Notes On SONOPHORESIS

Keyur Vasava

Definition
Use of therapeutic ultrasound to assist in diffusion of medication through the skin Increases the diameter of skin portals to allow the medication to pass Pores Hair follicles Sweat glands

Basics of ultrasound
Ultrasound is defined as sound having a frequency above 18 kHz. The ultrasound wave is longitudinal in nature (i.e. the direction of propagation is the same as the direction of oscillation). Longitudinal sound waves cause compression and expansion of the medium at a distance of half a wavelength, leading to pressure variations in the medium. The resistance of the medium to the propagation of sound wave is dependent on the acoustic impedance (Z), which is related to the mass density of the medium () and the speed of propagation (C), according to Equation : Z=C The specific acoustic impedances for skin, bone and air are 1.6 106, 6.3 106 and 400.0 kg/(m2 s)

Longitudinal vs. Transverse Waves

Longitudinal waves molecular displacement is along direction in which waves travel (bungee cord) Compression regions of high molecular density (molecules in high pressure areas compress) Rarefraction regions of low molecular density (molecules in low pressure areas expand) Transverse waves molecular displacement in direction perpendicular to wave (guitar string) Longitudinal waves travel in solids & liquids Soft tissue more like liquids US primarily travels as longitudinal wave

 Transverse waves cannot pass through fluids Absorption of US energy Blood 3% Fat 13% Muscle 24% Skin 39% Tendon 59% Cartilage 68% Bone 96% Physiological effects

Thermal
Increased molecular kinetic energy 1 C increase metabolic rate 2-3 C reduce muscle spasm and increase blood flow 4 C increase tissue extensibility Absorption of ultrasound increases temperature of the medium. Materials that possess higher ultrasound absorption coefficients, such as bone experience severe thermal effects compared with muscle tissue, which has a lower absorption coefficient. Non-thermal Microstreaming Cavitation

 Mast cell degranulation

Cavitation
Cavitation is the formation of gaseous cavities in a medium upon ultrasound exposure. The primary cause of cavitation is ultrasound-induced pressure variation in the medium. Cavitation involves either the rapid growth and collapse of a bubble (inertial cavitation), or the slow oscillatory motion of a bubble in an ultrasound field(stable cavitation). Collapse of cavitation bubbles releases a shock wave that can cause structural alteration in the surrounding tissue. Tissues contain air pockets that are trapped in the fibrous structures that act as nuclei for cavitation upon ultrasound exposure. The cavitational effects vary inversely with ultrasound frequency and directly with ultrasound intensity .

Schematic sketch of cavitation occurring in the keratino-cytes. Cavitation occurs preferentially at the interface between the keratinocytes and the lipid bilayers.

Micro streaming
Acoustic streaming is the development of unidirectional flow currents in fluid that are the result of the presence of sound waves. The primary cause of acoustic streaming is ultrasound reflections and other distortions that occur during wave propagation. Oscillations of cavitation bubbles might also contribute to acoustic streaming Acoustic streaming might be important when the medium has an acoustic impedance that is different from that of its surroundings, the fluid in the biological medium is free to move or when continuous wave application is used. acoustic streaming to help distinguish cystic from solid breast lesions acoustic streaming detection as a tool for distinguishing between liquid blood and clots or soft tissue in haematoma diagnosis. Skin Influences Medication uptake is improved when the skin is: Well hydrated Has a high density of skin portals Highly vascularised Relatively thin Younger skin tends to have better diffusion characteristics than older skin. Ultrasound Influences on Diffusion Thermal Effects Increase kinetic energy Increase portal cross-section

 Increase circulation Increase capillary permeability Nonthermal Effects Altered cell resting potential Increased cell membrane permeability Increased molecular permeability

Transducer
A device that converts one form of energy to another. Piezoelectric crystal: a crystal that produces (+) and (-) electrical charges when it contracts or expands. Crystal of quartz, barium titanate, lead zirconate, or titanate housed within transducer . Reverse (indirect) piezoelectric effect: occurs when an alternating current is passed through a crystal resulting in contraction & expansion of the crystal. US is produced through the reverse piezoelectric effect Vibration of crystal results in high-frequency sound waves.

Generation of ultra sound

Ultrasound is generated using a device referred to as a sonicator. It consists of an electrical signal generator which generates an electrical AC signal at the desired frequency and amplitude. This signal is applied across a piezoelectrical crystal (transducer) to generate ultrasound. Sonicators operating at various frequencies in the range of 20 kHz to 3 MHz are available commercially and can be used for sonophoresis

How to proceed
For sonophoresis delivery, the desired drug is dissolved in a solvent and applied on the skin. Ultrasound is applied by contacting the transducer with the skin through a coupling medium to ensure a proper contact between the transducer and the skin. This medium can be the same as the solvent used to dissolve the drug or it can be a commercially available ultrasound coupling gel (for e.g.Aquasonic, Polar, NJ)

Coupling Agents
To transfer ultrasound energy to the body it is necessary to use a contact medium because of the high impedance of air. Many types of contact media currently available for ultrasound transmission &can be broadly classified as oils, wateroil emulsions, aqueous gels and ointments.

Coupling Methods

Ultrasonic energy cannot pass through the air A coupling medium is required Medium should be water-based Coupling method should confirm to the body area The body area should be clean and relatively hair-free Direct Coupling Gel or Creams Only use approved coupling agents Apply liberally to area

 Remove air bubbles by passing sound head over area (before power is increased) Immersion Method Pad/Bladder Method

Coupling Ability of Various Media

Substance Saran Wrap Lidex ge, fluocinonide (.05%) Thera-Gesic Mineral oil US Transmission gel US Transmission lotion Chempad-L Hydrocortisone powder (1%) Hydrocortisone powder (10%) Transmission 98 97 97 97 96 90 68 29 7

Movement of the Transducer

4 cm2/sec Remaining stationary can cause problems Moving too rapidly decreases the total amount of energy absorbed per unit area ,May cause clinician to treat larger area and the desired temps May not be attained Slower strokes can be easily maintained If patient complains of pain or excessive heat, then decrease intensity but increase time

 Apply constant pressure not too much & not too little

Attenuation: Acoustic Impedance

Determines amount of US energy reflected at tissue interfaces If acoustic impedance of the 2 materials forming the interface is the same, all sound will be transmitted The larger the difference, the more energy is reflected & the less energy that can enter the 2nd medium US passing through air = almost all reflected (99%) US through fat = 1% reflected

Soft-tissue: bone interfaced = much reflected

frequency
There are three distinct sets of ultrasound conditions based on frequency range and applications : High-frequency or diagnostic ultrasound in clinical imaging (310 MHz). Medium-frequency or therapeutic ultrasound in physical therapy (0.73.0 MHz). Low-frequency or power ultrasound for lithotripsy, cataract emulsification, liposuction, cancer therapy, dental descaling and ultrasonic scalpels (18100 kHz).

How the Phonophoresis is work?

Stratum corneum consists of lipid/water bi-layers acts as a barrier that limits the penetration of substances through the skin. The drug molecules having molecular weight less than 500D can pass thought this barrier and other are

repelled. This is due to the microscopic gaps between the lipid heads of the bilayers being too small to allow them through. Application of ultrasound to the skin increases its permeability and enables the delivery of various substances into and through the skin. The mechanism involved in the Sonophoresis may be following 1. Cavitation: Open up the intracellular pathways. allowing substances with high molecular weights a higher degree of penetration. 2. Thermal effects : Reduced the density of lipid in the intercellular domain of the bi-layers. 3 Induction of convective transport 4 Mechanical effects : Occurrence of stresses due to pressure variation induced by ultrasound. MECHANISMS OF SONOPHORESIS Cavitation involves the generation and oscillation of gaseous bubbles in a medium and their subsequent collapse when such a medium is exposed to a sound wave, which may be an ultrasound. It can generate violent microstreams, which increase the bioavailability of the drugs This cavitation leads to the disordering of the lipid bilayers and formation of aqueous channels in the skin through which drugs can permeate. Cavitation inside the Skin as a Possible Sonophoresis Mechanism Cavitation outside the Skin as a Possible Sonophoresis Mechanism Thermal Effects The increase in the skin temperature resulting from the absorbance of ultrasound energy may increase the skin permeability coefficient because of an increase in the diffusion coefficient.

 A temperature increase of10C causes a twofold increase in the estradiol skin permeability. Category of Sonophoresis Simultaneous Sonophoresis This approach corresponds to a simultaneous application of drug and ultrasound to the skin. Although this method can be used to achieve a temporal control over skin permeability, it requires that the patients use a wearable ultrasound device for drug delivery. Pre treatment Sonophoresis The ultrasound method is used in a relative short period of time to permeabilize skin prior to drug delivery. The skin remains in a state of high permeability for several hours. Drugs can be delivered through permeabilized skin during this period.

Output Parameters
Output Frequency Duration Duty Cycle Output Intensity

Output Frequency
The most commonly used ultrasound conditions for sonophoresis (frequency 13 MHz, intensity 02 W/ cm2) are called the therapeutic ultrasound conditions 1 Determines the treatment depth 1 MHz Output Deep (5 to 7 cm) tissues

 Rotator cuff, vastus intermedius, gastroc 3 MHz Output Superficial (up to 3cm deep) tissues Patellar tendon, MCL, brachialis Remember that adipose tissue is transparent to ultrasound

Treatment Duration
Depends on: Size of the treatment area Output intensity Therapeutic goals Vigorous heating 1 MHz output 10 to 12 minuts 3 MHz output 3 to 4 minutes

Duty Cycle
Determine the proportion of thermal and non thermal effects High duty cycle: Predominantly thermal effects Low duty cycle: Predominantly nonthermal effects Thermal effect used in sub acute and chronic conditions Non thermal effects may be beneficial in acute stages Frequency of wave transmission

 Audible sound is transmitted bet 16kHz and20 kHz. Therapeutic US is between .75- 3MHz. The > the frequency the more focused the beam of sound produced In humans the lower the frequency the greater the depth of penetration. Velocity Velocity of US propagation is directly related to the density. The more dense and rigid materials have a higher velocity of transmission. Attenuation Transmitting through various tissues reduces the intensity of the US energy. Decreased energy may be due to absorption, Dispersion,or scattering of the sound wave after reflection or refraction. Therefore penetration and absorption are inversely related. As the frequency increases, the absorption increases, thus less energy is transmitted to deeper tissues

Application
In diagnostic, in gynaecology & obsteometery. It is also used for its direct action upon biological structures in sub cellular formation to certain organs like brain, PNS, receptors etc. In surgery it helps in incision ,connection, regeneration and treatment of biological tissues. Sonophoresis is also been used in drug enhancement in granulomas and tumours. sonophoresis is being investigated as a way of drawing compounds such as glucose out of the skin.

 enhance the transdermal permeability of various drugs, including insulin and recently the use of reverse sonophoresis for- glucose monitoring has also received attention Ultrasound Helps In Treating Tennis Elbow and Tendon Problems Sonophoresis is used in the treatment of damaged skin Painful muscular condition responds to noninvasive Ultrasound treatment. Hormone Delivery US with Topical Anesthesia rapidly decreases Pain of intravenous cannulation. Low-Frequency Ultrasonic Gene Delivery Ultrasound is used for Calcific Tendinitis of the Shoulder

Future Vaccination
Transcutaneous immunization provides access to the immune system of the skin, which is dominated by densely distributed and potent antigen presenting cells (Langerhans cells) The Vaccine, which is generally a large molecule or complex, has to penetrate the stratum corneum barrier. Normally, skin is not permeable under these conditions. In the future, drug release systems aided by ultrasound may be able to provide slow release of vaccines such as that for tetanus, which need repeated booster shots; or for an AIDS vaccine. Gene Therapy Another future application for ultrasound as a topical enhancer, which seems to show promise, lies in the field of topical gene therapy Delivery of insulin, heparin , coagulation factors

Beyond Tomorrow
With further research, patients may soon possess small pocketsize sonicators used to inject drugs whenever required. these devices could be coupled with sensors that can monitor drug concentrations in the blood to formulate a self controlled drug delivery method that can potentially eliminate patient compliance This method may, particularly, be a boon for haemophiliacs, cancer, diabetes Researchers are currently exploring cutaneous vaccination transdermal heparin transdermal glucose monitoring delivery of acetyl cholinesterase inhibitors for the treatment of Alzheimers disease treatment of bone diseases and Peyronies disease dermal exposure assessment

Recovery of skin properties after ultra sound

therapeutic ultrasound (1-3 MHz, 0-2W/cm2) does not induce any irreversible change in the skin permeability to drugs in vivo. Similar studies have alsobeen performed using very low frequency ultrasound (20 kHz, 125mW/cm2, 100ms pulse applied every second) trans-epidermal water loss (TEWL) No significant difference in TEWLvalues of the skin exposed to ultrasound and that not exposed to ultrasound was found.

Category of drugs

Analgesics, anti inflammatory, anti arthritic, immuno suppresent, steroids Local anesthetics Vitamins, enzymes Anticancer Proteins Antiviral Cardio tonic Antibiotics