![]() Aside from the clinical uses listed here, microbubbles are currently in use worldwide in many off label clinical imaging applications, including assessment of microvascular perfusion (e.g., myocardial, angiogenesis imaging ), imaging of the carotid to assess vascular stenosis and plaque stability, lesion and flow characteristics in the abdominal region, breast lesion detection, evaluation of inflammatory bowel disease, and assessment of ovaries, prostate and thyroid. Recently, Lumason™ was approved for liver imaging and in various pediatric applications. Microbubbles are approved in over 70 countries, predominately for cardiac applications, whereby their strong echo signal in the heart chambers improves left ventricular opacification (LVO). Table 1 lists the clinical contrast agents, along with details on their salient characteristics and clinically approved applications. This rate is comparable to most analgesics and antibodies (0.005%–0.015% ), and similar if not lower than for other contrast imaging agents, e.g., CT with a rate of 0.04%, MR with a rate of 0.002%–0.005%. Recent meta-analysis surveying microbubble tolerance indicates that the dominant cause of severe adverse effects is pseudoanaphylaxis (CARPA), with an estimated rate on the order of 0.004%–0.009%. There have been millions of diagnostic injections of contrast agent microbubbles worldwide, and they are accompanied by an excellent safety profile. Microbubble suspensions, typically on the order of 10 9 bubbles/ml, are injected intravenously into a peripheral vein in the arm, with a whole-body dose ranging from 0.2 to 2 ml. The bubbles are stabilized by a thin bio-compatible encapsulation layer-typically a phospholipid monolayer, to offer a sufficient compromise between bubble vibration flexibility and resistance to dissolution in-vivo over timescales relevant for imaging, e.g., half-lives of minutes. Due to the compressibility of their gas cores, microbubbles vibrate about their equilibrium radius in an ultrasound field and possess scattering cross-sections several orders of magnitude higher than a solid particle of the same size. Unlike contrast agents used in other modalities, such as MRI and CT, the relatively large size of ultrasound contrast agents ensures that they remain strictly intravascular and act as red blood cell tracers. Ultrasound contrast agents comprise of a suspension of small spheres of gas with a low solubility in blood (e.g., perfluorocarbon), typically ranging in size from below 1 to 8 µm in diameter. This technique has limitations however when dealing with regions of slow blood flow, large tissue motion and/or low hematocrit percentage. For larger vessels, the relative motion of red blood cells compared to the surrounding tissue can be exploited to assess blood velocity using Doppler techniques, a strategy employed in many clinical applications (e.g., obstetrics, assessment of peripheral artery disease, cardiology ). Consequently, blood appears dark on conventional ultrasound images and blood flow characteristics cannot be readily assessed. At typical diagnostic frequencies ( ≈1–10 MHz), the intrinsic scattering from the blood pool, however, is typically several orders of magnitude lower than tissue due to the size and properties of red blood cells. These scattered signals are recorded by the same transmitting transducer and used to generate an image. As an ultrasonic wave (which is a longitudinal wave) is transmitted into the body, reflections are generated from tissue interfaces that are characterized by different acoustic properties, i.e., speed of sound and density. Ultrasound imaging is a well-established clinical tool for the morphological assessment of soft tissues, employed frequently in obstetrics, cardiology, and radiology.
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