We have developed a new high-frequency ultrasound scanning system that provides the opportunity to obtain a two-dimensional map of blood flow in the anterior segment of the eye in one second, with spatial resolution on the order of 40 microns and velocity resolution on the order of 0.2 mm/s. This represents approximately an order of magnitude improvement in resolution over existing techniques, and provides the first non-invasive opportunity to evaluate blood flow in arterioles and venules in opaque tissues. In addition, a new strategy to estimate capillary volume and flow rate has been developed by combining a theoretical model and a system to interrogate individual contrast microbubbles. This new suite of tools can be applied to improve the understanding of the mechanisms of ophthalmic diseases including glaucoma and age-related macular degeneration as well as the mechanisms and effectiveness of treatment options. Here, we specifically address glaucoma. The clinical significance of an improvement in the management of ophthalmic diseases is enormous since 3 million people in the US alone suffer from glaucoma, 100,000 per year suffer some form of ocular trauma, and over 6 million people in the US suffer from degenerative retinal diseases. Most experts agree that glaucoma is a series of conditions characterized by a particular form of optic nerve damage that is often associated with elevated intra-ocular pressure, although the mechanisms responsible for damage and successful therapy are not understood. Many drug therapies for glaucoma are assumed to decrease intra-ocular pressure through the constriction of arterioles in the ciliary body, however, it has been impossible to measure these changes in ciliary body blood flow, or to measure optic nerve head perfusion. Our new technique to estimate arteriolar diameter and flow rate will be evaluated in a human study of glaucoma therapies. Contrast-assisted methods for the estimation of capillary volume and flow rate will be developed for the high resolution requirements of ophthalmology. This requires the further development of our experimental system, the evaluation of new contrast agents with higher resonant frequencies, and the validation of our new strategies for the estimation of capillary density. These new techniques will be used to evaluate perfusion in the ciliary body and in the optic nerve head in an animal model study of drug therapies, and compared with the output of a scanning laser Doppler flowmeter. In conjunction with this study, mechanical damage to the vessel wall will be directly assessed through the use of fluorescent markers.
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