Medical Ultrasound (aka Sonography or Ultrasonography) is a non-invasive imaging technique used to image inside the body. The process directs high-frequency sound waves (20KHz—which is above the human hearing threshold) into the body using a transducer (a hand-held probe). Detected echoes are then electronically converted by the ultrasound system into images of the tissues and organs targeted by the sound waves. Common ultrasound uses include fetal growth monitoring during pregnancy, as well as imaging the heart, blood vessels, eyes, thyroid, brain, breast, abdominal organs, and muscles.
Other current forms of ultrasound include Doppler and Color Doppler to measure and visualize blood flow in blood vessels within the body, as well as many exciting new forms and uses of ultrasound that permit its use as a surgical or therapeutic tool.
New Directions Research
Medical Ultrasound is a rapidly evolving area of research. The modality is unique in that it can function both as an imaging tool and/or as a therapeutic interventional tool. For example, recent advances in diagnostic ultrasound imaging include several new forms of elastography, which allow the evaluation of tissue elasticity and compressibility. Another example is high-frequency imaging, which has led to “biomicroscopy”, where ultra-high-resolution images are produced by high-frequency transducers (20MHz-100MHz and beyond). Also, new manufacturing methods allow the miniaturization of transducers and imaging devices, leading to the development of palm-size, hand-held ultrasound imaging systems. Further advances in transducer technology are leading to production of far smaller and lighter transducers, which will add new capabilities in medical diagnosis, patient monitoring, and image guided therapy.
On the therapy side, high-intensity focused ultrasound, ultrasound lithotripsy and histotripsy, and ultrasound-mediated thrombolysis and drug delivery offer exciting additions to the practice of medicine. These trends may lead toward dramatic improvements in patient diagnosis and treatment.
The generation of ultrasound signals was made possible by the discovery of piezoelectricity, a property of some crystals that allows them to both convert electric energy into sound waves, or conversely, convert sound wave energy into electricity. These discoveries were pioneered by Pierre Curie (husband of Marie Curie) and his brother Jacques, around 1880 (ref 2, 3). Later, around 1900, Paul Langevin, a physicist, student of Pierre Curie’s, developed the first ultrasound hydrophone, which was a precursor of today’s ultrasound transducer, and later patented the first ultrasonic imaging system, but it was only for detection of submerged ships and other under-water objects, as part of France’s involvement in the first world war (ref 3). During the Second World War, other engineers further developed the underwater ultrasound detector developed by Langevin into echo-sounding sonar (1920-1945) (ref. 4,5,6). Soon after, ultrasound sonar was used to image living humans. This led to more experimentation on humans, and a few years later, to the development of practical medical ultrasound units, and came into wide use during the 1960’s and 1970’s (ref 7). The field of ultrasound continues to grow, and new capabilities and uses are still being discovered. Presently, ultrasound is an important and indispensable tool in the clinic, for medical diagnosis and therapy, and its capabilities are expanding.
Diagnostic Ultrasound Innovations
Diagnostic ultrasound technology has expanded from traditional B-mode, or “sonographic” imaging (i.e. the kind of ultrasound the gynecologist uses) toward functional and intraoperative imaging, with major improvements in resolution and contrast made possible by use of contrast agents and innovative signal processing. Also, new transducer materials are leading the trend toward miniaturization, microfabrication, and faster digital processing, which allow newer display formats and diagnosis capabilities. The following represent some areas of major diagnostic innovation and possible future growth:
- High-frequency and Very High-frequency imaging
Transducer development in the area above 20MHz MHz range (ref. 8,9, 10) and higher than 100 MHz (very High frequency) show great promise in carving out new niches for diagnostic applications. Higher frequencies interpret into higher image resolution, at the cost of lower penetration (ref 10). Also, there is active development of miniature transducers and arrays for use in catheter-guided applications, especially in intravascular ultrasound (IVUS). These developments may improve diagnostic capabilities by producing more image detail and function inside blood vessel walls, allowing identification of plaques, and vessel wall properties. Other current uses for high-frequency ultrasound include ophthalmology, and dermatology. Ophthalmology ultrasound applications allow for detailed examination of microscopic structures within the eye, especially those which are not easily imaged by optical means. Dermatological ultrasound imaging holds promise in the development of new, non-invasive techniques for diagnosing skin diseases and tissue injury (burns, trauma, and radiation exposure). In addition, very high-frequency transducers (operating higher than 100MHz) make acoustic microscopy possible in vivo.
- Functional Imaging capabilities
Include Spectral Doppler, Color-flow Doppler, Power Doppler, Tissue-motion Doppler and Elastography. Doppler ultrasound allows the detection, measurement (spectral Doppler) and visualization (Color Doppler) of flowing blood within blood vessels ref 11), using various formats that color-code the direction of blood flow within a blood vessel. Color Flow Doppler maps moving volumes of blood within a blood vessel, where the direction of the flow is coded in different colors for flow toward or away from the transducer. Power Doppler displays a color-coded image of the volume of blood that is flowing in a particular region (e.g. the kidneys) being interrogated. Tissue-motion Doppler produces color-coded maps of tissue movement and velocity, where the colors indicate how fast and in what direction the tissue moves. This is especially useful in imaging moving parts of the heart, such as the heart valves. Elastography displays a color-coded map of relative tissue stiffness, or compressibility and elasticity of tissue components, based on tissue response to an external pressure, and allows the characterization of tissue properties, as well as differentiation of tumors (less elastic) from normal tissue (more elastic). New uses and techniques for elastography are being developed, which include real-time evaluation of liver fibrosis (ref 12, as well as various components of the beating heart (ref 13, 14). If used with intra-vascular ultrasound (IVUS), the addition elastography offers the possibility of not only location and imaging of plaques on the walls of blood vessels, but also identification of types of plaque, by hardness or softness, as well as producing detailed 2D and 3D maps of the plaque location, its thickness and structure, in addition to the color Doppler characterization of blood flow (ref 15, 16).
- Low-cost, miniature transducers and arrays
By using new transducer materials and new manufacturing methods, ultrasound arrays can be produced in a manner similar to the production of computer chips. Some of these arrays (CMUT) are less expensive to produce, and have several advantages over existing types of transducers. For instance, one type, called 2D-CMUT arrays, can be configured as Dynamic Arrays— for active US beamforming in either transmit and/or receive mode. These arrays allow for very fast real-time 3D imaging (ref 17). Active arrays are able to change the shape of the US beam by either mechanical activation of individual elements or sets of elements, and/or by use of electronic digital control for active image formation. These innovations allow for greater flexibility and capability of an imaging system, at lower cost than conventional hand-wired components, which are labor-intensive and costlier to produce.
Microfabrication of transducers, high-capacity miniature computer chips, and microcircuits all contribute to the miniaturization of previously large components of ultrasound devices and make it possible to produce small ultrasound units, or very small ultrasound detectors (ref 18). Research in miniature ultrasound arrays offers very exciting new areas of investigation, especially in IVUS, cardiac and endoscopic surgical applications.
Benefits of miniature array technology are already in clinical use, in the form of hand-held ultrasound imaging devices that have technical characteristics formerly found only in mainframe devices. An example is a new device developed using NIBIB funded research that resulted in the production of the GE V-scanner, a palm-size scanner, with color-Doppler capability, which is currently in clinical use (ref 19).
- Contrast Agent Enhanced Imaging
Ultrasound contrast agents (which consist of microscopic bubbles with an albumin or lipid hard shell) allow the enhancement and visualization of previously difficult to see blood flow dynamics, especially in the heart and blood vessels, and also for outlining heart tissue structures and functions (ref 20).
- Harmonic Imaging
A signal processing technique that selects 2nd and higher harmonics of the ultrasound frequency to cut down or eliminate image noise, which is normally contained in the first harmonic. This technique increases the signal-to-noise ratio (contrast) and resolution, and helps in producing higher quality images of body regions that were previously difficult to image (ref 21, 22).
- Photoacoustics and Thermoacoustics
A new method for producing ultrasound signals by interrogating tissue with electromagnetic signals, either in the optical range, radiofrequency range, or the thermal range, and produce high-frequency pressure waves that can be detected as ultrasound signals. This modality increases both the resolution and the contrast of imaged structures, and offers the advantages of both optical and ultrasonic modalities. This is usually accomplished by use of pulsed lasers or fiber optic strands that act as transmitters that radiate ultrasound signals. A separate ultrasound receiver is usually employed to detect the ultrasound echoes. This technique allows the production and detection of very high frequency ultrasound signals that would be difficult or impossible to produce from traditional piezoelectric ceramic transducers. Another advantage of optoacoustic transducers is their small size, which allows many micro-applications. A more experimental technique, thermoacoustics, uses an interrogating signal that can originate from microwaves or optical-range wavelengths, and these in turn, generate ultrasound waves in tissue that can produce images that have higher signal-to-noise ratios than x-rays, and thus, better differentiation of tissues (ref. 23).
- Intraoperative Interventional Imaging
Ultrasound is an excellent and important method for imaging interventions in the body. For example, US-guided needle biopsy is a means for a physician to guide a needle to a selected target, where a biopsy is collected. Also ultrasound is used for following the path of a catheter inside selected points in blood vessels. It can also be used for endoscopic surgical imaging applications, where an ultrasound probe can be used for laparoscopic guidance, or can be directed into the esophagus (transesophageal ultrasound), or, there are also combinations of endoscopic imaging with interventional ultrasound, where ultrasound imaging is used to guide such ultrasound therapies as HIFU, cavitation, thrombolysis, and contrast-agent drug delivery. These represent unprecedented capabilities for medical applications.
Interventional and Therapy Ultrasound Applications
As stated earlier, ultrasound can be used as an imaging modality and as an interventional tool, including the possibility of non-invasive surgery, which could become very significant. Various ultrasound interventional capabilities are being developed, but most of them are still in the research stage. One procedure—treatment of uterine fibroids, has been approved by FDA for clinical use at this time (ref 24). Other procedures are still experimental, but undergoing clinical trials and others remain in the area of pre-clinical research. The following list includes many of these promising areas:
- High-Intensity Focused Ultrasound (HIFU)
Is a non-invasive interventional tool that uses concentrated, high acoustic intensity ultrasound beam(s) to a targeted tissue volume that allows thermal absorption-based ablation (coagulation, necrosis) of tissue (ref 25). Advances in transducer materials and array design and beam control have helped to improve the accuracy and reliability of this modality, and the possibility exists of using this tool for non-invasive surgery.This technique could be used to destroy tumors, cauterize injured organs or blood vessels, or ablate lesions. Monitoring the tissue damage can be done by ultrasound imaging, MRI or CT imaging, or by using ultrasound elastography to monitor the coagulation and necrosis. Recently, combining MRI image guidance with HIFU has allowed accurate temperature monitoring. Improvements in the accuracy of targeting of the ablation zones have helped to make this technique very promising. An exciting area of research is the use of HIFU for non-invasive treatment of brain tumors (26). There is also active research in using this tool for non-invasively opening the blood-brain barrier (27). Also, other possible applications include targeted drug delivery (described below), cellular apoptosis, and enhanced gene transfection therapies.
- Cavitation and Histotripsy
Contrast agent microbubbles are being used in combination with HIFU to enhance lesion destruction due to cavitation.Cavitation is a mechanical phenomenon that occurs in fluids and tissues in the presence of microbubbles at specific acoustic intensity levels, and can be very damaging.Although this effect is actively avoided during diagnostic imaging, ( most ultrasound devices are required to display a Mechanical Index, a guide to cavitation probability), cavitation can be actively exploited to lower the threshold at which it can be used for tumor or lesion ablation and enhance the extent of ablation, and reduce exposure time. Histotripsy is a technique that uses ultrasound cavitation to produce extremely well-controlled microscopic cutting and ablation, and could become a very useful non-invasive surgical tool (ref 28).
- Ultrasound Thrombolysis ( Sonothrombolysis)
Ultrasound has been found to have the ability to dissolve clots, either by itself, or in combination with clot-dissolving drugs, and/or contrast agents. Research is currently being conducted which explores the possibility of non-invasive clot dissolution for the treatment of stroke (ref 29), for deep vein thrombosis (ref 30), for coronary occlusion, and other throbomboytic functions. Most of these projects are still in the early, small-animal or medium-animal development stage, but some have entered first-in-human stage, which may lead to clinical adoption in the not too distant future. Histotripsy, described previously, is also being used as a thrombolysis tool for deep-vein thrombosis (ref 30).
- Targeted Drug Delivery
Ultrasound has the unique capability of being able to facilitate delivery of drugs across biological barriers, such as blood-brain barrier (ref 31, 32), or through the skin, or other organs by a process known as sonophoresis (ref 33, 34).The blood-brain barrier is one of the body’s protective mechanisms that keep most substances out of the brain, but by using ultrasound, this barrier opens for a short amount of time, which allows for drugs that have large-size molecules to penetrate, and deliver these drugs to the brain. Research is being conducted in the treatment of Alzheimer’s and other dementias by the use of selected drugs (ref 32). Also, contrast agents have recently emerged as a new targeted drug delivery tool. Tumor-specific drugs are being encapsulated inside contrast agent bubbles, which have ligands on their surface that cause them to attach to a target organ, such as a tumor.This is being investigated as a possibility for targeted drug delivery for direct tumor treatment or adjunctive treatment, in addition to HIFU or x-ray therapy.The drug-bearing bubbles are injected in the bloodstream and their movements are imaged and followed by conventional ultrasound.Once the contrast agent reaches the target organ or tumor, a HIFU beam is aimed at the tumor, causing the bubbles to burst, which then release the therapeutic drug into the tumor. This method spares healthy tissues from possible effects of the drug. If successful, this technique could be used as a targeted form of chemotherapy. It is also possible to deliver DNA to the targeted organ by using loaded microbubbles, a method known as transfection. (ref 35)
- Wound and Bone Healing
Although presently poorly understood and still under investigation, ultrasound has been found to accelerate the healing of chronic wounds (ref 36). Current research aims at identifying the mechanisms by which cells initiate the healing of wounds (ref 37, ref 38). Ultrasound has also been observed to accelerate bone healing, and this application has been approved by FDA for clinical use (ref. 39, 40).
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