Contrast microbubbles offer unique versatility in medical imaging. First generation agents were used as tracers of blood flow permitting assessment of perfusion defects. More recently, research has focused on molecular targeted agents that enable the detection of the molecular signature of disease. Finally, the use of contrast microbubbles as a means of precipitating drug and gene delivery in a highly focal manner - potentially under real-time ultrasound imaging guidance - provides a technology that encompasses molecular imaging, functional imaging and therapy. In each of these technologies, it is critical to understand the behavior of the microbubble in response to high intensity incident ultrasound pulses. Existing bubble models assume spherical symmetry and over time it is anticipated that these models will be replaced by models accounting for asymmetric modes of vibration. These models are only credible if supported by the experimental validation that the proposed camera will provide. The camera will also enable analysis of the response of microbubbles to radiation force effects that the collaborators have previously established as being vital to the efficacy of microbubble-based molecular imaging and drug delivery. The camera will also facilitate understanding of the behavior of """"""""next generation"""""""" multilayered bubbles that include a drug payload in the shell. Additional research will investigate the vessel, and cell, permeabilization process that is believed to be important to successful drug and gene delivery, which is practically impossible to visualize except by means of the combined high speed camera and inverted research microscope that is contemplated in this proposal. Current ultra-high-speed video microscopy systems designed for microbubble imaging include the Brandaris at Erasmus University in Rotterdam and the Imacon 468 systems at the University of Michigan and UC Davis. While these older technology systems have enabled a substantial body of preliminary research, physical constraints in their time and spatial resolution, dynamic range, and light sensitivity have limited the ability of these systems to be useful to microbubble researchers interested in high-frequency or high amplitude bubble imaging, or situations where bubbles oscillate non-symmetrically or in low-light environments such as in-vivo. The 12 bit dynamic range, with an intensifier gain of up to 2000 will yield 4 bits more dynamic range than prior systems and a factor of 4 fold more sensitivity than the Imacon 468 system. These substantial improvements will allow imaging in reduced light conditions (i.e. in-vivo) and imaging with maximum frame rate at higher optical magnification than previously possible. The 3 ps streak time resolution will allow recording of bubble events much over 1000 times faster than previously possible.
The proposed high speed camera with microscope will enable fundamental research into the complex behavior of ultrasound contrast agents with fine spatial resolution and approximately five nanosecond temporal resolution. Using the knowledge gained, we plan to improve the design of ultrasound contrast agents used in both disease detection and in disease treatment. A long term goal involving ultrasound contrast is to enable detection and treatment of disease using early detection of molecular signatures of disease rather than waiting to detect late stage anatomic responses to disease - at which point treatment may involve higher risk, more side effects, higher patient and societal cost and greater patient discomfort.
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