Ultrasonic waves are mechanical waves which create oscillations in the media through which they pass. The signals created can be utilized for diagnostic purposes (ultrasound scans, Doppler ultrasonography, elastography) or therapeutic purposes (lithotripsy, phacoemulsification, etc.). They are already used to treat certain types of cancer, uterine fibroids, and even glaucoma. Moreover, major technological progress achieved over several years is opening up numerous prospects for the development of new powerful and precise devices, with diverse applications: cardiology, neurology, psychiatry, etc.
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Understanding ultrasonic waves and their biomedical applications
Like sound waves, ultrasonic waves are mechanical waves which materialize by vibrating molecules of matter. While the audible sound wave frequency lies between 20 Hz for the lowest frequency and 20,000 Hz for the highest frequency, the ultrasound frequency is higher, between 20 kHz and 10 THz. Beyond which the hypersonic range begins.
Ultrasonic waves induce oscillations of molecules, around their point of equilibrium, in the medium through which they pass. This oscillation is gradually diffused, in a given direction from the starting point. According to the density of the medium through which they pass, ultrasonic waves are propagated at a variable high speed: the resistance of a material is qualified by its acoustic impedance (marked Z and measured in Pascal seconds per meter) which influences this speed. Furthermore, an ultrasonic wave passing through a given medium rebounds as an echo when it reaches the interface of a new medium with a different acoustic impedance from the first. Hence, analysis of the backscattered signal can provide information on the medium studied.
In the medical field, ultrasonic waves have a number of advantages:
- These waves are hazard-free (notably, no ionizing radiation).
- They can be generated using a relatively small, inexpensive device.
- They produce images which are observed and interpreted while performing the examination.
France, the birthplace of ultrasound techniques
France was the vanguard of ultrasound technology: the adventure began with Pierre Curie who created the theory of piezoelectricity, allowing ultrasonic waves to be created from an electric current, in 1880. Thirty or so years later, his pupil Paul Langevin developed the first device able to emit and receive ultrasonic waves, leading to their first military use during the Second World War (sonar).
The development of ultrasound use in the medical field was next to emerge, notably through ultrasonography developed by the British. The first ultrasound probe was developed during the 1950s, followed by the first 2D ultrasound examination in the early 1970s, both of which would be used in obstetrics. A pioneering researcher, Léandre Pourcelot, Director of Inserm unit 316 "Nervous system from fetus to infant" at the Tours Faculty of Medicine (1988 to 2003) was responsible for the development and use of Doppler ultrasonography for assessing blood flow and vascular resistance.
Diagnostic imaging techniques
The use of ultrasonic waves for diagnostic purposes is based on the formation of images from signals backscattered by tissue (ultrasonography), or on blood flow measurement (Doppler ultrasonography).
Ultrasound examination involves emitting ultrasonic waves targeting the tissues and organs to be examined, then collecting and analyzing the ultrasound echoes according to the distance and impedance of the rebound media.
In conventional two-dimensional (2D) ultrasonography, scanning (manual, mechanical, electronic) makes it possible to emit several burst lines, in different directions. Computer processing of the echoes collected enables the media through which the waves pass to be represented according to their impedance, to recreate a two-dimensional image representing a section of the analyzed zone:
- low-impedance (low-echo) media are shown in black: these may correspond to liquid media or soft tissue,
- high-impedance (high-echo) media are shown in white.
With this device, mechanical waves are emitted by piezoelectric materials: these are materials which have the ability to be distorted when subjected to electrical stress. This deformation is evidenced by a mechanical wave which is focused in the direction of the tissues to be analyzed. A probe then captures the wave echoes.
The gel conventionally used when performing external ultrasound examination makes it possible to avoid interference liable to arise due to air between the probe and the skin, since it has comparable impedance to the latter.
More recently, 3D ultrasonography was developed and, as its name suggests, is able to generate a three-dimensional image. In this case, mechanical or electronic scanning makes it possible to accumulate the data obtained at different echo points from different emission points. These are processed on computer to generate the 3D image.
The improvement in piezoelectric probes together with calculation and acquisition capability enable 4D imaging, i.e., 3D over time, to be envisaged. These methods are already used in research laboratories, and their development could soon give rise to an ultrafast acquisition method, allowing organs or unborn infants to be visualized with unparalleled precision.
Doppler ultrasonography is widely used for non-invasive examination of blood vessels. This technique is based on the Doppler effect: when a wave source (or its observer) is in motion, the frequency of the emitted wave varies according to the direction and speed of direction. A symbolic example of the Doppler effect is the sound of a car siren which goes from high to low when approaching then passing a motionless observer. Applied to blood flow, this principle makes it possible to measure the reflected frequency and compare it to the emitted frequency, according to the speed of movement of red blood cells in the vessel.
Compared to diagnostic ultrasonography, therapeutic ultrasound utilizes higher intensity waves which are delivered continuously to a precise point of the tissue. These induce thermal warming and local changes (creation of vapor-filled bubbles, necrosis, coagulation) which will contribute to the desired therapeutic effect. Ultrasonic waves are thus used to destroy benign or malignant lesions (tumors, calcifications, calculi, etc.).
High-intensity focused ultrasound (or HIFU) allows treatment to be repeated, without any risk in terms of dose limit as is the case with ionizing treatments, enabling even deep organs to be reached without the need for incision, unlike radiofrequency or laser treatments. However, some tissue is less accessible than others, depending on the type of tissue which the waves must first pass through (namely bone). At present, HIFU is mainly used for the treatment of certain types of cancer (liver, prostate), uterine fibroids, and glaucoma. It is coupled to a precise monitoring system to observe tissue destruction in real time, thanks to MRI monitoring of local temperature changes.
Lithotripsy is a technique based on the use of ultrasound to break up renal or biliary calculi: shock waves emitted at regular intervals create local vapor-filled bubbles which accumulate and then implode on the surface of the calculi (cavitation phenomenon). These cause them to disintegrate gradually into fragments less than a millimeter in size, which are then eliminated via the natural channels.
Based on the same principle, phacoemulsification destroys the opaque crystalline lens during cataract treatment. The fragments are then eliminated via an irrigation-aspiration system.
Which wave parameters determine their use?
A wave is characterized by several parameters: its amplitude, signal burst duration, and the number of signal burst repetitions.
In an imaging context, the amplitude of the waves used is approximately one megapascal, emitted in a microsecond. In a therapeutic context (HIFU), the amplitude is the same, but the burst lasts several seconds, creating high acoustic energy and intensity. Lastly, in lithotripsy, the amplitude should be much higher, so as to offer sufficient power to mechanically destroy calcifications, but very short, to avoid it heating.
Longer bursts, but of limited amplitude, are able to modulate neuron activity. Using ultrasound emitted over a short duration (100 microseconds) also creates remote tissue palpation (elastography).
Challenges facing research in the field of ultrasonic waves
The technological progress achieved in the field of ultrasonic waves has occurred at an exponential rate. Numerous scientific and technological developments have been combined with conventional methods to enhance their performance. These enable more quantitative and more functional, increasingly precise tissue images to be obtained. In the longer term, miniaturized ultrasonography systems will even allow the possibility of neuromodulation by implanting probes. At the same time, the cost of these devices should fall, allowing widespread use.
Towards new diagnostic applications
Advances have initially focused essentially on speed of data and acquisition processing. Owing to a new principle in the transmission of ultrasonic waves (acoustic holography using plane waves), images are acquired at a much faster rate than before (50 to 10,000 images per second): ultrafast ultrasound imaging not only provides standard ultrasonography data, but also offers other data, such as tissue stiffness.
This method, known as elastography, is already improving the diagnosis and evaluation of liver disease and thyroid disease, with a non-invasive approach. The role of ultrasound in imaging is, in fact, constantly being redefined by technological progress which is regularly breaking new ground. Hence, these methods are being evaluated in new fields, such as the prognostic evaluation of tumor hardness. Hardness of cardiac tissue is another area for investigation: until now, cardiac stiffness is a parameter which has evaded other evaluation techniques. However, measurement of this parameter would facilitate the diagnosis of heart failure in nearly half of affected patients, for whom direct measurement is impossible.
Ultrafast Doppler is vastly improving the sensitivity of conventional Doppler ultrasonography, making it possible to study smaller-caliber vessels. Ultrafast throughput offers greater sensitivity and enables observation of vessels in which blood flow is not sufficiently fast to be measured by the conventional Doppler technique. This thus represents a new method for in vivo exploration of vascular network dynamics, from the largest to the smallest caliber vessels, in which neurovascular coupling takes place (arteriole-neuron interface). This instrument notably offers new methods for functional exploration and evaluation measurements in neurovascular disorders. Proof of concept has already been provided and its clinical use in the evaluation of neonatal brain function should develop further in the next few years.
Super-resolution has also made it possible to develop an ultrasound microscopy method, to evaluate the human capillary network, only a few microns in diameter, to a depth of several centimeters, in a non-invasive manner. According to this approach, vapor-filled microbubbles created by ultrasound send the waves in all directions. Coupled to ultrafast acquisition, this approach makes it possible to detect the position of each independent bubble at each moment, to offer a map of the microvessels to a microscopic scale from the surface of the body. There are vast prospects in research in neuroscience, oncology, diabetes (where damage to microvessels is a major preoccupation) and in the cardiovascular field. This approach is valuable in that it sheds light on early pathophysiological mechanisms which are only currently identified at more advanced stages of disease, in larger vessels.
Towards new therapeutic applications
Several innovative therapeutic approaches, utilizing different types of ultrasonic waves, are currently in development:
In the psychiatry field, waves with intermediate strength relative to those used in imaging and therapy could enable ultrasound neuromodulation, as an alternative to transcranial magnetic stimulation (TMS) currently used in the treatment of depression refractory to medication.
Furthermore, in the same way as for lithotripsy of renal calculi, combining diagnostic and therapeutic ultrasound in the same device is an approach currently in development with a view to observing and treating cardiac valve disease and aortic stenosis related to calcification: this approach makes it possible to locate the calcified zones and simultaneously apply shock waves enabling them to be destroyed. The proof of concept of was provided by researchers from Institut Langevin and led to the creation of a start-up (Cardiawave). This method could become a simple, non-invasive alternative to conventional surgery, which is delicate to perform in the elderly (who constitute the majority of patients concerned). The first clinical trials have been planned. A similar approach has also been developed in the management of venous thrombi (phlebitis).
Lastly, drug delivery to target tissues is an emerging therapeutic approach indirectly utilizing ultrasound: Microdroplets carrying an encapsulated drug are administered into the blood circulation. Once the product has reached the target tissue, the cavitation phenomenon related to the vapor-filled bubbles created by ultrasound is used to trigger the release of the drug. This approach is receiving particularly close attention in the field of cancer treatment, where the objective is to limit the toxicity associated with treatment in healthy cells, while optimizing the therapeutic activity in the tumor.
This approach is, moreover, of interest with a view to making certain tissues more accessible to drugs, particularly in terms of allowing them to cross the blood-brain barrier (BBB). This structure, the role of which is to limit the influx of toxic substances from the circulation into brain tissue, makes it difficult to treat central nervous system disorders (particularly tumors). Owing to the mechanical oscillations induced, ultrasonic waves make the BBB temporarily permeable, enabling drugs to cross the barrier. Local treatment delivery (biological therapy, gene therapy) using ultrasound, combined with visual monitoring by MRI, is currently the subject of animal studies. This would offer a non-invasive procedure for treating certain brain disorders.
The technological research accelerator (ART): a unique Inserm structure to boost the transition from ultrasound research to application
Inserm inaugurated its first technological research accelerator (ART) in November 2016, dedicated to biomedical ultrasound. This new organizational structure aims to bring together physicists, biologists, clinical practitioners, and a team of engineers, with a view to accelerating the development of devices or prototype techniques, and their use by research laboratories and partner hospitals.
Established at ESPCI Paris, the technological research accelerator (ART) has developed approximately fifteen unique prototypes worldwide to date, intended for use in the fields of cardiovascular disease, neuroscience, and cancer. Some have already been put to use in clinical research, such as ultrasound elastography and functional neuroimaging.
This structure serves to accelerate the development and dissemination of cutting-edge technologies alongside laboratories and partner hospital departments, offering them a major advantage in the international arena.