WO2000015300A1 - Method for peeling of epithelial tissue and apparatus and system for use therefor - Google Patents

Method for peeling of epithelial tissue and apparatus and system for use therefor Download PDF

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Publication number
WO2000015300A1
WO2000015300A1 PCT/IL1999/000505 IL9900505W WO0015300A1 WO 2000015300 A1 WO2000015300 A1 WO 2000015300A1 IL 9900505 W IL9900505 W IL 9900505W WO 0015300 A1 WO0015300 A1 WO 0015300A1
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method according
cm
mhz
epithelial tissue
layer
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PCT/IL1999/000505
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French (fr)
Inventor
Yoni Iger
David Shalhevet
Ariela Albalak
Emanuel Segal
Dmitry Elman
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Ultra Cure Ltd.
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Priority to IL12623698A priority Critical patent/IL126236D0/en
Priority to IL126236 priority
Application filed by Ultra Cure Ltd. filed Critical Ultra Cure Ltd.
Publication of WO2000015300A1 publication Critical patent/WO2000015300A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00Ultrasound therapy
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00743Type of operation; Specification of treatment sites
    • A61B2017/00747Dermatology
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00743Type of operation; Specification of treatment sites
    • A61B2017/00747Dermatology
    • A61B2017/00761Removing layer of skin tissue, e.g. wrinkles, scars or cancerous tissue
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00Ultrasound therapy
    • A61N2007/0004Applications of ultrasound therapy
    • A61N2007/0034Skin treatment

Abstract

The present invention concerns methods for peeling of outer layers of epithelial tissue, notably skin, using ultrasound. The invention further concerns devices and systems used in said methods.

Description

METHOD FOR PEELING OF EPITHELIAL TISSUE AND APPARATUS AND SYSTEM FOR USE THEREFOR

FIELD OF THE INVENTION

The present invention concerns methods, devices and systems for peeling of epithelial tissue.

BACKGROUND OF THE INVENTION

Resurfacing is a term used to denote a plurality of cosmetic and surgical procedures used to remove damaged skin zones, such as wounds, trauma or acne scars, pigmentation disorders and the like or to remove aged skin for wrinkle removal and skin rejuvenation. The most common procedure used in resurfacing is peeling wherein the outer layers of the skin are removed.

The main modalities used for peeling are chemabrasion, dermabrasion and laserbrasion, the former being the most prominent modality (Fulton J.E. Jr. Dermabrasion, chemabrasion, and laserabrasion. Historical perspectives, modern dermabrasion techniques, and future trends. Dermatol. Surg, 22(7):619-628, (1996)). Peeling of small demarcated zones, can be performed using liquid nitrogen spray for cryosurgery (Graham G.F., Cryosurgery: a useful tool in the treatment of selected infectious diseases. Int. J. Dermatol. 33(2): 107-108, (1994)). Dermabrasion is carried out by controllably removing the skin's top layers through controlled surgical scraping. It is carried out with a hand-held dermabrader, a device consisting of stainless steel wire brushes, or diamond fraizes, which are rotated by means of high speed rotary drill, and thus scrape away the outer skin layers.

Chemopeeling may be carried out with a variety of agents depending on the desired depth of peeling. AHA- Alpha hydroxy acid is used for superficial peeling; TCA- Trichloro acetic acid used for medium depth peeling; and phenols used for deep peeling. The chemical substances are topically applied to the desired regions for a defined time period (Ryan F; La Fourcade C Skin care, chemical face peeling, and skin rejuvenation. Plast. Surg. Nurs., 15(3): 167-171, (1995)).

Laserabrasion consists on using high-energy, pulsed and scanned C02 and other laser technologies for tissue vaporization (West TB Laser resurfacing of atrophic scars. Dermatol. Clin., 15(3):449-457, (1997)).

Dermabrasion and laserpeeling are used in particular for deep peeling with the expectation that later re-epithialization and collagen remodeling will result in a more youthful appearance.

The three procedures have similar complication profiles including pigmentary disturbances, erythema, infection, and scarring (Ragland HP and McBurney E, Complications of resurfacing. Semin. Cutan. Med. Surg., 15(3):200-207, (1996)). Thus, proper preoperative skin preparation, postoperative wound care, adequate physician training, and physician alertness is required to reduce the frequency and severity of these complications. It would have been highly desirable to provide a technique for skin peeling which would minimize the above adverse side effects.

Ultrasound is a mechanical wave with a frequency above the audible range that propagates by motion of particles within the media. The motion causes compression and retraction of the particles so that a pressure wave travels along with mechanical disturbances. Ultrasound is used in a plurality of medical and diagnostic procedures such as imaging of internal organs, sterilization, digestion, superficial eye-lens epithelial surgery, bile stone perforation, and anti-cancerous treatment.

Ultrasound features several physical phenomena which will be used in the present invention . The main phenomena are:

"Focused Ultrasonic Beam'''- a beam whose area gets progressively smaller and its intensity progressively higher as the beam is further away from the transmitter until it reaches the focal point. Further away from the focal point, the beam width increases ajar. The "acoustic focal point" is determined as to the region of the beam where the area is smallest and the energy is highest.

"Ultrasonic Longitudinal Waves''' - A manner of propagation of ultrasound through solids or liquids is due to the compressions and decompression along the direction of wave propagation, leading to compression or tension stress. The movement of the particles in these waves is parallel to the direction of the propagation of the waves.

"Ultrasonic Shear Waves'1'' - Another manner of propagation of ultrasound through solids, is a wave of shear stress along the waves' propagation. Its velocity is smaller that than of the longitudinal wave. Shear waves are created all over the irradiated solid, but their effects are noticeable in particular in the interfaces between different types of solid materials causing shear stress. The movement of the particles in the solid substance with shear waves is essentially perpendicular to the propagation of the wave.

"Streaming - The propagation of ultrasound through liquid, which causes compression and decompression of liquids leading to their movement. The liquid movement is due to the pressure waves created by the ultrasonic beam and is essentially parallel to the direction of the ultrasonic beam. "Cavitatio ''' is the effect of the rapid creation of gas bubbles in liquid due to ultrasonic irradiate, pulsation of these bubbles and their final collapse. This phenomenon is caused by rapid transduction from super-pressure to sub-pressure which the ultrasonic force produces on the bubbles. The bubbles are created around "nuclei of cavitation" which may be particles (for example pre-existing gas bubbles in the liquids), non-homogenity in the liquid and the like.

"Resonance" - A phenomenon where the ultrasonic field acts on a substance or body at the self frequency of to substance/body. At such a condition, a relatively low ultrasonic field can impact high energy. This phenomenon is amplified when standing waves are created i.e. when reflected wave has the same phase and opposite direction as the indirect wave. Resonance may be created by several types of ultrasonic waves, such as shear waves or longitudinal waves. Since the velocity of shear waves under the same conditions is about half of that of longitudinal waves, the resonance frequency created by theses waves will also be about half. Resonance is created when the forced frequency equals the self frequency.

SUMMARY OF THE INVENTION

The present invention concerns a method for removing the outer layers of the epithelial tissue, for example, for the purpose of skin peeling. Skin is given as a most common example of epithelial tissues, as is further detailed below, however the method of the invention also concerns other epithelial tissues. The method of the present invention comprises applying a force to separate between the outer layer of the epithelial tissue and deeper epithelial layers, wherein said force is an ultrasonic irradiation. Although in the following many time reference is made to skin, many of the parameters and explanations are suitable mutatis mutandis to other epithelial tissues. The term "epithelial tissue " may refer both to keratinized tissue (skin) as well as moist epithelium such as the external layer of the eye, the layer lining the mouth or the digestive tract, the layer lining the vagina or the reproductive tract, as well as any other surface or lining of tubes or cavities of the body. Where the epithelial tissue is skin, the peeling may be carried out for clinical reasons such as removal of pre-cancerous region. However, most commonly the skin peeling is purely for cosmetic purposes such as rejuvenation of skin, removal of spots, pigmentation marks, wrinkles, etc.

The term "to separate " refers to the following two situations: a first situation where the outer layer to be removed is completely or partially destroyed and disintegrated, and the deeper epithelial layers remain intact, and a second situation where the outer epithelial layer remains essentially intact, but the interface between said outer layer and said deeper layer is destructed, so that the two become detached and separated and the outer layer is removed. The two types of separation may be performed sequentially or simultaneously.

The term "layer " in the context of the present invention, does not mean a physiologically separate layer but rather to a certain depth of epithelial tissue. The term "layer " may refer to a certain thickness of a physiological distinct epithelial tissue such as, for example, where the epithelial tissue is skin, the epidermis or epidermal parts such as the stratum corneum, or alternatively may refer to a certain depth of skin tissue comprising physiological skin cells such as the dermis and the epidermis together.

In accordance with the present invention, there are several different modalities for carrying out the separation between the outer epithelial layer and deeper epithelial layers for the purpose of epithelial peeling, in particular skin peeling, as will be explained hereinbelow. These modalities may be operated separately, one or more of these modalities may be operated simultaneously, or one after the other as the case may be and as will be explained hereinbelow. Thus the present invention provides in accordance with a first aspect thereof a method for separating the outer epithelial layer from deeper layers using focused ultrasonic beams.

Therefore, in accordance with a first aspect of the invention termed "focal beam aspect", the present invention provides a method and procedure for the removal of outer epithelial layers using a focused ultrasonic beam applied according to co-pending Patent Application (PCT/IL97/00406) incorporated herein by reference. Briefly, this application refers to an ultrasonic system, having an ultrasound transmitter element capable of producing a focused ultrasonic beam, the latter referring to a beam which area is becoming progressively smaller, and its intensity per unit area progressively higher as the beam is further away from the ultrasound transmitter, where at the acoustic focal point the area of the beam is smallest and the intensity of the beam is the highest. Such a beam is produced by a transmitter and focusing means, such as acoustic lenses or focusing transducer. The system of this application may also comprises a container holding a liquid medium coupled at one end to the ultrasound transmitter element, for guiding the focused ultrasonic beam to the desired location, in this case the desired epithelial area to be destroyed, the container or the "guide " having such parameters so that the ultrasound beam propagates therein without bouncing on the side walls of the container.

The removal of the outer epithelial layer using a focal beam, may take place by one of the following manners. By one manner, it is possible to place the focal point of the beam in such depth as it destroys the interface between the outer layer to be removed and the deeper layer to be maintained. Thus, while the outer layer may be essentially intact, the interface layer of cells present beneath said outer layer which constitutes the link between the outer layer and the deeper layer is destroyed, and thus the outer layer is detached from the underlaying tissue. The precise destruction of the interface layer should be carried out using a focused beam having such parameters where the zone of physiological destruction is concentrated essentially only in the focal point of the beam. If the intensity of the beam is higher than the intensity which is required for the destruction of the epithelial tissue not only at the focal point of the beam, but also at regions above and below this point such regions of the beam will be termed "destruction zone ". All epithelial regions which are within these destruction zones are destroyed, and by moving the beam on the epithelial area to be removed, all the tissue in the destruction zone is completely disintegrated and destroyed. By this alternative even the outer layer is destroyed.

The method for the destruction of the desired zone comprises exposing the tissue to focused beam, where the focus is short, up to 1 mm, it is created by using high (MHz) frequencies or low F numbers (relation between acoustic focus established by curve of lens and diameter of transducer). The depth-relation destruction can be performed also using a longer focus created at lower frequencies or with relatively high F numbers, but where the bulk of the focal length is harbored inside the device of the ultrasonic apparatus used for guiding and only proximal portion of the focal zone or region adjacent to that zone affect the desired tissue. Under this region, regardless of focus size, layers are destroyed and removed - initially superficial layers and later deeper layers.

For example the ultrasonic parameters to perform the focal beam aspect may be as follows: Frequency: 20 kHz to 25 MHz, preferably 1 MHz to 10 MHz, most preferably 3 MHz to 7 MHz.

7 7 9

Intensity at focus: 5 W/cm to 750 W/cm , preferably 30 W/cm to 500 W/cm2, most preferably 100 W/cm2 to 300 W/cm2.

Duration: 1 millisecond to 10 seconds, preferably 0.01 second to 2 seconds, most preferably 0.1 second to one second.

The present invention provides in accordance with a second aspect thereof termed "the cavitational aspect" a method for removal of outer epithelial layers using the cavitation effect of ultrasound.

The term "cavitation " refers to formation of gas bubbles, oscillation of these bubbles, and their collapse, which cause destructive effect on biological tissue, in particular during the collapsing phase. The physiological effect of cavitation is the formation of cellular holes, enlargement of intracellular spaces, detachment of cells from tissue and their destruction. In accordance with the caviational aspect of the invention, the removal of the outer epithelial layer may be carried out by two modes. By one mode, the cavitational effect is carried out in the epithelial itself, taking advantage of the natural liquid and gas content of the tissue.

However, in accordance with a preferred mode of this aspect, the epithelial is immersed or in contact, prior to irradiation or simultaneously therewith, with a liquid which enhances the formation of bubbles, oscillation thereof, and their collapse. An example of such liquid is water, or enriched water having cavitational enhancing agents. Such agents, can serve as grains around which bubbles may be formed. Examples of such agents are rough particles for example, Al203-Siθ2 of a size smaller than or in the order of the resonance size when self frequency equals focal frequency of the bubble at a specific frequency. For example, resonance size of gas in water at 1 MHz is about 3 microns.

Another example is gas enriched water, such as C02 enriched water. The gas enriched water provides the external substance, and the gas provides cavitation nuclei to enhance oscillation cavitation. Yet another example of cavitation enhancing agent is a substance which has a low boiling point for increasing the gas pressure during the bubble collapse. This enhances the cavitation effect. An example of such a substance is ethanol. It should be noted that for the purpose of the invention the cavitation may take place in the vicinity of the epithelial tissue. The ultrasonic parameters to perform this activity may be for example as follows:

Frequency: 20 kHz to 5 MHz, preferably 0.1 MHz to 2 MHz, most preferably 0.3 MHz to 1 MHz.

Intensity: 0.01 W/cm2 to 50 W/cm2, preferably 0.5 W/cm2 to 20 W/cm2,

2 2 most preferably 1 W/cm to 10 W/cm . Duration: 0.1 second to 100 minutes, preferably 10 second to 30 minutes, most preferably 1 minute to 10 minutes. Duration should be determined according to frequency, and should be sufficient to allow collapse of cavitation bubble and according to non limiting example at least two cycles. The present invention provides in accordance with a third aspect thereof termed "stress aspect" a method for the removal of the outer layer of the epithelial tissue using a combination of ultrasonic waves which propagates in solids such as a combination of ultrasonic shear waves and longitudinal waves.

Therefore, in accordance with said third aspect of the invention the present invention provides a method of removing the outer epithelial layer using stress caused by a combination of longitudinal and shear ultrasonic waves or other wave modes.

The method for the detachment and removal of the desired zone comprises exposing the epithelial tissue to ultrasound at particular predetermined angles, that should be calculated or empirically established as will be explained in the Detailed Description of the Invention, said exposure should take place via an ultrasonic coupling medium of water or gel, for causing detachment and shedding of tissue surfaces. Under this mode, peeling is carried out utilizing shear-stresses created at particular irradiation angles in combination with longitudinal waves running in parallel to the tissue surface. These combined forces result in deformations of epithelial tissue parallel to the plane of applied stress. It breaks the junctions between the cellular layers and separates them from each other, causing detachment and removal of desired affected tissues, such as for example stratum corneum of the skin. The ultrasonic parameters to perform this aspect may be for example as follows:

Frequency: 20 kHz to 30 MHz, preferably 0.1 MHz to 20 MHz, most preferably 3 MHz to 10 MHz. 2 2 2

Intensity: 0.1 W/cm to 50 W/cm , preferably 0.5 W/cm , most preferably

2 2

1 W/cm to 10 W/cm . Proportional positive correlation exists between the intensity and effect achieved.

Duration: 0.1 second to 50 minutes, preferably 10 second to 10 minutes, most preferably 30 seconds to 3 minutes.

The desired angles should be those allowing maximal desired effect with minimal penetration of the propagated wave. Angle might be changed in time, due to changes of the acoustic properties of the epithelial e.g., where the epithelial is skin with accumulation of water in the stratum corneum. The angle from perpendicular axis may be for example 50° to 90°, preferably 55° to 85°, most preferably 60°-80°; for compression waves the angles can be for example 50° to 60° , preferably 55° to 59°, most preferably 59°.

The present invention provides in accordance with a fourth aspect thereof termed "resonance aspect" a method for the removal of outer epithelial layer resonance frequencies. Resonance is formed when the forced frequency equals the self frequency of the irradiate component. It can be created by shear waves, longitudinal waves or a combination of the two.

According to the resonance peeling embodiment of the invention, there are two modes of activation. By one mode, the resonance of the ultrasonic radiation frequency corresponds to the frequency of components of the epithelial itself, such as for example where the epithelial is skin, stratum corneum or the entire epidermis, thereby creating a resonance effect in the desired tissue.

By another option, a medium such as gel, or water, is brought into contact with the epithelial. The medium contains helper agents which resonance frequencies are known. The irradiation frequency of the ultrasound activation is intended to be in correlation with the frequency of these helper agents.

The irradiation by appropriate frequencies is carried out for relatively long periods in terms of cycles, and results in enlargement of the intercellular spaces and detachment and shedding of tissue surfaces. Since the resonance frequency of different epithelial tissue such as for example where the epithelial tissue is skin, the epidermis, dermis etc. is different, it is possible to destroy and to remove, by an appropriate ultrasonic resonance parameters, only the desired tissue.

The resonance frequencies f„ depends on the specific tissue thickness t, and on the speed of sound v in the specific tissue according to the equation:

77 * V

/„ (2*0 f , where n is a positive natural number. According to a non

limiting example, for the basic frequency where n = 1, using v = 1500 m/s for longitudinal waves in skin and t = 100 microns for thickness of epidermis, f = 7.5

MHz, which is a physiologically applicable frequency. However, according to yet another non-limiting example, the resonance can be created also by shear waves, of about half the speed of the longitudinal waves, and then the resonance can be achieved at f = 4MHz.

In the stratum corneum, it can be achieved by working under the resonance frequency of the stratum corneum layers or the air trapped in between, for example, the resonance frequency of air bubbles in water irradiated at 1 MHz is 3 microns. Examples of externally added agents which can enhance resonance of air bubbles are si-Al particles used in ceramics.

The ultrasonic parameters to perform this activity might be for example as follows: Frequency: 0.1 MHz to 100 MHz, preferably 1 MHz to 35 MHz, most preferably 5 MHZ to 20 MHz. The frequency is the most affecting parameter for resonance, and is determined according to the dimensions of the treated zone.

Intensity: 0.1 W/cm2 to 50 W/cm2, preferably 0.5 W/cm2 to 20 W/cm2,

2 2 most preferably 1 W/cm to 10 W/cm . Duration: 10 milliseconds to 20 minutes, preferably 1 second to 10 minutes, most preferably 10 seconds to 3 minutes. Duration should enable several cycles. The present invention provides in accordance with a fifth aspect thereof, termed the "streaming aspect" a method for the removal of epithelial tissue using ultrasonic streaming and irradiation pressure which are the forces created by ultrasonic irradiation in liquid. The streaming effect makes use of the movement of a liquid medium in the vicinity of the outer epithelial layer to be removed. This movement, causes controlled mechanical rubbing of the layer, and gentle removal thereof. The best effect is achieved when movement of the liquid should be close to parallel to tissue surface. However, it is preferable that the irradiation is not parallel, but very close to parallel. For example, 60 to close to 90 to a place which is perpendicular to the skin surface, i.e., angles of 0 to 30 from epithelium surface.

The streaming is formed by the irradiation pressure which facilitates movement of molecules in the liquid and is therefore depending on the absorbance of the waves in the liquid medium. The velocity of streaming increases with non-linear characteristics of the ultrasonic beam and the coupling medium. The method for the removal of outer epithelial layers by streaming, comprises exposing the tissue to ultrasound waves running close to parallel to the tissue and in its adjacent environment, and via a low viscosity coupling medium of e.g. water for causing mechanical rubbing of the surfaces leading to instability of the irradiated zone, opening of intercellular junctions and removal of superficial layers. Both streaming and irradiation pressure are mentioned together here, since their actual effect is carried out via the same mode of irradiation of liquid in parallel, or close to parallel, to the tissue surface. The streaming run in and affect via the outer medium, while the irradiation pressure run in and affect (though at relatively low intensity) via the tissue itself. The streaming effect can be enhanced using added agents for augmenting mechanical rubbing of the epithelial such as inert small size particles having a diameter at the order of micron or micron parts. The streaming effect is also enhanced using liquids of lower viscosities. Examples of such liquids are specified in Hodgma M.S. et al. (1961), Handbook of Chemistry and Physics; Chemical Rubber, pub. Cleveland, Ohio, pp. 3600.

The ultrasonic parameters to perform this activity might be for example as follows: Frequency: 20 kHz to 20 MHz, preferably 0.1 MHz to 10 MHz, most preferably 1 MHz to 3 MHz.

Intensity: 0.1 W/cm2 to 100 W/cm2, preferably 0.5 W/cm2 to 25 W/cm2,

2 2 most preferably 2 W/cm to 10 W/cm .

Duration: 0.1 second to 1 hour, preferably 10 seconds to 20 minutes, most preferably 30 seconds to 5 minutes.

The present invention provides in accordance with a sixth aspect thereof a method for the removal of outer epithelial layers using irradiation in the presence of sonosensitized compounds. Therefore, in accordance with a sixth aspect of the invention termed " sonodynamic aspect", the present invention provides a method for the removal of layers at the surfaces of epithelial tissue by ultrasonic activity of sonosensitized compounds, capable of affecting components such as O2 for inducing the production of highly active, short lived oxidatives such as singlet oxygen or radicals or are capable of undergoing exothermic reactions after being exposed to ultrasound. Examples of such agents are specified in detail in PCT/IL98/00231. The agents act by creating oxidizing or exothermic responses, resulting in perforation and disruption of cellular membranes, followed by their detachment at the affected zones. The method for the removal of the outer epithelial layers comprises exposing the tissue to ultrasound in the presence of a sonosensitizable agent alone or a sonosensitizable agent together with a helper agent, (the latter capable of augmenting the activity of the sonosensitizable agent) where the irradiation causes either oxidation or denaturation of the desired outer epithelial layer as for example where the layer is skin the stratum corneum membranes and detachment of the affected zones.

The sonsensitizable compounds are compositions capable of undergoing oxidative or exothermic reactions upon ultrasonic irradiation. Examples of such compounds for oxidative reactions are gallium-porphyrins, dimethylsulfoxide, dimethylformamide, adramycin and the like with helper agents such as 02, chloride, kalium permanganate and the like capable of contributing to the effect, for example, by the releasing of radicals or other oxidatives. Examples of compounds for exothermic effect, either by denaturation or by producing high amounts of gases and mechanical force, thereafter destructuring the stratum corneum, are NaN3, nitrocellulose, nitrated metallorganic, oxidation of carbohydrate compounds and the like.

The sonosensitizable compound and optionally the helper agent can be topically applied to the epithelial tissue either as solution or as grains of up to 1 μ diameter, and can be delivered into the air spaces of the superficial tissue layers, for example where the layer is skin the stratum corneum, and not deeper into the living epidermis. The penetration into upper epithelial layers such as deeper into the skin can be improved by massaging or using slight ultrasonic delivery (according to co-pending PCT Application No. PCT/IL97/00405 incorporated herein by reference). The epithelial tissue such as skin is irradiated with ultrasound having the required properties for the activation of the compound. While activated, the compound of gaseous release, for example NaN3, produces amount of gaseous material capable of enlarging and tearing the air spaces, and shedding off the superficial stratum corneum membranes.

The ultrasonic parameters to perform this activity may be for example as follows:

Frequency: 20 kHz to 40 MHz, preferably 0.1 MHz to 10 MHz, most preferably 0.5 MHz to 5 MHz. Intensity: 0.1 W/cm2 to 100 W/cm2, preferably 0.5 W/cm2 to 30 W/cm2,

2 2 most preferably 1 W/cm to 10 W/cm .

Duration: 0.2 second to 1 hour, preferably 10 seconds to 30 seconds, most preferably 30 seconds to 5 minutes.

In accordance with the seventh aspect of the invention termed "the delivery aspect" ultrasound is used to enhance the delivery of chemical peeling agents to the epithelial tissue. As specified in co-pending Application PCT/IL 97/00405 ultrasound may be used to augment penetration of various chemical agents to the epithelial by exposing the tissue to a first irradiated ultrasound stimulus having such parameters as to cause format of opening in the skin tissue without causing irreversible damage; and within a time period where a substantial portion of said opening remains opened, a second driving ultrasound stimulus should be administered in the presence of the chemical epithelial peeling agents, effective in driving the chemical agent through said opening. Thus, when it is desired to deliver into the epithelial chemical agents capable of removal of the outer layer of the epithelial, two ultrasound irradiation stimuli should be given, the first one to create openings in the epithelial, and the second to drive the chemical compounds through said openings into deeper layers of the epithelial.

Examples of chemical products capable of removal of outer layer of the epithelial tissue are enzymes, in particular proteolyte enzymes such as trypsin: toxins derived from gram positive cocci such as the epidermolytic or exfoliating toxin A toxin of Staphylococcus Aureus, which causes a local and controlled separation of the skin layers from a deeper skin layer, and later shedding of the epidermal layer. Other products are specified in Fitzpatrick T.B. et al. (1997) Atlas and Synopsis of Clinical Dermatology; McGraw Hill, pub. New York, p.1030.

The parameters may be for example as follows:

For the first ultrasound irradiate for creation of the openings.

Frequency: 20 kHz to 3 MHz; preferably 100 kHz to 1.5 MHz, most preferably 500 kHz to 1 MHz. Duration: 0.01 sec. to 20 min., preferably 0.1 sec. to 60 sec, most preferably less than 1 sec.

Intensity: 0.1 - 500 W/cm2, preferably 0.1-500 W/cm2, preferably 0.5-100 W/cm , most preferably 3 to 50 W/cm .

For the second ultrasound irradiate intended to drive the chemical epithelial peeling agents though the openings: Frequency: 20 kHz to 50 MHz, preferably 2-15 MHz, most preferably 3 to 5 MHz.

Duration: 0.01 sec. to 20 min., preferably 0.1-5 min., most preferably 5 to 10 sec.

2 2 Intensity: 0.1 - 50 W/cm , preferably 0.1 to 10 W/cm , most preferably 0.5 to 5 W/cm2.

The period between the first and second irradiate should preferably not exceed 20 min., preferably not exceed 5 min., most preferably, not exceed 1 min. Alternatively, the first and second stimulus may be administered simultaneously by themselves or in combination with other waves.

Each of the individual methods according to the various embodiments of the invention may be carried out independently.

The precise mode, or modes combination, undertaken should be chosen in accordance with the desired affect. For example, where it is desired to move a small zone in the outer layer of the skin, for example, a superficial wrinkle, or a pigmentation spot, a focused beam may be used which is more precise than the other modes and can perform remodelling of dermal collagen fibers. Resonance can be performed on well defined zones of the skin such as scars, birth marks and the like. Cavitation waves will initially always effect the outer layers of the stratum, and can serve for superficial removal of large sections of the skin for rejuvenation purposes. Shear stress is used where defined layers exist.

It is possible also to use several of the methods of the different embodiments together, either by irradiating the epithelial tissue simultaneously with irradiation having different parameters, so as to bring together simultaneously to effect, such as, for example, cavitation and shear forces. It is also possible irradiate the epithelial concurrently with two or more types of ultrasound irradiation, so as to perform several methods of outer layer of skin removal one after the other.

In accordance with a preferred embodiment of the invention, the cavitational aspect, and the shear force embodiment are carried out together. All aspects, but the streaming and cavitational aspects may be performed on untreated epithelial tissue, as well as pretreated epithelial tissue, i.e., tissue pre-soaked with a solution. The tissue to be treated should be in contact with a liquid serving as coupling medium. For the cavitation and streaming aspects of the invention, the liquid serves not only as a coupling medium, but also as an essential compound required to carry out the effect (cavitation by creation and collapse of bubbles in liquid and streaming movement of the liquid).

The ultrasonic parameters required to create the desired effect may be theoretically calculated, as will be explained hereinbelow in the Detailed Description of the Invention in relation to irradiation angle. Alternatively, or in addition, these parameters may be determined empirically, for example, by measurement of protein released from the tested epithelial tissue after each of the ultrasonic aspects or using histological methods as will be described hereinbelow in the Detailed Description of the Invention. The parameters of energy irradiation of the pulse are according to the desired mechanism. Therefore, when several mechanisms are used, shifting between energy parameters might be required. For most of the parameters, except for resonance, there exist a reverse relationship between the intensity and the duration, i.e., the lower the intensity (above certain threshold), the higher the duration should be.

The present invention further concerns an apparatus for carrying out the method of the invention.

While, state of the art apparatuses are suitable for several embodiments of the inventions, some modifications in state of the art apparatuses are desired. For the focal beam epitheial removal aspect of the invention, it is most desirable to use an apparatus with acoustic focusing means, as well as a container (guide) capable of holding the beam, as specified in PCT/IL97/00405 or alternatively working in the near field acoustic zone in distances of maximal energy at the center of the beam. For the compression aspect of the invention, it is best to use an apparatus, where the angle of the delivered ultrasonic beam can be manipulated, for example, by having adjustable delivery surface in contact with the epithelial of the treated patients, the angle between irradiate zone and desired tissue can be manipulated according to the desired angle.

In accordance with the cavitation aspect of the invention, and the resonance embodiment of the invention, the streaming embodiment of the invention and the sonodynamic embodiment of the invention, where external cavitational augmenting agents, resonance enhancing agents, mechanical rubbing agents or sonodynamic agents and helper agents to said sonodynamic agents are required, it is best to use an ultrasonic apparatus as a part of a system which also contains one or more reservoirs for the above agents. It is also preferable that the system would include a kind of control unit for monitoring both the activity of the ultrasound irradiation delivery member, as well as timing the amount of administration of the various agents, their level, and their movement to and out of various components of the system.

In the following, the invention will be disclosed with reference to some non-limiting examples.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 shows a schematic drawing of a device for skin peeling using focused ultrasonic beam;

Fig. 2 shows peeling-associated protein release from skin after exposure to ultrasound irradiation in the presence of water, C02 enriched water; in the presence or absence of ultrasound;

Fig. 3 shows a schematic representation of the propagation of wave through water/skin interface using state of the art angle (top) or critical angle (bottom);

Fig. 4 shows peeling-associated release of benzoic acid from skin of five experimental fish groups, as a function of time after exposure to perpendicular irradiation (P38,P40), or to angled irradiation (A38,A40) and control results without exposure (C);

Fig. 5 shows histological section of mouse tail irradiated under both cavitation and shear stress effect (top) is the tail before irradiation and (bottom) is the tail irradiated for 15 mins. at frequency of 1 MHz at an angle of about 60°;

Fig. 6 shows a schematic representation of an ultrasonic system for skin peeling;

Figs. 7 and 8 are schematic illustrations of two different embodiments of a peeling device, respectively, suitable to be used in the system of Fig. 6, both utilizing the irradiation at a grazing angle;

Fig. 9 is a illustration of a peeling device suitable to be used in the system of Fig. 6, but utilizing the normal irradiation of the epithelium surface;

Fig. 10 is a schematic illustration of a peeling device showing some more features of the present invention; Figs. 11 and 12 schematically illustrate two more embodiments of a peeling device suitable to be used in the system of Fig. 6, both utilizing the irradiation in the direction opposite to the epithelium surface;

Fig. 13 illustrates the main components of a peeling device constructed according to another embodiment of the invention, utilizing the guidance of incident energy to a desired location; and

Fig. 14 illustrates the main components of a peeling device constructed according to yet another embodiment of the invention, utilizing the guidance of incident energy to a desired location.

DETAILED DESCRIPTION OF THE INVENTION EXPERIMENTAL PROCEDURES

(A) Ultrasound device

The ultrasound devices used were: 1. Sonicator 720 (Mettler electronics, California, USA) for frequencies of 1 MHz and 3 MHz, power output up to 2.2 W/cm2, pulse mode 20 % duty cycle or continuous mode.

2. Focused beam ultrasound (Imasonic, Besancon, France) for frequencies of 3.9 MHz to 7.4 MHz, power up to 300 W/cm2.

3. Noise signal (Sonotron, Nahal Soreck, Israel) for wide band frequencies of 10 kHz till 35 MHz at similar intensity (white noise), power up to 30 W/cm .

(B) Irradiation

Irradiation was performed via an aquatic solution or acoustic coupling gel attached to the desired tissue.

EXAMPLES Example 1 Device for skin peeling using a focused ultrasonic beam

(A) Device

Schematic representation of a device is shown in Fig 1. The focused ultrasonic beam peeling provides a method and procedure for the destructure and removal of surfaces of tissues using modified version of ultrasonic focused beam device described in Applicants' previous patent application (PCT/IL97/00406) incorporated herein by reference. An ultrasound system 1 of the invention is shown schematically in Fig 1. The system comprises a signal generator coupled to an amplifier and matching unit (both not shown) and an ultrasonic focused transducer 2 contained in a sleeve 3 having a screw mechanism (not shown). The screw mechanism changes the distance between transducer and the desired location at the target tissue and thus changes the size of the ultrasound beam and enabling the creation of the focal point of the radiation and hence the destruction zone at desired depth of the skin. Irradiation side 14 of the transducer, produces focused beam 5 that has an elongated focus 9. Zone 10 describes the length of the effective zone of the beam, which is longer compared to the flow 9 itself. Spanning the focus effective zone is zone 11 that cannot produce a destruction region as the parameters of the irradiation are not sufficient to destruct biological tissue. Irradiation is carried out via tapered end 13 of container 4 attached to sleeve 3. The container 4 contains water or another ultrasonic coupling media such as ultrasonic gel. It can also be composed of solid material creating irradiation horn which is a solid device made of ultrasonic conductive material which serves as a wave guide. It can be attached to a focus transducer, but can also be used to focus regular beams by guiding particular lobes of the beam. Since all the irradiate is solid, it creates an ulstrasonic focused beam at a fixed distance. Tapered end 13 is attached to the patient skin 12. The focused beam has an effective zone length 10 of intensity high enough to cause denaturation of tissue proteins in that region. The focused beam is used to irradiate and affect superficial components of the skin, including dermis 6 epidermis 7.

(B) Irradiation

The system was tested with rabbits. Rabbit ears were locally anaesthetized, using topically applied Emla cream (lidocain-containing cream; Astra, Sweden). Twenty minutes later the ultrasonic focusing device of Fig 1 , was placed with tapered end 13 adjacent to the skin surface. Irradiation was carried out at intensity of 3 W/mm where tapered end 13 was moved over the skin tissue 12 in circles so that each point at the skin surface was irradiated for no more than 1 second. The irradiation caused formation of wet scabs that formed incrustation after several hours. The crust was shed off two days later, exposing a newly formed skin tissue beneath (data not shown).

Example 2 Skin peeling using ultrasound cavitation alone and in combination with sensitizers

(A) Procedure Mice were divided into four groups. In group A and B, tails were immersed in 45 ml tap water at 20°C. in Group C and D tails were immersed in C02 enriched water (soda water) at 20°C. In Group E 5xl0"5M HPD (hematoporphyrin), which is a sonosensitizable agent, was added to the water. Each tail was irradiated at ultrasonic frequency of 1 MHz, 2.2 W/cm2 for 5 minutes. Groups D and E (not shown) were irradiated under the same conditions as Group B. Group A and C served as control for immersion without any activation of ultrasound.

The destructive effect on the skin was monitored using total protein analyzing kit (Microprotein 611-A, Sigma). This method is based on measuring the shift in photometric absorption that occurs when the pyrogallol red molybdate binds basic amino acid groups of protein molecules. The increase in absorbance at 600 nm is directly related to the protein concentration of the sample. The protein concentration of the sample reflects proteins released from the tissue as part of the peeling process.

(B) Results

The results are shown in Fig. 2. As can be seen, controls of tails soaked in water or C02 enriched water without ultrasound irradiation resulting in similar release (A and C, respectively). Irradiation of tail with water (B) improves the release of proteins by factor of 3 in comparison to soaking the tail in water (A) with no irradiation. Irradiation of tails immersed in C02 (D) enriched water improved the release of proteins 5 times in comparison to immersion of the tail in CO2 enriched water with no irradiation (C). Therefore, cavitational effect of irradiation increased the peeling and the accompanied release of proteins from the skin surface. Comparing water enriched with CO2 gaseous versus irradiation in water alone shows that under the former the results are improved by 63%. Irradiation with HPD revealed the highest protein release of 32.6±0.8 mg/ml (data is not shown in the graph). It increased the release of total protein 4 times as compared to irradiation in Cθ2-enriched water and about 7 times more than irradiation in regular water. It is therefore demonstrated that cavitation in the presence of HPD caused improved peeling and accompanied release of proteins from skin. The rate of effect is HPD > CO2 enriched water > water. The improved peeling effect is attributed to the combined effect of cavitation and oxidation effect, derived from the ultrasonic activation of HPD.

Example 3 Skin peeling using ultrasonic shear waving

Shear forces are created by propagation of the shear waves . The method consists of the transmission of longitudinal waves Aj through water or gel. Water does not support shear waves, whereas solids does. Therefore at the interface, between the water and skin, there is a reflected longitudinal wave r into the water and two waves into the skin. One wave is longitudinal and the other one is a shear wave As, as shown in figure 3a.

The intensity partition, between the two waves in the skin depend on the angle between the irradiation probe and the skin θι and the physical properties of the water and the skin was calculated. The physical properties of the water, ultrasound velocity, and density, are known in details, but the parameters of the skin are not precisely known. In the literature (Nyborg L.N. Biological effects of ultrasound: mechanisms and clinical applications, NCRP pub., Bethesda, Maryland (1983)) the longitudinal velocity for skin is given as c =1720±45 m/s, and the density - p=924±24 kg/m . An average of 60 ratios of cs/c of different materials gives cs/c =0.51±0.8 and accordingly we estimated cs=880m/s. For water the following values were taken: cw=1487m/s and p=999kg/m at a temperature of 25°c. Relation between incident angle - θi and angles of a reflected longitudinal θr, transmitted longitudinal ΘL and transmitted shear θs wave were found from the next Snell equation relation:

Cω _ Cω _ Cω _ Cs ύnθ 1. sin# r mθ Lτ sin# s

Angles θi. θr, ΘL and θs are measured perpendicular to the skin surface, θi is always equal to θr- The incident angle is called "critical angle " θc when cw/(cι*sin (θi) >1, because at angles above this angle, the transmitted longitudinal wave does not penetrate the skin surface but reflected from it. At this angle, the longitudinal wave runs in parallel to the skin surface. For the chosen sound velocities chosen in our non-limiting experiment, θc is equal to 59°. Directions of a reflected longitudinal and transmitted longitudinal and shear waves at the critical angle are shown on the Fig. 3b. At the critical angle an angle between skin surface and transmitted longitudinal wave is 5.5° and transmitted shear wave is 54°.

Fish were anaesthetized in benzoic acid at concentration of 0.5 gr/0.5 liter tap water for 5 minutes and were subsequently rinsed for an additional minute in clean water together with gentle stirring. The benzoic acid served both for anesthesia and also as marker for spectrophotometer analysis. Fish were later placed in 260 ml. fresh water containers and exposed to sonication at 3 MHz, 2.2 W/cm"" continuous mode at an θc angle of either 60° (A38, A40) or 90° - i.e. perpendicular (P38, P40). Since the benzoic acid is partially absorbed by the mucus and glycocalyx of the fish skin, the irradiation effects were monitored by measuring amount of benzoic acid released from the fish to the water (area under the main peak of benzoic acid between 242-326 nm), in addition to the macroscopic observation of skin pieces released to the water. Samples were taken and analyzed also using histological procedures.

(B) Results

The results are shown in Fig. 4 as the amount of benzoic acid released as a function of time. As can be seen, the treatment of fish skin by an angled ultrasonic beam (A38 or A40) resulted in a higher mucus and skin peeling, as revealed by the higher release of benzoic acid from the fish skin, relative to the perpendicular irradiation attack (P38 or P40). The higher release at the angled irradiation was consistent during the different sampling periods, starting already at time 0, immediately after initiation of the irradiation, as shown in graph 4. Control samples, of non-irradiated fish, showed also some release due to the natural metabolism of the skin. Histological analysis revealed enlargement of intercellular spaces and significant detachment and peeling of cells under the angled irradiation.

Detachment was occasionally observed also in perpendicular irradiated fish, without enlargement of the intercellular spaces. The two phenomena were absent in the controls (data not shown).

Example 4 Histological results of skin peeling using ultrasonic shear waving

Tails of anaesthetized mice were treated in water medium by both cavitation and shear stress concomitantly. This was done by exposing the tails for 15 minutes to ultrasound at frequency of 1 MHz, intensity of 2.2 W/cm , at angle of about 60°. The results are shown in Fig. 5, wherein 1 is the dermis, 2 is the basal lamina separating the dermis from the epidermis, 3 is the inner layers of the living cells of the epidermis, 4 is the stratum corneum dead layers of the epidermis, and 5 is the medium outer to the skin. The pictures describe the histological structure (light microscopy, x 400) of skin sections of mice tail biopsies. Picture 1 describes the structure after exposed the tissue below the threshold of damage, at 0.7 W/cm under similar conditions mentioned above. As can be seen, the structure is preserved and remains close to control structure. Picture 2 describes the structure after exposing the tissue to the combined mechanisms at intensity of 2.2 W/cm which is above the threshold of cavitation. As is shown, dermis 1 remained normal, basal lamina 2 was detached and epidermal layers 3 were disruptured. Thickness of stratum corneum 4 was markedly decreased, comparing to stratum corneum 4 at picture 1. After irradiation above the threshold the outer medium is filled with linear particles of bilayers phospholipids. The picture 2 thus, demonstrates superficial peeling of stratum corneum, probably due to cavitation. It further demonstrates deeper peeling resulting from the detachment and disrapture of living epidermal layers, along the basal lamina probably due to shear waves. These phenomena were reflected also in increase of the protein content of the solution (data not shown).

Example 5 An ultrasonic system for skin peeling

5 Fig. 6 shows system 2 used for carrying out the method of the invention for peeling of tissue surfaces by ultrasonic irradiation. The system 2 is composed of container device 21 with attached treatment device 30, an ultrasonic delivery member 22, a first reservoir 24 containing a helper agent capable of augmenting ultrasonic radiation such as a sonosensitizable agent; a second reservoir 25 ιo containing another such helper agent; and a computerized control unit 25.

Container device 21, is attached to the treatment device 30 via screw mechanism 21b controlled by motor (not shown). Said screw mechanism is used to adjust the distance between treatment device 30 and ultrasonic delivery member 22 as will be explained below. Both container 21 and treatment device

15 30 hold the acoustic coupling medium, for example, an ultrasonic gel. In practice, the opening 30c of treatment device 30 is placed on the tissue to be treated, for example a skin region of the patient, which is to be peeled for cosmetic or medical purposes. The device has protrusion 30b with an outlet 30a via which excess of gas formed during cavitation or other reactions can be released from the

20 system without accumulation and disturbance of the ultrasonic beam. The treatment side of treatment device 30 has an angle α- This part 30 can be displaced according to the desired angle needed to affect the skin via e.g., shear stress, the desired tissue, so that angle α is adjustable either by a screw mechanism or by replacing treatment device 30 with another treatment device

25 having a different angle.

The ultrasonic energy is transferred to container 21 and attachment 30 via delivery member 22 which in the present case is an ultrasonic transducer having affective zone 22a. The ultrasonic irradiation is originated from source 23, comprising a signal generator, an amplifier and optionally a matching unit (not

30 shown in the figure). Ultrasonic irradiation delivery member 22 is composed of at least one transducer capable of producing either a regular or focused beam of different frequencies, intensities, pulse modes and duration, for creating the desired effect directly or via helper agents. The delivery member 22 can be also composed of wide band noise transducer creating several effects simultaneously, or of several transducers for creating several effects such as cavitation and shear stress simultaneously or in a certain combination. Preferably, member 22 should be replaceable for switching between the different modalities of the invention.

The distance between the energy delivery member 22 and opening 30c is adjustable by use of motor 21b, which can change the overall length of container 21 and attachment 30. Said change alters the position of the ultrasonic energy in relation of opening 30c, and thus determine the distribution of the ultrasonic energy.

Attachment 30 has an outlet opening 30d and container 21 has an inlet opening 21a. Coupling medium is circulated between the two openings through filter 27b via pipe 27 and into reservoir 24 by the pump 28. Filter 27b is intended to purify the circulating solution from impurities released from the treated biological zone, such as peeled stratum corneum pieces and cells, etc.. Outlet 30d and inlet 21a can each be independently closed according to desired effect. For example, outlet 30d can be closed while 29 is open, enabling release of liquid and washing off the treated area.

The level of the active components or helper agents which are present in the solution recycled into reservoir 24, is detected using probes 24a and 21c. Said probes are suitable to detect the level of e.g., CO2 bubbles for enhanced cavitation,, sonosensitizable helper agent (or any other additive agent) so that the agents may be replenished in order to maintain a predefined level of helpers or additives in the solution. For example, where the helper agent is CO2 the probe may be a CO2 oxygen electrode. If the level of the helper agent, e.g., C02, is too low as detected by the probes, additional CO2 agents can be delivered by pump 25a from second reservoir 25 via tube 25b into first reservoir 24, and from there to the container 21. In reservoir 24, the added helper agent is mixed with the recycled solution by stirrer 24b.

If it is desired, samples of the solution present in the reservoir 25 can be obtained to an external container by tap 29 for various monitoring and physical, chemical or biological determinations. The whole system is controlled by computerized control unit 26 which measures and collects information from detectors 24a and 21a, measuring the level and volume of the components in reservoirs 24 and 25 and in container 21 and treatment device 30. The computerized control unit 26 controls the activity of pumps 25a and 28 and of motor 21b. The computerized system also controls the operation of irradiation source 23 coupled with transducer 22, and determines the intensity, frequency and duration of pulse or pulses given. The control unit further gives details as to the exact device 30 that is needed to achieve certain desired effect.

According to one application, irradiation can be also carried out via solid material, for example resonance effects or shear waves can be also achieved using shear transducer or when treatment device 30 has certain desired angle but is made of solid. In such case circulation of coupling media as well as existence of opening 30c are not needed, in particular conditions such as beauty spots, keratosis. System 1 described in figure 1 can be also part of system 2 of figure 6. The system 2 shown in figure 6, is applicable for peeling treatment of superficial zones of tissues such as epithelial tissues, including the skin, in particular conditions such as beauty spots, pressure wounds, gangrene, the digestive tract, reproductive system, eye epithelium, and the like.

Following are several examples of a peeling device suitable to be used in the system of figure 6.

Example 6 Skin peeling device

Fig. 7 illustrates a peeling device packed in a housing 38 having a certain, angle 39a (above the critical angle) of orientation with respect to the skin 40. The housing carries a transducer 31 accommodated at its one end and is formed with an opening 39 at its opposite end, a space between the transducer and the opening serving as a container 37 for acoustic waves propagation. The transducer 31 is coupled to a power source (not shown) via a cable 32. The front end of the peeling device is attached to the skin 40 with an attachment device 41, which can, for example, be a rubber or suction tube. Schematically described ultrasonic waves 33, 34 irradiated by the transducer 31 propagate through the container 37 towards the opening 39. Opposite walls 35 and 36 of the container 37 are preferably not parallel to each other, but rather the wall 35 is slightly inclined towards the wall 36, and the surface of the wall 35 is formed of reflective agent or covered by a coating reflective agent for ultrasonic waves. In other words, the wall 35 serves as a reflector (constituting a wave directing assembly). As a result, the waves schematically described as 33 do not markedly change their direction all along the path through the container 37, and propagate directly towards the opening 39, while the waves 34 impinge onto the reflector 35 and are reflected therefrom towards the opening 39.

The provision of such an inclined reflector 35 enables to desirably reduce the size of the opening 39, thereby making the treatment more convenient. Indeed, a substantially small skin area is irradiated with substantially most of the energy produced by the transducer. It should, however, be noted that, when operating with sufficient energy

(e.g., utilizing a higher power source), the wall 35 could serve as an absorber, rather than a reflector. In this case, only those waves that propagate through the container 37 without any interaction with the wall 35 will reach the opening 39. Obviously, it is assumed that these waves have energy sufficient to create the peeling effect.

Additionally, the reflector 35 may be oriented similar to the opposite wall 36. The container 37 may be made of several different materials, providing the epithelium-attached side thereof is filled with a medium enabling the cavitation effect. This medium is supplied into the container via a tube 37a, which is preferably close to the treatment zone, with an outlet tube 37b. It should also be noted that the space between the energy source and the epithelium to be treated could be composed of a solid ultrasonic conductor, gel or aquatic medium. That end of the device, which is close to the epithelium to be treated, should always be filled with water (or other suitable solutions enabling the cavitation) preferably with gas source w/wo helper agents. That portion of the device, which is located proximate to the transducer, should preferably be cooled. Additionally, suitable means for increasing the acoustic intensity at desired zones along the beam propagation may be used.

It is important to note that the provision of the orientation angle 39b of the device serves solely for providing the desired angle of incidence of the ultrasonic waves onto the skin area under treatment. This is important for maximizing the treatment effect and minimizing side effects (e.g., the waves' penetration into the body depth).

All the geometrical dimensions of the peeling device defining the radiation incidence angles, the distances between the transducer and epithelium, the device length, the location of the obtained effect along the acoustic beam, etc. should be determined in accordance with the desired effects and with the biological/acoustic/technological limitations. However, the constructional materials of the device within the passage of the ultrasonic beam should contain ultrasonic conducting agents. The container 37 should be designed so as to enable w/wo phased array of the waves and/or other focusing means to be provided. The peeling device shall preferably be provided with suitable rotation/vibration elements, enabling good dispersion of the energy

Example 7 Skin peeling device

Fig. 8 shows a peeling device which is constructed generally similar to the previously described example of figure 7, but has a somewhat different geometry of a container 50, as compared to that of the container 37 (Fig. 7). Similarly, a transducer 45 and an opening 51 are provided at opposite ends of the device, and its front end is attached to an epithelium surface 52 via an acoustic coupling media contained in the container 50. As indicated above, this medium is such as to enable the cavitation effect at least in the vicinity of the opening 51. An inlet tube 46 is provided for supplying the appropriate medium preferably close to the treatment zone in the vicinity of the opening 51. An outlet tube 47 is preferably nourished from the zones proximate to the transducer.

In the present example, the device is oriented at a certain angle with respect to the surface 52, except for a wall portion 53 of the container 50. This wall portion 53 may be oriented substantially perpendicular to the surface 52 (as in the present example of Fig. 8), or at any other appropriate angle enabling the waves to reach the desired location at the desired angle. The wall portion 53 is made either reflective or absorbing with respect to the ultrasonic waves generated by the transducer. If the reflective wall 53 is considered, it is oriented so as to provide reflection of incident waves at a correct angle, namely diminishing non desired penetration of waves into the body. Should the absorbing wall 53 be used, the amount of emitted energy would be such as to provide sufficient amount of unabsorbed energy reaching the treatment zone for achieving the desired effects.

Waves 48, 49 generated by the transducer 45 propagate through the container 50 towards the opening 51. The waves 49 propagate directly towards the opening 51, while the waves 48 impinge onto the wall portion 53, and are either reflected towards the opening 51 at the correct angle or absorbed, as the case may be.

Example 8 Skin peeling device

Fig. 9 illustrates the front end of a peeling device, which, in distinction to the previously described examples, is oriented substantially perpendicular to the epithelium surface 85, except for lower portions 83 of the container's opposite walls 82. These wall portions 83 are desirably inclined with respect to the surface 85 and are formed with reflective coatings. Additionally, an absorber element 90 is accommodated in the path of ultrasonic waves generated by a transducer 81 and propagating through a central portion of the container. In other words, the absorber 90 cuts off the schematically described central waves 86, 87 preventing their propagation towards an opening 84, i.e., the treatment zone, which waves 86, 87 propagate with an "incorrect" angle with respect to the epithelium surface 85. As for schematically shown waves 88 and 89, they are emitted by periphery regions of the transducer and therefore do not interact with the element 90 during their propagation within the container, but are reflected from the acoustic reflectors 83 into the opening 84 to create the desired effect at the interface with or inside epithelium 85. The absorber element 90 and the reflectors 83 constitute the wave directing assembly. In the present example, the element 90 is shaped like a regular cone. It should, however, be noted that such an absorber could be of other shapes, for example like a disk. Moreover, the cone 90 may have reflective walls, rather than absorbing. In this case, the element 90 has appropriate geometrical design, and additional reflectors are appropriately accommodated in the path of the waves reflected from the element 90, so as to direct these waves onto the epithelium surface 85 at the correct angles (with or without the interaction with the reflectors 83).

Example 9 Skin peeling device Fig. 10 illustrates a peeling device having another important features of the present invention. It should be understood that these features could be utilized in the above-described devices of figures 7-9, and the features of the present invention described with reference to figures 7-9 could be utilized in the example of figure 10. In the present example, the container of the peeling device is formed of several separated compartments, e.g., three compartments 61, 63 and 64, separated from each other by partitions 68 and 69. This enables, for example, the separation of the cavitation effect according to desired needs at desired locations along the beam propagation. More specifically, the cavitation effect is limited to desired zones whereas other zones within the container remain free of cavitation. To this end, the compartment 61 having an inlet opening 62 and an outlet opening (which is not specifically shown) is filled with a non-cavitationable liquid, the compartment 63 is composed of a solid acoustic conductor, gel, degassed water or the like, and the compartment 64 having an inlet opening 65 and an outlet opening (not shown) contains a cavitationable liquid. The non-cavitationable liquid contained in the compartment 61 may, for example, be of a kind suitable for cooling a transducer unit 60.

The transducer 60 irradiates acoustic waves directed towards a reflector or absorber 66 and an opening 70. The waves propagate via the compartment 61, enter the compartment 63 via the partition 68, and then propagate into the compartment 64 via the partition 69. The cavitation and shear stresses, and possible other phenomena, are created mainly in the compartment 64, and create effect at the interface of this compartment and the desired epithelium area 71 via the opening 70. It should be noted that the container could be composed of any other number of compartments and partitions. For example, the partition 69 can be removed, and the compartments 63 and 64 can be combined into a common unit. According to this non limiting example, the ultrasonic conductor within the "fused" compartment is ice. The waves freely propagate through the ice space (e.g., without creation of cavitation in the solid ice), and impinge onto the epithelium surface 71. The heat of the epithelium 71 slightly dissolves the ice attached to the opening 70, enabling the cavitation effect within the liquid at the interface with the epithelium 71.

Example 10 Skin peeling device

Fig. 11 and 12 illustrate two different constructions, respectively, of a peeling device, in which a transducer is accommodated at the central region of a container rather than at the end thereof.

In Fig. 11, a transducer 91, coupled to a power source (not shown) via a cable 94, is held in place by a support unit 93. Waves 97, 98 emitted by the transducer 91 initially propagate towards a reflector 95, which can be made of different materials and can have different shapes defined by different geometries of the device. The reflector 95 can be an integral part of a container housing 92 or be attached thereto. Waves are reflected from the reflector 95 onto a reflector 96 that reflects them towards an opening 101. The container 92 is filled with a transmitting medium 99 enabling the propagation of acoustic waves therethrough. The opening 101 is attached to epithelium 102 via an attachment device 100, which may be formed of rubbers or suction units. Such double reflection is aimed for instance at providing a certain desired distance between the acoustic source and the treated epithelium. The device preferably has radial symmetry. In the present example, a supply tube 104 and an outlet tube 103 of the cavitation-enabling media are provided. As indicated above, the container 92 may be composed of several compartments filled with different media. According to the example of Fig. 12, the reflective surface of a container has a substantially spherical shape defining a curvature 112. A transducer 110 held in a correct position by a support unit 111 irradiates schematically described acoustic waves 113 in a certain direction. The transducer 110, and its possible geometrical slopes (except for the irradiating zone), can be made of absorbing or reflecting materials. Although the waves' propagation is not specifically illustrated here, it is understood that the emitted waves reach the curvature 112 and are reflected therefrom. Suitable dimensions of the curvature 112, as well as those of the transducer 110, are selected (calculated) to achieve desired yield and at a desired orientation at an opening 116 attached to epithelium 117. The device preferably contains an inlet tube 114 and an outlet tube 115, and can be also composed of several compartments leaving a thin cavitationable layer in the vicinity of the opening 116 at the interface with epithelium 117. The inlet and outlet tubes 114 and 115 can also be replaced between themselves, and the tube 114 can also be used for further suction, for secure attachment to epithelium 117. Example 11 Skin peeling device

Fig. 13 illustrates a peeling device having a somewhat different construction, as compared to the previously described examples. Here, the peeling device comprises a transducer body 120 and an irradiation phase 121 oriented at a certain desired angle relative to the transducer body 120. Waves 122 emitted by the phase 121 propagate through a medium 123, which contains an acoustic conducting material that can, for example, be solid. Dimensions of the medium 123 may be selected (calculated), for example, in accordance with the material of the medium itself, or with the acoustic parameters used in the system. The waves enter a cavitation-enabling liquid medium in a compartment 125 having inlet and outlet tubes 127 and 127a, thereby creating the desired effect at epithelium 129 via an opening 124. The device has a so-called "bagel" shape with radial symmetry and is preferably attached to the desired epithelium by an attachment device 128, preferably with a suction groove. The outlet tube 127a can be used for suction activity via the attachment device 128, to create sufficiently secure attachment to the epithelium surface 129. A space 126 contains acoustically insulating materials, such as air or solid materials of low acoustic conductivity.

Example 12 Skin peeling device

Fig. 14 illustrates a peeling device has a two-part construction, composed of an irradiating unit 130 with a transducer 132, and treatment unit 131. Treatment unit 131, according to this non limiting example, might be disposable. To put the device in operation, the irradiating unit 130 is attached to the treatment unit 131 by any suitable means. It should, however, be noted that the two-part construction is aimed mainly at enabling the treatment unit (i.e., contacting with the patient's body) to be disposable. Generally, the units 130 and 131 can form one integral part of the device.

An irradiating phase 133 of the transducer 132 emits ultrasonic waves 135, 136, which propagate through a receiving interface 134, when the irradiating and treatment zones are acoustically coupled to each other (not shown). The waves 135 and 136 propagate via a guiding element 146 and impinge onto an epithelium surface 140 through an opening 141. The guiding element 146 is composed of an ultrasonic conducting material and is accommodated either perpendicular or at any other desired angle to the epithelium surface 140. The emitted waves reach a reflecting wall 137, and being reflected therefrom, propagate towards a treatment cell 139 via a wall 138. These waves create the desired phenomena at the treatment cell 139 and affect the epithelium 140 impinging thereon at a desired angle, at the area attached to opening 141. A cavitation-enabling liquid is supplied in a tube 143, which might constitutes both inlet and outlet tubes. A tube 142 can be used as outlet, when tube 143 does not serve for that purpose, and in addition as a suction tube serving to create a certain degree of vacuum at an attachment device 145, thereby enabling sufficiently good attachment to the epithelium surface. A space 144 is either empty, i.e., contains air, or, alternatively, is filled with a medium having very low acoustic conductivity.

Claims

CLAIMS:
1. A method for removing a desired zone of an outer layer of epithelial tissue comprising applying a force to separate between the outer layer of the epithelial tissue and deeper layers of epithelial tissue to be maintained wherein said force is an ultrasonic irradiation.
2. A method according to Claim 1, wherein said epithelial tissue is skin.
3. A method according to Claim 2, wherein said removal of a desired zone is for cosmetic purposes.
4. A method according to Claims 1 to 3, comprising irradiating said desired zone by a focused ultrasonic beam having such parameters so as to cause destruction of epithelial tissue at a predetermined depth.
5. A method according to Claim 4, wherein the ultrasound irradiation has the frequency of 20 kHz to 25 MHz, intensity of 5 W/cm2 to 750 W/cm2 and duration of 1 milisecond to 10 seconds.
6. A method according to Claim 5, wherein the ultrasound irradiation has the frequency of 1 MHz to 10 MHz, intensity of 30 W/cm2 to 500 W/cm2 and duration of 0.01 second to 2 seconds.
7. A method according to Claim 6, wherein the ultrasound irradiation has the frequency of 3 MHz to 7 MHz, intensity of 100 W/cm2 to 300 W/cm2 and duration of 0.1 second to 1 seconds.
8. A method according to Claims 1 to 3, comprising irradiating the desired zone of epithelial tissue with an ultrasonic irradiation having such parameters so as to cause a cavitation affect within or in the vicinity of the epithelial tissue leading to controlled destruction of the outer layers of the epithelial tissue.
9. A method according to Claim 8, wherein the cavitation effect is carried out in the outer layer of the epithelial tissue itself.
10. A method according to Claim 8, comprising immersing the zone of the epithelial tissue, prior to or simultaneously with radiation, in an ultrasonic coupling medium, and wherein the cavitation takes place in the coupling medium, thereby causing removal of the outer layer of the epithelial tissue.
1 1. A method according to Claim 10, wherein the coupling medium is enriched by cavitation enabling agents for facilitation of cavitation.
12. A method according to Claim 11, wherein the agents are rough solid particles having dimensions of about the size of cavitation bubbles at resonance.
13. A method according to Claim 10, wherein the size of the rough particles is 0.1 to 50 microns.
14. A method according to Claim 11, wherein the cavitation enabling agents are dissolved gases.
15. A method according to Claim 14, wherein the gas is C02.
16. A method according to Claim 14, wherein the cavitation enabling agent is capable of increasing the gas pressure of the collapsing bubbles.
17. A method according to Claim 8, wherein the ultrasound irradiation has the frequency of 20 kHz to 5 MHz, intensity of 0.1 W/cm to 50┬░ W/cm2 and duration of 0.1 second to 100 minutes.
18. A method according to Claim 17, wherein the ultrasound irradiation has the frequency of 0.1 MHz to 2 MHz, intensity of 0.5 W/cm2 to 20 W/cm2 and duration of 10 seconds to 30 minutes.
19. A method according to Claim 18, wherein the ultrasound irradiation has the frequency of 0.3 MHz to 1 MHz, intensity of 1 W/cm2 to 10 W/cm2 and duration of 1 minute to 10 minutes.
20. A method according to Claims 1 to 3, comprising contacting the outer layer of the epithelial tissue with a coupling medium and irradiating the layer with an ultrasound irradiation at an angle wherein ultrasonic waves create maximum amplitude of the force effect being combination of shear waves and longitudinal waves running essentially parallel to the surface of the irradiated layer leading to separation of the outer layer of the epithelial tissue from deeper layers of the tissue.
21. A method according to Claim 20, wherein irradiation is carried out in perpendicular to the layer of the epithelial tissue to create maximum shear waves.
22. A method according to Claim 20, wherein irradiation is carried out at critical angle comprising both shear waves and longitudinal waves.
5 23. A method according to Claims 21 or 22, wherein the irradiated epithelial tissue is in contact with an acoustic coupling medium.
24. A method according to Claim 23, wherein irradiation is carried out using transducer that directly excites shear waves.
25. A method according to Claim 24, wherein the acoustic coupling medium is 10 of a very high viscosity.
26. A method according to Claims 20 to 25, wherein the ultrasound irradiation has the frequency of 20 kHz to 30 MHz, intensity of 0.1 W/cm2 to 50 W/cm2 and duration of 1 second to 100 minutes.
27. A method according to Claim 26, wherein the ultrasound irradiation has 15 the frequency of 0.1 MHz to 15 MHz, intensity of 0.5 W/cm2 to 20 W/cm2 and duration of 10 second to 10 minutes.
28. A method according to Claim 27, wherein the ultrasound irradiation has the frequency of 1 MHz to 5 MHz, intensity of 1 W/cm to 5 W/cm and duration of 30 seconds to 5 minutes.
20 29. A method according to Claims 1 to 3, comprising irradiating the layer of the epithelial tissue with ultrasonic irradiation of a frequency essentially the same as the resonance frequency of at least one component of the epithelial tissue, capable of destruction of desired zones of the epithelial tissue.
30. A method according to Claim 29, wherein the epithelial tissue is the skin, 25 and the component is air pockets between keratinocytes of the stratum corneum.
31. A method according to Claims 1 to 3, comprising immersing the layers of the epithelial tissue in a liquid medium containing helper agents and irradiating the tissue with ultrasonic irradiation having resonance frequencies of said helper agents, capable of destruction of desired zones of the layer of the epithelial tissue.
32. A method according to Claim 31, wherein the helper agents are externally introduced gases.
33. A method according to Claim 31, wherein the helper agents are externally delivered solid particles.
5 34. A method according to Claims 29 to 33, wherein the resonance is created by longitudinal waves.
35. A method according to Claims 29 to 33, wherein the resonance is created by shear waves.
36. A method according to Claims 29 to 33, wherein the resonance is created ╬╣o by combination of ultrasonic wave types.
37. A method according to Claims 29 to 35, wherein the ultrasound irradiation has the frequency of 0.1 MHz to 100 MHz, intensity of 0.1 W/cm2 to 50 W/cm2 and duration of 10 miliseconds second to 20 minutes.
38. A method according to Claim 37, wherein the ultrasound irradiation has 15 the frequency of 1 MHz to 35 MHz, intensity of 0.5 W/cm2 to 20 W/cm2 and duration of 1 second to 10 minutes.
39. A method according to Claim 38, wherein the ultrasound irradiation has the frequency of 5 MHz to 20 MHz, intensity of 1 W/cm to 10 W/cm2 and duration of 10 seconds to 3 minutes.
20
40. A method according to Claims 1 to 3, comprising immersing the layer of the epithelial tissue in a coupling liquid or gel medium and irradiating said medium with ultrasonic irradiation at an angle close to parallel to the layer, thereby causing movement of the medium essentially parallel to the layer's surface leading to mechanical rubbing of the epithelial layer's surface by said
25 medium and to peeling of said epithelial layer.
41. A method according to Claim 40, comprising irradiation via acoustic coupling medium of low viscosity.
42. A method according to Claim 41, wherein the acoustic coupling medium contains agents capable of augmenting the mechanical rubbing of the layer of
30 epithelial tissue by close to parallel waves.
43. A method according to Claim 42, wherein the agents are small size solid particles, having diameter at the order of 0.1-10 ╬╝m.
44. A method according to Claims 40 to 43, wherein irradiation is carried out at angles of 60 to 90 in respect a plane perpendicular to the surface of the layer
5 of the epithelial tissue.
45. A method according to Claims 40 to 43, wherein the ultrasound irradiation has the frequency of 20 kHz to 20 MHz, intensity of 0.1 W/cm2 to 100 W/cm2 and duration of 0.1 second to 60 minutes.
46. A method according to Claim 45, wherein the ultrasound irradiation has 10 the frequency of 0.1 MHz to 10 MHz, intensity of 0.5 W/cm2 to 25 W/cm2 and duration of 10 seconds to 20 minutes.
47. A method according to Claim 46, wherein the ultrasound irradiation has
9 the frequency of 1 MHz to 5 MHz, intensity of 2 W/cm to 10 W/cm and duration of 30 seconds to 5 minutes. 15 48 A method according to Claims 1 to 3, comprising irradiating the epithelial layer in the presence of a sonosensitizable compound.
49. A method according to Claim 48, wherein the sonosensitizable compound is capable of release oxidating agents.
50. A method according to Claim 49, wherein the agent is selected from the 20 group consisting of: dimethylsulfoxide, porphyrins, dimethylformalide, adramycin.
51. A method according to Claim 48, wherein the sonosensitizable compound is capable of undergoing exothermic reaction or producing gases.
52. A method according to Claim 51, wherein the agent is selected from the 25 group consisting of: for instance nitrocellulose, NaN3 nitrated metallorganic compounds, oxidation of carbohydrates compounds.
53. A method according to Claim 48, wherein the sonosensitizable compound is capable of altering the viscosity of solution.
54. A method according to Claims 48-53, wherein the ultrasound irradiation has the frequency of 20 kHz to 40 MHz, intensity of 0.1 W/cm2 to 100 W/cm2 and duration of 0.1 second to 60 minutes.
55. A method according to Claim 54, wherein the ultrasound irradiation has the frequency of 0.1 MHz to 10 MHz, intensity of 0.5 W/cm2 to 30 W/cm2 and duration of 10 seconds to 30 minutes.
56. A method according to Claim 55, wherein the ultrasound irradiation has the frequency of 0.5 MHz to 5 MHz, intensity of 1 W/cm2 to 10 W/cm2 and duration of 30 seconds to 5 minutes.
57. A method according to Claims 1 to 3, comprising contacting the layer of the epithelial tissue with an ultrasonic coupling medium and exposing the layer simultaneously or sequentially to ultrasound irradiation under the following conditions:
(i) irradiating the layer of epithelial tissue with an ultrasonic irradiation having such parameters so as to cause a cavitational effect in the epithelial tissue or in the coupling medium in contact with the layer of the epithelial tissue; and (ii) ensuring that maximal intensity of the combination of shear waves and longitudinal waves are created.
58. A method according to Claims 1 to 3, comprising:
(i) exposing the layer of epithelial tissue to a first irradiate ultrasound stimulus being such as to cause transient formation of openings in epithelial cells or epithelial tissue, without causing irreversible damage to the epithelial tissue; the opening being of a size allowing entry therethrough, of chemical peeling agents capable of causing controlled destruction of epithelial tissue;
(ii) within a time period where at least a portion of said openings remain open, exposing the epithelial tissue to a second driving ultrasound stimuli; said second ultrasound stimulus being effective in driving at least part of said agents through said openings without causing any irreversible damage to the epithelial tissue, thereby causing entry of said agents to desired layer of the epithelial tissue and controlled destruction of said layer.
59. A method according to Claim 58, wherein the first and second stimulus are applied simultaneously.
60. A method according to Claim 58, wherein the interval between the first and second stimulus is up to 15 minutes.
61. A method according to Claim 58 wherein the first stimulus has the frequency of 20 kHz to 3 MHz duration of 0.01 sec. to 20 min. and intensity of
0.1 to 500 W/cm2.
62. A method according to Claim 61 wherein the first stimulus has the frequency of 100 kHz to 1.5 MHz, duration of 0.1 sec. to 30 sec. of intensity of
0.5 - 100 W/cm2.
63. A method according to Claim 62 where the first stimulus has the frequency of 500 kHz to 1 MHz, duration of less than 1 sec. of intensity of 3 - 50 W/cm .
64. A method according to Claim 58 where the second stimulus has the frequency of 20 kHz to 50 MHz, duration of 001 sec. to 20 min. of intensity of 0.1 - 10 W/cm2.
65. A method according to Claim 64, wherein the second stimulus has the frequency of 2 - 15 MHz duration of 0.1 - 5 min. and intensity of
0.1 - 10 W/cm2.
66. A method according to Claim 65 wherein the second stimulus has the frequency of 3 - 5 MHz, duration of 5 - 10 sec. and intensity of 0.5 - 5 W/cm2.
67. A device for removing an outer layer of epithelial tissue for use in any of the methods of Claims 1 to 66, or a combination of one or more of the methods of
Claims 1 to 66.
68. A system for removing an outer layer of epithelial tissue comprising the device of Claim 67.
69. A device substantially as hereinbefore described.
70. A system substantially as hereinbefore described.
71. A method according to Claim 11, wherein the agents are chemically dissolved in C Cl .
72. A method according to Claim 16, wherein the cavitation enhancing agent is ethanol.
73. A method according to Claim 20, wherein the angle of incidence of the ultrasound irradiation on the layer of epithelial tissue comprises passing the irradiation through a wave directing assembly containing at least one reflective surface.
74. A method according to Claim 20, wherein the angle of incidence of the ultrasound irradiation on the layer of epithelial tissue comprises passing the irradiation through a wave directing assembly containing at least one absorbing surface.
75. A method according to Claim 8, wherein the cavitation effect is prevented from being created within a zone other than a zone located in the vicinity of the layer of epithelial tissue.
76. A method according to Claim 75, comprising the step of sequentially passing the irradiation through at least two different separated media, wherein one medium is substantially non-cavitationable, and the other medium is capable of creating the cavitation effect in the vicinity of the layer of epithelial tissue.
77. A peeling device to be applied to the patient's layer of epithelial tissue at a desired location for removing an outer layer of epithelial tissue within said desired location, the device comprising a housing having a transducer for generating ultrasonic radiation which is located at one end of the housing thereinside, and being formed with an opening at the opposite end thereof for attaching to said desired location on the layer, wherein the radiation impinges onto the desired location such as to apply a force to separate between the outer layer of the epithelial tissue to be removed and deeper layers of the epithelial tissue to be maintained.
78. The device according to Claim 77, wherein said housing is oriented at a predetermined angle relative to the desired location and comprises a radiation directing assembly accommodated in the path of generated radiation, so as provide a certain desired angle of incidence of the radiation onto the epithelial tissue.
PCT/IL1999/000505 1998-09-16 1999-09-16 Method for peeling of epithelial tissue and apparatus and system for use therefor WO2000015300A1 (en)

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