Sonophoresis

Cavitation is generally determined to be the dominant mechanism that drives sonophoresis. It can be described as the distortion, expansion, and contraction of gas bubbles in a liquid medium.[4] The frequency of the ultrasound waves helps determine the bubble parameters, such as size and shape. There exist two types of cavitation, stable and transient. Stable cavitation is when cavitation bubbles persist over many acoustic pressure cycles without collapsing. On the other hand, transient cavitation is where these cavitation bubbles uncontrollably and rapidly grow and decay over many acoustic pressure cycles.[1] However, while cavitation is considered the primary mechanism for sonophoresis, the gas bubbles that contribute to cavitation are generated by a process termed rectified diffusion.[1]

Rectified diffusion is the process where cavitation bubbles experience growth.[1] The growth of these bubbles occurs by encountering a negative pressure half cycle, expanding the gas inside the bubble. Similarly, the gas bubble will dramatically decay in size when encountering the other positive half of the pressure cycle.[1] There are further factors that manipulate the oscillation of the bubbles’ size, such as temperature and composition of the gas and liquid phases. Depending on the dramatization of the oscillation from previously mentioned factors, stable or transient cavitation occurs. A rapid process will lead to transient cavitation bubbles, whereas a slower process will lead to stable cavitation bubbles.[1]

An important consideration when transferring energy to a patient would be the thermal energy generated from heating of the biological tissue due to energy losses from the ultrasound waves. It has been shown that increases in temperature can increase skin permeability through several factors.[1] Two factors are increased kinetic energy and diffusivity of drugs, which allow for compounds to pass through the stratum corneum. Moreover, hair follicles and sweat glands are dilated, allowing for more points of entry for compounds. The enhanced circulation of blood that comes as a result of increased temperature from ultrasound parameters also allows for better diffusion of compounds.[1] While the intensity and duty cycle of the ultrasound are directly proportional to the corresponding thermal effects, surprisingly thermal effects are not a considerable mechanism for HFS in ranges from 1 – 2 degrees Celsius.[1] However, once larger temperature changes are observed, such as an excess of 10 degrees Celsius, permeant transport was increased.[1] When it comes to LFS, thermal effects are an important consideration on the side of safety. Thermal effects need to be minimized at higher amplitudes, as burns and necrosis of tissues can occur due to exposure to high, sustained temperatures.[1] A simple solution to counteract sustained exposure to high temperatures is to periodically replace the coupling agent every so often.[5]

Iontophoresis is similar to sonophoresis as it is a method for transdermal drug delivery but does so by applying a voltage gradient across the skin. Since there are differences in pathways between iontophoresis and sonophoresis, a combination of these two methods allows for greater enhancement.[2] For example, Le et al. displayed, for the case of heparin, that a combination of iontophoresis and sonophoresis resulted in a 56-fold enhancement of heparin flux in comparison to sonophoresis having a 3-fold enhancement and iontophoresis having a 15-fold enhancement.[6]

Electroporation allows the cell membrane to open up after applying an electric field. By applying short, high voltage pulses to the stratum corneum, the lipid structure will become disorganized and allow enhancement of drug delivery.[3] There are currently very few reports of the combination of these modalities being used together. However, in these reports, there is mention that the transdermal enhancement created by the combination was greater than the sum of the individual enhancers, suggesting that electroporation and sonophoresis work together synergistically.[3]

In previous literature, it has been demonstrated that ocular delivery of drugs can be achieved with high efficacy and minimal invasion. With 20 kHz ultrasound waves at an average temporal intensity of 2 W/cm^2applied every second, the permeability of drugs with varying lipophilicity were investigated, such as atenolol and carteolol, increased by 2.6 and 2.8-fold respectively.[3]

Topical gene therapy is another area for investigation in combination with sonophoresis. Since there exists a need to enhance gene transfer into cells, sonophoresis has the ability to achieve higher transfection rate through acoustic cavitation.[8] Additionally, there is the advancement of using microbubbles with a contrast agent to diagnostically image the brain, as LFS and cavitation allows for disruption of the blood brain barrier.[9]

Currently, research being done on sonophoresis is poorly standardized. For example, the emission of ultrasound waves further away from the source results in a greater beam area, which drastically changes the ultrasound energy at the targeted area.[3] More challenges surround the cost of the actual ultrasound devices used in sonophoresis in more clinical settings. There still yet exists a low-cost device with high efficacy.[10] Additionally, as previously mentioned, the precise mechanisms as to how sonophoresis works is currently yet to be discovered. Further research into the mechanisms, and the dominant mechanisms, can allow for better optimization of sonophoresis parameters, which will increase the efficacy of treatments.