Methods and devices for non-thermal treatment of endometriosis

Abstract

Methods and devices for the non-thermal treatment of endometriosis. Non-thermal treatment of endometrial lesions results in electroporation of endometrial cells and ultimately necrosis of the lesions. A lesion is identified and electric field parameters are determined to substantially remove all endometrial cells in the target lesion. Applying an electric field to the lesion creates a treatment zone in which the cells necrotize without substantially interfering with the cell matrix. The device comprises a generator capable of applying an electric field to the endometrial lesion through one or more electrodes.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to co-pending U.S. Provisional Patent Application Serial No. 63 / 362,086, filed on March 29, 2022, the entire disclosure of which is incorporated herein by reference. Technical Field

[0003] The present invention relates to non-thermal treatment of endometriosis and, more particularly, to methods and apparatus for delivering electric field therapy and removing endometrial lesions in a subject in need thereof. Background of the Invention

[0005] Endometriosis is a disease caused by the growth of endometrial cells outside of their normal environment (the uterus). With this disease, endometrial cells that normally thicken and break down in the uterus during a woman's menstrual cycle also take on a life of their own in other tissues, such as the ovaries, fallopian tubes, and pelvis. Although no longer in the uterus, these cells continue to function (thicken and then break down) and respond to hormonal stimulation as if they were in the uterus, causing pain and other symptoms.

[0006] An estimated 3 million new cases of endometriosis occur each year, particularly in women between the ages of 25 and 40, those with a family history of endometriosis but no children, and those with irregular menstrual cycles.

[0007] Endometriosis can cause pelvic cramping and pain, lower back pain, abdominal pain, heavy menstrual bleeding, fatigue, possible fertility issues, and has been linked to a higher likelihood of developing ovarian cancer. These symptoms can be quite mild in nature or they can be more severe, resulting in treatment options ranging from over-the-counter pain medications to surgical intervention.

[0008] As described above, conventional treatment options depend on the severity of endometriosis and the patient's symptoms. Many non-invasive treatments rely on interrupting the natural hormone cycle of affected women, including hormone therapy, GnRH drugs, oral contraceptives, etc. These treatments limit the natural process of ovulation and therefore prevent the decomposition of endometrial tissue outside the uterus (the source of most pain). In more severe cases, surgical intervention is required to remove endometrial tissue, especially when the tissue causes significant lesions. In the most severe cases, a hysterectomy is required, with or without bilateral salpingo-oophorectomy, to remove some (if not all) of the diseased tissue. More typically, endometrial lesions are removed by using laser ablation, in which the diseased tissue is heated for removal and the surrounding tissue and blood vessels are sealed.

[0009] These thermal ablative surgical solutions often cause heat-induced damage to the surrounding healthy tissue and then leave scarring / fibrosis where the lesion was removed.

[0010] These heat-induced injuries may negatively affect the subject's fertility, especially when the treatment involves the ovaries.

[0011] It is against this background that the present disclosure is provided. Summary of the invention

[0012] Embodiments according to the present invention include apparatus and methods for non-thermal treatment of endometriosis. Embodiments are significant improvements over conventional treatments that rely on the application of heat to ablate harmful cells. Non-thermal treatment of endometrial lesions results in electroporation of endometrial cells and ultimately necrosis of the lesion. Unlike thermal treatments, non-thermal treatments avoid scarring and damage to non-lesional cells.

[0013] The device includes a generator capable of applying an electric field to an endometrial lesion through one or more electrodes. In some aspects, two electrodes can be inserted into the lesion and spaced between 1 mm and 50 mm from each other, and more typically spaced 2 mm to 20 mm. Voltages of about 500 volts to about 3,000 volts are typically used to treat the lesions, with pulses of about 25 μs to about 200 μs. The total number of pulses depends on the effect on the target lesion, but can be 1 to 10 or more. The generated electric field forms a non-thermal treatment zone, causing electroporation of cells within the zone. The cell matrix remains undamaged.

[0014] The method includes treating an endometrial lesion that requires non-thermal removal. The lesion is identified and electric field parameters are determined to remove substantially all endometrial cells in the target lesion. Applying the electric field to the lesion creates a treatment zone in which cells are necrotic while the cell matrix is ​​substantially undisturbed. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 Treatment jaws according to embodiments described herein are shown positioned on an exemplary endometrial lesion.

[0016] Figure 2 Thermal treatment of the same endometrial lesion using conventional therapy is shown, with particular attention paid to the 460C at the edge of the treatment zone.

[0017] Figure 3 A treatment zone of an electric field according to embodiments herein is shown.

[0018] Figure 4is an alternative monopolar electrode according to embodiments herein, showing an exemplary treatment zone. At least one of the electrodes may be placed in a body cavity, such as a uterine manipulator or rectal probe. Unlike an RF return pad that is connected to the skin and requires capacitive coupling through the skin to achieve ionic current flow, the electrode will contain the electric field within the body.

[0019] Figure 5 is a flow chart illustrating a method for treating endometriosis according to embodiments herein.

[0020] Fig. 6A A pair of electrodes with a 10 mm spacing is shown, each electrode having a 0.43 mm diameter. Figure 6B The same pair of electrodes is shown placed into a potato.

[0021] FIG. 7 shows the use of toluidine blue to clarify damaged cell membranes caused by the examples herein. Fig. 7A Untreated cells are shown. Figure 7B Treated cells are shown.

[0022] FIG8 shows the stained treatment area at zero (A), three hours after treatment (B), and twenty-three hours after treatment (C).

[0023] Fig.9A , Fig. 9B and Fig. 9C Shows the corresponding Fig. 8A , Figure 8B and Figure 8C The therapeutic electric field lines.

[0024] Fig.10 is a schematic diagram showing the voltage and current recorded during treatment.

[0025] Fig.11A A bipolar gripping device for generating an electric field according to embodiments herein is shown. The device is shown placed into a hole in a potato (B), with corresponding cell damage (C) and contours added in FIG. 7D. DETAILED DESCRIPTION

[0026] Embodiments according to the present invention include devices and methods for non-thermal treatment of endometriosis. Aspects of these embodiments rely on delivering an electric field of sufficient magnitude and intensity to cause electroporation of the treated cells, but without causing damage to the connective tissue (or stroma) surrounding and separating the endometrial cells. This unique delivery of the electric field, in the absence of thermal ablation, causes endometrial cell necrosis, but limits scar formation (and damage to the stroma), which is the primary beneficial effect of the present embodiments.

[0027] In one embodiment, a device for treating endometrial lesions is provided. The device is capable of delivering an electric field to the lesion so that a treatment zone is 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 aspects, the electrodes for delivering the electric field are spaced 1mm to 50mm apart, and in more typical aspects, 2mm to 20mm apart. Voltages between 500 volts and 3,000 volts are typical. Isosurfaces are formed. In some aspects, the electric field is delivered at a pulse length of 25μs to 200μs, and more typically 75μs to 125μs. Multiple pulses may be applied, such as 1 to 20 pulses or more typically 5 to 15 pulses. There is a rest period between pulses to restore the impedance of the tissue. The treatment is continuously applied until the application causes necrosis of the endometrial lesions.

[0028] In another embodiment, a method of treating a subject with endometriosis is provided. The method includes identifying or determining whether the subject has endometriosis, determining the location, size, and volume of endometrial lesions in the subject, and determining the strength and location of an appropriate electric field required for non-thermal treatment of one or more lesions. In some aspects, a subsequent determination is made to ensure that one or more lesions have been removed.

[0029] Endometriosis :

[0030] Endometriosis is a disease in which endometrial tissue grows and proliferates outside of its normal environment, the uterus. As such, endometriosis is characterized by endometrial tissue located in, for example, the ovaries, fallopian tubes, and tissue that lines the pelvis. In extreme cases, endometrial tissue may be found outside of a woman's pelvis, although this is fairly rare. Although not found in the uterus, endometrial tissue is still regulated by a woman's normal monthly hormone cycle, which ultimately leads to the breakdown of the tissue. The result of the breakdown of endometrial tissue outside of the uterus can lead to inflammation, swelling, and scarring of the surrounding and underlying tissues, all of which can cause pain, bloating, bleeding, and other similar symptoms.

[0031] In cases where the ovaries are affected, it may also lead to infertility and increase the likelihood of ovarian cancer.

[0032] Approximately 2% to 10% of women aged 25 to 40 years have endometriosis. Conventional treatment for these women may include analgesics, painkillers, etc. In more difficult cases, laparoscopy is used to thermally remove the endometrial lesions, and in very difficult cases, hysterectomy (removal of the uterus, fallopian tubes, and ovaries) is used. When laparoscopy is the primary treatment, removal results in destruction of the endometrial cells and stroma, with subsequent fibrosis and scarring of the damaged areas.

[0033] The embodiments herein provide alternative treatments for removing (removing without causing endothermic damage) endometrial lesions. In this embodiment, an electric field of appropriate strength is used to introduce electroporation of the cell membrane in the treatment area, thereby causing endometrial cell necrosis, 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.

[0034] Electric Field Therapy :

[0035] An embodiment according to the present invention utilizes electric current to generate a predetermined electric field having an intensity that can be used to treat endometrial lesions. The voltage, the gap between the electrodes, the depth of the electrodes into the lesion, and the 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 shape and size of a particular lesion to the resulting electric field. The resulting electric field can then be used to substantially completely remove the treated lesion.

[0036] In one embodiment, parallel two needle electrodes are placed in the lesion at intervals of 1mm to 50mm to create a treatment zone for a specific lesion. The distance between the electrodes is determined by the shape of the lesion, so distances of 1mm to 50mm, 5mm to 25mm, and 1mm to 10mm are expected. The depth of electrode insertion into the lesion is determined by the volume of the lesion, where the electrode can be inserted to half the depth of the lesion, i.e., if the lesion is 20mm thick, the electrode will be placed 10mm into the lesion. Electrode materials may include stainless steel, platinum, platinum / iridium, etc. The electrode diameter may vary, but the outer diameter is typically between 1mm and 4mm.

[0037] In a typical embodiment, a voltage between 500 volts and 3,000 volts may be pulsed into the electrodes to generate an electric field. The pulse may last from 0.5 μs to 50 μs, and more typically from 0.8 μs to 1.25 μs, with an appropriate rest time (about 75 ms to 150 ms, which is necessary to restore tissue impedance). In some aspects, the user performs an appropriate number of pulses to cause necrosis of substantially all cells in the endometrial lesion. The input of the voltage may be varied by the number of pulses and electrode placement to ensure that substantially all endometrial cells are electroporated during the treatment. For example, in some aspects, treatment may require only one pulse, while in other aspects, treatment may require 2 pulses with an appropriate rest time in between. In yet other cases, 3 pulses, 4 pulses, 5 pulses, 6 pulses, 7 pulses, 8 pulses, 9 pulses, 10 pulses, or 11 or more pulses (each pulse having an appropriate rest time between voltage applications) may be applied to the lesion.

[0038] In this way, a specific treatment zone corresponds to the lesion, and the treatment zone is then formed by an appropriate electric field to cause cell necrosis by electroporation (i.e., introducing small holes in the cell membrane of the cells in the treatment zone). There is little or no residual heating of the cells. The small holes in the cells will eventually cause necrosis in a short time without destroying the cell matrix, i.e., without scarring.

[0039] In an alternative embodiment, the two electrodes may be placed in a treatment jaw configuration, such as Figure 1 As shown in . For context, a cross section of the peritoneum is shown with the ureters and endometrial lesions extending upward. The shape and length of the two electrodes can vary, but are shown in this figure as having a semi-circular cross-sectional shape with the flat side of each electrode along the outer portion of the endometrial lesion. The electrodes have sufficient length to abut some or nearly all of the lesions within the "treatment jaws." An exemplary treatment area is shown when the treatment jaws are used according to the embodiments herein.

[0040] like Figure 2 As shown in , the same lesion was treated with thermal ablation. From the thermal imaging, it can be seen that although the lesion was destroyed, the outer edge of the treatment area reached a temperature of 460 C. This temperature is sufficient to cause clinical damage to adjacent tissue during the treatment time.

[0041] As corresponding Figure 3 As shown in , the same lesion treated according to embodiments herein shows little or no thermal heating of adjacent tissue (using bipolar jaw electrodes). Figure 4 In the embodiment described herein, monopolar electrodes were used to deliver the electric field. Again, little or no thermal doming of adjacent tissue was observed. These figures suggest that the use of electric fields to remove endometrial lesions provides a safer platform than thermal ablation of the same lesions.

[0042] like Figure 4 As shown in , a method of safely treating target tissue and returning energy safely to the generator when applying high energy for surgical treatment can be achieved by several different techniques. When utilizing conventional means, a return pad (RF pad) is used to return the high energy. Conventional methods place the RF pad on the patient's skin to complete the RF circuit. The skin contains layers that do not conduct efficiently and create a capacitive / resistive path through the skin. Using a conventional return pad in the described treatment presents difficulties in maintaining the desired square wave and increases the likelihood of muscle contraction because the IRE path needs to flow through skeletal muscle.

[0043] An improved approach is to utilize a metal probe (such as a uterine manipulator) to return the IRE energy to the generator without the problems that come with using an RF pad. If a metal probe (uterine manipulator) is placed in the uterus, the layers of the uterus are very conductive and the conduction path back to the IRE generator can be improved. A square wave will remain a square wave and the pulse width will not decrease. Additionally, the probe in the uterus will reduce the possible paths through the skeletal muscle, thereby reducing the likelihood of muscle contraction (with the RF pad) and resulting in muscle contraction. The IRE waveform is as close to the desired square wave as possible. This allows the transmembrane voltage to be applied to the cells over the full range of the square wave and creates a lower threshold for IRE therapy.

[0044] The electric field causes damage to the affected cells, resulting in electroporation of the cell membrane. However, the electric field does not cause damage or disruption of the extracellular matrix. This is a significant advance in the field, as removal of the extracellular matrix can lead to fibrosis and scarring, which are common side effects of conventional therapies such as thermal ablation.

[0045] Treatment of endometrial lesions :

[0046] Embodiments according to embodiments herein include methods for non-thermal treatment of endometriosis. In some aspects, a subject in need of the present embodiment is identified. The subject is typically a female between the ages of 18 and 55, and more typically a female between the ages of 25 and 40. The subject will also typically have endometrial lesions severe enough to require thermal laparoscopy or other similar conventional treatments. Once the subject is identified, embodiments of the present invention will be used to remove the lesions in lieu of thermal-based laparoscopy.

[0047] This identification generally includes identification of the location of the lesion, the surface area of ​​the lesion, and the depth or volume of the lesion. Lesion identification can be accomplished by MRI or other similar methods.

[0048] An electric field of appropriate strength and size is determined to treat an endometrial lesion in a subject. Such an electric field includes identification of many parameters, including voltage, number of voltage applications or pulses, electrode material and number of electrodes used, gaps between electrodes, depth of electrode penetration into the lesion, and shape of the electrode applied to the lesion. In some aspects, it is also determined whether the electrodes need to be moved after the first treatment to maximize the efficiency of eliminating the lesion. Once identified, the treatment parameters are applied to the subject.

[0049] In some embodiments, the treatment area may be formed a second or more times to ensure that all endometrial cells have been addressed. Specifically, the treated cells have been electroporated so that the cell membrane is destroyed, thereby causing cell death.

[0050] In some embodiments, follow-up appointments are used to ensure that the electric field successfully removed the lesion. Follow-up may include additional application of appropriate electric fields to previously treated lesions.

[0051] Figure 5 5 is a flow chart showing an embodiment of the present invention. In operation 500, a subject presents with endometriosis and needs treatment of endometrial lesions. In operation 502, MRI or other similar methods are used to determine the size and location of the lesions. In operation 504, an analysis is performed to identify a set of parameters that will provide a sufficient electric field and thus provide a treatment zone that causes endometrial cell necrosis. 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 is considered for the delivery of the voltage, in operation 504d, the depth of electrode placement into the lesion is considered, and in operation 504e, the electrodes are placed in the endometrial lesions according to the previous operations. In operation 506, a voltage is applied to form an electric field and thus a treatment zone, in operation 508, the voltage pulses are applied for an appropriate number of times, and in operation 510, it is determined whether the treatment zone has successfully killed or destroyed endometrial cells, causing endometrial cell necrosis. Optionally, the subject is later examined to confirm removal of the endometrial lesion in operation 512. If the lesion has not been completely destroyed, the process starting from 502 or 504 is repeated through 510 until removal is complete.

[0052] The following examples are for illustrative purposes only and are not meant to be limiting of the content.

[0053] Examples

[0054] Example 1: Visualization of treatment zone with applied voltage The following example shows the results of nine different doses applied to potato slices. The doses applied show or simulate how the tissue is affected by the applied electric field. Pulsed electric fields (PEF) are used to induce cell necrosis in living tissue (potato cells). In order to determine the threshold of cell necrosis, potatoes are used as a tissue model. The potatoes used in this article are Ipomoea batatas, Russop and Sweet Potatoes. Potatoes treated in air will be compared with potatoes stained with toluidine blue to evaluate the visualization of the treatment zone.

[0055] The difference in each dose is the total on-time of the foot switch, which determines the total number of waveforms. High peak electric fields that alter tissue, but not enough energy to cause ohmic heating.

[0056] The nine different applications are shown in Table 1 below:

[0057] application Model Setting voltage Cycle Count Still Time Group Count Dead time Waveform 1 10mm needle 1kV 10 0.01 5 0.2sec 10 2 10mm needle 1kV 10 0.01 5 0.2sec 20 3 10mm needle 1kV 10 0.01 5 0.2sec 64 4 10mm needle 2kV 10 0.01 5 0.2sec 10 5 10mm needle 2kV 10 0.01 5 0.2sec 20 6 10mm needle 2kV 10 0.01 5 0.2sec 64 7 10mm needle 3kV 10 0.01 5 0.2sec 11 8 10mm needle 3kV 10 0.01 5 0.2sec 20 9 10mm needle 3kV 10 0.01 5 0.2sec 41

[0058] Table 1: Experiments using potato as a tissue model

[0059] In each experiment within the experiment, each individual will have a treatment zone containing necrotic cells and an electric field threshold edge. The voltage can be increased or decreased to change the zone size. In the experiment, a needle was inserted into a potato and the needle surface boundary condition was set to ground.

[0060] like Fig. 6A and Figure 6B As shown in FIG. 1 , needle electrodes (A) having a diameter of 0.43 mm and a spacing of 10 mm were placed into potatoes according to the experiments herein (B). Figure 2 The treatment area of ​​an exemplary sweet potato 18 hours after treatment is shown. Oxidation of PPO (polyphenol oxidase) in the potato causes visible black electroporated areas. Electric field contours were simulated in photoshop and placed on the image to determine the treatment threshold.

[0061] As shown in Figure 7, toluidine blue powder is mixed with distilled water (0.1 gram / 100ml) to prepare a stain and is immediately added to the treated potato to enhance the treatment area. The treated potato slices are placed face down in the prepared stain for five minutes, then rinsed with distilled water, and then patted dry. The figure shows untreated and treated red potato slices. This technology is used to enhance cell walls. The color change in the treatment area indicates damaged cells because damaged cells allow toluidine blue to be injected into the cells. Figure 8 shows the same experiment during 0 (A). 3hr (B) and 23hr (C).

[0062] Figure 9 shows the addition to Figure 4 A. Figure 4 B and Figure 4 Simulated electric field contours in C. This figure shows that at 3 hours, the shortest time after staining to identify the treated area is seen. The 3 hour area is roughly the same as the 23 hour area.

[0063] Fig.10 A voltage and current diagram is shown, where the current decreases during a single pulse compared to a constant current with a purely resistive load, but can increase by up to 50% when multiple pulses are applied. Similar changes have been observed in living animals and human tissue.

[0064] Fig.11A A bipolar gripping device according to embodiments herein is shown. The gripping device is shown placed into a hole in a potato (11B). An electric field is applied according to embodiments herein, and shown in 11C is a dark purple color where there is cell damage (and defects in the potato) caused by drilling the hole. Fig.11D The treatment area with contour lines placed on the view is shown.

[0065] The data presented herein show that potatoes treated with electric fields according to embodiments herein can be used to visualize cell death. Toluidine blue stain was added to the treated surface to enhance the treated area. To simulate the cell response to electroporation, as the current intensity was increased, potato cells responded in a manner similar to human tissue.

Claims

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

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

3. The method of claim 2, wherein the non-thermal treatment of the endometrial lesions results in necrosis of endometrial cells without significant damage to the accompanying cellular matrix.

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

5. The method of claim 3, wherein the subject is a female between the ages of 25 and 50.

6. The method of claim 1, wherein the electric field has a sufficient duration and voltage 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 the stromal 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. A method for creating a treatment zone at an endometrial lesion outside of a uterus of a subject, comprising: a. providing one or more electrodes for applying a pulse voltage to the endometrial lesion, wherein the pulse voltage produces the treatment area; b. determining the voltage and number of pulses required to form the treatment zone to substantially eliminate the endometrial lesions; c. applying the voltage and number of pulses to the endometrial lesions; d. determining whether additional pulses are needed to eliminate the endometrial lesions; as well as e. Apply any additional pulses to the endometrial lesion.

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

13. The method of claim 12, wherein there is little or no thermal heating of the treatment area caused by the applied voltage and number of pulses. The method of claim 12 , wherein the one or more electrodes are two electrodes.

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

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

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 the depth of the endometrial lesion.

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