METHOD AND DEVICE TO PRESERVE ORGANS AND TISSUE FOR TRANSPLANTATION

Abstract

A method of treating a harvested organ or tissue for preservation for implantation into a patient has the steps of, harvesting an organ or tissue from a donor; placing the harvested organ or tissue into a container; filling the container with a fluid for preservation; sealing the container once filled; directing one or more sound wave treatments into the container to destroy bacteria or molds or fungi or virus and to stimulate the organ or tissue; and storing the container at a hypothermic temperature of about 4 degrees C. for storage prior to implantation.

Claims

1. A method of treating a harvested organ or tissue for preservation for implantation into a patient comprising the steps of: harvesting an organ or tissue from a donor; placing the harvested organ or tissue into a container; filling the container with a fluid for preservation; sealing the container once filled; directing one or more sound wave treatments into the container to destroy bacteria or molds or fungi or virus and to stimulate the organ or tissue; and storing the container at a hypothermic temperature of about 4 degrees C. for storage prior to implantation.

2. The method of claim 1, wherein the container is configured to transmit sound waves through the container to the preservation fluid and the organ or tissue contained therein.

3. The method of claim 2, wherein the container is a flexible bag.

4. The method of claim 1, wherein the step of directing the one or more sound wave treatments includes placing an acoustic shock wave or pressure pulse emitting applicator against an external surface of the container.

5. The method of claim 1, wherein prior to sealing the container a vacuum is generated or the fluid overfilled to remove any residual air.

6. The method of claim 5, wherein the container is a flexible bag and after sealing, secondarily sealing a perimeter of the bag to tension the bag and create a positive pressure inside the bag.

7. The method of claim 1, wherein the sound wave treatments cause an improved blood supply, a disruption of cellular membranes and a cellular communication causing the cells of the organ or tissue to identify and attack the bacteria or mold or fungi or virus and further causes recruiting or stimulating an increase in anti-microbial peptides.

8. The method of claim 1 further comprises the step of: administering medications into the container including, but not limited to anti-viral medications, antibiotics, anti-fungal medications or anti-mold medications, wherein the sound wave treatment extends the useful life of the medications.

9. The method of claim 3 wherein the sound wave treatments increase the permeability of the organ or tissue cell membranes allowing an increase in releasing anti-microbial peptides and inflow of the medications into the cells while increasing the fluid and medications toward the bacteria or mold or fungi or virus.

10. The method of claim 8 wherein the sound wave treatment is provided either prior to, during or after administering medications or any combination thereof.

11. The method of claim 10 wherein an infection's resistance to medications is reduced by the sound wave treatments.

12. The method of claim 11 wherein the fluid preservative and medication's effectiveness against the infection is enhanced by the sound wave treatments.

13. The method of claim 8 wherein the dosages or strength of the medications can be reduced when used in combination with the sound wave treatments.

14. The method of claim 1 wherein the sound waves are acoustic shock waves or pressure pulses.

15. The method of claim 14 wherein the acoustic shock waves are focused or non-focused, convergent, divergent, planar or nearly planar, radial or spherical, shaped or otherwise reflected.

16. The method of claim 1 wherein the sound wave treatments are emitted by a generator.

17. The method of claim 16 wherein the generator is one of a radial, a spherical, a ballistic, a linear, a piezoelectric, or an electrohydraulic generator.

18. The method of claim 1 wherein the sound wave treatments can be administered with or without cavitation.

19. The method of claim 1 wherein the sound wave treatments can be administered with or without some cellular destruction and with or without a sensation of pain.

20. A method of treating an organ or tissue for transplantation with one or more infections of a microbial or viral source, the infections causing at least localized inflammation, the method comprises the steps of: harvesting an organ or tissue from a donor; locating a region or location of the infection; activating a pressure pulse or acoustic shock wave generating source; and emitting pressure pulses or acoustic shock waves and directing the pressure pulses or acoustic shock waves to impinge the inflammation directly or by indirectly impinging the organ or tissue to destroy, fracture, fragment or otherwise open the microbial or viral source to eradicate the source and reduce the inflammation; placing the harvested organ or tissue into a container; filling the container with a fluid for preservation; sealing the container once filled; directing one or more sound wave treatments into the container to destroy bacteria or molds or fungi or virus and to stimulate the organ or tissue; and storing the container at a hypothermic temperature of about 4 degrees C. for storage prior to implantation.

21. The method of claim 20 further comprises the step of: administering one or more drugs, antibiotics or other medication to the organ or tissue.

22. The method of treatment of claim 20 wherein the emitted pressure pulses or acoustic shock waves are convergent having one or more geometric focal volumes of points at a distance of at least X from the generator or source, the method further comprising positioning the organ at a distance at or less than the distance X from the source.

23. The method of treatment of claim 20 further comprises the step of: subjecting a tissue or organ to a surgical procedure to remove some or all of an infection growth.

24. The method of claim 20 wherein the sound waves are acoustic shock waves or pressure pulses.

25. The method of claim 24 wherein the acoustic shock waves are focused or non-focused, convergent, divergent, planar or nearly planar, radial or spherical, shaped or otherwise reflected.

26. The method of claim 20 wherein the sound wave treatments are emitted by a generator.

27. The method of claim 20, wherein prior to sealing the container a vacuum is generated or the fluid overfilled to remove any residual air.

28. The method of claim 27, wherein the container is a flexible bag and after sealing, secondarily sealing a perimeter of the bag to tension the bag and create a positive pressure inside the bag.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0042] The invention will be described by way of example and with reference to the accompanying drawings in which:

[0043] FIG. 1 is a simplified depiction of a pressure pulse/shock wave (PP/SW) generator with focusing wave characteristics.

[0044] FIG. 2 is a simplified depiction of a pressure pulse/shock wave generator with plane wave characteristics.

[0045] FIG. 3 is a simplified depiction of a pressure pulse/shock wave generator with divergent wave characteristics.

[0046] FIG. 4 is a perspective view of a shock wave generator device.

[0047] FIG. 5A is a perspective view of a heart being treated with a shock wave or pressure pulse applicator.

[0048] FIG. 5B is a perspective view of a heart in a container being treated with a shock wave or pressure pulse applicator.

[0049] FIG. 6A is a perspective view of a liver being treated with a shock wave or pressure pulse applicator.

[0050] FIG. 6B is a perspective view of a liver in a container being treated with a shock wave or pressure pulse applicator.

[0051] FIG. 7A is a perspective view of a kidney being treated with a shock wave or pressure pulse applicator.

[0052] FIG. 7B is a perspective view of a kidney in a container being treated with a shock wave or pressure pulse applicator.

[0053] FIG. 8 is a graph showing an exemplary ultrasound wave pattern.

[0054] FIG. 9 is a graph showing an exemplary sound wave pattern.

DETAILED DESCRIPTION OF THE INVENTION

[0055] In the extracorporeal shock wave or pressure pulse method of treating an organ or tissue, the administered shock waves or pressure pulses are directed to a treatment location or target site on the organ or tissue. In this invention, the term target site refers to either a location near the source of the infection, typically on a surface of the organ or tissue. As used herein, “near” recognizes that the emitted shock waves or pressure pulses are transmitted through the organ or tissue, preferably at or in close proximity to the treatment location or site.

[0056] The sound wave treatment can be applied directly to harvested organs or tissue. The fluids being preservative solutions that enhance duration times between harvesting and implantation. These fluids ideally protect the organ or tissue, but also suppress bacterial, viral and other contaminants that can adversely increase the risk of the implanted organ or tissue being rejected.

[0057] The organ or tissue, after being harvested, is placed in a convenient orientation to permit the source of the emitted waves to most directly send the waves to the target site to initiate shock wave stimulation of the target area. Assuming the target area is within a projected area of the wave transmission, a single transmission dosage of wave energy may be used. The transmission dosage can be from a few seconds to 20 minutes or more dependent on the condition. Preferably the waves are generated from an unfocused or focused source. The unfocused waves can be divergent or near planar and having a low-pressure amplitude and density in the range of 0.00001 mJ/mm.sup.2 to 1.0 mJ/mm.sup.2 or less, most typically below 0.2 mJ/mm.sup.2. These are typically generated by spherical or radial wave generators, ballistic or electrohydraulic wave or piezoelectric shock wave generators. The focused source can use a focused beam of waves or can optionally use a diffusing lens or have a far-sight focus to minimize if not eliminate having the localized focus zone within the organ or tissue. Preferably the focused shock waves are used at a similarly effective low energy transmission or alternatively can be at higher energy but wherein the organ or tissue target site is disposed pre-convergence inward of the geometric focal point of the emitted wave transmission. Understanding the higher the energy used, the more sensation of bruising the organ or tissue. In these cases, cavitation can and often does occur as well as bruising and come cell damage. This is preferably and easily avoidable.

[0058] These shock wave energy transmissions are effective in stimulating a cellular response and in some cases, such as unfocused low energy, and even low energy focused emissions can be accomplished without creating the localized hemorrhaging caused by rupturing cavitation bubbles in the organ or tissue of the target site. This effectively ensures the harvested organ or tissue does not have to experience the sensation of cellular damage so common in the higher energy focused wave forms having a focal point at or within the targeted treatment site. Higher energy acoustic shock waves or pressure pulses including focused waves can be used, but with care to avoid such damage.

[0059] The target site may be such that the organ or tissue or the generating source must be reoriented relative to the site and a second, third or more treatment dosage can be administered. At a low energy, the common problem of localized hemorrhaging is reduced making it more practical to administer multiple dosages of waves from various orientations to further optimize the treatment and cellular stimulation of the target site. Alternatively, focused high energy multiple treatments can be equally effective, but with some risk to organ or tissue bruising. The use of low energy focused or unfocused waves at the target site enables multiple sequential treatments. Alternatively, the wave source generators may be deployed in an array wherein the subject organ or tissue is effectively enveloped or surrounded by a plurality of low energy wave source generators which can be simultaneously bombarding the target site from multiple directions. Such arrays include linear type devices.

[0060] The goal in such treatments is to provide 100 to 3000 acoustic shock waves or pressure pulses. Typically, at a voltage of 14 kV to 28 kV across a spark gap generator in a single treatment preferably or one or more adjuvant treatments by targeting the site directly by impinging the emitted waves toward the infection or indirectly on the desired harvested organ or tissue.

[0061] The present method, in many cases, does not rely on precise site location per se. The physician's general understanding of the anatomy of the organ or tissue should be sufficient to locate a desirable direct path or to the target site to attack the infection be treated. The treated area can withstand a far greater number of shock waves based on the selected energy level being emitted. For example, at very low energy levels the stimulation exposure can be provided over prolonged periods as much as 20 minutes if so desired. At higher energy levels the treatment duration can be shortened to less than a minute, less than a second if so desired. The selected treatment dosage can include the avoidance or minimization of cell hemorrhaging and other kinds of damage to the cells or tissue while still providing a stimulating cellular release activation of upregulation of the antimicrobial peptide LL37, a protein that can bind with RNA to destroy the infection, and also vascular endothelial growth factor (VEGF) and other growth factors and can also be used to modulate and regulate hormonal secretions from a specific targeted gland by emitting waves to a desired direct path.

[0062] A key advantage of the present inventive methodology is that it is complimentary to conventional medical procedures to harvest organs or tissue. In the case of any other procedure, the area of the harvested organ or tissue can be post operatively bombarded with sound waves to stimulate cellular release of healing agents and growth factors. Most preferably one ESWT treatment is used with an intervening dwell time for cellular relaxation prior to secondary and tertiary treatments.

[0063] The underlying principle of these sound wave therapy methods is to stimulate the harvested organ or tissue. This is accomplished by deploying shock waves to stimulate strong cells in the tissue to activate a variety of responses, more particularly those that reduce inflammation and stop the infection. The sound waves including acoustic shock waves or pressure pulses transmit or trigger what appears to be a cellular communication throughout the entire anatomical structure of the harvested organ or tissue, this activates a generalized cellular response at the treatment or target site, in particular, but more interestingly a systemic response in areas more removed from the wave form pattern. This is believed to be one of the reasons molecular stimulation can be conducted at threshold energies heretofore believed to be well below those commonly accepted as required. Accordingly, not only can the energy intensity be reduced but also the number of applied shock wave impulses can be lowered from several thousand to as few as one or more pulses and still yield a beneficial stimulating response if desired.

[0064] The biological model motivated the design of sources with low pressure amplitudes and energy densities. First: spherical waves generated between two tips of an electrode; and second: nearly even waves generated by generated by generalized parabolic reflectors. Third: divergent shock front characteristics are generated by an ellipsoid. Unfocused sources are preferably designed for extended two dimensional areas/volumes like skin. The unfocused sources can provide a divergent wave pattern or a nearly planar wave pattern and can be used in isolation or in combination with focused wave patterns yielding to an improved therapeutic treatment capability that is noninvasive with few if any disadvantageous contraindications. Alternatively, a focused wave emitting treatment may be used wherein the focal point extends to the target site. In any event, the beam of acoustic waves transmitted needs to project in a large enough zone or area to stimulate or modulate the cells near the infection.

[0065] In one embodiment, the method of treatment has the steps of, generating either focused shock waves or unfocused shock waves, of directing these shock waves to the treatment site; and applying a sufficient number of these shock waves to induce activation of one or more growth factor or anti-microbial peptides like LL37, thereby inducing or accelerating a modulated adjustment to induce the host cells to attack the infection when the treated harvested organ or tissue is implanted.

[0066] The shock waves can be of a low peak pressure amplitude and density. Typically, the energy density values range as low as 0.000001 mJ/mm.sup.2 and having a high end energy density of below 1.0 mJ/mm.sup.2, preferably 0.40 mJ/mm.sup.2 or less, more preferably 0.20 mJ/mm.sup.2 or less. The peak pressure amplitude of the positive part of the cycle should be above 1.0 and its duration is below 1-3 micro-seconds.

[0067] The treatment depth can vary from the surface to the full depth of the harvested organ or tissue and the treatment site can be defined by a much larger treatment area. The above methodology is particularly well suited for surface as well as sub-surface soft tissue treatments in harvested organs or tissue.

[0068] An exemplary treatment protocol could have emitted shock waves in a broad range of 0.01 mJ/mm.sup.2 to 3.0 mJ/mm.sup.2 and 200-2500 pulses per treatment with a treatment schedule of 1-3 treatments being repeated during preservation and storage as a preventative prior to implantation.

[0069] The following invention description first provides a detailed explanation of acoustic shock waves or pressure pulses, as illustrated in FIGS. 1-9. As used herein and shown in FIG. 9, an acoustic shock wave is an asymmetric wave with an exceptionally rapid peak rise time and slower return time from the peak amplitude. Historically, these acoustic shock waves or pressure pulses were first used medically to destroy kidney stones. The wave patterns were directed to a focal point at a relatively high energy to blast the concrements into small urinary tract passable fragments.

[0070] A whole class of acoustic shock waves or pressure pulses for medical treatments were later discovered that employed low energy acoustic shock waves or pressure pulses. These low energy acoustic shock waves or pressure pulses maintained the asymmetric wave profile, but at much lower energies.

[0071] These low energy acoustic shock waves or pressure pulses advantageously could stimulate a substance without requiring a focused beam. The advantage of such an unfocused beam was the acoustic wave could be directed to pass through tissue without causing any cell rupturing which would be evidenced by a lack of a hematoma or bruising. This use of unfocused, low energy acoustic shock waves or pressure pulses provided an ability to treat a large volume of tissue virtually painlessly. Furthermore, the acoustic energy caused a short duration anesthetic sensation that effectively numbs the patient's pain over a period of days with a prolonged reduction in pain thereafter.

[0072] The use of low energy acoustic shock waves or pressure pulses that employ a focused beam has been spurred on as a viable alternative to the unfocused low energy shock waves because the focal point being of a small zone of energy has little or a small region of cell damage as the remaining portions of the wave pattern can provide a stimulating effect similar to the unfocused shock waves. Basically, the effect is the same with the users of focused waves achieving the benefits of the unfocused waves, but with a focal point of peak energy in a tiny localised region. So, for purposes of the present invention, the use of “soft waves” those defined by low energy beams will be applicable to both focused and unfocused beams of acoustic shock waves or pressure pulses.

[0073] The asymmetric acoustic wave pattern shown in FIG. 9 is contrasted to an ultrasonic wave pattern which is illustrated in FIG. 8. As shown, ultrasound waves are symmetrical having the positive rise time equal to the negative in a sinusoidal wave form. These ultrasound waves generate heat in the tissue and are accordingly believed not suitable for use on harvested organs or tissue.

[0074] With reference to FIGS. 1-3, a variety of schematic views of acoustic shock waves or pressure pulses are described. The following description of the proper amplitude and pressure pulse intensities of the shock waves 200 are provided below along with a description of how the shock waves actually function and have been taken from the co-pending application of the present inventors and replicated herein as described below. For the purpose of describing the shock waves 200 were used as exemplary and are intended to include all of the wave patterns discussed in the figures as possible treatment patterns.

[0075] FIG. 1 is a simplified depiction of a pressure pulse/shock wave (PP/SW) generator, such as a shock wave head, showing focusing characteristics of transmitted acoustic pressure pulses. Numeral 1 indicates the position of a generalized pressure pulse generator, which generates the pressure pulse and, via a focusing element, focuses it outside the housing to treat diseases. The affected infected tissue or organ is generally located in or near the focal point which is located in or near position 6. At position 17 a water cushion or any other kind of exit window for the acoustical energy is located.

[0076] FIG. 2 is a simplified depiction of a pressure pulse/shock wave generator, such as a shock wave head, with plane wave characteristics. Numeral 1 indicates the position of a pressure pulse generator according to the present invention, which generates a pressure pulse which is leaving the housing at the position 17, which may be a water cushion or any other kind of exit window. Somewhat even (also referred to herein as “disturbed”) wave characteristics can be generated, in case a paraboloid is used as a reflecting element, with a zone source (e.g. electrode) that is located in the focal point of the paraboloid. The waves 200 can be transmitted into harvested organs or tissue via a coupling media such as, e.g., ultrasound gel or oil and their amplitudes will be attenuated with increasing distance from the exit window 17.

[0077] FIG. 3 is a simplified depiction of a pressure pulse shock wave generator (shock wave head) with divergent wave characteristics. The divergent wave fronts may be leaving the exit window 17 at zone 11 where the amplitude of the wave front is very high. This zone 17 could be regarded as the source zone for the pressure pulses. In FIG. 1c the pressure pulse source may be a zone source infected, that is, the pressure pulse may be generated by an electrical discharge of an electrode under water between electrode tips. However, the pressure pulse may also be generated, for example, by an explosion, referred to as a ballistic pressure pulse. The divergent characteristics of the wave front may be a consequence of the mechanical setup. The source can include radial or spherical wave generators, or linear arrays of wave generators.

[0078] This apparatus, in certain embodiments, may be adjusted/modified/or the complete shock wave head or part of it may be exchanged so that the desired and/or optimal acoustic profile such as one having wave fronts with focused, planar, nearly plane, convergent or divergent characteristics can be chosen.

[0079] A change of the wave front characteristics may, for example, be achieved by changing the distance of the exit acoustic window relative to the reflector, by changing the reflector geometry, by introducing certain lenses or by removing elements such as lenses that modify the waves produced by a pressure pulse/shock wave generating element. Exemplary pressure pulse/shock wave sources that can, for example, be exchanged for each other to allow an apparatus to generate waves having different wave front characteristics are described in detail below.

[0080] In one embodiment, mechanical elements that are exchanged to achieve a change in wave front characteristics include the primary pressure pulse generating element, the focusing element, the reflecting element, the housing and the membrane. In another embodiment, the mechanical elements further include a closed fluid volume within the housing in which the pressure pulse is formed and transmitted through the exit window.

[0081] In one embodiment, the apparatus of the present invention is used in combination therapy. Here, the characteristics of waves emitted by the apparatus are switched from, for example, focused to divergent or from divergent with lower energy density to divergent with higher energy density. Thus, effects of a pressure pulse treatment can be optimized by using waves having different characteristics and/or energy densities, respectively.

[0082] While the above described universal toolbox of the various types of acoustic shock waves or pressure pulses and types of shock wave generating heads provides versatility, the person skilled in the art will appreciate that apparatuses that produce acoustic shock waves or pressure pulses having, for one example, nearly plane characteristics, are less mechanically demanding and fulfil the requirements of many users.

[0083] As the person skilled in the art will also appreciate that embodiments shown in the drawings are independent of the generation principle and thus are valid for not only electro-hydraulic shock wave generation but also for, but not limited to, PP/SW generation based on electromagnetic, piezoceramic and ballistic principles. The pressure pulse generators may, in certain embodiments, be equipped with a water cushion that houses water which defines the path of pressure pulse waves that is, through which those waves are transmitted. In a preferred embodiment, the organ or tissue directly or the fluid filled container holding these harvested organs or tissue is coupled via ultrasound gel or oil to the acoustic exit window (17), which can, for example, be an acoustic transparent membrane, a water cushion, a plastic plate or a metal plate.

[0084] In the pressure pulse or shock wave method of treating an infection within a harvested tissue or organ with a risk of exposure to an infection or post-occurrence of such infections requires the harvested tissue or organ to be positioned in a convenient orientation to permit the source of the emitted waves to most directly send the waves to the target site to initiate pressure pulse or shock wave stimulation of the target area with minimal, preferably no obstructing features in the path of the emitting source or lens other than the fluid filled container holding the organ or tissue. Assuming the infection target area or site is within a projected area of the wave transmission, a single transmission dosage of wave energy may be used. The transmission dosage can be from a few seconds to 20 minutes or more dependent on the condition. Preferably the waves are generated from an unfocused or focused source. The unfocused waves can be divergent, planar or near planar and having a low pressure amplitude and density in the range of 0.00001 mJ/mm.sup.2 to 1.0 mJ/mm.sup.2 or less, most typically below 0.2 mJ/mm.sup.2. The focused source preferably can use a diffusing lens or have a far-sight focus to minimize if not eliminate having the localized focus point within the tissue. Preferably the focused shock waves are used at a similarly effective low energy transmission or alternatively can be at higher energy but wherein the tissue target site is disposed pre-convergence inward of the geometric focal point of the emitted wave transmission. In treating some hard to penetrate infections, the pressure pulse more preferably is a high energy target focused wave pattern which can effectively attack the infection outer structure or barrier shield causing fractures or openings to be created to expose the colonies of microorganisms within the infection to the germicidal effects of the pressure pulses or shock waves. This emitted energy destroys the underlying microorganism's cellular membranes. In addition, the fragmentation of the infections outer barrier is then easily germicidally killed out of the harvested material. The surrounding healthy cells in the region treated are activated initiating a defense mechanism response to assist in eradication of any unwanted infection.

[0085] These shock wave energy transmissions are effective in stimulating a cellular response and can be accomplished without creating the cavitation bubbles in the tissue of the target site when employed in other than high energy focused transmissions. This effectively ensures the tissue or organ does not have to experience the sensation of hemorrhaging so common in the higher energy focused wave forms having a focal point at or within the targeted treatment site.

[0086] The limiting factor in the selected treatment dosage is to provide a stimulating stem cell activation or a cellular release or activation of the LL37 protein and VEGF and other growth factors while simultaneously germicidally attacking the infection barrier and any underlying colony of microorganisms.

[0087] The underlying principle of these pressure pulse or shock wave therapy methods is to attack the infection directly and to stimulate the harvested organ or tissue. This is accomplished by deploying shock waves to stimulate strong cells in the surrounding tissue to activate a variety of responses. The acoustic shock waves transmit or trigger what appears to be a cellular communication throughout the entire anatomical structure of the harvested organ or tissue, this activates a generalized cellular response at the treatment site, in particular, but more interestingly a systemic response in areas more removed from the wave form pattern. This is believed to be one of the reasons molecular stimulation can be conducted at threshold energies heretofore believed to be well below those commonly accepted as required. Accordingly, not only can the energy intensity be reduced in some cases, but also the number of applied shock wave impulses can be lowered from several thousand to as few as one or more pulses and still yield a beneficial stimulating response. The key is to provide at least a sufficient amount of energy to weaken the infections protective outer barrier or shield commonly found in biofilms. This weakening can be achieved by any fracture or opening that exposes the underlying colony of microorganisms.

[0088] The use of shock waves as described above achieved biological response within the cells and there appears to be a commonality in the fact that otherwise dormant cells within the tissue appear to be activated making the cell membranes more permeable to release anti-microbial peptides and absorb medications to attack infections which leads to the remarkable ability of the harvested organ or tissue to generate new growth or to regenerate weakened vascular networks increasing blood supply when implanted.

[0089] In one embodiment, the invention provides for germicidal cleaning of an infection, diseased or infected areas and for wound cleaning generally after exposure to surgical harvesting procedures.

[0090] The use of shock wave therapy requires a fundamental understanding of focused and unfocused shock waves, coupled with a more accurate biological or molecular model.

[0091] This means the physician can use these antibiotic treatments with far less adverse reactions if he combines the treatments with one or more exposures to acoustic shock waves either before introducing chemical antibiotic agents or shortly thereafter or both. This further means that the patient receiving the harvested organ or tissue has a recovery time that should be greatly reduced because the organ or tissue treated with shock waves will have initiated a healing response that is much more aggressive than heretofore achieved without the cellular stimulation provided by pressure pulse or shock wave treatments. The current use of medications to stimulate such cellular activity is limited to absorption through the bloodstream via the blood vessels. Acoustic shock waves stimulate all the cells in the region treated activating an almost immediate cellular release of infection fighting and healing agents. Furthermore, as the use of other wise conflicting chemicals is avoided, adverse side effects can be limited to those medicaments used to destroy the infectious cells. In other words, the present invention is far more complimentary to such antibiotic treatments in that the stimulation of otherwise healthy cells will greatly limit the adverse and irreversible effects on the surrounding non-infected tissues and organs.

[0092] A further benefit of the use of acoustic shock waves is there are no known adverse indications when combined with the use of other medications or drugs. In fact, the activation of the cells exposed to shock wave treatments only enhances cellular absorption of such medication making these drugs faster acting than when compared to non stimulated cells. As a result, it is envisioned that the use of one or more medicaments prior to, during or after subjecting the patient to acoustic shock waves will be complimentary to the treatment or pre-conditioning treatment for infection exposures. It is further appreciated that certain drug therapies can be altered or modified to lower risk or adverse side effects when combined with a treatment involving acoustic shock waves as described above.

[0093] FIG. 4 shows an exemplary shock wave device generator or source 1 with a control and power supply 41 connected to a hand-held applicator shock wave head 43 via a flexible hose 42 with fluid conduits. The illustrated shock wave applicator 43 has a flexible membrane at an end of the applicator 43 which transmits the acoustic waves when coupled to the external surface of the harvested organ or tissue or the fluid filled container holding this harvested material by using a fluid or acoustic gel. As shown, this type of applicator 43 has a hydraulic spark generator using either focused or unfocused shock waves, preferably in a low energy level, less than the range of 0.01 mJ/mm.sup.2 to 0.3 mJ/mm.sup.2. The flexible hose 42 is connected to a fluid supply that fills the applicator 43 and expands the flexible membrane when filled. Alternatively, a ballistic, piezoelectric or spherical acoustic shock wave device can be used to generate the desired waves.

[0094] In a preferred embodiment of the present invention, the container 50 is a flexible bag which is filled with the harvested organ or tissue and a preservative fluid. Once the flexible container 50 is filled, it is sealed while insuring all the residual air is displaced prior to sealing the bag 50. Thereafter, in a preferred embodiment, the filled sealed bag 50 has been tensioned by sealing a perimeter 52 around the filled bag 50. The secondary sealing of the bag 50 actually tensions the bag and provides a slight positive pressure inside the bag 50. This positive pressure helps drive the fluid into the harvested organ or tissue 100, as shown in FIG. 5B, the heart 100. Thereafter the shock wave applicator 43 is acoustically coupled to the bag 50 for transmission of the shock waves 200. The bag 50 can be turned to have the applicator 43 transmit to the opposite side of the bag 50. In this preferred embodiment, the harvested organ or tissue is protected by this tensioning of the flexible container 50. The organ or tissue is shielded from bruising by having the container 50 effectively pressured by the perimeter 52 tensioning the bag or container 50.

[0095] With reference to FIGS. 5A and 5B the organ 100 shown is a heart. In FIG. 5A a frontal view of the heart is shown wherein the frontal region is being bombarded with exemplary shock waves 200 wherein the shockwave applicator 43 is shown unobstructed to the tissue of the heart. The shockwave applicator 43 is connected through the cable 1 back to a control and power supply 41, as shown in FIG. 4. As illustrated the exemplary shock waves 200 emanate through the tissue of the heart 100 providing a beneficial regenerating and revascularization capability that heretofore was unachieved. The beneficial aspects of the present methodology are that the heart 100 as shown fully exposed in FIG. 5A is fully exposed such that the shock wave head 43 can be inserted therein and directed to contact or be in near contact to the heart tissue is such a way that the admitted exemplary shock waves 200 can most directly and in the most unobstructed way be transmitted to the heart. FIG. 5B shows the heart 100 being treated in a container 50 filled with preservative fluid 60.

[0096] With reference to FIG. 6A, the organ 100 is a liver. As shown, in addition to the liver 100, the stomach, spleen and duodenum are also shown. The shock wave applicator 43 is in contact with the liver 100 and is providing a therapeutic shock wave treatment as illustrated wherein the exemplary shock waves 200 are being transmitted through the tissue of the liver. It is believed that the use of such exemplary shock waves 200 can help in enhancing liver regeneration particularly those that have been degenerative and in conditions that might be prone to failure. Again, the harvested liver 100 is shown fully exposed such that the shock wave applicator 43 can provide a direct unobstructed path to deliver shockwave treatments to this organ as well. FIG. 6B shows the liver 100 being treated in a container 50 filled with preservative fluid 60. The container 50 is the same as described above and provides the added protection to the harvested liver 100.

[0097] In FIGS. 7A and 7B a kidney is shown as the organ 100 being treated. In this fashion the kidney similar to the liver or heart can be treated such that the shock wave applicator 43 can be in direct or near contact in an unobstructed path to admit shock waves 200 to this organ. This has the added benefit of generating maximum therapy to the harvested organ in such a way that the kidney can be stimulated more directly. Again, in each of these procedures as shown there is an invasive technique requiring the shock wave applicator 43 to enter the organ 100 which is fully exposed to the exemplary shock waves 200 as can either be accomplished by a surgical harvesting procedure or any other means that would permit entry of the shock wave applicator 43 to the harvested organ. FIG. 7B shows the kidney 100 being treated in a container 50 filled with preservative fluid 60 as was described above.

[0098] In each of the representative treatments as shown in FIGS. 5A-7B, the shock wave applicator 43 when used within a sterile sleeve or covering may simply be disinfected using a suitable antimicrobial disinfecting agent prior to use. Alternatively, the applicator 43 can be sterilized when used without a sterile sleeve. The sleeves or coverings, not shown, are preferably disposable and should be discarded after use. When treating any tissue or organ 100 the sterile sleeve holding the applicator 43 or in the case of using the applicator 43 without a sleeve the tissue contacting surface should be coupled acoustically by using known means such as sterile fluids or viscous gels like ultrasound gels or even NaCl solutions to couple the transmitted shock wave into the organ in an aseptic sterile fashion.

[0099] FIG. 8 is a graph depicting an exemplary ultrasound wave form or pattern. As shown, the ultrasonic wave pattern is a symmetrical uniform sinusoidal pattern. The positive and negative amplitudes are equal as is the rise time to peak pressure midway and the negative part of the wave. This ultrasound wave pattern exhibits heat generation and can be cell membrane damaging. Most importantly, absolutely heat destroys cells.

[0100] FIG. 9 is a graph depicting an exemplary sound wave form or pattern. In contrast to FIG. 8, the acoustic shock wave pattern is asymmetrical having a rapid rise to peak pressure followed by a slower negative portion. This acoustic wave has virtually no heat generation and can, when delivered at low energy pulses, pass through cell membranes with no cavitation effects.

[0101] In the figures, exemplary shock waves 200 are illustrated, it must be appreciated that any of the recognized shock wave patterns can be used in the shock wave treatment of the various harvested organs or tissues 100.

[0102] As illustrated, the device shown is an electrohydraulic acoustic shock wave generator, however, other devices that generate acoustic shock waves or pressure pulses can be used. Ultrasonic devices may be considered, but there is no data to support a sinusoidal wave form would work and therefore not considered as effective as the asymmetric wave generators. The acoustic shock waves or pressure pulses activate a cellular response within the reflexology treatment site. This response or stimulation causes an increase of nitric oxide and a release of a variety of growth factors such as VEGF and a release of anti-microbial peptides like LL37. As shown, the flexible membrane is protruding outward and the applicator 43 has been filled with fluid, the transmission or emission of acoustic shock waves or pressure pulses 200 is directed towards the organ 100.

[0103] The transmission of the shock waves 200 can be of a low energy density of 0.2 mJ/mm.sup.2 whether using focused or unfocused shock waves. The acoustic shock waves or pressure pulses pulse rapidly through the cells penetrating the cell membrane extremely rapidly due to the rapid rise to peak time and pass through exiting slower due to the slower return from peak amplitude. This asymmetric wave pattern rapidly compresses each cell on entry and slow decompresses the cell as it exits. This effective squeezing of each cell is believed to cause the release of growth factors such as VEGF and others and also creates nitric oxide, all beneficial to new blood vessel formation. This occurs as a transmission across the cell membranes without rupturing the native cells.

[0104] Furthermore, such acoustic shock wave forms can be used in combination with drugs, chemical treatments, irradiation therapy or even physical therapy and when so combined the stimulated cells will more rapidly assist the body's natural healing response and thus overcomes the otherwise potentially tissue damaging effects of these complimentary procedures.

[0105] The present invention provides an apparatus for an effective treatment of indications in harvested organs or tissues, which benefit from high or low energy pressure pulse/shock waves having focused or unfocused, nearly plane, convergent or even divergent characteristics. With an unfocused wave having nearly plane, plane, convergent wave characteristic or even divergent wave characteristics, the energy density of the wave may be or may be adjusted to be so low that side effects including pain are very minor or even do not exist at all.

[0106] In certain embodiments, the apparatus of the present invention is able to produce waves having energy density values that are below 0.1 mJ/mm.sup.2 or even as low as 0.000001 mJ/mm.sup.2. In a preferred embodiment, those low end values range between 0.1-0.001 mJ/mm.sup.2. With these low energy densities, side effects are reduced and the dose application is much more uniform. Additionally, the possibility of harming surface tissue is reduced when using an apparatus of the present invention that generates unfocused waves having planar, nearly plane, convergent or divergent characteristics and larger transmission areas compared to apparatuses using a focused shock wave source that need to be moved around to cover the affected area. The apparatus of the present invention also may allow the user to make more precise energy density adjustments than an apparatus generating only focused shock waves, which is generally limited in terms of lowering the energy output. Nevertheless, in some cases the first use of a high energy focused shock wave targeting a treatment zone may be the best approach followed by a transmission of lower energy unfocused wave patterns.

[0107] Tissue is strengthened, inflammation reduced, nerves regenerated, and stem cells recruited and activated. All acoustic waves, focused and unfocused, spherical, radial, ballistic, etc. could be used for treatments.

[0108] It will be appreciated that the apparatuses and processes of the present invention can have a variety of embodiments, only a few of which are disclosed herein. It will be apparent to the artisan that other embodiments exist and do not depart from the spirit of the invention. Thus, the described embodiments are illustrative and should not be construed as restrictive.

[0109] Variations in the present invention are possible in light of the description of it provided herein. While certain representative embodiments and details have been shown for the purpose of illustrating the subject invention, it will be apparent to those skilled in this art that various changes and modifications can be made therein without departing from the scope of the subject invention. It is, therefore, to be understood that changes can be made in the particular embodiments described which will be within the full intended scope of the invention as defined by the following appended claims.