Methods and devices for the non-thermal treatment of endometriosis

Abstract

Non-thermal treatment of endometriosis.

Description

[Technical field]

[0001] [CROSS REFERENCE TO RELATED APPLICATIONS] This application claims priority to co-pending U.S. Provisional Patent Application No. 63 / 362,086, filed March 29, 2022, the entire disclosure of which is incorporated herein by reference.

[0002] [Technical field] The present invention relates to the non-thermal treatment of endometriosis, and more particularly to methods and devices for electric field treatment and removal of endometriotic lesions in subjects in need thereof. [Background technology]

[0003] Endometriosis is a condition caused by endometrial cells growing outside of their normal environment, the uterus. In this condition, endometrial cells that typically thicken and break down in the uterus during a woman's menstrual cycle are found, for example, in the ovaries, fallopian tubes, and other tissues of the pelvis. Although these cells are not in the uterus, they continue to function (thicken and then break down) and respond to hormonal stimuli as if they were in the uterus, causing pain and other symptoms.

[0004] It is estimated that there are approximately 3 million new cases of endometriosis each year, particularly in women aged 25-40 years, childless women with a family history of endometriosis, and women who suffer from abnormal menstrual cycles.

[0005] Endometriosis can cause pelvic spasms and pain, lower back pain, abdominal pain, excessive menstrual bleeding, fatigue, possible fertility issues, and is associated with a higher likelihood of developing ovarian cancer. The symptoms of these conditions can be fairly mild in nature or more severe in nature, resulting in treatment options ranging from over-the-counter painkillers to surgical intervention.

[0006] Conventional treatment options, such as those mentioned above, depend on the severity of endometriosis and the patient's symptoms. Many non-invasive procedures rely on interrupting the affected woman's natural hormone cycle, including hormone therapy, GnRH drugs, oral contraceptives, and the like. These procedures limit the natural process of ovulation, thereby preventing the breakdown of endometrial tissue outside the uterus (the source of much of the pain). In more severe cases, surgical intervention is required for the removal of endometrial tissue, especially if the tissue has caused significant lesions. In the most severe cases, a hysterectomy with or without a bilateral salpingo-oophorectomy is required, thereby removing some, if not all, of the problematic tissue. More typically, endometrial lesions are removed through the use of laser ablation, where the problematic tissue is heated until it is removed, and the surrounding tissue and blood vessels are sealed.

[0007] These thermal ablative surgical solutions often result in heat-induced damage to the surrounding healthy tissue, leaving behind scarring / fibrosis where the lesion is then removed.

[0008] These heat-induced damages can adversely affect the subject's fertility, especially if the treatment involves the ovaries.

[0009] It is against this background that the present disclosure is provided. Summary of the Invention

[0010] Embodiments according to the invention include devices and methods for the non-thermal treatment of endometriosis. The embodiments are a significant improvement over conventional treatments that rely on the application of heat to ablate problematic cells. Non-thermal treatment of endometrial lesions results in electroporation of endometrial cells and ultimately necrosis of the lesions. Unlike thermal treatments, non-thermal treatments avoid scarring and damage to non-lesioned cells.

[0011] The device includes a generator capable of applying an electric field to the endometrial lesion via one or more electrodes. In some embodiments, two electrodes can be inserted into the lesion, spaced from each other by 1 mm to 50 mm, more typically 2 to 20 mm. A voltage of about 500 to about 3,000 volts is pulsed for treatment of the lesion, typically for about 25 to about 200 μs. The total number of pulses is determined by the effect on the target lesion, but can be 1 to 10 or more. The generated electric field creates a non-thermal treatment zone that causes electroporation of cells within the zone. The cell matrix remains undamaged.

[0012] The method involves treating an endometrial lesion requiring non-thermal ablation. The lesion is identified and electric field parameters are determined to substantially ablate all endometrial cells within the target lesion. Application of the electric field to the lesion creates a treatment zone in which cells undergo necrosis, leaving the cellular matrix substantially undisturbed. [Brief description of the drawings]

[0013] [Figure 1] 1 illustrates a treatment jaw placed on an exemplary endometrial lesion, according to an embodiment described herein. [Diagram 2] Illustrated is thermal treatment of the same endometrial lesion using conventional treatment, specifically 460C at the edges of the treatment zone. [Diagram 3] 1 illustrates an electric field treatment zone according to an embodiment herein. [Figure 4] 1 is an alternative monopolar electrode according to an embodiment herein showing an exemplary treatment zone. At least one of the electrodes may be placed within a body cavity, such as a uterine manipulator or a rectal probe. Unlike an RF return pad, which is connected to the skin and requires capacitive coupling through the skin for ionic current to flow, it contains an electric field within the body. [Diagram 5] 1 is a flow chart illustrating a method for treating endometriosis according to embodiments herein. [Figure 6A] A pair of electrodes are shown spaced 10 mm apart, with each electrode having a diameter of 0.43 mm. [Figure 6B] 4 shows the same pair of electrodes placed on a sweet potato. [Figure 7A] 1 illustrates the use of toluidine blue to reveal damaged cell membranes caused by embodiments herein; untreated cells are shown. [Figure 7B] 1 illustrates the use of toluidine blue to reveal damaged cell membranes caused by embodiments herein and shows treated cells. [Figure 8A] Shown is the stained treatment zone at time zero. [Figure 8B] Shown is the stained treatment zone 3 hours after treatment. [Figure 8C] Shown are stained treatment zones 23 hours after treatment. [Figure 9A] The electric field lines corresponding to the treatment in FIG. 8A are shown. [Figure 9B] The electric field lines corresponding to the treatment in FIG. 8B are shown. [Figure 9C] The electric field lines corresponding to the treatment in FIG. 8C are shown. [Figure 10] FIG. 1 is a schematic diagram showing voltages and currents recorded during treatment. [Figure 11A] 1 illustrates a bipolar gripping device for generating an electric field, according to embodiments herein. [Figure 11B] 1 illustrates a bipolar gripping device for generating an electric field according to embodiments herein.The device is shown placed in a potato hole. [Figure 11C] 1 illustrates a bipolar gripping device for generating an electric field according to embodiments herein, with corresponding damage to cells shown. [Figure 11D] 7A-7D show a bipolar gripping device for generating an electric field according to embodiments herein, with contour lines added. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] Embodiments according to the present invention include devices and methods for the non-thermal treatment of endometriosis. Aspects of these embodiments rely on delivering an electric field of sufficient size and strength to cause electroporation of treated cells, but without causing damage to the connective tissue (or matrix) that surrounds and separates endometrial cells. This unique delivery of an electric field in the absence of thermal ablation causes necrosis of endometrial cells, but limits scarring (and damage to the matrix), which is the main advantage of this embodiment.

[0015] In one embodiment, a device for the treatment of endometrial lesions is provided. The device can deliver an electric field to the lesion such that treatment zones are generated. Each treatment zone has an electric field threshold edge that can expand or contract based on the voltage applied by the device. In some embodiments, the electrodes for delivering the electric field are spaced 1-50 mm apart, and in more typical embodiments, 2-20 mm apart. Voltages of 500-3,000 volts are typical. An isosurface is generated. In some embodiments, the electric field is delivered for a pulse length of 25-200 μs, more typically 75-125 μs. Multiple pulses can be applied, for example, 1-20 pulses, or more typically 5-15 pulses. A rest period occurs between the pulses, which is used for restoration of tissue impedance. Application of the treatment is continued until its application causes necrosis of the endometrial lesion.

[0016] In another embodiment, a method for treating a subject with endometriosis is provided. The method includes identifying or determining whether a subject has endometriosis, determining the location, size, and volume of the subject's endometriotic lesion, and determining the appropriate electric field strength and location required to non-thermally treat the lesion(s). In some embodiments, a follow-up determination is made to ensure that the lesion(s) has been removed.

[0017] [Endometriosis:] Endometriosis is a condition in which endometrial tissue grows and proliferates outside of its normal environment. Therefore, endometriosis is characterized by endometrial tissue located in the tissue lining the ovaries, fallopian tubes, and pelvis, for example. In extreme cases, endometrial tissue can be found outside of a woman's pelvis, but this is fairly rare. Although not found in the uterus, endometrial tissue is still regulated by a woman's normal monthly hormone cycle, which ends with tissue breakdown. The result of endometrial tissue breakdown outside the uterus can cause inflammation, swelling, and scarring of surrounding and underlying tissue, all of which can cause pain, bloating, bleeding, and other similar symptoms.

[0018] If the ovaries are involved, it can also cause infertility and there is a higher chance of developing ovarian cancer.

[0019] Approximately 2-10% of women aged 25-40 have endometriosis. Conventional treatment for these women may include painkillers, analgesics, etc. In more difficult cases, laparoscopy is used to thermally remove endometrial lesions, and in very difficult cases, hysterectomy (removal of the uterus, fallopian tubes, and ovaries) is used. When laparoscopy is the primary procedure, removal results in destruction of endometrial cells and matrix with subsequent fibrosis and scarring of the damaged areas.

[0020] The embodiments herein provide an alternative treatment for removal of endometrial lesions, removal without endothermic damage. In this embodiment, an electric field of appropriate strength is used to induce electroporation of cell membranes in the treatment zone, thereby causing necrosis of endometrial cells, but leaving the intervening matrix intact. This treatment strategy significantly reduces the likelihood of fibrosis and scarring after lesion removal. The following embodiments provide significant improvements to conventional endometrial lesion treatments.

[0021] [Electric field treatment:] An embodiment according to the invention utilizes electrical current to generate a predetermined electric field having a strength useful for treating endometrial lesions. The voltage, gap between the electrodes, depth of the electrodes into the lesion, and shape of the electrodes determine the effectiveness of the electric field for any particular lesion. Each of these parameters can be modified to match the resulting electric field with the shape and size of a particular lesion. The resulting electric field can be used to substantially completely ablate the treated lesion.

[0022] In one embodiment, parallel two-needle electrodes are placed 1-50 mm apart within the lesion to create a treatment zone for a particular lesion. The distance between the electrodes is determined by the shape of the lesion, so distances of 1-50 mm, 5-25 mm, and 1-10 mm are anticipated. The depth of electrode insertion into the lesion is determined by the volume of the lesion, and the electrode can be inserted up to half the depth of the lesion, i.e., if the lesion is 20 mm thick, the electrode is placed up to 10 mm into the lesion. Electrode materials can include stainless steel, platinum, platinum / iridium, etc. The diameter of the electrode can vary, but is typically 1-4 mm in outer diameter.

[0023] In a typical embodiment, a voltage of 500-3,000 volts can be applied in pulses within the electrodes to induce an electric field. The pulses can last between 0.5-50 μs, more typically 0.8-1.25 μs, with appropriate rest periods (approximately 75-150 ms required to restore tissue impedance). In some aspects, the user performs an appropriate number of pulses to result in necrosis of substantially all cells within the endometrial lesion. The voltage input can be modified in pulse number and electrode placement to ensure that substantially all endometrial cells are electroporated during treatment. For example, in some aspects, the treatment may require only one pulse, while in other aspects, it may require two pulses with appropriate rest times between. In still others, three pulses, four pulses, five pulses, six pulses, seven pulses, eight pulses, nine pulses, ten pulses, or eleven or more pulses can be applied to the lesion (each with appropriate rest times between voltage applications).

[0024] Thus, a specific treatment zone is generated by an appropriate electric field and corresponds to a lesion that induces electroporation, i.e., necrosis of cells by introducing small holes in the cell membrane of cells within the treatment zone. There is little or no residual heating of the cells. The small holes in the cells ultimately induce necrosis within a short time frame without damaging the cell matrix, i.e., without scarring.

[0025] In an alternative embodiment, two electrodes may be arranged in a treatment jaw configuration as shown in FIG. 1. For context, a cross section of the peritoneum is shown with the ureter and endometrial lesion extending upward. The shape and length of the two electrodes can vary, but are shown in this figure as having a semicircular cross-sectional shape with the flat side of each electrode positioned along the outer portion of the endometrial lesion. The electrodes are long enough to abut some or almost all of the lesion within the "treatment jaw." Exemplary treatment zones are shown when the treatment jaw is used in accordance with an embodiment herein.

[0026] The same lesion is treated with thermal ablation, as shown in Figure 2. As can be seen from the thermal image, the lesion is destroyed, but the outer edge of the treatment zone reaches a temperature of 460° C. This temperature is sufficient to cause clinical damage to adjacent tissue over the treatment period.

[0027] As shown in corresponding Figure 3, the same lesion treated according to an embodiment herein (using bipolar jaw electrodes) shows little or no thermal heating of adjacent tissue. In Figure 4, an electric field is delivered according to an embodiment herein using a monopolar electrode. Again, little or no thermal heading of adjacent tissue is observed. These figures demonstrate that the use of electric fields to remove endometrial lesions provides a much safer platform than thermal ablation of the same lesion.

[0028] As shown in FIG. 4, during application of high energy for surgical procedures, the method of safely treating the target tissue and safely returning the energy to the generator can be accomplished by several different techniques. When utilizing conventional means, a return pad (RF pad) is used to return the high energy. In conventional methods, an RF pad is placed on the patient's skin to complete the RF circuit. The skin contains layers that do not conduct efficiently, resulting in a capacitive / resistive path through the skin. The use of a conventional return pad in the described procedure presents difficulties in maintaining the desired square wave and increases the likelihood of muscle contraction since the IRE pathway must flow through skeletal muscle.

[0029] An improved method is to utilize a metal probe, such as a uterine manipulator, to deliver the IRE energy back to the generator without experiencing the problems that come from using RF pads. When a metal probe (uterine manipulator) is placed inside the uterus, the layers of the uterus are highly conductive, improving the conduction path back to the IRE generator. The square wave remains a square wave and the pulse width is not reduced. Similarly, the probe inside the uterus reduces the possible paths through skeletal muscle, reducing the likelihood of muscle contraction (with RF pads) causing muscle contraction. The IRE waveform remains as close to the desired square wave as possible. This allows transmembrane voltage to be applied to the cells throughout the square wave, resulting in a lower IRE threshold for treatment.

[0030] The electric field provides disruption to the affected cells, causing electroporation of the cell membrane. However, the electric field does not cause the destruction or destruction of the extracellular matrix. This is a significant advance in the field, as removal of the extracellular matrix leads to fibrosis and scarring, which are common side effects of using conventional therapies such as thermal ablation.

[0031] [Methods of treatment for endometrial lesions:] Embodiments according to the present disclosure include methods for non-thermal treatment of endometriosis. In some aspects, a subject in need of the present embodiments is identified. The subject is typically a woman between the ages of 18-55, more typically between the ages of 25-40. The subject will also typically have endometrial lesions severe enough to require heat-based laparoscopy or other conventional treatments. Once the subject is identified, embodiments of the present invention are utilized to remove the lesions in lieu of heat-based laparoscopy.

[0032] Identification typically includes identification of both the location of the lesion, the surface area of ​​the lesion, and the depth or volume of the lesion. Identification of the lesion may be accomplished by MRI or other similar methodologies.

[0033] The electric field of suitable strength and size is determined for the treatment of the endometrial lesion of the subject.Such electric field includes the determination of many parameters, including voltage, number of voltage applications or pulses, the material and number of electrodes used, the gap between electrodes, the depth of the electrodes into the lesion, and the shape of the electrodes applied to the lesion.In some embodiments, it is also determined whether the electrodes need to be moved after the first treatment to maximize the efficiency of removing the lesion.Once determined, the treatment parameters are applied to the subject.

[0034] In some embodiments, the treatment zone can be created more than once to ensure that all endometrial cells are addressed. In particular, treated cells are electroporated to disrupt cell membranes, resulting in cell death.

[0035] In some embodiments, follow-up appointments are used to ensure that the electric field has been successful in removing the lesion. Follow-up may include additional application of the appropriate electric field to previously treated lesions.

[0036] FIG. 5 is a flow chart illustrating an embodiment according to the present invention. In operation 500, a subject presents with endometriosis requiring treatment of an endometrial lesion. In operation 502, an MRI or other similar approach is used to determine the size and location of the lesion. In operation 504, an analysis is performed to identify a set of parameters that provide a sufficient electric field so that the treatment zone will cause necrosis of endometrial cells. In operation 504a, the voltage and number of pulses are considered, in operation 504b, the rest period between pulses is considered, in operation 504c, the appropriate electrode type and configuration for the delivery of the voltage is considered, in operation 504d, the depth at which the electrodes are placed in the lesion is considered, and in operation 504e, the electrodes are placed in the endometrial lesion according to the previous operation. In operation 506, a voltage is applied to generate an electric field and thereby generate a treatment zone, in operation 508, the application of the voltage is pulsed an appropriate number of times, and in operation 510, a determination is made whether the treatment zone has successfully killed or damaged the endometrial cells so that they become necrotic. Optionally, the subject is examined at a later date to confirm removal of the endometrial lesion in operation 512. If the lesion has not been completely destroyed, the process beginning at 502 or 504 is repeated until removal is complete at 510.

[0037] The following examples are for illustrative purposes only and are not meant to be limiting. EXAMPLES

[0038] Example 1: Visualized treatment zone of applied voltage The following example shows the results of applying nine different doses to slices of red potato. The doses applied illustrate or mimic how tissue is affected by an applied electric field. A pulsed electric field (PEF) is used to induce cell necrosis in living tissue (potato cells). Potatoes are used as tissue phantoms to determine the threshold for cell necrosis. The potatoes used here are red potato, russet potato, and sweet potato. A comparison of potatoes treated in air and stained with toluidine blue is made to assess the visualization of the treatment zone.

[0039] The difference between each amount is the total on-time of the footswitch, which determines the total number of waveforms that deliver a high peak magnitude electric field to the tissue without enough energy to cause ohmic heating.

[0040] The nine different applications are shown in Table 1 below. [Table 1] Table 1: Experiments with tubers as tissue phantoms

[0041] In each experiment, each has a treatment zone containing necrotic cells, and an electric field threshold edge. The voltage can be increased or decreased to vary the zone size. In the experiments, a needle is inserted into the potato and the surface boundary condition of the needle is set to ground.

[0042] As shown in Figures 6A and 6B, needle electrodes with a diameter of 0.43 mm and a spacing of 10 mm (A) are placed in a sweet potato according to experiment (B) herein. Figure 2 shows the treatment zone in an exemplary Russet potato 18 hours after treatment. Oxidation of PPO (polyphenol oxidase) in the potato results in a visible black electroporation area. Electric field isolines were simulated and placed on the image in Photoshop to determine the treatment threshold.

[0043] As shown in Figure 7, toluidine blue powder was mixed in distilled water (0.1 grams / 100 ml) to formulate the stain and immediately added to the treated potatoes to strengthen the treatment zone. Slices of potatoes were treated treated side down in the formulated stain for 5 minutes, followed by rinsing with distilled water and then patting dry. The figure shows slices of untreated and treated russet potatoes. This technique is used to strengthen cell walls. A color change in the treatment zone indicates damaged cells as they allow toluidine blue to inject into the cells. Figure 8A shows the same experiment over the course of 0 hours; 3 hours (Figure 8B); and 23 hours (Figure 8C).

[0044] Figure 9 shows the simulated electric field contours added to Figures 4A, 4B, and 4C. This figure shows that at 3 hours, the minimum time after staining that a treatment zone can be identified. The 3 hour zone is approximately the same as the 23 hour zone.

[0045] Figure 10 shows a schematic diagram of voltage and current, where the current decreases during a single pulse but can increase by up to 50% when multiple pulses are applied compared to a constant current with a purely resistive load. Similar changes are observed in living animal and human tissues.

[0046] FIG 11A shows a bipolar gripping device according to embodiments herein. The gripping device is shown positioned in a hole in a potato (FIG 11B). An electric field is applied according to embodiments herein, and FIG 11C shows a dark purple color where there is cell damage (as well as defects within the potato) due to drilling the hole. FIG 11D shows the treatment zone with contour lines positioned on the diagram.

[0047] The data presented herein illustrates that tubers treated with electric fields according to embodiments herein can be used to visualize cell death. The addition of toluidine blue stain to the treated surface is used to enhance the treatment zone. To emulate the cellular response to electroporation, tuber cells respond similarly to human tissue as the magnitude of the current increases.

Claims

1. 1. A method for non-thermal treatment of endometrial lesions in a subject in need thereof, comprising: a. determining the location, size, and volume of the endometrial lesion in the subject; b. determining an electric field useful for treating the identified endometrial lesion; c) applying said electric field to said endometrial lesion for an appropriate time and voltage to treat said endometrial lesion.

2. The method of claim 1 , wherein determining the electric field comprises determining a number of voltage pulses and a width of each pulse at a given time increment.

3. 3. The method of claim 2, wherein the non-thermal treatment of the endometrial lesion causes necrosis of endometrial cells without significant damage to the associated cellular matrix.

4. The method of claim 3, wherein the electric field is provided by a pair of electrodes inserted about 5 mm to 20 mm apart in the endometrial lesion.

5. The method of claim 3, wherein the subject is a woman aged between 25 and 50 years.

6. 10. The method of claim 1, wherein the electric field has a duration and voltage sufficient to cause necrosis of cells within the endometrial lesion.

7. The method of claim 6 , wherein the electric field does not cause significant damage to matrix tissue of the endometrial lesion.

8. The method of claim 7, wherein the voltage is from about 500 volts to about 3,000 volts.

9. The method of claim 8, wherein the voltage is applied in two or more pulses lasting from 75 μs to about 125 μs.

10. The method of claim 9 , wherein the two electrodes are made of stainless steel.

11. 1. A method for creating a treatment zone at an endometrial lesion outside of a uterus in a subject, comprising: providing one or more electrodes for applying a pulsed voltage to the endometrial lesion, the pulsed voltage resulting in the treatment zone; b. determining the voltage and number of pulses required to create the treatment zone that substantially ablates the endometrial lesion; c. applying said voltage and pulse rate to said endometrial lesion; d. determining whether additional pulses are required to eliminate said endometrial lesions; e. applying an optional additional pulse to said endometrial lesion.

12. The method of claim 11, wherein the treatment zone causes necrosis of endometrial cells but has limited effect on the extracellular matrix.

13. 13. The method of claim 12, wherein the treatment zone has little or no thermal heating caused by the application of voltage and pulse number.

14. The method of claim 12 , wherein the one or more electrodes is two electrodes.

15. The method of claim 12 , wherein the one or more electrodes is a single electrode.

16. The method of claim 14, wherein the two electrodes are positioned within the endometrial lesion about 1 to about 20 mm apart.

17. 17. The method of claim 16, wherein the two electrodes are cylindrical and have two ends, and a first end of each electrode is inserted into the endometrial lesion to half its depth.

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