Ultrasound: The versatile energy source

The current use of ultrasound for both imaging and therapy may, at first sight, seem contradictory since successful therapy requires the induction of changes in biological structure and/or function, whereas diagnosis (especially in obstetrics, for which ultrasound imaging is best known) requires the gathering of information from tissue, but without harmful change to the tissues being interrogated. There are a number of differences between imaging and therapy ultrasound exposures which explain these differences in biological response. Imaging generally uses very short (a few µs long) pulses, powers of <∼300 mW, and pressure amplitudes <∼7 MPa [1], whereas therapy applications most often employ longer pulse trains (>ms long), and higher powers (>500 mW), or µs pulses and extremely high pressure amplitudes (>12 MPa) [2].

The use of ultrasound for therapy is an attractive option because of the diversity of effects it can produce, and the fact that it can be tightly controlled. Ultrasound is a pressure wave, capable of both thermal and mechanical effects in the medium through which it passes. Tissue heating arises from the absorption of the sound energy due primarily to frictional effects, and the mechanical effects are a consequence of the high positive and negative pressure amplitudes involved. When continuous wave or tone burst exposures are used, the heating of tissue can be exploited. However, when short, high amplitude pulses at low repetition rates are used, thermal effects can be avoided and mechanical effects can be called into play. These are the two ends of the mechanistic spectrum, but often, both thermal and mechanical effects are involved. Medical ultrasound uses frequencies in the low megahertz range, which give millimetric wavelengths in tissue [3]. The energy can therefore be tightly focused, to produce local effects solely in the focal region, without damage to overlying and surrounding tissues.

In the early days of therapy ultrasound it was thought that the primary benefit was gained from thermal effects, especially when used in physiotherapy. As the sound beam travels through tissue, its energy is attenuated, with some being scattered out of the main beam by the tissue structures, and some being absorbed. The energy loss is characterised by the attenuation coefficient, the sum of the scattering and absorption coefficients. These coefficients are much lower in ‘soft’ tissues than in bone. Mechanical effects arise in a number of ways. An ultrasound wave travelling through tissue exerts a force on obstacles in its path known as the acoustic radiation force. Since this force is dependent on the local acoustic pressure which varies spatially across the beam, shear stresses can be set up between structures, and especially at fluid/solid boundaries such as blood vessel walls. Where the fluid is free to move, acoustic streaming may result [4]. It has been suggested that these shear stresses may be responsible for the change in, for example Ca⁺⁺ concentration seen in cells as a result of ultrasound exposure [5]. The most disruptive source of mechanical effects from ultrasound is acoustic cavitation. This is defined as the activity of microbubbles which are exposed to an ultrasonic pressure wave. The bubbles may be drawn out of solution during the portion of the acoustic cycle when the pressure is negative (intrinsic cavitation), or may be introduced into the blood supply in the form of stabilised gas bubbles, such as are used as ultrasound contrast agents. The bubbles may be driven to oscillate stably, setting up streaming patterns, and shear stresses in their surroundings (‘stable’ or ‘non-inertial’ cavitation) or they may grow to resonant size, oscillate unstably, and implode, giving rise to very high pressures and temperatures in their immediate vicinity (‘inertial’ cavitation). This can lead to subtle changes, or to tissue tearing and obvious mechanical damage. Many of the therapeutic techniques currently under pre-clinical investigation involve the introduction of microbubbles with the aim of using their interaction with ultrasound at the intravascular lumen to cause a temporary opening of the blood–brain barrier, or other vessels, in order to enhance drug delivery [6–9]. It has also been suggested, for example, that inertial cavitation is needed before the adenovirus uptake can be enhanced in vivo [10]. The other source of bubbles in an ultrasound field is tissue water boiling. Histologically, the damage caused by large boiling bubbles is very similar to that seen after inertial cavitation.

Recent developments have also recognised the potential of using the thermal effects of ultrasound for increasing drug delivery. Chemotherapeutic agents can be incorporated into vehicles with temperature sensitive shells that can be administered systemically, but whose payload is only released when they reach a region that is at the temperature that disrupts their shell. The ability of ultrasound to selectively heat tissue volumes at depth makes it perfect for achieving this local drug release [11].

The extreme mechanical disruption caused by cavitating bubbles is being used in a technique known as histotripsy [2]. This is being used as an alternative to thermally induced tissue necrosis. Here, either a pressure amplitude that exceeds the intrinsic cavitation threshold is used, or non-linear propagation is maximised to enhance local heating such that the tissue water boils in a μs time frame.

Although ultrasonically induced thermal ablation by ultrasound is now in clinical use [12,13] there is still much work to be done in optimising treatment delivery and monitoring, both in terms of improving the ultrasound transducers being used [14,15], in overcoming the problems of organ motion [16] and in improving of thermometry and of techniques for imaging tissue effects [17,18].

As the field of therapy ultrasound expands, with different mechanistic effects being harnessed to give specific tissue effects, it becomes increasingly important not only to be able to measure and characterise the acoustic field [19] but also to develop dosimetric concepts that allow quantitative description and inter-comparison of treatments [20]. The existence of both thermally and cavitationally induced effects makes dosimetry a particularly difficult problem, as it is hard to identify a single ‘dose unit’ that reflects the extent of thermally and mechanically induced damage.

Ultrasound, whether used for its local ability to heat, or for the more subtle effects produced when bubbles vibrate, is an exciting, versatile technique that may find its role in applications ranging from cancer therapy to the treatment of Alzheimer’s disease. Many researchers are now undertaking pre-clinical research, with the expectation that many new treatment techniques will be able to be introduced into the clinic. An exciting aspect of ultrasound is its ability in many cases also to provide images of the treatment in real time [17].

Declaration of interest

The author reports no conflicts of interest. The author alone is responsible for the content and writing of the paper.