Sonophoresis

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Sonophoresis also known as phonophoresis, is a method that utilizes ultrasound to enhance the delivery of topical medications through the stratum corneum, to the epidermis and dermis. Sonophoresis allows for the enhancement of the permeability of the skin along with other modalities, such as iontophoresis, to deliver drugs with lesser side effects. Currently, sonophoresis is used widely in transdermal drug delivery, but has potential applications in other sectors of drug delivery, such as the delivery of drugs to the eye and brain.

Contents

Historical advancements

Sonophoresis, also known as phonophoresis, was dated back all the way to the 1950s in its first mention in a published report. [1] This report showcased that a hydrocodone injection yielded better outcomes for bursitis when combined with an ultrasound massage. [2] Following this, a series of publications from several investigators showed the increased therapeutic effect when combining ultrasound with hydrocortisone injections for various other disease states, further demonstrating the novelty of sonophoresis. [2] However, while some researchers provided evidence that ultrasound had a positive effect on the transdermal permeation of drugs, others contradicted this information by displaying research that showed no quantitative effect using ultrasound. [2] These early studies mainly investigated the combination of therapeutics with high-frequency sonophoresis (HFS), which can be categorized into frequencies greater than 0.7 MHz. [1] High frequency sonophoresis usually includes a range between 0.7 – 16 MHz. [1] Studies evolved and HFS was continually studied for four decades until a greater understanding of a mechanism of action, cavitation, was discovered. [1] Cavitational effects are inversely proportional to the frequency of the ultrasound applied, which led to further studies of low-frequency sonophoresis (LFS) for use in transdermal drug delivery due to studies showing greater efficacy in enhancing skin permeability in comparison to HFS. [1] Low-frequency sonophoresis usually includes a range between 20 and 100 kHz. [1] For this reason, currently HFS focuses on topical applications for penetration through the stratum corneum, whereas LFS focuses on transdermal drug delivery applications.

Background

Ultrasonic sonicators generate ultrasound waves, which is a longitudinal compression wave, by converting electrical energy into mechanical energy by deformation of piezoelectric crystals in response to an electric field. [1] [3] The frequency of the waves generated by this method can range from 20 kHz up to 3 MHz. [3] The ultrasound waves generated from this device allow for penetration through biological tissue by molecular oscillation of the biological tissue they travel through. [1] [3] The amplitude of the wave can be modified by manipulating the displacement of the ultrasound horn for each half cycle as they are proportional.

Mechanisms of action

While increased skin permeability is seen through sonophoresis, the precise mechanisms to describe sonophoresis are yet to be fully discovered. However, there are several important mechanisms that have been identified that contribute to the phenomenon of sonophoresis.

Cavitation

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

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]

Thermal effects

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]

Synergistic combination with other enhancement techniques

While sonophoresis alone is able to increase the permeability of skin by several factors depending on the procedure and the drug being delivered, a synergistic combination of sonophoresis with other enhancers, such as iontophoresis and electroporation, has shown greater enhancement as well as increased safety in reduction of individual enhancer parameters. [2]

Iontophoresis

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

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]

Future potential and other applications

Regarding high frequency sonophoresis (HFS), the future potential is very similar to its usage in the past. Many of the treatments involving HFS are topical and regional. [1] Commonly used drugs in these topical applications include anti-inflammatory medications such as cortisol and dexamethasone. However, there has been a notable shift towards using non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and ketoprofen. [1] NSAIDs commonly cause gastrointestinal side effects such as nausea and heartburn, which can all be bypassed by delivering NSAIDs using sonophoresis. [1] With its credible safety and useful ability in penetrating the stratum corneum, HFS remains an incredibly versatile option for delivering drugs topically. Low frequency sonophoresis (LFS), on the other hand, has a variety of applications that can be built upon in the future. Since LFS is not restricted by its ability to deliver molecules of varying sizes, drugs such as proteins, nanoparticles, and vaccines are all possible targets. [7]

Ocular delivery

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

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] Gene therapy using ultrasound and microbubbles is also being investigated for ocular disease. [10] In cardiovascular disease, for example, the efficiency of gene therapy can be improved by ultrasound targeted microbubble destruction where a gene-loaded microbubble can be burst to release its contents. [11]


Challenges

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. [12] Additionally 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.

Areas of sonophoretic research include the application of various drugs, dual-frequency sonophoresis, combined transdermal drug delivery techniques, and the use of nanoparticles to carry drugs. [13]

Related Research Articles

Iontophoresis is a process of transdermal drug delivery by use of a voltage gradient on the skin. Molecules are transported across the stratum corneum by electrophoresis and electroosmosis and the electric field can also increase the permeability of the skin. These phenomena, directly and indirectly, constitute active transport of matter due to an applied electric current. The transport is measured in units of chemical flux, commonly μmol/(cm2*hour). Iontophoresis has experimental, therapeutic and diagnostic applications.

In chemistry, the study of sonochemistry is concerned with understanding the effect of ultrasound in forming acoustic cavitation in liquids, resulting in the initiation or enhancement of the chemical activity in the solution. Therefore, the chemical effects of ultrasound do not come from a direct interaction of the ultrasonic sound wave with the molecules in the solution.

<span class="mw-page-title-main">Contrast-enhanced ultrasound</span>

Contrast-enhanced ultrasound (CEUS) is the application of ultrasound contrast medium 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 that are administered intravenously to the systemic circulation. Microbubbles have a high degree of echogenicity. 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, (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 in organs, measure blood flow rate in the heart and other organs, and for other applications.

<span class="mw-page-title-main">Transdermal</span>

Transdermal is a route of administration wherein active ingredients are delivered across the skin for systemic distribution. Examples include transdermal patches used for medicine delivery. The drug is administered in the form of a patch or ointment that delivers the drug into the circulation for systemic effect.

Therapeutic ultrasound refers generally to any type of ultrasonic procedure that uses ultrasound for therapeutic benefit. Physiotherapeutic ultrasound was introduced into clinical practice in the 1950s, with lithotripsy introduced in the 1980s. Others are at various stages in transitioning from research to clinical use: HIFU, targeted ultrasound drug delivery, trans-dermal ultrasound drug delivery, ultrasound hemostasis, cancer therapy, and ultrasound assisted thrombolysis It may use focused ultrasound (FUS) or unfocused ultrasound.

<span class="mw-page-title-main">Echogenicity</span> Ability to bounce an echo

Echogenicity or echogeneity is the ability to bounce an echo, e.g. return the signal in medical ultrasound examinations. In other words, echogenicity is higher when the surface bouncing the sound echo reflects increased sound waves. Tissues that have higher echogenicity are called "hyperechogenic" and are usually represented with lighter colors on images in medical ultrasonography. In contrast, tissues with lower echogenicity are called "hypoechogenic" and are usually represented with darker colors. Areas that lack echogenicity are called "anechogenic" and are usually displayed as completely dark.

<span class="mw-page-title-main">Phonophoresis</span>

Phonophoresis, also known as sonophoresis, is the method of using ultrasound waves to increase skin permeability in order to improve the effectiveness of transdermal drug delivery. This method intersects drug delivery and ultrasound therapy. By assisting transdermal drug delivery, phonophoresis can be a painless treatment and an alternative to a needle.

<span class="mw-page-title-main">Sonoporation</span> Technique in molecular biology

Sonoporation, or cellular sonication, is the use of sound in the ultrasonic range for increasing the permeability of the cell plasma membrane. This technique is usually used in molecular biology and non-viral gene therapy in order to allow uptake of large molecules such as DNA into the cell, in a cell disruption process called transfection or transformation. Sonoporation employs the acoustic cavitation of microbubbles to enhance delivery of these large molecules. The exact mechanism of sonoporation-mediated membrane translocation remains unclear, with a few different hypotheses currently being explored.

Microbubbles are bubbles smaller than one hundredth of a millimetre in diameter, but larger than one micrometre. They have widespread application in industry, medicine, life science, and food technology. The composition of the bubble shell and filling material determine important design features such as buoyancy, crush strength, thermal conductivity, and acoustic properties.

Home ultrasound is the provision of therapeutic ultrasound via the use of a portable or home ultrasound machine. This method of medical ultrasound therapy can be used for various types of pain relief and physical therapy.

<span class="mw-page-title-main">Sonodynamic therapy</span>

Sonodynamic therapy (SDT) is a noninvasive treatment, often used for tumor irradiation, that utilizes a sonosensitizer and the deep penetration of ultrasound to treat lesions of varying depths by reducing target cell number and preventing future tumor growth. Many existing cancer treatment strategies cause systemic toxicity or cannot penetrate tissue deep enough to reach the entire tumor; however, emerging ultrasound stimulated therapies could offer an alternative to these treatments with their increased efficiency, greater penetration depth, and reduced side effects. Sonodynamic therapy could be used to treat cancers and other diseases, such as atherosclerosis, and diminish the risk associated with other treatment strategies since it induces cytotoxic effects only when externally stimulated by ultrasound and only at the cancerous region, as opposed to the systemic administration of chemotherapy drugs.

Nanoparticles for drug delivery to the brain is a method for transporting drug molecules across the blood–brain barrier (BBB) using nanoparticles. These drugs cross the BBB and deliver pharmaceuticals to the brain for therapeutic treatment of neurological disorders. These disorders include Parkinson's disease, Alzheimer's disease, schizophrenia, depression, and brain tumors. Part of the difficulty in finding cures for these central nervous system (CNS) disorders is that there is yet no truly efficient delivery method for drugs to cross the BBB. Antibiotics, antineoplastic agents, and a variety of CNS-active drugs, especially neuropeptides, are a few examples of molecules that cannot pass the BBB alone. With the aid of nanoparticle delivery systems, however, studies have shown that some drugs can now cross the BBB, and even exhibit lower toxicity and decrease adverse effects throughout the body. Toxicity is an important concept for pharmacology because high toxicity levels in the body could be detrimental to the patient by affecting other organs and disrupting their function. Further, the BBB is not the only physiological barrier for drug delivery to the brain. Other biological factors influence how drugs are transported throughout the body and how they target specific locations for action. Some of these pathophysiological factors include blood flow alterations, edema and increased intracranial pressure, metabolic perturbations, and altered gene expression and protein synthesis. Though there exist many obstacles that make developing a robust delivery system difficult, nanoparticles provide a promising mechanism for drug transport to the CNS.

<span class="mw-page-title-main">Joseph Kost</span> Chemical engineering researcher

Joseph Kost is an Israeli academic, currently holder of The Abraham and Bessie Zacks Chair in Biomedical Engineering and the past Dean of the Faculty of Engineering Sciences at the Ben-Gurion University of the Negev.

Topical drug delivery (TDD) is a route of drug administration that allows the topical formulation to be delivered across the skin upon application, hence producing a localized effect to treat skin disorders like eczema. The formulation of topical drugs can be classified into corticosteroids, antibiotics, antiseptics, and anti-fungal. The mechanism of topical delivery includes the diffusion and metabolism of drugs in the skin. Historically, topical route was the first route of medication used to deliver drugs in humans in ancient Egyptian and Babylonian in 3000 BCE. In these ancient cities, topical medications like ointments and potions were used on the skin. The delivery of topical drugs needs to pass through multiple skin layers and undergo pharmacokinetics, hence factor like dermal diseases minimize the bioavailability of the topical drugs. The wide use of topical drugs leads to the advancement in topical drug delivery. These advancements are used to enhance the delivery of topical medications to the skin by using chemical and physical agents. For chemical agents, carriers like liposomes and nanotechnologies are used to enhance the absorption of topical drugs. On the other hand, physical agents, like micro-needles is other approach for enhancement ofabsorption. Besides using carriers, other factors such as pH, lipophilicity, and drug molecule size govern the effectiveness of topical formulation.

<span class="mw-page-title-main">Focused ultrasound for intracranial drug delivery</span> Medical technique

Focused ultrasound for intracrainial drug delivery is a non-invasive technique that uses high-frequency sound waves to disrupt tight junctions in the blood–brain barrier (BBB), allowing for increased passage of therapeutics into the brain. The BBB normally blocks nearly 98% of drugs from accessing the central nervous system, so FUS has the potential to address a major challenge in intracranial drug delivery by providing targeted and reversible BBB disruption. Using FUS to enhance drug delivery to the brain could significantly improve patient outcomes for a variety of diseases including Alzheimer's disease, Parkinson's disease, and brain cancer.

Ultrasound-triggered drug delivery using stimuli-responsive hydrogels refers to the process of using ultrasound energy for inducing drug release from hydrogels that are sensitive to acoustic stimuli. This method of approach is one of many stimuli-responsive drug delivery-based systems that has gained traction in recent years due to its demonstration of localization and specificity of disease treatment. Although recent developments in this field highlight its potential in treating certain diseases such as COVID-19, there remain many major challenges that need to be addressed and overcome before more related biomedical applications are clinically translated into standard of care.

Focused-ultrasound-mediated diagnostics or FUS-mediated diagnostics are an area of clinical diagnostic tools that use ultrasound to detect diseases and cancers. Although ultrasound has been used for imaging in various settings, focused-ultrasound refers to the detection of specific cells and biomarkers under flow combining ultrasound with lasers, microbubbles, and imaging techniques. Current diagnostic techniques for detecting tumors and diseases using biopsies often include invasive procedures and require improved accuracy, especially in cases such as glioblastoma and melanoma. The field of FUS-mediated diagnostics targeting cells and biomarkers is being investigated for overcoming these limitations.

<span class="mw-page-title-main">Invasomes</span> Drug delivery method, transdermal drug delivery

An invasome are a type of artificial vesicle nanocarrier that transport substances through the skin, the most superficial biological barrier. Vesicles are small particles surrounded by a lipid layer that can carry substances into and out of the cell. Artificial vesicles can be engineered to deliver drugs within the cell, with specific applications within transdermal drug delivery. However, the skin proves to be a barrier to effective penetration and delivery of drug therapies. Thus, invasomes are a new generation of vesicle with added structural components to assist with skin penetration.

Laser-assisted drug delivery (LADD) is a drug delivery technique commonly used in the dermatology field that involves lasers. As skin acts as a protective barrier to the environment, the absorption of topical products through the epidermis is limited; thus, different drug delivery modalities have been employed to improve the efficacy of these treatments. The use of lasers in LADD has been shown to enhance the penetration of drugs transdermal, leading to a higher absorption rate, limited systemic effects, and reduced duration of treatment. Although this technique has evolved in the past decade due to its efficacy through scientific research and clinical practice, there remain some limitations regarding the safety aspect that needs to be taken into consideration.

Ultrasound assisted extraction (UAE) is the process of passing waves of ultrasonic energy through a liquid suspension containing solid particles. A force parallel or perpendicular to the material's surface is produced as the waves collide with it.

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