WO2004069147A2

WO2004069147A2 - System for enhanced chemical debridement

Info

Publication number: WO2004069147A2
Application number: PCT/IL2004/000104
Authority: WO
Inventors: Lior Rosenberg
Original assignee: Mediwound Ltd.
Priority date: 2003-02-03
Filing date: 2004-02-03
Publication date: 2004-08-19
Also published as: WO2004069147A3

Abstract

A device (10), system and method for enhancing the functionality and efficiency of a chemical and/or enzymatic debriding agent with a physical debriding mechanism includes a container (11) which is optionallz implemented as a round cup and features an acoustic chamber (12) with an ultrasound source (18) at the top of the acoustic chamber (12).

Description

SYSTEM FOR ENHANCED CHEMICAL DEBRIDEMENT

FIELD OF THE INVENTION The invention is of a device, system and method for debridement of dead tissue, such as eschar or necrotic tissue, and in particular, is of a hybrid device, system and method for potentiating the effect of a chemical and/or enzymatic debriding agent.

BACKGROUND OF THE INVENTION Skin provides an important barrier against infectious agents such as bacteria, viruses, parasites and the like, as well as dangerous or toxic materials, and the dangerous effects of mechanical trauma, damage by ultraviolet light and the like. Damaged skin, however, may not only fail to provide such a barrier, but may itself become infected or otherwise prevent the body from healing the damaged area naturally. For certain types of injuries, such as burns or chronic wounds, for example, where the damaged tissue may be devitalized or dead, it must be removed in order for the injury to heal and prevent future complications.

Therefore, for these types of injuries, a process known as "debridement" of the damaged skin has been developed. The goal of the debriding process is to remove the damaged skin, with minimal or no damage to the healthy surrounding skin and also the layers of tissue below the damaged skin. The damaged skin may itself actually include dead tissue, which as used herein, includes diseased tissue, necrotic tissue and eschar. Eschar is devitalized tissue that has been damaged by burns (from thermal, chemical or electrical burn causes, for example) or by ischemia (as in the cases of pressure sores, diabetes, peripheral vascular disease ulcers or traumatic/post surgery compromised circulation, or tissue having otherwise compromised circulation). Without debridement, bacterial infection of the dead tissue and even sepsis may occur, leading to sloughing of the damaged tissue, often with the initially undamaged tissue becoming compromised by the infectious and inflammatory process of the dead tissue. This process may lead to death of the patient. If the patient survives and recovers, the delayed healing of the damaged tissue area may cause the development of granulation tissue that eventually forms contracted and disfiguring scar tissue, which lacks flexibility as well as other physiological functions and cosmesis (appearance), which are features of healthy skin. The eschar related complications are so important that the earliest debridement is the standard of care of any necrotic skin area. The debriding process is currently performed with physical or mechanical removal (excision) of the dead tissue, which is clearly disadvantageous because of the potential for damage to healthy tissue, both surrounding the eschar and also present below this tissue. For example, for surgical debridement with special knives called dermatomes, it is estimated that up to 30-50% of healthy tissue may be sacrificed during the debriding procedure. The mechanical - surgical debridement process requires a certain level of surgical skills that may not always be available. Mechanical debridement is also painful, requiring local or systemic analgesia. Therefore, the background art has focused on non-mechanical debriding processes, and also mechanical or physical processes which may be more eschar-specific, precisely focused and selective in order to avoid damage to healthy tissue.

For example, H. J. Klasen in the recent and comprehensive "A review on the non- operative effect of necrotic tissue from burn wounds", Burns 26 (2000), 207-222, reviews the past and present non-surgical debridement treatment of burn wounds, and describes enzymatic and chemical debriding agents, such as proteolytic enzymes and enzymes of plant origins. The review concludes that although enzymatic debridement would appear to be a useful and attractive form of treatment, it unfortunately suffers from highly variable results. PCT Application No. WO 98/53850 also teaches the use of chemical debriding agents such as enzymes for the treatment of burned skin. However, such chemical debriding agents alone may not prove sufficiently effective for all burn or other eschar situations, especially chronic wounds.

With regard to physical mechanisms for debridement, the background art includes teachings on the use of ultrasound for such debridement. For example, S.F. Schoenbach et al., in Plastic and Reconstructive Surgery, July 1980, 66(1), pp. 34-37, describe experiments performed on rats for reducing the bacterial count of infected full-thickness burn wounds by ultrasonic treatment.

PCT Application No. WO 98/32379 describes an ultrasound system for treatment of neoplastic or precancerous skin tissue. As for most applications of ultrasound, the ultrasound generating element is coupled to a container holding a liquid medium capable of transmitting ultrasound waves ("acoustic medium"), which is preferably a degassed solution such as water. In this application the solution may also contain substances that are activated by ultrasound to release free radicals. However, the use of an independently therapeutic or active solution is not taught or suggested by this reference.

Other uses of ultrasound for skin treatment have been described in French Patent Application No. 2,762,791, which discloses a probe for the simultaneous application of ultrasound and electrical current to the skin; US Patent No. 4,372,296, which describes a method of treating acne with ultrasound; and US Patent No. 5,656,015 describes an ultrasonic therapeutic system for the treatment of soft tissue. Again, these references are not focused on the removal of dead tissue.

SUMMARY OF THE INVENTION

The background art does not teach or suggest the combination of a chemical and/or enzymatic debriding agent with a physical debriding mechanism. The background art also does not teach or suggest such a combination in which each of the chemical and/or enzymatic debriding agent and the physical debriding mechanism are capable of being at least somewhat effective for debriding alone.

The present invention overcomes these deficiencies of the background art by providing a device, system and method for enhancing the functionality and efficiency of a chemical and/or enzymatic debriding agent with a physical debriding mechanism. The debriding agent alone and the physical mechanism alone are each capable of at least some debriding activity separately, without being used in the combination. In combination, however, they are synergistically more effective, such that the debriding efficacy is increased for the combination. Preferably, the physical debriding mechanism comprises an ultrasound source. More preferably, the ultrasound source comprises an ultrasound probe. Hereinafter, the term "debriding composition" includes both chemical and enzymatic debriding agents.

The present invention also optionally and preferably comprises a container for holding an acoustic medium for enabling the ultrasound source to effectively treat the area of skin, by transmitting the ultrasound waves and hence the cavitation phenomenon to the area of skin to be treated. The acoustic medium is preferably a liquid medium, but may optionally also be an acoustic gel or other semi-solid material which is capable of the cavitation phenomenon. Optionally, the acoustic medium comprises the debriding composition. Alternatively, the debriding composition may be applied separately, for example before or after treatment of the area with the ultrasound waves from the ultrasound source.

The container may optionally and preferably be constructed as an acoustic chamber or gel block, or any other container that is suitable for retaining the acoustic medium. Preferably the container allows contact between the acoustic medium and the skin, for the embodiments in which the acoustic medium also comprises the debriding composition. The debriding composition may also optionally be formulated as a liquid, or alternatively as a gel or other semi-solid material. Illustrative examples of semi-solid materials include but are not limited to, gels, pastes, creams and the like. The debriding composition contains a debriding agent, which is preferably a chemical or enzymatic debriding agent. Illustrative examples of such agents include but are not limited to vegetable preparations including but not limited to, bromelain derivatives, including but not limited to, Debridase, Ananaim, Comosain; papain derivatives; bacterial derivative enzymes, including but not limited to, streptokinase (Varidase™), sutilains (Travase™), collagenase (Santyl™-Smith & Nephew LTD), trypsin, fibrolysin-desoxyribonuclease; chemical combinations such as Aserbin™ cream; and acids, including but not limited to, piruric, salycilic or phosphoric acids. Although Debridase is used below in the specific Examples, this is for the purposes of clarity only and is not meant to be limiting in any way.

According to preferred embodiments of the present invention, at least one characteristic of the wound is considered when calibrating the combination of the debriding agent and ultrasound energy, which as described in greater detail below, may optionally be applied sequentially but are preferably applied together at the same or similar time, more preferably such that the debriding agent formulation acts as the acoustic medium for the ultrasound energy. Characteristics of the wound optionally include but are not limited to, whether the wound is acute or chronic, or at least has eschar that is characteristic of a chronic wound; origin of the wound (for example trauma as opposed to reduced or poor circulation); presence or absence of healthy tissue at the edges of the wound; characteristics of the wound bed; and presence or absence of foreign matter or debris in the wound bed.

The ultrasound energy is optionally and preferably calibrated according to the total effective energy and/or time, in which the total effective energy is preferably selected according to at least one of ultrasound energy output, distance from the probe or other ultrasound source to the wound, or characteristics of the acoustic medium, or a combination thereof. Optionally, total effective energy is also determined at least partially according to the frequency of ultrasound energy. The combination of debriding agent and ultrasound energy (preferably calibrated as described above), regardless of the order of application, preferably forms the system of the present invention. It should be noted that the terms "debriding agent" and "debriding composition" are used interchangeably for the description of the operation of the present invention, except where otherwise noted.

According to the present invention, there is provided a system for debridement of skin, comprising: (a) a device comprising an ultrasound source and a container coupled to the ultrasound source, the container being adapted to be placed over an area of skin to be debrided, the container containing an acoustic medium for enabling the area of skin to be debrided to be exposed to ultrasonic radiation from the ultrasound source; and (b) a debriding composition for being in contact at least temporarily with the area of skin to be debrided.

Preferably, the acoustic medium includes the debriding composition. More preferably, the container further comprises an opening for enabling the debriding composition to contact the area of skin to be debrided. Most preferably, the container further comprises a peripheral seal for sealing the opening against the area of skin to be debrided.

Alternatively and preferably, the system further comprises an inlet in the container for inserting the debriding composition. More preferably, the system further comprises an outlet in the container for removing the debriding composition. Most preferably, the system further comprises an outlet in the container for creating a vacuum for sealing the opening against the area of skin.

Preferably, the container further comprises an opening for being placed against the area of skin to be debrided, and also further comprises an inlet, such that the debriding composition may be inserted into the container before, during or after treatment with the ultrasonic radiation. More preferably, the container further comprises an outlet for removing at least one of the acoustic medium and the debriding composition. Also more preferably, the container further comprises a peripheral seal for sealing the opening against the area of skin to be debrided. Preferably, the ultrasound source comprises a piezoelectric ultrasound source unit.

Also preferably, the device further comprises a spacer for maintaining the ultrasound source at a distance from the skin to be debrided. More preferably, the spacer is combined with the container. Preferably, the debriding composition comprises at least one of a chemical debriding agent and an enzymatic debriding agent. More preferably, the debriding composition further comprises at least one of a liquid and a semi-solid carrier. Also more preferably, the debriding composition further comprises a stabilizer. Also more preferably, the debriding composition comprises a vegetable preparation. Most preferably, the vegetable preparation comprises a bromelain derivative. Most preferably, the bromelain derivative comprises Debridase.

Preferably, the ultrasound source is maintained at a calibrated distance from the skin. Also preferably, a total effective energy of the ultrasound source is determined for debriding the skin. More preferably, the total effective energy is determined according to at least one of a distance of the ultrasound source from the skin, energy output of the ultrasound source or a characteristic of the acoustic medium, or a combination thereof. Most preferably, the acoustic medium comprises a gel formulation. Also most preferably, the acoustic medium comprises the debriding composition.

According to another embodiment of the present invention, there is provided a device for combined debridement of skin with a debriding composition for being in contact at least temporarily with an area of skin to be debrided, comprising: (a) an ultrasound source; and (b) a container coupled to the ultrasound source without interfering with operation of the ultrasound device, the container being adapted to be placed over the area of skin to be debrided, the container containing an acoustic medium for enabling the area of skin to be debrided to be exposed to ultrasonic radiation from the ultrasound source; wherein treatment of the area of skin to be debrided is performed through a combination of an effect of the ultrasonic radiation and an effect of the debriding composition. Preferably, the acoustic medium includes the debriding composition. More preferably, the container further comprises an opening for enabling the debriding composition to contact the area of skin to be debrided. Most preferably, the container further comprises a peripheral seal for sealing the opening against the area of skin to be debrided. Also most preferably, the device further comprises an inlet in the container for inserting the debriding composition. Preferably, the device further comprises an outlet in the container for removing the debriding composition. Preferably, the device further comprises an outlet in the container for creating a vacuum for sealing the opening against the area of skin.

Also preferably, the device further comprises a spacer for maintaining the ultrasound source at a distance from the skin to be debrided. More preferably, the spacer is combined with the container. Also more preferably, the distance is determined according to a total effective energy for being delivered to the skin. Most preferably, the total effective energy is further determined according to at least one of energy output of the ultrasound source or a characteristic of the acoustic medium, or a combination thereof.

According to another embodiment of the present invention, there is provided a method for treating an area of skin to be debrided, comprising: contacting the area of skin with a debriding composition; and applying ultrasonic radiation to the area of skin; wherein the contacting and the applying are performed in any order.

Preferably, the applying and the contacting are performed concurrently.

Alternatively and preferably, the applying is performed before the contacting.

Also alternatively and preferably, the contacting is performed before the applying.

Preferably, the debriding composition comprises at least one of a chemical debriding agent and an enzymatic debriding agent. More preferably, the debriding composition further comprises at least one of a liquid and a semi-solid carrier. Also more preferably, the debriding composition further comprises a stabilizer.

Also more preferably, the debriding composition comprises a vegetable preparation. Most preferably, the vegetable preparation comprises a bromelain derivative. Also most preferably, the bromelain derivative comprises Debridase.

According to still another embodiment of the present invention, there is provided a system for debridement of skin, comprising: (a) a device comprising an ultrasound source and an acoustic medium for enabling an area of skin to be debrided to be exposed to ultrasonic radiation from the ultrasound source, wherein the ultrasound source is placed in contact with the acoustic medium manually; and (b) a debriding composition for being in contact at least temporarily with the area of skin to be debrided.

Preferably, the acoustic medium includes the debriding composition. Also preferably, the debriding composition comprises at least one of a chemical debriding agent and an enzymatic debriding agent. More preferably, the debriding composition further comprises at least one of a liquid and a semi-solid carrier.

Most preferably, the debriding composition further comprises a stabilizer.

Preferably, the debriding composition comprises a vegetable preparation. More preferably, the vegetable preparation comprises a bromelain derivative. Most preferably, the bromelain derivative comprises Debridase.

According to yet another embodiment of the present invention, there is provided a method for treating an area of skin to be debrided, comprising: applying a debriding composition to the area of skin; and applying ultrasound energy to the area of skin. Preferably, the debriding composition forms an acoustic medium for the ultrasound energy. More preferably, the ultrasound energy is calibrated according to at least one of a distance of the ultrasound source from the skin, energy output of the ultrasound source or a characteristic of the acoustic medium, or a combination thereof.

Most preferably, the acoustic medium comprises a gel formulation. Preferably, the ultrasound energy is at least partially calibrated according to a time period for treatment. Also preferably, the ultrasound energy is calibrated according to at least one characteristic of the area of skin. More preferably, the area of skin comprises a wound, and the ultrasound energy is calibrated according to at least one characteristic of the wound. Most preferably, the wound comprises an acute wound, a chronic wound or a wound featuring chronic wound eschar. Also most preferably, the acute wound comprises an abrasion wound, a wound with foreign matter, surgically or a traumatically injured tissue or flap, or a combination thereof.

Preferably, the wound featuring chronic wound eschar also features necrotic tissue.

Also preferably, the chronic wound comprises a wound associated with reduced circulation in the extremities, diabetes, old age, a skin ulcer, a venous or arterial ulcer, a pressure sore, a post-surgical wound or a wound associated with trauma that has become chronic, or a combination thereof. Preferably, wherein before applying the debriding composition to the area of skin, the method further comprises: mechanically cleaning the area of skin.

The method also preferably further comprises: mechanically cleaning the area of skin after the applying the ultrasound energy. The method also preferably further comprises: applying a protective barrier to an edge of the area of skin to be treated before the applying the ultrasound energy.

BRIEF DESCRIPTION OF THE DRAWINGS The invention is herein described, by way of example only, with reference to the accompanying drawings, wherein:

FIG. 1 shows a cross-sectional view of a first exemplary embodiment of a device according to the present invention;

FIG. 2 shows a cross-sectional view of another exemplary embodiment of a portion of the device according to the present invention;

FIG. 3 illustrates another exemplary embodiment of the present invention;

FIG. 4 shows still another exemplary embodiment of the device according to the present invention;

FIG. 5 represents the eschar area inside the chamber with the ultrasound probe in place covering the lower part of the eschar;

FIG. 6 represents the eschar area inside the chamber with the ultrasound probe in place;

FIG. 7 represents the eschar area after 30 minutes at a distance of 5 millimeters of treatment with the Debridase and ultrasonic radiation (20 kHz, 10W/cm² ) according to the present invention;

FIG. 8 represents the eschar area after 60 minutes of treatment with saline and ultrasonic radiation ( 20 kHz, 10W/cm² );

FIG. 9 represents the eschar area after 60 minutes of treatment with hydrated Debridase in an occlusive dressing; FIG. 10 shows a 9 day old experimental necrotic flap before treatment according to the present invention;

FIG. 11 shows the 9 day old necrotic flap of FIG 10 after 30 minutes of treatment with ultrasound (20 kHz, 10W/cm²) and Debridase according to the present invention; FIG. 12 shows the flap after an additional 30 minutes of treatment with ultrasound (free hand20 kHz, 10W/cm²) and Debridase according to the present invention;

FIG. 13 shows that after the wound is wiped (after the treatment according to the present invention performed with regard to Figures 11 and 12), the wound is entirely clean; FIG. 14 shows a 7 day old experimental necfotic flap. A: before enzymatic treatment by Debridase Gel Dressing; B: after 2 courses (8 hours) with Debridase Gel Dressing with partial debridement;

FIG. 15 shows: A: a 7 day old experimental necrotic flap before treatment according to the present invention; B: Application of a standard intensity (20 kHz, 10W/cm² ) ultrasound at a distance of 3 millimeters in the presence of Debridase solution according to the present invention;

Fig. 16: The necrotic flap of Figure 15 after 30 minutes application of a standard intensity (20 kHz, 10W/cm²) ultrasound at a distance of 3 millimeters in the presence of Debridase solution according to the present invention showing a complete debridement of the area under the probe;

FIG. 17 shows the 7 day old necrotic flap A: after 5 minutes of treatment with double intensity (20W/cm²) ultrasound at a distance of 1 millimeter and Debridase solution according to the present invention showing debridement corresponding to the probe's size; B: same flap after a second 5 minutes of treatment with double intensity (20W/cm²) ultrasound at a distance of 1 millimeter and Debridase according to the present invention showing additional debridement;

FIG. 18 shows a schematic block diagram of an experimental arrangement for determining ultrasound intensity; and

FIG. 19 is a graph of ultrasound intensity as compared to distance in three types of acoustic media: water alone (squares), water plus Debridase (diamonds) and Debridase gel (triangles).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is of a device, system and method for enhancing the functionality and efficiency of a chemical and/or enzymatic debriding agent with a physical debriding mechanism. The debriding agent alone and the physical mechanism alone are each capable of at least some debriding activity separately, without being used in the combination. In a synergistic combination, however, they are more effective, such that the debriding efficacy is increased for the combination. Preferably, the physical debriding mechanism comprises an ultrasound source. More preferably, the ultrasound source comprises an ultrasound probe.

The ultrasound source is preferably capable of delivering ultrasound, at a frequency measured in Hz and a power measured in W/cm², of sufficient power and frequency to be effective for treating dead tissue, in terms of having some type of debriding effect. A non- limiting example of such a sufficient power and frequency is 20 kHz and from about 10 to about 20 W/cm²; another such non-limiting example is 57 kHz and from about 8 to about 20 W/cm² The ultrasound source is optionally and more preferably a piezo-electric ultrasound source unit.

The present invention also optionally and preferably comprises a container for holding an acoustic medium for enabling the ultrasound source to effectively treat the area of skin, by transmitting the ultrasound waves to the area of skin to be treated. The acoustic medium is preferably a liquid medium, but may optionally also be an acoustic gel or other semi-solid material. Optionally, the acoustic medium comprises the debriding composition. Alternatively, the debriding composition may be applied separately, for example before or after treatment of the area with the ultrasound waves from the ultrasound source.

The container may optionally and preferably be constructed as an acoustic chamber or gel block, or any other container that is suitable for retaining the acoustic medium. Preferably the container allows contact between the acoustic medium and the skin, for the embodiments in which the acoustic medium also comprises the debriding composition.

The debriding composition may also optionally be formulated as a liquid, or alternatively as a gel or other semi-solid material. Illustrative examples of semi-solid materials include but are not limited to, gels, pastes, creams and the like. The debriding composition contains a debriding agent, which is preferably a chemical or enzymatic debriding agent. Illustrative examples of such agents include but are not limited to, vegetable preparations including but not limited to, bromelain derivatives, including but not limited to, Debridase, Ananaim, Comosain; papain derivatives; bacterial derivative enzymes, including but not limited to, streptokinase (Varidase™), sutilains (Travase™), collagenase (Santyl ™- Smith & Nephew), trypsin, fibrolysin-desoxyribonuclease; chemical combinations such as Aserbin™ cream; and acids, including but not limited to, salicylic, piruric or phosphoric acids. The debriding composition also preferably includes a solvent or other carrier for the debriding agent, optionally with stabilizers and the like. The debriding composition is preferably at least temporarily in contact with the area of skin to be treated during debridement.

According to preferred embodiments of the present invention, the device preferably comprises the ultrasound source, more preferably connected to an appropriate power source; a spacer for fixing the location of the ultrasound source from the skin to ^'be treated; and a container for containing the acoustic medium, and therefore for acting as an acoustic chamber. Optionally and more preferably, the device further comprises a seal for sealing the lower edges of the container and the skin tissue, and for more preferably acting as an adhesive barrier. The device also more preferably comprises a positioner for holding the device in the proper spatial location, relative to the skin to be treated.

The spacer may optionally and preferably form part of the container, or alternatively, may be a separate component for external support of the ultrasound source. The spacer preferably maintains the probe at a distance of from about 1 to about 8 millimeters from the target treatment area, but without interfering with the normal oscillation of the ultrasound probe.

The container may optionally be rigid or more flexible, and is preferably constructed of any suitable material, such as a plastic or plastic composite or metal sheet for example. The container may optionally include an inlet port for the acoustic medium and/or other liquid and/or gaseous substances and/or a combination thereof, preferably for the optional implementation in which the acoustic medium comprises the debriding composition. The inlet port is also preferred when the debriding composition is either inserted to the container before treatment with the ultrasound source and then removed, or alternatively when the debriding composition is inserted to the container after treatment with the ultrasound source. Of course, both such treatment methods could be employed together, such that the debriding composition is inserted before and/ or after treatment with ultrasound. The container also preferably comprises an outlet port, for example to allow exchange of the chamber contents, optionally and more preferably for removing the debriding composition before treatment with ultrasound, and/or (alternatively or additionally) more preferably for removing and/or adding the debriding composition to the container after treatment with ultrasound. The outlet port may also optionally be used to create a vacuum for securing the container to the skin tissue.

Also optionally, such inlet and outlet ports may be used even if the debriding composition is present during treatment with the ultrasound source, since for example the debriding composition may have a different debriding agent and/or formulation at each stage of the treatment, and/or because the debriding composition may optionally be more effective if new debriding composition is inserted after treatment with the ultrasound source. The ports may optionally and preferably be used also for rinsing, flushing or exchanging the fluids inside the chamber (within the container) in any given stage of the procedure.

The seal preferably has sufficient adhesion to prevent undesired displacement of the container (and hence the acoustic chamber) during the treatment. According to a preferred embodiment of the present invention, the seal may optionally comprise a seal body, such as a polyurethane foam or soft silicone element or an inflatable cushion or the like, which may optionally be provided with a bio-compatible adhesive such as an acrylic glue or a thick gel-like substance, to increase the adherence of the seal body to the skin and to seal the container.

The positioner may optionally be the same as the seal or different. According to a preferred embodiment of the present invention, the positioner preferably comprises a plurality of suction ventoses positioned around the container, or a single large ventose that entirely covers the container. Optionally and alternatively, the positioner may comprise a round elastic funnel around the edges of the container, preferably serving as a ventose. Alternatively, the entire container may comprise a suction cup. As a further alternative, mechanical elements such as elastic bandages, straps, or adhesive tapes or the like may optionally be used to position the container. When the positioner is the same as the seal, an adhesive layer under the seal may optionally hold the container in place. For all of these different alternatives, the normal oscillations of the ultrasound probe should not be obstructed. The system according to the present invention preferably comprises the device according to the present invention and the debriding composition, whether such a debriding composition is held in the container, and whether treatment with the debriding composition is performed before, after or during ultrasound treatment, or a combination thereof.

According to optional, alternative embodiments of the present invention, at least one of the ultrasound source and the debriding composition alone is not sufficiently effective as a treatment, for example by being administered at subtreatment levels. In this case, the combination is preferably such that a synergistic effect is present, such that for example the combination preferably provides greater treatment efficacy than either component alone. Examples of wounds which may optionally be treated with the present invention include acute wounds, particularly abrasion wounds and wounds with foreign matter or particles (such as may be obtained from scraping the skin along a surface such as a road, as for a biking or motorcycling accident for example), traumatic or surgical necrotic flaps and wounds characterized by necrosis; and chronic wounds, which are described in greater detail below.

Acute wounds are characterized by freshly devitalized tissue (fresh eschar) that preserves the tissue's original moisture and some of the gross morphological structure. As described in greater detail below, optionally fewer measures are required for treatment of acute wounds with the system of the present invention.

Chronic wounds are characterized by the presence of dry or grossly modified eschar, which prevents the wound from healing and increases the difficulty of treatment. Necrosis of the tissue surrounding the wound and in the wound bed is a complicating factor in the treatment of such wounds. Chronic wounds are a characteristic of and/or associated with many different medical conditions, including pressure, reduced circulation of the extremities, diabetes, old age and post trauma or surgery.

Examples of chronic wounds include but are not limited to, skin ulcers (including those associated with diabetes, such as diabetic plantar ulcers), venous or arterial ulcers, pressure sores such as bedsores for example, post trauma or surgery wounds that are recalcitrant, difficult and/or slow to heal .

Chronic wound beds often feature less healthy or unhealthy surrounding tissue which may also be more sensitive. Therefore, preferably treatment with the present invention is calibrated to the characteristics of the chronic wound, particularly with regard to the wound bed. Such calibration may optionally include adjusting the total effective energy of the ultrasound radiation, by adjusting the output ultrasound energy and/or distance of the ultrasound probe from the wound, preferably also including selection of an appropriate acoustic medium, which is more preferably a debriding agent in a water (and/or aqueous solution) or gel, such as Debridase gel for example. Although the gel may result in a reduction in intensity of the ultrasound energy and hence in the total effective energy, such a reduction, for which compensation is optionally made by the application of different energy output and/or distance of the source from the area of skin (wound), may be protective of the more delicate tissue in and/or around the wound. Another characteristic for calibration is preferably length of time of treatment. According to preferred embodiments of the present invention, a chronic wound is preferably treated as follows. The wound is preferably first mechanically cleaned and soaked, for example with saline in the presence or absence of antiseptics, hydrogels and so forth. More preferably, such pretreatment results in removing superficial keratin if possible. Next, preferably a debriding agent solution, more preferably a gel formulation (such as Debridase gel for example) is applied to the wound until it is apparent that its debriding effect has been exhausted. A further mechanical cleaning and soaking process is preferably then performed.

The present invention is then preferably applied to any non-debrided areas, as a combination of debriding agent (solution or gel) and ultrasound energy. As previously described, more preferably one or more, and most preferably all, of the following factors are considered in determining this process: selection of debriding agent medium (for example a gel may optionally be selected for ease of use or as a protective measure for reducing ultrasound intensity); total effective energy (distance of the ultrasound probe or other device and/or output energy of the probe and/or other ultrasound source); and time (length) of treatment. Also more preferably, some type of protection may optionally be applied to the edge's of the wound, for example with a cream such as petroleum or silicon jelly or some other type of barrier, as previously described.

Optionally, a further mechanical cleaning and soaking process is performed after debridement, for example in order to further remove eschar and also in order to further clean the wound.

The frequency of application of the above treatment process is preferably determined according to the characteristic(s) of the wound, for example by medical personnel.

EXAMPLE 1 ILLUSTRATIVE DEVICE AND SYSTEM The principles and operation of the present invention may be better understood with reference to the drawings and the accompanying description. Figures 1-4 show schematic illustrations of various exemplary embodiments of the device according to the present invention, as vertical cross-sections. As used herein, the term "vertical cross-section" refers to a cross-section on a plane which is substantially perpendicular to the surface of the area being treated, and is preferably a symmetry plane of the device. According to preferred but exemplary embodiments of the present invention as shown, the device, or at least a portion thereof, is preferably round in shape, so that each vertical cross-section is the same and Figures 1-4 represent any such cross-section. It should be noted that the device according to the present invention, as described in greater detail below, may optionally feature all components during manufacture and/or before use. Alternatively, such components may be generated at the moment of use by conveniently combining these components. For example, any one or more components may optionally be added to the device to generate the complete device at the moment of use. Preferably, at least one of the ultrasound source and the debriding composition are added to the device at the moment of use, while respecting the working principle of the ultrasound device, such as not interfering with the normal oscillation of the ultrasound probe.

Referring now to the drawings, Figure 1 shows a device 10 according to the present invention, as a cross-sectional view. Device 10 features a container 11, which is optionally and preferably implemented as a round cup as shown. Container 11 may optionally be constructed of any convenient material, such as metal or plastic, or combination of both for example, and may optionally be rigid or flexible. Container 11 preferably features an acoustic chamber 12 as shown. At the bottom of container 11 and around the periphery of container 11, a seal 13 is preferably located. Seal 13 more preferably comprises a body 14, optionally and preferably made from elastic foam, and an adhesive layer 15 which preferably contacts the skin of the patient during treatment. Adhesive layer 15 preferably retains container 11 in the appropriate position with sufficient adhesive strength during treatment. For the purposes of illustration only and without any intention of being limiting, an area of skin 16 of the patient to be treated is schematically indicated, as is dead tissue 17 at area of skin 16. As shown, device 10 is preferably placed such that container 11 overlays dead tissue 17. The schematic indication of skin 16 and dead tissue 17 is not repeated in the following drawings, but should be considered as obviously implicit, in view of the use of device 10.

Container 11 is preferably closed at the top, and also preferably supports an ultrasound source 18, shown at the top area of acoustic chamber 12. Ultrasound source 18 is preferably connected with conductors 19, passing through an opening (sealed if desired) at the top of container 11, optionally to a controller and preferably to a power source (not shown).

For this embodiment, an inlet conduit 20 is preferably present at container 11, for example, for the introduction of the debriding composition and/or acoustic medium into acoustic chamber 12. It should be noted that the debriding agent, such as the chemical and/or enzymatic debriding agent for example, may optionally be introduced separately into acoustic chamber 12 from some type of solvent or other carrier, and then mixed. Also optionally, the debriding agent may be introduced separately into acoustic chamber 12 from the acoustic medium, and then mixed. Inlet conduit 20 may optionally and preferably feature a one-way valve 20A. The debriding composition may also optionally be introduced into acoustic chamber 12 as a unit

21.

An outlet 22 may also optionally be provided as shown, for example for evacuating liquid and/or semi-solid material from acoustic chamber 12, and/or for creating a vacuum. Outlet 22 may also optionally and preferably feature a one-way valve 22 A.

The distance of ultrasound source 18 from dead tissue 17 is preferably determined by the height of acoustic chamber 12, as ultrasound source 18 is preferably fixed to the inside of the top of container 11.

Figure 2 schematically illustrates another embodiment of a portion of the device according to the present invention, in which a container 24, preferably constructed of a flexible material such as a flexible film for example, is preferably provided with an adhesive barrier 23. An ultrasound source 28 is preferably connected to a power source

(not shown) with conductors 29, and is preferably supported by a spacer 26. Spacer 26 may optionally be constructed as a tripod as shown, but alternatively may have any convenient structure. Spacer 26 preferably determines the distance of ultrasound source 28 from the dead tissue to be treated (not shown). The device may optionally be held in place by a mechanical element, such as straps, an elastic dressing or adhesive tape (not shown).

Figure 3 illustrates another embodiment of the present invention, in which a device

30, generally similar to device 10 of Figure 1, is held in place with an overlaying element 31. Overlaying element 31 may optionally be an anchoring ventose, and is preferably positioned on the area of skin to be treated by applying a vacuum through an outlet 32.

Overlaying element 31 is preferably provided with a seal 33, to permit a vacuum being established therein. Device 30 also preferably comprises a container 37, including an acoustic chamber 38. Container 37 also preferably supports an ultrasound source 34 provided with conductors 35, and also preferably includes a peripheral seal 36 that may optionally be similar to seal 13 of Figure 1. Seal 36 preferably isolates acoustic chamber 38 from the compartment between overlaying element 31 and container 37, in which the vacuum is created.

Figure 4 shows still another embodiment of the device according to the present invention, in which a container 41 includes an acoustic chamber 40. Container 41 retains an ultrasound source 42 with a plurality of conductors 43. An inlet 44 preferably enables a liquid and/or semi-solid material, such as a gel for example, to be introduced to acoustic chamber 40, which as noted above, may optionally contain one or more of the debriding composition or the acoustic medium, or a combination thereof.

An annular cavity 46 preferably provides a seal and a positioner at the periphery of the bottom of container 41, in which a vacuum may optionally be created through outlet 47, so that annular cavity 46 preferably acts as a ventose to secure the device in place.

EXAMPLE 2 IN VIVO STUDIES I Several in vivo animal studies were performed to illustrate the efficacy of the present invention. This Example and Figures 5-9 show pictures of a first in vivo animal study with deep contact burns. It should be noted that the method of treatment described herein is for the purposes of illustration only and is without any intention of being limiting.

The animal experimental model was of a chronic desiccated eschar, considered to be a "worst case scenario" for debridement. The testing animals were young pigs of 20-25 kg of weight. Under general anesthesia and proper monitoring according to proper animal treatment protocols, the bristles along the spine were shaved and the burns were induced. The different test areas were marked and photographed.

A series of deep contact burns, 2 cm in diameter, were left to desiccate for three days, creating a dry eschar, similar to a typical chronic, untreated wound eschar. For treatment, a circular chamber 3 cm in diameter was glued around each area. An ultrasound probe was installed, having a diameter of 1.2 cm that covers half of each eschar site, with its surface covering the lower part of the eschar at a distance of 3 millimeters. At this stage, the chamber was filled with the test material, containing Debridase and saline, or with the control (saline alone). A third control site was a similar eschar treated with hydrated

Debridase in an occlusive dressing, without the use of ultrasonic radiation.

Figure 5 (represents the burn area inside the chamber with the ultrasound probe in place covering the lower part of the eschar. Figure 6 represents the burn area inside the chamber with the ultrasound probe in place, immersed in the dissolved Debridase as the acoustic medium, after 20 minutes of treatment with the ultrasonic radiation. As shown, the

Debridase solution is stained with blood.

Figure 7 represents the burn area after 30 minutes of treatment with the Debridase solution and ultrasonic radiation. A completely debrided lower area "A" can be seen under the ultrasound probe, contrasted by the upper area "B", which the probe did not cover and where the eschar remained.

Figure 8 represents the burn area after 60 minutes of treatment with saline and ultrasonic radiation. As can be seen, the eschar is completely intact without any signs of debridement. Figure 9 represents the burn area after 60 minutes of treatment with hydrated

Debridase in an occlusive dressing. Some initial debridement can be seen at the edges

(marked by arrow C) where the eschar is thinner, but a thick area of eschar remains in the center.

The above animal study showed that the use of a debriding agent/composition (represented by Debridase) alone produced a limited debridement as expected. The use of ultrasonic radiation alone without any debriding agent did not have any debriding effect.

However, the combination of the debriding composition and locally applied ultrasonic radiation produced a significant debridement, with a greater overall effect than the debriding agent/composition alone, and also more rapidly than the debriding agent/composition alone.

EXAMPLE 3 IN VIVO STUDIES II For the second study, the ischemic flap model of inflicting chronic eschar was chosen as most closely imitating the actual clinical behavior of eschar in human chronic wound patients. The model is obtained by incising the skin of young domestic pigs, approx. 20-25 kg as described above, to create long and narrow flaps (3 x 7 cm) where, due to the very negative base/length ratio, the ends of the flaps are ischemic and will necrotize. This necrotizing course follows exactly the natural course of necrotizing ischemic soft tissue in humans.

The skin was allowed to be ischemic for variable lengths of time before treatment. It was found that leaving the flaps for 6 days causes a dry, black eschar in the ischemic distal area to form, while leaving the flaps for 9 days causes the eschar to start to slough at its connection to the viable tissue. Figure 10 shows a 9 day old necrotic flap before treatment according to the present invention.

Also, the efficacy of Debridase was tested after exposure to ultrasonic radiation at 20 kHz 10W/cm² for 30 minutes in order to establish its activity after such exposure. The 6 days model of ischemia was used with the formal 4 hour Debridase in hydrating gel, with and without ultrasonic radiation. The 9 days model of ischemia was used in combinations with ultrasonic radiation and Debridase. The ultrasound source featured the previous probes, with an output of 20 kHz and 10 W/cm² or 57 kHz and 8W/cm². Ultrasound was also used as a pretreatment primer before application of the Debridase, together with the Debridase (gel replaced by saline) and in conjunction with SLS (surface active compounds).

For the 9 days model of ischemia, the following combinations were used: control treatment of 4 hours with Debridase in water; a first application of ultrasonic radiation at 20 kHz /10W/cm² with Debridase in water (DWD) for 30 minutes with a second application of ultrasonic radiation at 20 kHz /10W/cm² with Debridase in gel for 30 minutes, with freehand (manual) use of the ultrasound probe on a Debridase in hydrating gel, such that the probe was used without an acoustic chamber and with the ultrasound probe manually held over the eschar; a pretreatment for five minutes with ultrasonic radiation and SLS, followed by 4 hours Debridase in hydrating gel; a pretreatment for five minutes with ultrasonic radiation and then 4 hours Debridase in hydrating gel; and treatment with Debridase in water and SLS for 4 hours.

RESULTS

The model The 6 days model seems to represent the "fresh" chronic eschar that is still attached to the living tissue. The eschar is not decomposed (necrotic) as yet and is not completely dry. The 9 days model represents the more chronic, contaminated eschar that starts to macerate. The main body of these eschars is a hard, dry, black mass but along its edges the maceration process begins. The transition line between the eschar and the living tissue is well defined and in some points a furrow starts to form indicating the level of the future sloughing.

Debridement Debridase in water (saline solution) that was exposed to ultrasonic radiation proved to be effective, similar to the combination of ultrasonic radiation with the previously tested composition of Debridase in hydrating gel or saline.

The combination of ultrasound and Debridase proved to be effective in debridement of the standard desiccated burn model eschar.

The first set of debridement trials were performed with the 6 days model of ischemic flaps and the formal 4 hours Debridase in hydrating gel (without ultrasound). In all 5 areas, a beginning of debridement of the eschar could be seen in the areas that were less desiccated and from the edges where the Debridase in hydrating gel had contact with the dermis. At the edges of the living tissue, which featured an inflammatory reaction, the surface was debrided and raw tissue was exposed. None of the five eschars was debrided completely in one single Debridase in hydrating gel application (without ultrasound). The second set of debridement trials were performed with the 6 and 9 days model of ischemic flaps. Different combinations were tested as described above. The results were as follows. For the treatment with ultrasonic radiation and 4 hours Debridase in hydrating gel, the healthy tissue edges were cleaned, with nearly complete separation of the eschar without much effect on the desiccated eschar itself. Using ultrasonic radiation together with Debridase in water provided similar results as 4 hours Debridase in hydrating gel treatment. Figure 11 shows a 9 day old necrotic flap after 30 minutes of treatment with ultrasound and Debridase solution. Figure 12 shows the flap after an additional 30 minutes of treatment with ultrasound (free hand) and Debridase. Figure 13 shows that after the wound is wiped (after the treatment according to the present invention performed with regard to Figures 11 and 12), the wound is entirely clean.

As shown in these Figures, the additional free-hand use of the ultrasound probe on Debridase in hydrating gel without a chamber showed improved cleaning of the living edges of skin tissue. Wiping the area to remove the gel caused the entire eschar to be removed together with a "tail" of a necrotic subdermal tissue attached to the full thickness eschar. The tissue that was left seemed to be clean.

Pretreatment with ultrasound for five minutes with SLS, followed by 4 hours Debridase in hydrating gel provided some cleaning at the edges of the skin, and was similar to treatment with Debridase in hydrating gel alone.

Pretreatment with ultrasound for five minutes followed by 4 hours Debridase in hydrating gel was similar to treatment with Debridase in hydrating gel alone. Due to technical difficulties in keeping the liquid Debridase plus water in the chamber, it was replaced after 30' with Debridase in hydrating gel. Treatment with Debridase in water plus SLS for 4 hours was similar to treatment with Debridase in hydrating gel alone.

EXAMPLE 4 ULTRASOUND FACTORS IN TREATMENT A second set of in vivo (animal) trials was performed to assess other factors in the combination of ultrasound application and Debridase. Three treatment modalities were compared: a first treatment mode involving Debridase in hydrating gel alone, without ultrasound as a control (Figure 14); a second treatment mode involving Debridase in saline and ultrasound at a first total effective energy (Figures 15 and 16); and a third treatment mode involving Debridase in saline and ultrasound at a second total effective energy (Figure 17). As described in greater detail below, increasing the total effective energy of ultrasound decreased the amount of time for complete debridement. Treatment without ultrasound failed to produce complete debridement.

Figure 14 shows a wound (6 days desiccated flap, which is a flap 6 days after being formed; see above for a description of how wounds were created) after having been treated twice with the standard 4 hour treatment course of Debridase in hydrating gel, without application of ultrasound, as a control. The results demonstrate a good debridement of the more superficial eschar but the central, full thickness dry eschar was not affected. Thus, complete debridement was not achieved.

Figure 15 shows a similar 6 days desiccated flap being treated by a combination of ultrasound (20 kHz /10W/cm² at a distance of 3-4 millimeters from the wound) and

Debridase solution resulting in a complete debridement of the area under the ultrasound probe in 30 minutes, as shown with regard to Figure 16. This combination of power (10 W/cm²) and distance from the wound (3-4 millimeters) forms the first example of the total effective energy from the ultrasound.

Figure 17 shows a similar 6 days desiccated flap after treatment with a different combination of ultrasound having a different total effective energy (20 kHz /20 W/cm² at a distance of 1 millimeter from the wound) and Debridase solution resulting in a complete debridement of the area under the ultrasound probe in only 5 minutes. Displacing the probe sidewise and re-applying the same setting for 5 minutes increased accordingly the debrided area. Thus increasing the total effective energy decreased the amount of treatment time required for complete debridement. The total effective energy preferably depends upon a combination of at least the distance of the ultrasound probe from the wound and the power output of the probe (expressed as W/cm² ). Optionally, the total effective energy may be affected by the frequency of the ultrasound radiation, but in these examples a single frequency (20 kHz) was used. As seen from these examples, increasing the power output of the probe and/or decreasing the distance from the probe to the wound increases the total effective energy received by the wound. As the total effective energy is increased, the time required for treatment with the ultrasound probe and Debridase to reach some treatment endpoint, such as complete debridement, decreases.

CONCLUSIONS

Debridase remains effective after being exposed to ultrasonic radiation, and the combination of Debridase together with ultrasonic radiation treatment is useful, including optionally with simultaneous application. Currently, pretreatment with ultrasound and/or SLS before application of Debridase does not show any additional benefit, but this may be due to the particular combination selected.

EXAMPLE 5 EFFECT OF ULTRASOUND INTENSITY This Example considers the effect of ultrasound energy and/or the effect of the

Debridase medium on debridement. These two factors were examined in order to provide more information with regard to the effect of ultrasound dynamics on treatment, and specifically of the interplay of the effect of ultrasound energy and the type of medium used for Debridase on ultrasound intensity; as described above, the intensity of the ultrasound energy or total effective energy at the wound has a direct effect on treatment results. These factors were considered with regard to the measurement of intensity in an in vitro system, without any biological tissue or other matter, in order to isolate the relationship between these factors on intensity.

For this Example, the acoustic medium featured distilled water alone (as a control), distilled water with Debridase or Debridase gel. The equipment included an ultrasound generator from Sonics & Materials Inc. (USA; Model: VCX400); an oscilloscope, which was the Analog Digital Oscilloscope HM 407; and a computer (operating the computer program SP 107 for the oscilloscope).

The equipment was set up as shown with regard to Figure 18. As shown, an ultrasound (US) generator 502 generates ultrasound for being transmitted by an ultrasound (US) probe 504, which is inserted into a cuvette 506. US probe 504 causes ultrasound radiation to be propagated within cuvette 506. A hydrophone 508 is also inserted into cuvette 506 for converting the pressure of the propagated ultrasound into an electrical signal. Oscilloscope 510 presents and measures the electrical signal, which is then analyzed by a computer 512 operating the previously described oscilloscope software program. The software is able to determine the sound pressure from the voltage as provided by the oscilloscope according to the following calculation: Hydrophone voltage (V) from oscilloscope is used to determine the sound pressure (P) according to the following equation: P=V/Sc when : V - hydrophone voltage

Sc - voltage sensitivity for hydrophone. Sc = 26.3 μV/Pa Intensity (J) found according to the following equation:

J = P²/(2pe) when : p - density of medium e - sound velocity As expected, initial experiments showed that ultrasound intensity varied as the inverse proportion of the distance, when the ultrasound probe was positioned at a distance of from about 0.5 mm to about 7mm from the hydrophone (data not shown).

However, interestingly the choice of acoustic medium had a significant effect on the intensity of the ultrasound radiation. Figure 19 shows these results in a graph form. As shown, water alone and water with Debridase as an acoustic medium resulted in ultrasound radiation being propagated with similar intensity. By contrast, the use of Debridase gel as an acoustic medium resulted in a relatively low ultrasound intensity, such that significantly higher initial ultrasound energy levels at output would be required to receive similar intensity levels in the cuvette. In terms of the effect in vivo, it would appear that increased ultrasound energy output is required when Debridase gel is being used as the acoustic medium on a wound in order to achieve a similar total effective energy at the wound as for when water is used as the acoustic medium.

EXAMPLE 6 METHOD OF TREATMENT

The method of treatment according to the present invention preferably comprises contacting the skin of a patient with a debriding composition, and applying ultrasonic radiation to the skin. These processes may optionally and preferably be performed in any order, including simultaneously. More preferably, these processes are performed repeatedly for at least one repetition, and more preferably a plurality of repetitions.

Optionally, only one of the two processes may be performed for a particular repetition. As previously described, the method of the present invention is useful for debridement, preferably for removal of dead skin tissue.

The duration of treatment, the intensity of the ultrasonic radiation, the distance between the probe and the target eschar, the concentration and overall amount of the debriding agent in the composition, as well as the amount of the composition itself, may optionally and preferably be each determined individually, for example by the attending physician. The debriding composition, along with the overall treatment method, is preferably used in a therapeutically effective amount. As used herein, the term "therapeutically effective amount" means the total amount of each active component of the pharmaceutical composition or method that is sufficient to show a meaningful patient benefit, i.e., debridement, treatment, healing, prevention or amelioration of the relevant medical condition, or an increase in rate of treatment, healing, prevention or amelioration of such conditions. When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously.

The amount of the present invention which will be effective in the treatment of a particular disorder or condition will depend on the nature of the disorder or condition, and may be determined by standard clinical techniques by those of average skill within the art. In addition, in vitro assays may optionally be employed to help identify optimal dosage ranges that is related to the nature of the debriding compound and the factors influencing the ultrasound technology. The precise dose to be employed in the formulation will also depend on the overall severity of the disease or disorder, and should be decided according to the judgment of the practitioner and each patient's circumstances.

The duration and intensity of treatment and the distance between the probe and the target eschar according to the present invention may also vary, depending on the nature and severity of the skin condition being treated and the condition and potential idiosyncratic response of each individual patient.

Examples of wounds which may optionally be treated with the present invention include acute wounds, particularly abrasion wounds and wounds with foreign matter or particles (such as may be obtained from scraping the skin along a surface such as a road, as for a biking or motorcycling accident for example), surgical or traumatic necrotic flaps or tissues and wounds characterized by necrosis; and chronic wounds, which are described in greater detail with regard to the Example below.

Acute wounds are characterized by freshly devitalized tissue (fresh eschar) that preserves the tissue's original moisture and some of the gross morphological structure. Such an eschar may be changed by physical (heat, or desiccation) or chemical (application of basic material, SSD (SilverSulfaDiazine), or iodine factors. Such changes may lead to a "mummified" eschar, typical of the chronic wound's eschar, that may resist the action of debriding agents. The surrounding tissues are in most cases rather intact or even if injured, may recover. Treatment of acute wounds is preferably performed as follows:

a. Care of the "healthy" wound edges:

The surrounding tissue is healthy and not affected by the debridement such that special protection is not needed. Debridase can be applied freely to these tissues.

b. Debridement of the eschar (necrotic dead tissue)

The fresh moist eschar, once cleaned of the superficial keratin layer, may dissolve after the application of hydrated Debridase, but may also be treated with the combination of the present invention. Stubborn eschars may be treated initially with hydrated Debridase followed by treatment with the present invention, and/or may be treated more than once with the present invention with good results.

c. Cleaning deposits (pus, fibrins) from the wound's bed

Acute wounds usually are not covered with adherent deposits thus foreign body deposits (i.e. dirt and gravel for example) can be removed easily. Some deposits such as the post-SSD treatment pseudoeschar may behave in a similar way as the chronic wound deposits and may need a similar method for their debridement.

EXAMPLE 7 CHRONICWOUND TREATMENT The treatment of chronic wounds is an increasingly difficult medical problem.

These wounds may be characterized by the presence of dry eschar, which prevents the wound from healing and increases the difficulty of treatment. Secondary damage of the tissue surrounding the wound. and in the wound bed is a complicating factor in the treatment of such wounds. Chronic wounds are a characteristic of and/or associated with many different medical conditions, including reduced circulation in the extremities, pressure, diabetes, old age, trauma, surgery, drug-related extravasations and others. Examples of chronic wounds include but are not limited to, skin ulcers '(including those associated with diabetes, such as diabetic foot ulcers), venous or arterial ulcers, pressure sores such as bedsores for example, post-surgical wounds and wounds associated with trauma which have become chronic.

Frequently the process of chronic wound formation and changes to the wound thereof are at least exacerbated by attempts to treat the wound. For example, the application of topical medicaments including but not limited to, iodine compounds, SSD, other silver compounds, oils, minerals or vegetable essences for example, or the application of physical agents including but not limited to, dry or wet heat, desiccation, or hypertonic solutions for example, can at least exacerbate the changes to a wound which occur as an initially acute wound becomes chronic. Fresh eschar of an acute wound that has been changed by physical or chemical factors and became "mummified" is altered to become to all practical considerations chronic wound eschar.

Chronic wound eschar may vary greatly and each may present a different diagnostic and treatment entity altogether. The non surgical debridement of such a heterogeneous group of eschars is preferably performed according to a complex and preferably multi-path treatment algorithm, as described in greater detail below.

a. Care of the "healthy" wound edges: The surrounding tissue may be unhealthy, for example due to previous trauma, diabetes, and/or peripheral vascular disease: venous or arterial, with decreased resistance to any additional insult. Protection of these edges is mandatory. The present debridase formulation with the use of a petroleum jelly adhesive barrier that is part of the Debridase's occlusive dressing formulation is adequate for the basic protection of the edges, although special care should be made to ensure that the barrier covers the susceptible tissues.

b. Debridement of the eschar (necrotic dead tissue)

The old "mummified" inert eschar has been transformed by time, physical and/or chemical factors and in many cases is still covered by the original adherent keratin layer; therefore, this chronic wound eschar is much less prone to being dissolved by enzymatic debriding agents. One approach is debridement that starts from the edges of the wound, slowly separating the entire eschar from its bed. This "peripheral debridement" method is effective but is also slow and is preferably performed, for example due to the length or number of applications, with protection of the edges of the wound. A central dissolution of the entire eschar (or a significant portion thereof) through its surface optionally and preferably features several additional conditions, including but not limited to, moisturizing the desiccated eschar; loosening the eschar, which may be compact with a dense or hard consistency; and removing the isolating surface keratin or introducing the enzyme into the eschar through the keratin. In order to reach these goals, Debridase (as a non-limiting example of a debriding agent) is preferably used in combination with (preferably low-frequency) ultrasound as previously described. More preferably, the method of treatment is calibrated according to the characteristic(s) of the wound. Cleaning deposits (pus, fibrins) from the bed of a chronic wound is preferably performed according to such a method. Chronic wounds may be covered with adherent deposits such as pus, fibrin, macerated necrotic tissue or post SSD-treatment pseudoeschar. These deposits and/or eschars are preferably removed in order to prepare the wound bed properly . However, the characteristics of these materials may be quite different, as some may be dissolved and debrided readily by a simple application of Debridase, while others may be more resistant and may therefore require application of the combination of ultrasound and Debridase according to the present invention.

The deeper portion of a wound bed and/or the bed of a deep wound may optionally and preferably receive special protection. A normal wound bed may be able to withstand harsher treatments; however, the bed of a chronic wound, particularly the deeper portion of such a bed and/or the bed of a deep wound, may be more sensitive. Chronic wound beds often feature less healthy or unhealthy surrounding tissue which may also be more sensitive. Therefore, preferably treatment with the present invention is calibrated to the characteristics of the chronic wound, particularly with regard to the wound bed. Such calibration may optionally include adjusting the total effective energy of the ultrasound radiation, by adjusting the output ultrasound energy and/or distance of the ultrasound probe from the wound, preferably also including selection of an appropriate acoustic medium, which is more preferably Debridase gel. Although Debridase gel results in a reduction in intensity of the ultrasound energy and hence in the total effective energy, such a reduction may be protective of the more delicate tissue in and/or around the wound. Another characteristic for calibration is preferably length of time of treatment.

According to preferred embodiments of the present invention, a chronic wound is preferably treated as follows. The wound is preferably first mechanically cleaned and soaked, for example with saline in the presence or absence of antiseptics, hydrogels and so forth. More preferably, such pretreatment results in removing superficial keratin if possible.

Next, preferably a Debridase solution (solution of a debriding agent), more preferably Debridase gel is applied to the wound until its efficacy is exhausted. A further mechanical cleaning and soaking process is preferably then performed.

The present invention is then preferably applied to any non-debrided areas, as a combination of Debridase (debriding agent, solution or gel) and ultrasound energy. As previously described, more preferably one or more, and most preferably all of the following factors are considered in determining this process: selection of Debridase medium (for example a gel may optionally be selected as a protective measure for reducing ultrasound intensity); total effective energy (distance of the ultrasound probe or other device and/or output energy of the probe); and time (length) of treatment. Also more preferably, some type of protection may optionally be applied to the edge's of the wound, for example with a cream such as petroleum jelly or some other type of barrier, as previously described.

Optionally, a further mechanical cleaning and soaking process is performed after debridement, for example in order to further remove eschar and also in order to further clean the wound. The frequency of application of the above treatment process is preferably determined according to the characteristic(s) of the wound, for example by medical personnel.

Without wishing to be limited by a single hypothesis, it would appear that the combination of Debridase and ultrasound energy both removes eschar and other material from the wound, and also hydrates the tissue of the wound. Such hydration may assist in removal of eschar and other material while reducing or even eliminating damage to surrounding tissue, again without wishing to be limited by a single hypothesis.

Other Embodiments

It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

What is claimed is:

1. A system for debridement of skin, comprising:

(a) a device comprising an ultrasound source and a container coupled to said ultrasound source, said container being adapted to be placed over an area of skin to be debrided, said container containing an acoustic medium for enabling said area of skin to be debrided to be exposed to ultrasonic radiation from said ultrasound source; and

(b) a debriding composition for being in contact at least temporarily with said area of skin to be debrided.

2. The system of claim 1, wherein said acoustic medium includes said debriding composition.

3. The system of claim 2, wherein said container further comprises an opening for enabling said debriding composition to contact said area of skin to be debrided.

4. The system of claim 3 , wherein said container further comprises a peripheral seal for sealing said opening against said area of skin to be debrided.

5. The system of claim 3, further comprising an inlet in said container for inserting said debriding composition.

6. The system of claim 5, further comprising an outlet in said container for removing said debriding composition.

7. The system of claim 5, further comprising an outlet in said container for creating a vacuum for sealing said opening against said area of skin.

8. The system of claim 1, wherein said container further comprises an opening for being placed against said area of skin to be debrided, and also further comprises an inlet, such that said debriding composition may be inserted into said container before, during or after treatment with said ultrasonic radiation.

9. The system of claim 8, wherein said container further comprises an outlet for removing at least one of said acoustic medium and said debriding composition.

10. The system of claim 8, wherein said container further comprises a peripheral seal for sealing said opening against said area of skin to be debrided.

11. The system of claim 1, wherein said ultrasound source comprises a piezoelectric ultrasound source unit.

12. The system of claim 1, wherein said device further comprises a spacer for maintaining said ultrasound source at a distance from said skin to be debrided.

13. The system of claim 12, wherein said spacer is combined with said container.

14. The system of claim 1, wherein said debriding composition comprises at least one of a chemical debriding agent and an enzymatic debriding agent.

15. The system of claim 14, wherein said debriding composition further comprises at least one of a liquid and a semi-solid carrier.

16. The system of claim 14, wherein said debriding composition further comprises a stabilizer.

17. The system of claim 14, wherein said debriding composition comprises a vegetable preparation.

18. The system of claim 17, wherein said vegetable preparation comprises a bromelain derivative.

19. The system of claim 18, wherein said bromelain derivative comprises Debridase.

20. The system of claim 1, wherein said ultrasound source is maintained at a calibrated distance from the skin.

21. The system of claim 1, wherein a total effective energy of said ultrasound source is determined for debriding the skin.

22. The system of claim 21, wherein said total effective energy is determined according to at least one of a distance of said ultrasound source from the skin, energy output of said ultrasound source or a characteristic of said acoustic medium, or a combination thereof.

23. The system of claim 22, wherein said acoustic medium comprises a gel formulation.

24. The system of claims 22 or 23, wherein said acoustic medium comprises said debriding composition.

25. A device for combined debridement of skin with a debriding composition for being in contact at least temporarily with an area of skin to be debrided, comprising:

(a) an ultrasound source; and

(b) a container coupled to said ultrasound source without interfering with operation of said ultrasound device, said container being adapted to be placed over the area of skin to be debrided, said container containing an acoustic medium for enabling the area of skin to be debrided to be exposed to ultrasonic radiation from said ultrasound source; wherein treatment of the area of skin to be debrided is performed through a combination of an effect of said ultrasonic radiation and an effect of the debriding composition.

26. The device of claim 25, wherein said acoustic medium includes said debriding composition.

27. The device of claim 26, wherein said container further comprises an opening for enabling said debriding composition to contact said area of skin to be debrided.

28. The device of claim 27, wherein said container further comprises a peripheral seal for sealing said opening against said area of skin to be debrided.

29. The device of claim 27, further comprising an inlet in said container for inserting said debriding composition.

30. The device of claim 29, further comprising an outlet in said container for removing said debriding composition.

31. The device of claim 29, further comprising an outlet in said container for creating a vacuum for sealing said opening against said area of skin.

32. The device of claim 25, wherein said container further comprises an opening for being placed against said area of skin to be debrided, and also further comprises an inlet, such that said debriding composition may be inserted into said container before, during or after treatment with said ultrasonic radiation.

33. The device of claim 32, wherein said container further comprises an outlet for removing at least one of said acoustic medium and said debriding composition.

34. The device of claim 32, wherein said container further comprises a peripheral seal for sealing said opening against said area of skin to be debrided.

35. The device of claim 25, wherein said ultrasound source comprises a piezoelectric ultrasound source unit.

36. The device of claim 25, wherein said device further comprises a spacer for maintaining said ultrasound source at a distance from said skin to be debrided.

37. The device of claim 36, wherein said spacer is combined with said container.

38. The device of claims 36 or 37, wherein said distance is determined according to a total effective energy for being delivered to the skin.

39. The device of claim 38, wherein said total effective energy is further determined according to at least one of energy output of said ultrasound source or a characteristic of said acoustic medium, or a combination thereof.

40. A method for treating an area of skin to be debrided, comprising: contacting the area of skin with a debriding composition; and applying ultrasonic radiation to the area of skin; wherein said contacting and said applying are performed in any order.

41. The method of claim 40, wherein said applying and said contacting are performed concurrently.

42. The method of claim 40, wherein said applying is performed before said contacting.

43. The method of claim 40, wherein said contacting is performed before said applying.

44. The method of claim 40, wherein said debriding composition comprises at least one of a chemical debriding agent and an enzymatic debriding agent.

45. The method of claim 44, wherein said debriding composition further comprises at least one of a liquid and a semi-solid carrier.

46. The method of claim 44, wherein said debriding composition further comprises a stabilizer.

47. The method of claim 44, wherein said debriding composition comprises a vegetable preparation.

48. The method of claim 47, wherein said vegetable preparation comprises a bromelain derivative.

49. The method of claim 48, wherein said bromelain derivative comprises Debridase.

50. A system for debridement of skin, comprising:

(a) a device comprising an ultrasound source and an acoustic medium for enabling an area of skin to be debrided to be exposed to ultrasonic radiation from said ultrasound source, wherein said ultrasound source is placed in contact with said acoustic medium manually; and

51. The system of claim 50, wherein said acoustic medium includes said debriding composition.

52. The system of claim 50, wherein said debriding composition comprises at least one of a chemical debriding agent and an enzymatic debriding agent.

53. The system of claim 52, wherein said debriding composition further comprises at least one of a liquid and a semi-solid carrier.

54. The system of claim 53, wherein said debriding composition further comprises a stabilizer.

55. The system of claim 50, wherein said debriding composition comprises a vegetable preparation.

56. The system of claim 55, wherein said vegetable preparation comprises a bromelain derivative.

57. The system of claim 56, wherein said bromelain derivative comprises Debridase.

58. A method for treating an area of skin to be debrided, comprising: applying a debriding composition to the area of skin; and applying ultrasound energy to the area of skin.

59. The method of claim 58, wherein said debriding composition forms an acoustic medium for said ultrasound energy.

60. The method of claim 59, wherein said ultrasound energy is calibrated according to at least one of a distance of said ultrasound source from the skin, energy output of said ultrasound source or a characteristic of said acoustic medium, or a combination thereof.

61. The method of claim 60, wherein said acoustic medium comprises a gel formulation.

62. The method of either of claims 60 or 61, wherein said ultrasound energy is at least partially calibrated according to a time period for treatment.

63. The method of any of claims 60-62, wherein said ultrasound energy is calibrated according to at least one characteristic of the area of skin.

64. The method of claim 63, wherein the area of skin comprises a wound, and said ultrasound energy is calibrated according to at least one characteristic of said wound.

65. The method of claim 64, wherein said wound comprises an acute wound, a chronic wound or a wound featuring chronic wound eschar.

66. The method of claim 65, wherein said acute wound comprises an abrasion wound, a wound with foreign matter, surgically or a traumatically injured tissue or flap, or a combination thereof.

67. The method of claim 65, wherein said wound featuring chronic wound eschar also features necrotic tissue.

68. The method of claim 65, wherein said chronic wound comprises a wound associated with reduced circulation in the extremities, diabetes, old age, a skin ulcer, a venous or arterial ulcer, a pressure sore, a post-surgical wound or a wound associated with trauma that has become chronic, or a combination thereof.

69. The method of any of claims 58-68, wherein before applying said debriding composition to the area of skin, the method further comprises: mechanically cleaning the area of skin.

70. The method of any of claims 58-69, further comprising: mechanically cleaning the area of skin after said applying said ultrasound energy.

71. The method of any of claims 58-70, further comprising: applying a protective barrier to an edge of the area of skin to be treated before said applying said ultrasound energy.