Development and characterization of hollow polymeric microcapsules for use as contrast agents for diagnostic ultrasound.

摘要

This thesis concerns the development and characterization of a new type of rigid-shelled ultrasound contrast agent. A novel method was devised for producing hollow, gas-filled, polymer microcapsules, sized to less than 10 mum in diameter for contrast imaging. This method involved the encapsulation of a solid, volatile core material, and its subsequent evacuation by sublimation. The biodegradable polymer, 50/50 poly(D,L-lactide-co-glycolide), was the main focus of this study. Polymer-based contrast agents have many advantages, such as their applicability for concomitant imaging and drug delivery.; Three encapsulation techniques were evaluated: solvent evaporation, coacervation, and spray drying. The polymer molecular weight and polydispersity in the solvent evaporation and coacervation techniques strongly affected microcapsule size and morphology. Efficient mechanical agitation and shear were crucial for obtaining high yields in the desired size range (less than 6 mum). In spray drying, a factorial design approach was used to optimize conditions to produce microcapsules. The main factors affecting spray drying were found to be the temperature driving force for drying and initial polymer concentration. The smallest microcapsule mean diameters were produced by spray drying (3--4 mum) and solvent evaporation (5--6 mum). Zeta potential (zeta) studies for all microcapsule types indicated that the encapsulation technique affected their surface properties due to the orientation of the polymer chains within nascent polymer droplets. Microcapsules with the most hydrophilic tendency were produced with solvent evaporation (zeta ∼ -50 mV).; In vitro acoustic testing revealed that the 20--41 mum size fractions of coacervate microcapsules were the most echogenic. In vivo ultrasound studies with both solvent evaporation and coacervate microcapsules showed visible enhancement of the color Doppler image in the rabbit kidney for the samples less than 10 mum in diameter.; A mathematical model was also developed in this work, using the fully-compressible, two-dimensional Navier-Stokes equation, to predict acoustic phenomena in coupled gas and liquid systems. The model was validated in water by using a complete equation of state and proved to be appropriate for both thermoacoustic and ultrasound wave generation. This model can be extended to predict the oscillations of bubbles more accurately than the Rayleigh-Plesset equation, since it inherently includes viscous and thermal losses, and the compressibility of both the gas and liquid.