VASCULAR BUBBLE GENERATION FOR DIAGNOSIS AND THERAPY

这是一个修订后的建议，以发展和评估控制发电 动脉微泡使用强烈的，聚焦超声脉冲， 可能的诊断和治疗用途。 自上次提交以来， 动脉微泡已经在体外流动的全血中产生 用725 kHz超声穿过模拟人的犬组织 经皮生成。在血液中观察到的阈值强度为 2.3比之前的1.8 MHz低10倍， 真实放置的椎骨是可接受的。短剂量 超声成像，小于40微米的气泡，产生于 选择的动脉，应可用于诊断和监测那些 血管和灌注异常，目前评估更多 缓慢而昂贵，可能更具侵入性， 需要动脉导管插入术的血管造影术。稀疏分布20 到40微米的气泡应该可用于重新聚焦超声波束， 分辨率成像，即使对于成像 穿过头骨第一次也是最确定的一次大丸剂的医疗用途 预计将识别供血动脉， 治疗靶点，如肿瘤和动静脉畸形。 供血动脉凝固，或反复， 更广泛的推注，将闭塞目标， 超声波或化学疗法或手术。超声波领域的知识 其产生的血管微泡对血管的损伤可忽略不计， 闭塞将有助于改善安全诊断和治疗指南 超声. 气泡将在各种条件下产生和表征 针对上述目标。研究将包括气泡大小 使用和不使用造影剂时的分布、成分和寿命 接种和在两个或更多个超声频率，脉冲幅度和 持续时间和血液速度。目前在大剂量生产方面的成功， 动脉壁损伤最小的暴露动脉显然是由于 聚焦在血管内。低频和其他技术将是 用于以较低的热和空化产生所需的气泡 损伤，甚至，可能，在更小，更深的血管， 不可能包含焦点。体内研究将 最初在脑血管系统上进行，因为有很好的机会 大脑是最敏感也是最好研究的专业 动脉气体损伤的器官，尽管体积是最小值的75万倍 超声成像体积。神经病学诊断和治疗是在 需要更好的技术，最后，经皮动脉生成 颈动脉最容易生成两种类型的诊断 计划在动物模型中进行颈动脉推注，以验证 阈值、颅内成像显示和初步评价 通过光学组织学证实的可能不良反应，有色 微球和放射自显影。供血动脉显示 将通过血管闭塞进行病变治疗的描绘 在犬的甲状腺血管中

This is a revised proposal to develop and evaluate controlled generation of arterial microbubbles using intense, focused ultrasound pulses for possible diagnostic and therapeutic use. Since the previous submission, arterial microbubbles have been generated in flowing whole blood in vitro with 725 kHz ultrasound passing through canine tissues simulating human transcutaneous generation. Threshold intensities observed in blood were 2.3 times less than at the previous 1.8 MHz and temperature rise on realistically-placed vertebral bone was acceptable. Short boluses of ultrasonically imageable, less than 40 micron bubbles, generated in selected arteries, should be usable for diagnosis and monitoring of those vascular and perfusion abnormalities which currently are evaluated more slowly and expensively, and probably more invasively, with MRI or with angiography requiring arterial catheterization. Sparse distributions of 20 to 40 micron bubbles should be usable to refocus ultrasound beams for high resolution imaging through aberrating overlying tissues, even for imaging through the skull. The first and most certain medical use of bolus generation is expected to be identification of feeder arteries to therapeutic targets such as tumors and arterio-venous malformations. Coagulation of the feeder arteries, or thrombus generated by repeated, more extensive boluses, will occlude the target for safer, more effective ultrasound or chemical therapy or surgery. Knowledge of ultrasonic fields which produce vascular microbubbles of negligible damage up to vascular occlusion will help improve guidelines for safe diagnostic and therapeutic ultrasound. Bubbles will be produced and characterized under various conditions directed to the above goals. Studies will include bubble size distributions, constituents and longevity with and without contrast agent seeding and at two or more ultrasound frequencies, pulse amplitudes and durations and blood velocities. Current success at bolus production in exposed arteries with minimal arterial wall damage apparently is due to focusing within the vessel. Lower frequencies and other techniques will be utilized for desired bubble generation with lower thermal and cavitational damage, even, possibly, in smaller, deeper vessels where luminal containment of the focus is not possible. In vivo studies will be performed initially on the cerebral vasculature, as there is a good chance of success and the brain is the most sensitive and best studied major organ for arterial gas damage, albeit at volumes 750,000 times the minimum ultrasonically imageable volume. Neurologic diagnosis and treatment is in need of better techniques and, finally, transcutaneous arterial generation will be easiest in the carotid. Generation of the two types of diagnostic carotid boluses is planned in animal models for verification of thresholds, demonstration of intracranial imaging and initial evaluation of possible adverse effects demonstrable by optical histology, colored microspheres and autoradiography. Demonstration of feeder artery delineation for lesion treatment by vascular occlusion will be performed in the canine thyroid vasculature.