contrast-enhanced ultrasound
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Contrast-enhanced ultrasound (CEUS) is the application of
ultrasound Ultrasound is sound waves with frequency, frequencies higher than the upper audible limit of human hearing range, hearing. Ultrasound is not different from "normal" (audible) sound in its physical properties, except that humans cannot hea ...
contrast medium A contrast agent (or contrast medium) is a substance used to increase the contrast of structures or fluids within the body in medical imaging. Contrast agents absorb or alter external electromagnetism or ultrasound, which is different from radiop ...
to traditional medical sonography. Ultrasound contrast agents rely on the different ways in which sound waves are reflected from interfaces between substances. This may be the surface of a small air bubble or a more complex structure. Commercially available contrast media are gas-filled
microbubbles Microbubbles (MBs) are bubbles smaller than one hundredth of a millimetre in diameter, but larger than one micrometre. They have widespread application in industry, life science, and medicine. The composition of the bubble shell and filling materia ...
that are administered intravenously to the
systemic circulation The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
. Microbubbles have a high degree of
echogenicity Echogenicity (misspelled sometimes as echogenecity) or echogeneity is the ability to bounce an echo, e.g. return the signal in ultrasound examinations. In other words, echogenicity is higher when the surface bouncing the sound echo reflects increa ...
(the ability of an object to reflect ultrasound waves). There is a great difference in echogenicity between the gas in the microbubbles and the soft tissue surroundings of the body. Thus, ultrasonic imaging using microbubble contrast agents enhances the ultrasound
backscatter In physics, backscatter (or backscattering) is the reflection of waves, particles, or signals back to the direction from which they came. It is usually a diffuse reflection due to scattering, as opposed to specular reflection as from a mirror, a ...
, (reflection) of the ultrasound waves, to produce a sonogram with increased contrast due to the high echogenicity difference. Contrast-enhanced ultrasound can be used to image blood
perfusion Perfusion is the passage of fluid through the circulatory system or lymphatic system to an organ or a tissue, usually referring to the delivery of blood to a capillary bed in tissue. Perfusion is measured as the rate at which blood is deliver ...
in organs, measure
blood flow Hemodynamics or haemodynamics are the dynamics of blood flow. The circulatory system is controlled by homeostatic mechanisms of autoregulation, just as hydraulic circuits are controlled by control systems. The hemodynamic response continuously m ...
rate in the
heart The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide t ...
and other organs, and for other applications. Targeting
ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...
s that bind to
receptors Receptor may refer to: *Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...
characteristic of
intravascular The blood vessels are the components of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues of the body. They also take waste and carbon dioxide away f ...
diseases can be conjugated to
microbubbles Microbubbles (MBs) are bubbles smaller than one hundredth of a millimetre in diameter, but larger than one micrometre. They have widespread application in industry, life science, and medicine. The composition of the bubble shell and filling materia ...
, enabling the microbubble complex to accumulate selectively in areas of interest, such as
diseased A disease is a particular abnormal condition that negatively affects the structure or function of all or part of an organism, and that is not immediately due to any external injury. Diseases are often known to be medical conditions that a ...
or abnormal tissues. This form of molecular imaging, known as targeted contrast-enhanced ultrasound, will only generate a strong ultrasound signal if targeted microbubbles bind in the area of interest. Targeted contrast-enhanced ultrasound may have many applications in both
medical diagnostics Medical diagnosis (abbreviated Dx, Dx, or Ds) is the process of determining which disease or condition explains a person's symptoms and signs. It is most often referred to as diagnosis with the medical context being implicit. The information re ...
and medical therapeutics. However, the targeted technique has not yet been approved by the FDA for clinical use in the United States. Contrast-enhanced ultrasound is regarded as safe in adults, comparable to the safety of
MRI contrast agent MRI contrast agents are contrast agents used to improve the visibility of internal body structures in magnetic resonance imaging (MRI). The most commonly used compounds for contrast enhancement are gadolinium-based. Such MRI contrast agents shorten ...
s, and better than
radiocontrast agent Radiocontrast agents are substances used to enhance the visibility of internal structures in X-ray-based imaging techniques such as computed tomography (contrast CT), projectional radiography, and fluoroscopy. Radiocontrast agents are typically io ...
s used in
contrast CT scan Contrast CT, or contrast enhanced computed tomography (CECT), is X-ray computed tomography (CT) using radiocontrast. Radiocontrasts for X-ray CT are generally iodine-based types. This is useful to highlight structures such as blood vessels that ...
s. The more limited safety data in children suggests that such use is as safe as in the adult population.


Bubble echocardiogram

An
echocardiogram An echocardiography, echocardiogram, cardiac echo or simply an echo, is an ultrasound of the heart. It is a type of medical imaging of the heart, using standard ultrasound or Doppler ultrasound. Echocardiography has become routinely used in th ...
is a study of the
heart The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide t ...
using ultrasound. A bubble echocardiogram is an extension of this that uses simple air bubbles as a contrast medium during this study and often has to be requested specifically. Although colour Doppler can be used to detect abnormal flows between the chambers of the heart (e.g., persistent (patent) foramen ovale), it has a limited sensitivity. When specifically looking for a defect such as this, small air bubbles can be used as a contrast medium and injected intravenously, where they travel to the right side of the heart. The test would be positive for an abnormal communication if the bubbles are seen passing into the left side of the heart. (Normally, they would exit the
heart The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide t ...
through the
pulmonary artery A pulmonary artery is an artery in the pulmonary circulation that carries deoxygenated blood from the right side of the heart to the lungs. The largest pulmonary artery is the ''main pulmonary artery'' or ''pulmonary trunk'' from the heart, and t ...
and be stopped by the lungs.) This form of bubble contrast medium is generated on an ''
ad hoc Ad hoc is a Latin phrase meaning literally 'to this'. In English, it typically signifies a solution for a specific purpose, problem, or task rather than a generalized solution adaptable to collateral instances. (Compare with ''a priori''.) Com ...
'' basis by the testing clinician by agitating
normal saline Saline (also known as saline solution) is a mixture of sodium chloride (salt) and water. It has a number of uses in medicine including cleaning wounds, removal and storage of contact lenses, and help with dry eyes. By injection into a vein it ...
(e.g., by rapidly and repeatedly transferring the saline between two connected syringes) immediately prior to injection.


Microbubble contrast agents


General features

There are a variety of microbubble contrast agents. Microbubbles differ in their shell makeup, gas core makeup, and whether or not they are targeted. * Microbubble shell: selection of shell material determines how easily the microbubble is taken up by the
immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...
. A more
hydrophilic A hydrophile is a molecule or other molecular entity that is attracted to water molecules and tends to be dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clarendon Press. In contrast, hydrophobes are no ...
material tends to be taken up more easily, which reduces the microbubble residence time in the circulation. This reduces the time available for contrast imaging. The shell material also affects microbubble mechanical elasticity. The more elastic the material, the more acoustic energy it can withstand before bursting. Most commonly, microbubble shells are composed of
albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All the proteins of the albumin family are water-soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Albumins ...
,
galactose Galactose (, '' galacto-'' + '' -ose'', "milk sugar"), sometimes abbreviated Gal, is a monosaccharide sugar that is about as sweet as glucose, and about 65% as sweet as sucrose. It is an aldohexose and a C-4 epimer of glucose. A galactose molec ...
,
lipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include ...
, or
polymers A polymer (; Greek '' poly-'', "many" + ''-mer'', "part") is a substance or material consisting of very large molecules called macromolecules, composed of many repeating subunits. Due to their broad spectrum of properties, both synthetic an ...
.
Hydrophobic In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, th ...
particles have also been applied to stabilize microbubble shells. * Microbubble gas core: The gas core is primary part of the ultrasound contrast microbubble that determines its echogenicity. When gas bubbles are caught in an ultrasonic
frequency Frequency is the number of occurrences of a repeating event per unit of time. It is also occasionally referred to as ''temporal frequency'' for clarity, and is distinct from ''angular frequency''. Frequency is measured in hertz (Hz) which is eq ...
field, they
compress compress is a Unix shell compression program based on the LZW compression algorithm. Compared to more modern compression utilities such as gzip and bzip2, compress performs faster and with less memory usage, at the cost of a significantly l ...
,
oscillate Oscillation is the repetitive or periodic variation, typically in time, of some measure about a central value (often a point of equilibrium) or between two or more different states. Familiar examples of oscillation include a swinging pendulum ...
, and reflect a characteristic echo. This generates the strong and unique sonogram in contrast-enhanced ultrasound. Gas cores can be composed of
air The atmosphere of Earth is the layer of gases, known collectively as air, retained by Earth's gravity that surrounds the planet and forms its planetary atmosphere. The atmosphere of Earth protects life on Earth by creating pressure allowing f ...
, or heavy gases like
perfluorocarbon Fluorocarbons are chemical compounds with carbon-fluorine bonds. Compounds that contain many C-F bonds often has distinctive properties, e.g., enhanced stability, volatility, and hydrophobicity. Fluorocarbons and their derivatives are commerci ...
, or
nitrogen Nitrogen is the chemical element with the symbol N and atomic number 7. Nitrogen is a nonmetal and the lightest member of group 15 of the periodic table, often called the pnictogens. It is a common element in the universe, estimated at se ...
. Heavy gases are less water-soluble so they are less likely to leak out from the microbubble leading to microbubble dissolution. As a result, microbubbles with heavy gas cores last longer in circulation. To increase
harmonic A harmonic is a wave with a frequency that is a positive integer multiple of the ''fundamental frequency'', the frequency of the original periodic signal, such as a sinusoidal wave. The original signal is also called the ''1st harmonic'', the ...
pulsation A pulse, in physiology, is the throbbing of arteries resulting from heartbeat. Pulse, The Pulse or Pulses may also refer to: Botany * Pulse (legume), any agriculturally significant annual leguminous food crop, such as peas, beans, lentils, and ...
behavior, liquid and solid cores have been added to the gas contents. Regardless of the shell or gas core composition, microbubble size is fairly uniform. They lie within a range of 1–4 micrometres in diameter. That makes them smaller than
red blood cell Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
s, which allows them to flow easily through the circulation as well as the microcirculation.


Specific agents

* Perflutren lipid microspheres (brand names Definity, Luminity) are
perfluorocarbon emulsions Perfluorocarbon emulsions are emulsions containing either bubbles or droplets which have perfluorocarbons inside them. Some of them are commonly used in medicine as ultrasound contrast agents, and others have been studied for use as oxygen therapeu ...
composed of
octafluoropropane Octafluoropropane (C3F8) is the perfluorocarbon counterpart to the hydrocarbon propane. This non-flammable synthetic material has applications in semiconductor production and medicine. It is also an extremely potent greenhouse gas. Manufacture O ...
encapsulated in an outer
lipid shell A liposome is a small artificial vesicle, spherical in shape, having at least one lipid bilayer. Due to their hydrophobicity and/or hydrophilicity, biocompatibility, particle size and many other properties, liposomes can be used as drug deliver ...
. * Octafluoropropane gas core with an albumin shell (''Optison'') is another
perfluorocarbon emulsion Perfluorocarbon emulsions are emulsions containing either bubbles or droplets which have perfluorocarbons inside them. Some of them are commonly used in medicine as ultrasound contrast agents, and others have been studied for use as oxygen therapeut ...
that is an
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA)-approved microbubble and made by
GE Healthcare GE HealthCare is a subsidiary of American multinational conglomerate General Electric incorporated in New York and headquartered in Chicago, Illinois. As of 2017, it is a manufacturer and distributor of diagnostic imaging agents and radiopharma ...
). *
Sulphur hexafluoride Sulfur hexafluoride or sulphur hexafluoride (British spelling) is an inorganic compound with the formula SF6. It is a colorless, odorless, non-flammable, and non-toxic gas. has an octahedral geometry, consisting of six fluorine atoms attached t ...
microbubbles (''SonoVue''
Bracco (company) The Bracco Group is an Italian multinational active in the healthcare sector with more than 3,300 employees worldwide, which operates in a variety of business areas. *Diagnostic imaging, with products for X-ray imaging, including computed tomog ...
). It is mainly used to characterize liver lesions that cannot be properly identified using conventional (b-mode) ultrasound. It remains visible in the blood for 3 to 8 minutes, and is expired by the lungs. * Air within a lipid/galactose shell (formerly Levovist, an FDA-approved microbubble that was made by Schering). * Perflexane lipid microspheres (formerly Imagent or Imavist) was an injectable suspension developed by
Alliance Pharmaceutical An alliance is a relationship among people, groups, or states that have joined together for mutual benefit or to achieve some common purpose, whether or not explicit agreement has been worked out among them. Members of an alliance are called ...
approved by the FDA (in June 2002) for improving visualization of the left ventricular chamber of the heart, the delineation of the endocardial borders in patients with suboptimal echocardiograms. Beside its use to assess cardiac function and perfusion it is also used as an enhancer of the images of prostate, liver, kidney and other organs.


Targeted microbubbles

Targeted microbubbles are under preclinical development. They retain the same general features as untargeted microbubbles, but they are outfitted with ligands that bind specific receptors expressed by cell types of interest, such as inflamed cells or cancer cells. Current microbubbles in development are composed of a lipid monolayer shell with a perfluorocarbon gas core. The lipid shell is also covered with a
polyethylene glycol Polyethylene glycol (PEG; ) is a polyether compound derived from petroleum with many applications, from industrial manufacturing to medicine. PEG is also known as polyethylene oxide (PEO) or polyoxyethylene (POE), depending on its molecular we ...
(PEG) layer. PEG prevents microbubble aggregation and makes the microbubble more non-reactive. It temporarily "hides" the microbubble from the immune system uptake, increasing the amount of circulation time, and hence, imaging time. In addition to the PEG layer, the shell is modified with molecules that allow for the attachment of
ligands In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electro ...
that bind certain
receptors Receptor may refer to: *Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...
. These ligands are attached to the microbubbles using
carbodiimide In organic chemistry, a carbodiimide (systematic IUPAC name: methanediimine) is a functional group with the formula RN=C=NR. They are exclusively synthetic. A well known carbodiimide is dicyclohexylcarbodiimide, which is used in peptide synthesis. ...
,
maleimide Maleimide is a chemical compound with the formula H2C2(CO)2NH (see diagram). This unsaturated imide is an important building block in organic synthesis. The name is a contraction of maleic acid and imide, the -C(O)NHC(O)- functional group. Malei ...
, or biotin-streptavidin coupling. Biotin-streptavidin is the most popular coupling strategy because biotin's affinity for
streptavidin Streptavidin is a 66.0 (tetramer) kDa protein purified from the bacterium '' Streptomyces avidinii''. Streptavidin homo-tetramers have an extraordinarily high affinity for biotin (also known as vitamin B7 or vitamin H). With a dissociation co ...
is very strong and it is easy to label the ligands with biotin. Currently, these ligands are
monoclonal antibodies A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodies ca ...
produced from animal cell cultures that bind specifically to receptors and molecules expressed by the target cell type. Since the antibodies are not humanized, they will elicit an immune response when used in human therapy. Humanizing antibodies is an expensive and time-intensive process, so it would be ideal to find an alternative source of ligands, such as synthetically manufactured targeting
peptides Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A p ...
that perform the same function, but without the immune issues.


Types

There are two forms of contrast-enhanced ultrasound, untargeted (used in the clinic today) and targeted (under preclinical development). The two methods slightly differ from each other.


Untargeted CEUS

Untargeted microbubbles, such as the aforementioned SonoVue, Optison, or Levovist, are injected intravenously into the systemic circulation in a small bolus. The microbubbles will remain in the systemic circulation for a certain period of time. During that time, ultrasound waves are directed on the area of interest. When microbubbles in the blood flow past the imaging window, the microbubbles'
compressible In thermodynamics and fluid mechanics, the compressibility (also known as the coefficient of compressibility or, if the temperature is held constant, the isothermal compressibility) is a measure of the instantaneous relative volume change of a f ...
gas cores
oscillate Oscillation is the repetitive or periodic variation, typically in time, of some measure about a central value (often a point of equilibrium) or between two or more different states. Familiar examples of oscillation include a swinging pendulum ...
in response to the high frequency sonic energy field, as described in the
ultrasound Ultrasound is sound waves with frequency, frequencies higher than the upper audible limit of human hearing range, hearing. Ultrasound is not different from "normal" (audible) sound in its physical properties, except that humans cannot hea ...
article. The microbubbles reflect a unique
echo In audio signal processing and acoustics, an echo is a reflection of sound that arrives at the listener with a delay after the direct sound. The delay is directly proportional to the distance of the reflecting surface from the source and the list ...
that stands in stark contrast to the surrounding tissue due to the orders of magnitude mismatch between microbubble and tissue echogenicity. The ultrasound system converts the strong echogenicity into a contrast-enhanced image of the area of interest. In this way, the bloodstream's echo is enhanced, thus allowing the clinician to distinguish
blood Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the c ...
from surrounding tissues.


Targeted CEUS

Targeted contrast-enhanced ultrasound works in a similar fashion, with a few alterations. Microbubbles targeted with ligands that bind certain molecular markers that are expressed by the area of imaging interest are still injected systemically in a small bolus. Microbubbles theoretically travel through the circulatory system, eventually finding their respective targets and binding specifically. Ultrasound waves can then be directed on the area of interest. If a sufficient number of microbubbles have bound in the area, their compressible gas cores oscillate in response to the high frequency sonic energy field, as described in the
ultrasound Ultrasound is sound waves with frequency, frequencies higher than the upper audible limit of human hearing range, hearing. Ultrasound is not different from "normal" (audible) sound in its physical properties, except that humans cannot hea ...
article. The targeted microbubbles also reflect a unique echo that stands in stark contrast to the surrounding tissue due to the orders of magnitude mismatch between microbubble and tissue echogenicity. The ultrasound system converts the strong echogenicity into a contrast-enhanced image of the area of interest, revealing the location of the bound microbubbles. Detection of bound microbubbles may then show that the area of interest is expressing that particular molecular marker, which can be indicative of a certain disease state, or identify particular cells in the area of interest.


Applications

Untargeted contrast-enhanced ultrasound is currently applied in
echocardiography An echocardiography, echocardiogram, cardiac echo or simply an echo, is an ultrasound of the heart. It is a type of medical imaging of the heart, using standard ultrasound or Doppler ultrasound. Echocardiography has become routinely used in t ...
and
radiology Radiology ( ) is the medical discipline that uses medical imaging to diagnose diseases and guide their treatment, within the bodies of humans and other animals. It began with radiography (which is why its name has a root referring to radiat ...
. Targeted contrast-enhanced ultrasound is being developed for a variety of medical applications.


Untargeted CEUS

Untargeted microbubbles like Optison and Levovist are currently used in echocardiography. In addition, SonoVue ultrasound contrast agent is used in radiology for lesion characterization. * Organ Edge Delineation: microbubbles can enhance the contrast at the interface between the tissue and blood. A clearer picture of this interface gives the clinician a better picture of the structure of an organ. Tissue structure is crucial in echocardiograms, where a thinning, thickening, or irregularity in the heart wall indicates a serious heart condition that requires either monitoring or treatment. * Blood Volume and Perfusion: contrast-enhanced ultrasound holds the promise for (1) evaluating the degree of blood perfusion in an organ or area of interest and (2) evaluating the blood volume in an organ or area of interest. When used in conjunction with Doppler ultrasound, microbubbles can measure myocardial flow rate to diagnose valve problems. And the relative intensity of the microbubble echoes can also provide a quantitative estimate on blood volume. * Lesion Characterization: contrast-enhanced ultrasound plays a role in the differentiation between benign and malignant focal liver lesions. This differentiation relies on the observation or processing of the dynamic vascular pattern in a lesion with respect to its surrounding tissue
parenchyma Parenchyma () is the bulk of functional substance in an animal organ or structure such as a tumour. In zoology it is the name for the tissue that fills the interior of flatworms. Etymology The term ''parenchyma'' is New Latin from the word π ...
.


Targeted CEUS

*
Inflammation Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
: Contrast agents may be designed to bind to certain proteins that become expressed in inflammatory diseases such as
Crohn's disease Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea (which may be bloody if inflammation is severe), fever, abdominal distension ...
,
atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheroma, atheromatous plaque. At onset there are usu ...
, and even
heart attacks A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may tra ...
. Cells of interest in such cases are
endothelial cell The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
s of blood vessels, and
leukocytes White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
: ** The inflamed blood vessels specifically express certain receptors, functioning as
cell adhesion molecules Cell adhesion molecules (CAMs) are a subset of cell surface proteins that are involved in the binding of cells with other cells or with the extracellular matrix (ECM), in a process called cell adhesion. In essence, CAMs help cells stick to each ...
, like VCAM-1, ICAM-1, E-selectin. If microbubbles are targeted with ligands that bind these molecules, they can be used in contrast echocardiography to detect the onset of inflammation. Early detection allows the design of better treatments. Attempts have been made to outfit microbubbles with monoclonal antibodies that bind
P-selectin P-selectin is a type-1 transmembrane protein that in humans is encoded by the SELP gene. P-selectin functions as a cell adhesion molecule (CAM) on the surfaces of activated endothelial cells, which line the inner surface of blood vessels, and act ...
,
ICAM-1 ICAM-1 (Intercellular Adhesion Molecule 1) also known as CD54 (Cluster of Differentiation 54) is a protein that in humans is encoded by the ''ICAM1'' gene. This gene encodes a cell surface glycoprotein which is typically expressed on endothelial ...
, and
VCAM-1 Vascular cell adhesion protein 1 also known as vascular cell adhesion molecule 1 (VCAM-1) or cluster of differentiation 106 (CD106) is a protein that in humans is encoded by the ''VCAM1'' gene. VCAM-1 functions as a cell adhesion molecule. Stru ...
, but the adhesion to the molecular target was poor and a large fraction of microbubbles that bound to the target rapidly detached, especially at high shear stresses of physiological relevance. **
Leukocytes White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
possess high adhesion efficiencies, partly due to a dual-ligand
selectin The selectins (cluster of differentiation 62 or CD62) are a family of cell adhesion molecules (or CAMs). All selectins are single-chain transmembrane glycoproteins that share similar properties to C-type lectins due to a related amino terminus a ...
-
integrin Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...
cell arrest system. One ligand:receptor pair (
PSGL-1 Selectin P ligand, also known as SELPLG or CD162 (cluster of differentiation 162), is a human gene. SELPLG codes for PSGL-1, the high affinity counter-receptor for P-selectin on myeloid cells and stimulated T lymphocytes. As such, it plays a crit ...
:selectin) has a fast bond on-rate to slow the leukocyte and allows the second pair (integrin:
immunoglobulin An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
superfamily), which has a slower on-rate but slow off-rate to arrest the leukocyte, kinetically enhancing adhesion. Attempts have been made to make contrast agents bind to such ligands, with techniques such as dual-ligand targeting of distinct receptors to polymer microspheres, and
biomimicry Biomimetics or biomimicry is the emulation of the models, systems, and elements of nature for the purpose of solving complex human problems. The terms "biomimetics" and "biomimicry" are derived from grc, βίος (''bios''), life, and μίμησ ...
of the leukocyte's selectin-integrin cell arrest system, having shown an increased adhesion efficiency, but yet not efficient enough to allow clinical use of targeted contrast-enhanced ultrasound for inflammation. *
Thrombosis Thrombosis (from Ancient Greek "clotting") is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (thro ...
and
thrombolysis Thrombolysis, also called fibrinolytic therapy, is the breakdown (lysis) of blood clots formed in blood vessels, using medication. It is used in ST elevation myocardial infarction, stroke, and in cases of severe venous thromboembolism (massive p ...
: Activated
platelets Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...
are major components of blood clots (thrombi).
Microbubbles Microbubbles (MBs) are bubbles smaller than one hundredth of a millimetre in diameter, but larger than one micrometre. They have widespread application in industry, life science, and medicine. The composition of the bubble shell and filling materia ...
can be conjugated to a recombinant
single-chain variable fragment A single-chain variable fragment (scFv) is not actually a fragment of an antibody, but instead is a fusion protein of the variable regions of the heavy (VH) and light chains (VL) of immunoglobulins, connected with a short linker peptide of ten ...
specific for activated
glycoprotein IIb/IIIa In medicine, glycoprotein IIb/IIIa (GPIIb/IIIa, also known as integrin αIIbβ3) is an integrin complex found on platelets. It is a receptor for fibrinogen and von Willebrand factor and aids platelet activation. The complex is formed via calcium ...
(GPIIb/IIIa), which is the most abundant platelet surface receptor. Despite the high shear stress at the thrombus area, the GPIIb/IIIa-targeted microbubbles will specifically bind to activated platelets and allow real-time molecular imaging of thrombosis, such as in
myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...
, as well as monitoring success or failure of pharmacological thrombolysis. *
Cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
: cancer cells also express a specific set of receptors, mainly receptors that encourage
angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
, or the growth of new blood vessels. If microbubbles are targeted with ligands that bind receptors like
VEGF Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...
or activated
glycoprotein IIb/IIIa In medicine, glycoprotein IIb/IIIa (GPIIb/IIIa, also known as integrin αIIbβ3) is an integrin complex found on platelets. It is a receptor for fibrinogen and von Willebrand factor and aids platelet activation. The complex is formed via calcium ...
, they can non-invasively and specifically identify areas of cancers. *
Gene Delivery Gene delivery is the process of introducing foreign genetic material, such as DNA or RNA, into host cells. Gene delivery must reach the genome of the host cell to induce gene expression. Successful gene delivery requires the foreign gene delive ...
:
Vector DNA In molecular cloning, a vector is any particle (e.g., plasmids, cosmids, Lambda phages) used as a vehicle to artificially carry a foreign nucleic sequence – usually DNA – into another cell, where it can be replicated and/or expressed. A vec ...
can be conjugated to the microbubbles. Microbubbles can be targeted with ligands that bind to receptors expressed by the cell type of interest. When the targeted microbubble accumulates at the cell surface with its DNA payload, ultrasound can be used to burst the microbubble. The force associated with the bursting may temporarily permeablize surrounding tissues and allow the DNA to more easily enter the cells. Targeted theranostic microbubbles (directed at
VCAM-1 Vascular cell adhesion protein 1 also known as vascular cell adhesion molecule 1 (VCAM-1) or cluster of differentiation 106 (CD106) is a protein that in humans is encoded by the ''VCAM1'' gene. VCAM-1 functions as a cell adhesion molecule. Stru ...
) have been employed to deliver miR126 in a preclinical setting to stop the development of
AAA AAA, Triple A, or Triple-A is a three-letter initialism or abbreviation which may refer to: Airports * Anaa Airport in French Polynesia (IATA airport code AAA) * Logan County Airport (Illinois) (FAA airport code AAA) Arts, entertainment, and me ...
in vivo. * Drug Delivery: drugs can be incorporated into the microbubble's lipid shell. The microbubble's large size relative to other drug delivery vehicles like
liposomes A liposome is a small artificial Vesicle (biology and chemistry), vesicle, spherical in shape, having at least one lipid bilayer. Due to their hydrophobicity and/or hydrophilicity, biocompatibility, particle size and many other properties, lipo ...
may allow a greater amount of drug to be delivered per vehicle. By targeted the drug-loaded microbubble with ligands that bind to a specific cell type, microbubble will not only deliver the drug specifically, but can also provide verification that the drug is delivered if the area is imaged using ultrasound. Ultrasound-guided drug delivery has been successfully applied in the treatment of
pancreatic cancer Pancreatic cancer arises when cell (biology), cells in the pancreas, a glandular organ behind the stomach, begin to multiply out of control and form a Neoplasm, mass. These cancerous cells have the malignant, ability to invade other parts of t ...
.


Advantages

On top of the strengths mentioned in the medical sonography entry, contrast-enhanced ultrasound adds these additional advantages: * The body is 73% water, and therefore, acoustically homogeneous. Blood and surrounding tissues have similar echogenicities, so it is also difficult to clearly discern the degree of blood flow, perfusion, or the interface between the tissue and blood using traditional ultrasound. * Ultrasound imaging allows real-time evaluation of blood flow. * Destruction of microbubbles by ultrasound in the image plane allows absolute quantification of tissue perfusion. * Ultrasonic molecular imaging is safer than molecular imaging modalities such as radionuclide imaging because it does not involve radiation. * Alternative molecular imaging modalities, such as
MRI Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves ...
,
PET A pet, or companion animal, is an animal kept primarily for a person's company or entertainment rather than as a working animal, livestock, or a laboratory animal. Popular pets are often considered to have attractive appearances, intelligence, ...
, and
SPECT Single-photon emission computed tomography (SPECT, or less commonly, SPET) is a nuclear medicine tomographic imaging technique using gamma rays. It is very similar to conventional nuclear medicine planar imaging using a gamma camera (that is, ...
are very costly. Ultrasound, on the other hand, is very cost-efficient and widely available. * Since microbubbles can generate such strong signals, a lower intravenous dosage is needed, micrograms of microbubbles are needed compared to milligrams for other molecular imaging modalities such as
MRI contrast agent MRI contrast agents are contrast agents used to improve the visibility of internal body structures in magnetic resonance imaging (MRI). The most commonly used compounds for contrast enhancement are gadolinium-based. Such MRI contrast agents shorten ...
s. * Targeting strategies for microbubbles are versatile and modular. Targeting a new area only entails conjugating a new ligand. * Active targeting can be increased (enhanced microbubbles adhesion) by
Acoustic radiation force Acoustic radiation force (ARF) is a physical phenomenon resulting from the interaction of an acoustic wave with an obstacle placed along its path. Generally, the force exerted on the obstacle is evaluated by integrating the acoustic radiation pressu ...
using a clinical ultrasound imaging system in 2D-mode and 3D-mode.


Disadvantages

In addition to the weaknesses mentioned in the medical sonography entry, contrast-enhanced ultrasound has the following disadvantages: * Microbubbles don't last very long in circulation. They have low circulation residence times because they either get taken up by immune system cells or get taken up by the
liver The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
or
spleen The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes .
even when they are coated with PEG. * Ultrasound produces more heat as the frequency increases, so the ultrasonic frequency must be carefully monitored. * Microbubbles burst at low ultrasound frequencies and at high mechanical indices (MI), which is the measure of the negative acoustic pressure of the ultrasound imaging system. Increasing MI increases image quality, but there are tradeoffs with microbubble destruction. Microbubble destruction could cause local microvasculature ruptures and
hemolysis Hemolysis or haemolysis (), also known by several other names, is the rupturing (lysis) of red blood cells (erythrocytes) and the release of their contents (cytoplasm) into surrounding fluid (e.g. blood plasma). Hemolysis may occur in vivo o ...
. * Targeting ligands can be immunogenic, since current targeting ligands used in preclinical experiments are derived from
animal culture Animal culture can be defined as the ability of non-human animals to learn and transmit behaviors through processes of social or cultural learning. Culture is increasingly seen as a process, involving the social transmittance of behavior among p ...
. * Low targeted microbubble adhesion efficiency, which means a small fraction of injected microbubbles bind to the area of interest. This is one of the main reasons that targeted contrast-enhanced ultrasound remains in the preclinical development stages.


See also

*
Doppler effect The Doppler effect or Doppler shift (or simply Doppler, when in context) is the change in frequency of a wave in relation to an observer who is moving relative to the wave source. It is named after the Austrian physicist Christian Doppler, who d ...
*
Echocardiography An echocardiography, echocardiogram, cardiac echo or simply an echo, is an ultrasound of the heart. It is a type of medical imaging of the heart, using standard ultrasound or Doppler ultrasound. Echocardiography has become routinely used in t ...
*
Medical imaging Medical imaging is the technique and process of imaging the interior of a body for clinical analysis and medical intervention, as well as visual representation of the function of some organs or tissues (physiology). Medical imaging seeks to rev ...
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Medical ultrasonography Medical ultrasound includes diagnostic techniques (mainly medical imaging, imaging techniques) using ultrasound, as well as therapeutic ultrasound, therapeutic applications of ultrasound. In diagnosis, it is used to create an image of internal ...
*
Sonography Medical ultrasound includes diagnostic techniques (mainly medical imaging, imaging techniques) using ultrasound, as well as therapeutic ultrasound, therapeutic applications of ultrasound. In diagnosis, it is used to create an image of internal ...
*
Ultrasound Ultrasound is sound waves with frequency, frequencies higher than the upper audible limit of human hearing range, hearing. Ultrasound is not different from "normal" (audible) sound in its physical properties, except that humans cannot hea ...


References


External links


Optison Information from GE Healthcare


{{DEFAULTSORT:Contrast-Enhanced Ultrasound Biological engineering Cardiology Medical equipment Medical ultrasonography