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INTRODUCTIONINTRODUCTIONSonophoresis was shown to enhance trasdermal Sonophoresis was shown to enhance trasdermal drug transport about 40 years ago by Fellinger and drug transport about 40 years ago by Fellinger and Schmidt who showed that application of ultrasound Schmidt who showed that application of ultrasound increases transport of hydrocortisone across the increases transport of hydrocortisone across the skin.skin.

15 more drugs including steroidal anti-inflammatory 15 more drugs including steroidal anti-inflammatory drugs(hydrocortisone,dexamethasone),Non-drugs(hydrocortisone,dexamethasone),Non-steroidal anti-inflammatory drugs(salicylates and steroidal anti-inflammatory drugs(salicylates and ibuprofen),anaesthetic drugs(lidocaine),and ibuprofen),anaesthetic drugs(lidocaine),and protiens such as insulin were studied.protiens such as insulin were studied.

1)The skin accounts for 1)The skin accounts for about 15% of adult’s wt.about 15% of adult’s wt.

2)Protective layer with 2)Protective layer with large no of dead large no of dead cells,hence acts as cells,hence acts as barrier to penetrationbarrier to penetration

3)Penetration varies with 3)Penetration varies with humidity,pigmentation,humidity,pigmentation,age,chemical statusage,chemical status

4)Of all layers Stratum 4)Of all layers Stratum Corneum (SC) offers Corneum (SC) offers max resistance.max resistance.

5)SC consists of 5)SC consists of kertinocytes and lipid kertinocytes and lipid bilayerbilayer

6)Lipid bilayer confers 6)Lipid bilayer confers impermeable character impermeable character to skinto skin

7)Permeability can be 7)Permeability can be increased by increased by Chemicals,Electrical Chemicals,Electrical Fields or Ultrasound Fields or Ultrasound which disrupt lipid which disrupt lipid bilayer of SC and bilayer of SC and increase permeability.increase permeability.

Sonophoresis or Sonophoresis or ultrasound can be used ultrasound can be used to create holes in the to create holes in the skin for fluids to travel skin for fluids to travel into or out of the skin. into or out of the skin. By emitting sound at a By emitting sound at a particular frequency, particular frequency, the sound waves the sound waves disrupt the lipid-bilayer disrupt the lipid-bilayer of the stratus corneum of the stratus corneum (outermost layer of skin (outermost layer of skin which has the most which has the most barrier properties), barrier properties), creating more and creating more and larger microchannels in larger microchannels in the skin. Drugs can be the skin. Drugs can be administered through administered through these channels these channels

Generation of Ultrasound for Generation of Ultrasound for SonophoresisSonophoresis

Ultrasound is a sound wave possessing frequencies Ultrasound is a sound wave possessing frequencies above 20 kHz . These wavesabove 20 kHz . These waves

are characterized by two main parameters, frequency are characterized by two main parameters, frequency and amplitudeand amplitude. .

The waves used for sonophoresis ie(acoustic waves)which reduce the resistance offered by SC lie in the frequency range of 20 KHz to 20 MHz

UltraS is generated with the help of a device called sonicator which is a AC electric signal generator.It produces a AC electric signal which is applied across a piezoelectric crystal i.e. transducer.

Ultrasound is applied by bringing the transducer in contact with the skin .

For sonophoretic delivery, the desired drug is dissolved in a solvent and applied to the skin.

The coupling medium can be the same as the solvent used to dissolve the drug or it can be a commercial ultrasound coupling e.g.,gel ,Aquasonic .It

Helps to match impedence of tissue with the impedence of the transducer,so that the UltraS gets properly into the tissue.

Selection of Ultrasound Selection of Ultrasound parametersparameters

Proper selection of ultrasound parameters is Proper selection of ultrasound parameters is required to ensure safe and efficaciousrequired to ensure safe and efficacious

sonophoresissonophoresisUltrasound frequencyUltrasound frequency

a)Therapeutic Frequency UltraS(1-3 Mhz)a)Therapeutic Frequency UltraS(1-3 Mhz)

b)Low Frequency UltraS(Below 1Mhz)b)Low Frequency UltraS(Below 1Mhz)

c)High Frequency UltarS(Above 3Mhz)c)High Frequency UltarS(Above 3Mhz)

2.Ultrasound Intensity2.Ultrasound Intensity Various ultrasound intensities in the range of 0.1 to 2 Various ultrasound intensities in the range of 0.1 to 2

W/cm^2 W/cm^2

3.3. Pulse Length Pulse Length US can be applied in a continous or pulse mode.The US can be applied in a continous or pulse mode.The

latter is frequently used because it reduces severity of latter is frequently used because it reduces severity of side effects such as thermal effects.side effects such as thermal effects.

Cavitational effects which play crucial role in Cavitational effects which play crucial role in sonophoresis vary significantly with the pulse length.sonophoresis vary significantly with the pulse length.

It was also found that urea permeability of cuprophane It was also found that urea permeability of cuprophane membrane increased from 6 to 56% as pulse length membrane increased from 6 to 56% as pulse length increased from 100 to 400 ms.increased from 100 to 400 ms.

Distance of theTransducer from the skinDistance of theTransducer from the skinThe UltraS pressure (or intensity)field around a The UltraS pressure (or intensity)field around a

transducer is complex.transducer is complex.The intensity passes through a series of minima & The intensity passes through a series of minima &

maxima in a region near the transducer.maxima in a region near the transducer.The region in which the UltraS intensity passes The region in which the UltraS intensity passes

through the series of minima & maxima is referred through the series of minima & maxima is referred to as the near field,whereas the region beyond the to as the near field,whereas the region beyond the near field is referred to as the far field.near field is referred to as the far field.

The length of the near field of a transducer having The length of the near field of a transducer having an area of 1cm^2,operating at 1Mhz is 1.66cm.an area of 1cm^2,operating at 1Mhz is 1.66cm.

Mechanisms of SonophoresisMechanisms of Sonophoresis In order to understand the mechanisms of In order to understand the mechanisms of

sonophoresis, it is important to identify various sonophoresis, it is important to identify various effects of ultra sound exposure on human tissue effects of ultra sound exposure on human tissue since one or more of these effects may contribute to since one or more of these effects may contribute to the mechanism of sonophoresis .the mechanism of sonophoresis .

Exposure EffectsExposure Effects 1)Thermal Effects1)Thermal Effects Absorption of ultrasound results in a temperature Absorption of ultrasound results in a temperature

increase of the medium. Materials with high increase of the medium. Materials with high ultrasound absorption coefficients such as bones, ultrasound absorption coefficients such as bones, experience severe thermal effects compared to experience severe thermal effects compared to muscle tissues which have a low absorption muscle tissues which have a low absorption coefficient. coefficient.

The absorption coefficient of a medium increases The absorption coefficient of a medium increases proportionally with the ultrasound indicating that the proportionally with the ultrasound indicating that the thermal effects of ultrasound are proportional to the thermal effects of ultrasound are proportional to the ultrasound frequency. The increase in the temperature of ultrasound frequency. The increase in the temperature of a medium upon ultrasound exposure at a given a medium upon ultrasound exposure at a given frequency varies proportionally with the ultrasound frequency varies proportionally with the ultrasound intensity and exposure time. The thermal effects can be intensity and exposure time. The thermal effects can be substantially reduced by pulsed application. substantially reduced by pulsed application.

2)Acoustic Streaming2)Acoustic Streaming Acoustic streaming, by definition, is the development Acoustic streaming, by definition, is the development

of time-independent high fluidof time-independent high fluid velocities in a medium under the influence of an velocities in a medium under the influence of an

ultrasound wave. The primary causesultrasound wave. The primary causes of acoustic streaming are the reflections and other of acoustic streaming are the reflections and other

distortions of the wave propagation. Oscillations of distortions of the wave propagation. Oscillations of cavitation bubbles may also contribute to acoustic cavitation bubbles may also contribute to acoustic streaming. The shearstreaming. The shear

stresses developed by streaming velocities may affect stresses developed by streaming velocities may affect the neighbouring structures. the neighbouring structures.

3)Cavitational Effects3)Cavitational Effects

Cavitation is the formation of gaseous cavities in a Cavitation is the formation of gaseous cavities in a medium upon ultrasound exposure.medium upon ultrasound exposure.

The primary cause of cavitation is the ultrasound The primary cause of cavitation is the ultrasound induced pressure variation in the medium. Cavitation induced pressure variation in the medium. Cavitation involves either rapid growth or collapse of a bubble involves either rapid growth or collapse of a bubble or slow oscillatory motion of a bubble in the or slow oscillatory motion of a bubble in the ultrasound field. Cavitation affects tissues in several ultrasound field. Cavitation affects tissues in several ways. Specifically, collapse of cavitation bubbles ways. Specifically, collapse of cavitation bubbles releases a shock wave which can cause structural releases a shock wave which can cause structural alterations in its surroundings.alterations in its surroundings.

Types of SonophoresisTypes of SonophoresisLow frequency sonophoresisLow frequency sonophoresis1)Application of low frequency UltraS at 48kHz1)Application of low frequency UltraS at 48kHz

Enhanced transdermal transport of lidocaine and insulinEnhanced transdermal transport of lidocaine and insulin

2)Blood glucose level of a hairless rat immersed in 2)Blood glucose level of a hairless rat immersed in beaker filled with insulin soln & placed in US bath beaker filled with insulin soln & placed in US bath (48kHz) decreased by 50% in 240 min.(48kHz) decreased by 50% in 240 min.

3)Mitragotri has shown that application of even lower 3)Mitragotri has shown that application of even lower frequencies i.e.20 kHz enhances transdermal frequencies i.e.20 kHz enhances transdermal transport of low M.wt drugs like transport of low M.wt drugs like corticosterone,hydrocortisone& high M.wt protiens corticosterone,hydrocortisone& high M.wt protiens like insulin,y interferon.like insulin,y interferon.

Enhancement of transdermal transport Enhancement of transdermal transport brought about by low frequency UltraS is brought about by low frequency UltraS is more significant than therapeutic frequency more significant than therapeutic frequency UltraS.UltraS.

Comparison of enhancement ratios showed Comparison of enhancement ratios showed that enhancement brought by low frequency that enhancement brought by low frequency UltraS is upto 1000 fold higher than UltraS is upto 1000 fold higher than therapeutic frequency UltraStherapeutic frequency UltraS

Cavitational effects in fluids are inversely Cavitational effects in fluids are inversely proportional to UltraS frequency,hence play proportional to UltraS frequency,hence play imp role in low frequency sonophoresis.imp role in low frequency sonophoresis.

Exact Mechanism for higher efficacy Exact Mechanism for higher efficacy of low frequency USof low frequency US

Cavitation brought about by low Cavitation brought about by low frequency UltraS causes frequency UltraS causes disordering of SC lipids.disordering of SC lipids.

Oscillation of cavitation bubbles Oscillation of cavitation bubbles may cause significant water may cause significant water penetration into disordered lipid penetration into disordered lipid regions.regions.

This causes formation of This causes formation of aqueous channels through aqueous channels through which permeants may pass-thus which permeants may pass-thus enhancing transdermal enhancing transdermal transport.That is the reason why transport.That is the reason why low frequency UltraS can low frequency UltraS can enhance transdermal tranport of enhance transdermal tranport of drugs which exhibit low passive drugs which exhibit low passive permeability.permeability.

High frequency SonophoresisHigh frequency Sonophoresis

1)This region of ultrasound corresponds to a frequency higher

than 3 MHz. 2)Absorption coefficient of UltraS varies directly with

UltraS frequency,hence high frequency UltraS would concenrate more in epidermis leading to higher enhancements.

3)To asses this,effect of high frequency ultraS (2-15 Mhz) on permeability of salicylic acid through hairless guinea pig skin in vitro was studied and it was found that 20min application of UltraS at 2Mhz did not significantly enhance amount of salicylic acid penetrating the skin.But 10Mhz under same condition resulted in 4 fold increase.

Mechanism of High Frequency SonophoresisMechanism of High Frequency Sonophoresis

Sonophoresis of lanthanum tracers across hairless Sonophoresis of lanthanum tracers across hairless mice at 16 Mhz was performed.Then the skin was mice at 16 Mhz was performed.Then the skin was observed under electron microscope after observed under electron microscope after sonophoresis & it was found that Lanthanum sonophoresis & it was found that Lanthanum tracer penetrated to dermal levels of skin & tracer penetrated to dermal levels of skin & distributed within lipid bilayer.distributed within lipid bilayer.

Hypothesis-Micronuclei(air pockets) present in the Hypothesis-Micronuclei(air pockets) present in the SC oscillate and collapse which results in SC oscillate and collapse which results in enhanced skin permeation.enhanced skin permeation.

Therapeutic frequency of Therapeutic frequency of SonophoresisSonophoresis

Corresponds to frequency in the range of 1 to 3 Corresponds to frequency in the range of 1 to 3 MHz and intensity upto 2 W/cm^2.MHz and intensity upto 2 W/cm^2.

Sonophoresis of antiinflammatory drugs was Sonophoresis of antiinflammatory drugs was possible deeper into the tissue,especially muscles possible deeper into the tissue,especially muscles which are deep into the body.which are deep into the body.

It was reported that application of UltraS in the It was reported that application of UltraS in the therapeutic range delivered hydrocortisone about therapeutic range delivered hydrocortisone about 5cm deep into pig tissues.This property has been 5cm deep into pig tissues.This property has been used to deliver hydrocortisone to joints in used to deliver hydrocortisone to joints in treatment of rheumatoid arthritis.treatment of rheumatoid arthritis.

Mechanism of Therapeutic frequency Mechanism of Therapeutic frequency SonophoresisSonophoresis

Based upon cavitation experiments,it was Based upon cavitation experiments,it was concluded that cavitation inside the skin plays a concluded that cavitation inside the skin plays a major role in enhancing transdermal transport major role in enhancing transdermal transport upon therapeutic sonophoresis.upon therapeutic sonophoresis.

The exact mechanism was therapeutic frequency The exact mechanism was therapeutic frequency sonophoresis causes cavitation in the sonophoresis causes cavitation in the keratinocytes of the SC.Oscillation of the keratinocytes of the SC.Oscillation of the cavitation bubbles due to US causes oscillations in cavitation bubbles due to US causes oscillations in the lipid bilayer,causing structural disordering of the lipid bilayer,causing structural disordering of the SC lipids.Shock waves generated by collapse the SC lipids.Shock waves generated by collapse of cavitation bubbles also contributes to structure of cavitation bubbles also contributes to structure disordering.disordering.

DEVICES USED IN SONOPHORESISDEVICES USED IN SONOPHORESIS

1)SonoPrep Skin Permeation 1)SonoPrep Skin Permeation DeviceDeviceThe SonoPrep device

consists of a battery operated power and control unit, a hand piece containing the ultrasonic horn and the disposable coupling medium cartridge, and a return electrode. Ultrasonic hand piece attached to the patient’s skin. The clinician pushes the hand piece down on the patient’s skin to activate the ultrasonic horn.

The patient holds the return electrode so that the device automatically shuts itself off, based on a drop in skin impedance once the proper level of skin permeation is achieved. Applies relatively low frequency ultrasonic energy to the skin for 15 seconds.

Ultrsonic horn vibrates 55000 times per sec,applying energy to skin and creates cavitation bubbles that expand and contract which disrupts lipid bilayer creating reversible microchannels in skin through which fluids & analytes can be extracted & large drug molecules can be delivered.

Easy for the health care professional to administer. The permeability is reversible, the skin goes back to its

normal state within 24 hours.

Other Reported DevicesOther Reported Devices

1. A sonophoresis device with a flat flextensional ultrasound 1. A sonophoresis device with a flat flextensional ultrasound transducer is proposed. The optimum diameter, thickness transducer is proposed. The optimum diameter, thickness and material types of vibration plate are simulated by FEM.and material types of vibration plate are simulated by FEM.

2. 2. Dual Flat Flextensional Ultrasound Transducers for Dual Flat Flextensional Ultrasound Transducers for Enhancement of Transdermal Drug Delivery Enhancement of Transdermal Drug Delivery

The development of a lightweight, simple-structure and The development of a lightweight, simple-structure and low-power-consumption sonophoresis device for drug low-power-consumption sonophoresis device for drug delivery is required. For this purpose, a new sonophoresis delivery is required. For this purpose, a new sonophoresis device with dual flat flextensional ultrasound transducers device with dual flat flextensional ultrasound transducers was fabricated and investigated in this work. was fabricated and investigated in this work.

SafetySafety TheThe safety aspects of sonophoresis involve the reversibility safety aspects of sonophoresis involve the reversibility

of the skin barrier properties after turning the ultrasound off, of the skin barrier properties after turning the ultrasound off, and the effect of ultrasound on the living parts of the skin and and the effect of ultrasound on the living parts of the skin and underlying tissues. underlying tissues.

1) Recovery of the Skin Barrier Properties after Sonophoresis1) Recovery of the Skin Barrier Properties after Sonophoresis Numerous reports suggest that the application of Numerous reports suggest that the application of

therapeutic ultrasound (1-3 therapeutic ultrasound (1-3 MHz, upto 2 W/cm2) does not induce any irreversible change MHz, upto 2 W/cm2) does not induce any irreversible change in the skin permeability to drugs in vivo. in the skin permeability to drugs in vivo.

2)Biological effects of US2)Biological effects of US Ultrasound over a wide frequency range has been used in Ultrasound over a wide frequency range has been used in

medicine over the last century. For example, medicine over the last century. For example, therapeutic ultrasound ( 1-3 MHz) has been used for therapeutic ultrasound ( 1-3 MHz) has been used for massage, low frequency ultrasound in dentistry (23-40 kHz) , massage, low frequency ultrasound in dentistry (23-40 kHz) , and high frequency ultrasoundand high frequency ultrasound

(3-10 MHz) for diagnostic purposes. (3-10 MHz) for diagnostic purposes.

Thermal effects may be important whenThermal effects may be important when 1. The tissue has a high protein content1. The tissue has a high protein content 2. A high intensity continuous wave ultrasound is used2. A high intensity continuous wave ultrasound is used 3. Bone is included in the heated volume3. Bone is included in the heated volume 4. Vascularization is poor4. Vascularization is poor Cavitation may be important whenCavitation may be important when 1. Low frequency ultrasound is used1. Low frequency ultrasound is used 2. Gassy fluids are exposed2. Gassy fluids are exposed 3. Small gas-filled spaces are exposed3. Small gas-filled spaces are exposed 4. The tissue temperature is higher than normal4. The tissue temperature is higher than normal

Streaming may be important whenStreaming may be important when 1. The medium has an acoustic impedance different from 1. The medium has an acoustic impedance different from

its surroundingsits surroundings 2. The fluid in the biological medium is free to move2. The fluid in the biological medium is free to move 3. Continuous wave application is used3. Continuous wave application is used

APPLICATIONS OF SONOPHORESISAPPLICATIONS OF SONOPHORESIS

[1] Ultrasound Helps In Treating Tennis Elbow And Tendon [1] Ultrasound Helps In Treating Tennis Elbow And Tendon ProblemsProblems

Ultrasound may help treat a wide variety of sports injuries .It is found Ultrasound may help treat a wide variety of sports injuries .It is found that it is possible to successfully treat chronic tendon problems such as that it is possible to successfully treat chronic tendon problems such as "tennis elbow," "jumper's knee" with the help of ultrasound, as an "tennis elbow," "jumper's knee" with the help of ultrasound, as an alternative to surgery.alternative to surgery.

Tendons are the connective tissue that attach mscles to the bones.They Tendons are the connective tissue that attach mscles to the bones.They are vulnerable to wear & tear,become weaker &subject to tiny breaks in are vulnerable to wear & tear,become weaker &subject to tiny breaks in their fibres.When tendon is over used some tendon tissue is replaced by their fibres.When tendon is over used some tendon tissue is replaced by scar tissue instead of normal elastic tendon tissue.scar tissue instead of normal elastic tendon tissue.

Ultrasound is used to better visualize abnormal Ultrasound is used to better visualize abnormal tendons,identify the areas of tendon containing tendons,identify the areas of tendon containing scar tissue and determine if the scar tissue is scar tissue and determine if the scar tissue is infiltrated with calcification.Then the needle infiltrated with calcification.Then the needle therapy is applied to treat the problem.therapy is applied to treat the problem.

[2] Sonophoresis is used in the [2] Sonophoresis is used in the treatment of damaged skintreatment of damaged skin

Sonophoresis has an advantage that the compounds do not Sonophoresis has an advantage that the compounds do not have to be ionised.have to be ionised.

Process of cavitation takes place during the treatment but the Process of cavitation takes place during the treatment but the cavities disappear after the treatment and histological cavities disappear after the treatment and histological examination has shown that the skin is normal after the examination has shown that the skin is normal after the treatmenttreatment

With sonophoresis it is possible to get 4000% better With sonophoresis it is possible to get 4000% better penetration after 5min of sonophoresis at 20 kHz than with penetration after 5min of sonophoresis at 20 kHz than with topical application.topical application.

Higher levels of vitamin A in skin results in higher levels of Higher levels of vitamin A in skin results in higher levels of retinoic acid which then stimulates the mRNA responses which retinoic acid which then stimulates the mRNA responses which leads to faster growth of keratinocytes and greater production leads to faster growth of keratinocytes and greater production of collagen.of collagen.

When Vitamin C is included in the cocktail the wrinkles can When Vitamin C is included in the cocktail the wrinkles can actually be melted away.actually be melted away.

3]Painful muscular condition responds to non-3]Painful muscular condition responds to non-invasive UltraS treatment.invasive UltraS treatment.

4] Hormone Delivery4] Hormone Delivery5]US with Topical Anesthesia rapidly decreases 5]US with Topical Anesthesia rapidly decreases

Pain of intravenous cannulationPain of intravenous cannulation.. 6] Low-Frequency Ultrasonic Gene Delivery6] Low-Frequency Ultrasonic Gene Delivery 7] Ultrasound is used for Calcific Tendinitis of 7] Ultrasound is used for Calcific Tendinitis of

the Shoulderthe Shoulder

[8] The dolphin therapy and [8] The dolphin therapy and sonophoretic modelsonophoretic model

The dolphin therapy The dolphin therapy arouses a great interest arouses a great interest in the whole world, since in the whole world, since it causes analgesic it causes analgesic effects, removal of effects, removal of depression, and depression, and improvementimprovement of learning of learning abilities of the children abilities of the children suffering from autism. suffering from autism.

CONCLUSION:- APPLICATIONS & AND FUTURE CONCLUSION:- APPLICATIONS & AND FUTURE SCOPESCOPE

In surgery,sonophoresis helps in incision i.e.In surgery,sonophoresis helps in incision i.e.(dissection),welding(connection),built-up(regeneration) and (dissection),welding(connection),built-up(regeneration) and treatment of biological tissues.treatment of biological tissues.

Sonophoresis is also being considered very useful in drug Sonophoresis is also being considered very useful in drug enhancement in granulomas and tumours. enhancement in granulomas and tumours.

Hyperthermia and Sonophoresis are gaining grounds as Hyperthermia and Sonophoresis are gaining grounds as effective adjuncts to cancer chemotherapy. effective adjuncts to cancer chemotherapy.

The physics of ultrasound propagation in the tissues and The physics of ultrasound propagation in the tissues and the barrier properties of the neoplastic tissues will define the barrier properties of the neoplastic tissues will define the ultrasound parameters which should improve the the ultrasound parameters which should improve the efficiency of Sonophoresis as an adjunct to chemotherapy efficiency of Sonophoresis as an adjunct to chemotherapy