, which is an even more exclusive property than the generation of higher harmonics, for improved Contrast-to-Tissue ratio (CTR). The aim of this work was first, the design of a set-up for nonlinear imaging of Poly-Vinyl Alcohol (PVA) based UCAs on The Verasonics Research System with special focus on nondestructive Subharmonic Imaging. The second part of the work addressed the evaluation of the subharmonic response provided by the agents in the developed setup. Six different imaging techniques were developed. These were Fundamental B-mode imaging (FB), Pulse Inversion imaging (PI), and a Contrast Pulse Sequence based on three pulses (CPS3), with and without a focus on the subharmonic component by the implementation of a Linear Bandpass Filter (LBF). Experiments were performed on a tissue mimicking flow phantom and the performance of the agents for each technique was determined in terms of CTR and CNR. The PVA agents provided a backscattering enhancement of the order of 23 dB through FB imaging. However, the performance of the FB technique was unsatisfactory in terms of CTR. The CPS3 sequence performed best of the six techniques with an improvement of 14 dB and 13 dB in CTR and CNR, respectively, compared with the FB technique. Combining the LBF around the subharmonic component with the multi-pulse techniques of PI and CPS3 resulted in a degraded CTR performance due to significant amount of signals from tissue around the subharmonic component and insufficient subharmonic detection from the PVA agents.