The powerful microbubble: from bench to bedside, from intravascular indicator to therapeutic delivery system, and beyond.

This review discusses the development, current applications, and therapeutic potential of ultrasound contrast agents. Microbubbles containing gases act as true, intravascular indicators, permitting a noninvasive, quantitative analysis of the spatial and temporal heterogeneity of blood flow and volumes within the microvasculature. These shelled microbubbles are near-perfect reflectors of acoustic ultrasound energy and, when injected intravenously into the bloodstream, reflect ultrasound waves within the capillaries without disrupting the local environment. Accordingly, microbubble ultrasound contrast agents are clinically useful in enhancing ultrasound images and improving the accuracy of diagnoses. More recently, ultrasound contrast agents have been used to directly visualize the vasa vasorum and neovascularization of atherosclerotic carotid artery plaques, thus suggesting a new paradigm for diagnosis and treatment of atherosclerosis. Future applications of these microscopic agents include the deliver of site-specific therapy to targeted organs in the body. Medical therapies may use these microbubbles as carriers for newer therapeutic options.

[1]  S. Kaul,et al.  Delivery of Drugs with Ultrasound , 2001, Echocardiography.

[2]  Samuel A Wickline,et al.  Targeted ultrasonic contrast agents for molecular imaging and therapy. , 2001, Current problems in cardiology.

[3]  M. S. Klein,et al.  Assessment of myocardial perfusion in humans by contrast echocardiography. I. Evaluation of regional coronary reserve by peak contrast intensity. , 1988, Journal of the American College of Cardiology.

[4]  L Weinert,et al.  Determination of Right Atrial and Right Ventricular Size by Two-Dimensional Echocardiography , 1979, Circulation.

[5]  D. Gutterman Adventitia-dependent influences on vascular function. , 1999, American journal of physiology. Heart and circulatory physiology.

[6]  S. Kaul,et al.  Noninvasive Quantification of Coronary Blood Flow Reserve in Humans Using Myocardial Contrast Echocardiography , 2001, Circulation.

[7]  H. Feigenbaum,et al.  Identification of Ultrasound Echoes from the Left Ventricle by Use of Intracardiac Injections of Indocyanine Green , 1970, Circulation.

[8]  K. Moulton Plaque angiogenesis and atherosclerosis. , 2001, Current atherosclerosis reports.

[9]  Chun Yuan,et al.  Quantitative Magnetic Resonance Imaging Analysis of Neovasculature Volume in Carotid Atherosclerotic Plaque , 2003, Circulation.

[10]  K. Moulton ArePlaque angiogenesis and atherosclerosis , 2001 .

[11]  S. Kaul,et al.  Quantification of Images Obtained During Myocardial Contrast Echocardiography , 1994, Echocardiography.

[12]  J. Ophir,et al.  Ultrasonic backscatter from contrast producing collagen microspheres. , 1980, Ultrasonic imaging.

[13]  G. W. Willard Ultrasonically Induced Cavitation in Water: A Step‐by‐Step Process , 1953 .

[14]  P. Heidenreich,et al.  Quantitation of renal blood flow by contrast ultrasonography: preliminary results. , 1989, Cardiologia.

[15]  E. Zajac,et al.  Ability of the no-reflow phenomenon during an acute myocardial infarction to predict left ventricular dysfunction at one-month follow-up. , 1995, The American journal of cardiology.

[16]  J. V. Nixon,et al.  In vitro study of the effects of volume changes on parameters of the radiofrequency amplitude versus time curve with sonicated albumin. , 1993, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[17]  V L Newhouse,et al.  Second harmonic ultrasonic blood perfusion measurement. , 1993, Ultrasound in medicine & biology.

[18]  A. Barger,et al.  Hypothesis: vasa vasorum and neovascularization of human coronary arteries. A possible role in the pathophysiology of atherosclerosis. , 1984, The New England journal of medicine.

[19]  Simon C Watkins,et al.  Microbubbles targeted to intercellular adhesion molecule-1 bind to activated coronary artery endothelial cells. , 1998, Circulation.

[20]  Samuel A Wickline,et al.  Nanotechnology for molecular imaging and targeted therapy. , 2003, Circulation.

[21]  Y. Taniyama,et al.  Alternation in the coronary blood flow velocity pattern in patients with no reflow and reperfused acute myocardial infarction. , 1996, Circulation.

[22]  P. Gaehtgens,et al.  Fahraeus effect and cell screening during tub flow of human blood. I. Effect of variation of flow rate. , 1978, Biorheology.

[23]  S. Kaul,et al.  Role of capillaries in determining CBF reserve: new insights using myocardial contrast echocardiography. , 1999, The American journal of physiology.

[24]  E. Carstensen,et al.  Ultrasonic detection of cavitation at catheter tips. , 1970, The American journal of roentgenology, radium therapy, and nuclear medicine.

[25]  Jason A. Lowry,et al.  Arterial gene therapy for therapeutic angiogenesis in patients with peripheral artery disease. , 1995, Circulation.

[26]  E. G. Tickner,et al.  Why do the lungs clear ultrasonic contrast? , 1980, Ultrasound in medicine & biology.

[27]  R. Stuart Mackay,et al.  Decompression Studies Using Ultrasonic Imaging of Bubbles , 1978, IEEE Transactions on Biomedical Engineering.

[28]  M. Quiñones,et al.  Demonstration of physiological transit time of sonicated meglumine diatrizoate in a microvascular preparation , 1987 .

[29]  M. Brown,et al.  Regulation of low-density lipoprotein receptors: implications for pathogenesis and therapy of hypercholesterolemia and atherosclerosis. , 1987, Circulation.

[30]  F J Ten Cate,et al.  Safety and efficacy of a new transpulmonary ultrasound contrast agent: initial multicenter clinical results. , 1990, Journal of the American College of Cardiology.

[31]  J. Matsumura,et al.  Development of Echogenic, Plasmid-Incorporated, Tissue-Targeted Cationic Liposomes that Can Be Used for Directed Gene Delivery , 2000, Investigative radiology.

[32]  S. Kaul,et al.  Functional Significance of Collateral Blood Flow in Patients With Recent Acute Myocardial Infarction: A Study Using Myocardial Contrast Echocardiography , 1992, Circulation.

[33]  S. Feinstein,et al.  Pitfalls in quantitative contrast echocardiography: the steps to quantitation of perfusion. , 1993, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[34]  J. Lindner,et al.  Assessment of inflammation with contrast ultrasound. , 2001, Progress in cardiovascular diseases.

[35]  R. Mofidi,et al.  Association between plaque instability, angiogenesis and symptomatic carotid occlusive disease , 2001, The British journal of surgery.

[36]  M. Marcus,et al.  Role of vasa vasorum in nourishment of the aortic wall. , 1981, The American journal of physiology.

[37]  W. Nayler,et al.  Calcium-mediated damage during post-ischaemic reperfusion. , 1988, Journal of molecular and cellular cardiology.

[38]  P. Burns,et al.  Harmonic hepatic US with microbubble contrast agent: initial experience showing improved characterization of hemangioma, hepatocellular carcinoma, and metastasis. , 2000, Radiology.

[39]  N de Jong,et al.  A computerized system that uses high-frequency data for analysis of myocardial contrast echocardiograms. , 1990, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[40]  A. Kitabatake,et al.  Lack of Myocardial Perfusion Immediately After Successful Thrombolysis: A Predictor of Poor Recovery of Left Ventricular Function in Anterior Myocardial Infarction , 1992, Circulation.

[41]  A R Jayaweera,et al.  Quantification of myocardial blood flow with ultrasound-induced destruction of microbubbles administered as a constant venous infusion. , 1998, Circulation.

[42]  M. Goldman,et al.  Intraoperative cardioplegic contrast echocardiography for assessing myocardial perfusion during open heart surgery. , 1984, Journal of the American College of Cardiology.

[43]  G M Pohost,et al.  Contrast echocardiography in acute myocardial ischemia: I. In vivo determination of total left ventricular "area at risk". , 1984, Journal of the American College of Cardiology.

[44]  G. Buckberg,et al.  Total and Regional Myocardial Blood Flow Measurements with 25μ, 15μ, 9μ, and Filtered 1–10μ Diameter Microspheres and Antipyrine in Dogs and Sheep , 1974 .

[45]  E. Ritman,et al.  Simvastatin Preserves the Structure of Coronary Adventitial Vasa Vasorum in Experimental Hypercholesterolemia Independent of Lipid Lowering , 2002, Circulation.

[46]  D. Baim,et al.  Incidence and treatment of 'no-reflow' after percutaneous coronary intervention. , 1994, Circulation.

[47]  P. Quigley,et al.  Digital subtraction contrast echocardiography: a new method for the evaluation of regional myocardial perfusion. , 1988, British heart journal.

[48]  F. Romeo,et al.  Contrast echocardiography: Transmission of echoes to the left heart across the pulmonary vascular bed , 1980 .

[49]  S. Kaul,et al.  Noninvasive imaging of inflammation by ultrasound detection of phagocytosed microbubbles. , 2000, Circulation.

[50]  P. Serruys,et al.  Pulmonary wedge injections yielding left-sided echocardiographic contrast. , 1980, British heart journal.

[51]  R V Shohet,et al.  Echocardiographic destruction of albumin microbubbles directs gene delivery to the myocardium. , 2000, Circulation.

[52]  Akira Ishimaru,et al.  Wave propagation and scattering in random media , 1997 .

[53]  J. V. Nixon,et al.  Myocardial contrast echocardiography for the assessment of coronary blood flow reserve: validation in humans. , 1993, Journal of the American College of Cardiology.

[54]  M. Ziskin,et al.  Contrast agents for diagnostic ultrasound. , 1972, Investigative radiology.

[55]  S. Kaul,et al.  Myocardial contrast echocardiography in humans: I. Safety--a comparison with routine coronary arteriography. , 1986, Journal of the American College of Cardiology.

[56]  J G Miller,et al.  Contrast Echocardiography: Current and Future Applications , 2000 .

[57]  I. Kronzon,et al.  Microbubble formation: In vitro and in vivo observation , 1982, Journal of clinical ultrasound : JCU.

[58]  C. Tei,et al.  Hyperemic response of intracoronary contrast agents during two-dimensional echographic delineation of regional myocardium. , 1984, Journal of the American College of Cardiology.

[59]  M. Hori,et al.  Clinical implications of the 'no reflow' phenomenon. A predictor of complications and left ventricular remodeling in reperfused anterior wall myocardial infarction. , 1996, Circulation.

[60]  G. Buckberg,et al.  Total and regional myocardial blood flow measurements with 25 micron, 15 micron, 9 micron, and filtered 1-10 micron diameter microspheres and antipyrine in dogs and sheep. , 1974, Circulation research.

[61]  Nayler Wg,et al.  Contractile activity and reperfusion-induced calcium gain after ischemia in the isolated rat heart. , 1988 .

[62]  P. Heidenreich,et al.  Assessment of renal blood flow with contrast ultrasonography. , 1993, Anesthesia and analgesia.

[63]  S. Powsner,et al.  Contrast ultrasonography of the kidney: a new method for evaluation of renal perfusion in vivo. , 1987, Circulation.

[64]  E. G. Tickner,et al.  The source of ultrasound contrast effect , 1980, Journal of clinical ultrasound : JCU.

[65]  F J Ten Cate,et al.  Two-dimensional contrast echocardiography. I. In vitro development and quantitative analysis of echo contrast agents. , 1984, Journal of the American College of Cardiology.

[66]  S. Kaul,et al.  Measurement of myocardial blood flow velocity reserve with myocardial contrast echocardiography in patients with suspected coronary artery disease: comparison with quantitative gated Technetium 99m sestamibi single photon emission computed tomography. , 2003, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[67]  M. Monaghan,et al.  Digital radiofrequency echocardiography in the detection of myocardial contrast following intravenous administration of Albunex. , 1993, European Heart Journal.

[68]  E. Halpern,et al.  Prostate cancer: contrast-enhanced us for detection. , 2001, Radiology.

[69]  S. Kaul,et al.  Quantifying myocardial blood flow with contrast echocardiography. , 1993, American journal of cardiac imaging.

[70]  L. Rayleigh,et al.  The theory of sound , 1894 .

[71]  M. Fishbein,et al.  Two-dimensional contrast echocardiography. II. Transpulmonary studies. , 1984, Journal of the American College of Cardiology.

[72]  R. Bing,et al.  Microbubble dynamics visualized in the intact capillary circulation. , 1984, Journal of the American College of Cardiology.

[73]  M. Hori,et al.  Temporal changes in myocardial perfusion patterns in patients with reperfused anterior wall myocardial infarction. Their relation to myocardial viability. , 1995, Circulation.

[74]  H. Feigenbaum,et al.  Intracavitary echoes in patients with mitral prosthetic valves. , 1975, Journal of clinical ultrasound : JCU.

[75]  R. Wilson,et al.  Methods of measurement of myocardial blood flow in patients: a critical review. , 1987, Circulation.

[76]  S. Feinstein,et al.  Safety and Feasibility of Renal Blood Flow Determination During Kidney Transplant Surgery with Perfusion Ultrasonography , 1995, Anesthesia and analgesia.

[77]  O. L. Kwan,et al.  In vivo correlation of thermodilution cardiac output and videodensitometric indicator-dilution curves obtained from contrast two-dimensional echocardiograms. , 1984, Journal of the American College of Cardiology.

[78]  Temporal Changes in Myocardial Perfusion Patterns in Patients with Reperfused Anterior Wall Myocardial Infarction: Their Relation to Myocardial Viability , 1995 .

[79]  Harald Becher,et al.  Handbook of Contrast Echocardiography , 2000, Springer Berlin Heidelberg.

[80]  Y Wu,et al.  Acoustically active lipospheres containing paclitaxel: a new therapeutic ultrasound contrast agent. , 1998, Investigative radiology.

[81]  G A Klassen,et al.  Role of autoregulation in spatial and temporal perfusion heterogeneity of canine myocardium. , 1978, The American journal of physiology.

[82]  K. Sueishi,et al.  Intimal neovascularization in human coronary atherosclerosis: its origin and pathophysiological significance. , 1995, Human pathology.

[83]  D. Crossman,et al.  Microbubble-enhanced ultrasound for vascular gene delivery , 2000, Gene Therapy.

[84]  W. Spotnitz,et al.  Intraoperative Assessment of Myocardial Perfusion Using Contrast Echocardiography , 1990, Echocardiography.

[85]  J. Folkman Tumor angiogenesis: therapeutic implications. , 1971, The New England journal of medicine.

[86]  S. Kaul,et al.  In vivo myocardial kinetics of air-filled albumin microbubbles during myocardial contrast echocardiography. Comparison with radiolabeled red blood cells. , 1994, Circulation research.

[87]  J. V. Nixon,et al.  Usefulness of myocardial contrast echocardiography in detecting the immediate changes in anterograde blood flow reserve after coronary angioplasty. , 1993, The American journal of cardiology.

[88]  S. Feinstein,et al.  Effect of contrast enhancement on measurement of carotid artery intimal medial thickness , 2004 .

[89]  M. Ziskin,et al.  Ultrasonic detection of in-vivo cavitation and pressure effects of high-speed injections through catheters. , 1969, Investigative radiology.

[90]  Peter S. Prieto,et al.  High Speed Interface For Myocardial Sonicated Echocontrast Studies , 1987, Other Conferences.

[91]  S. Kaul,et al.  Myocardial contrast echocardiography. , 2004, Circulation.

[92]  F. T. ten Cate,et al.  Super harmonic imaging: a new imaging technique for improved contrast detection. , 2002, Ultrasound in medicine & biology.

[93]  K. Zierler Theoretical Basis of Indicator‐Dilution Methods For Measuring Flow and Volume , 1962 .

[94]  E. Unger,et al.  Ultrasound enhances gene expression of liposomal transfection. , 1997, Investigative radiology.

[95]  S. Kaul Myocardial contrast echocardiography: 15 years of research and development. , 1997, Circulation.

[96]  E. Unger,et al.  Local drug and gene delivery through microbubbles. , 2001, Progress in cardiovascular diseases.

[97]  R Gramiak,et al.  Echocardiography of the aortic root. , 1968, Investigative radiology.

[98]  R. Kloner,et al.  The "no-reflow" phenomenon after temporary coronary occlusion in the dog. , 1974, The Journal of clinical investigation.

[99]  G. J. Crystal,et al.  Small vessel and total coronary blood volume during intracoronary adenosine. , 1981, The American journal of physiology.

[100]  S. Powsner,et al.  Quantitation of echo-contrast effects. , 1986, American journal of physiologic imaging.

[101]  S. Feinstein,et al.  Assessment of myocardial perfusion during CABG surgery with two-dimensional transesophageal contrast echocardiography. , 1991, Anesthesiology.

[102]  S. Kaul,et al.  An association between collateral blood flow and myocardial viability in patients with recent myocardial infarction. , 1992, The New England journal of medicine.

[103]  E Krupinski,et al.  The use of a thrombus-specific ultrasound contrast agent to detect thrombus in arteriovenous fistulae. , 2000, Investigative radiology.

[104]  B. Satiani,et al.  Superficial venous thrombosis of the lower extremities: analysis of risk factors, and recurrence and role of anticoagulation , 2004, Vascular medicine.

[105]  A R Jayaweera,et al.  Method for the quantitation of myocardial perfusion during myocardial contrast two-dimensional echocardiography. , 1990, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[106]  C. Tei,et al.  Myocardial Contrast Echocardiography: A Reproducible Technique of Myocardial Opacification for Identifying Regional Perfusion Deficits , 1983, Circulation.

[107]  V. R. McCready,et al.  Microbubble contrast agent for color Doppler US: effect on breast masses. Work in progress. , 1996, Radiology.

[108]  E. G. Tickner,et al.  Assessment of Myocardial Perfusion Abnormalities with Contrast‐enhanced Two‐dimensional Echocardiography , 1982, Circulation.

[109]  K. Zierler,et al.  On the theory of the indicator-dilution method for measurement of blood flow and volume. , 1954, Journal of applied physiology.

[110]  C. Autore,et al.  Tissue-type plasminogen activator therapy versus primary coronary angioplasty: impact on myocardial tissue perfusion and regional function 1 month after uncomplicated myocardial infarction. , 1998, Journal of the American College of Cardiology.