Treating the reproductive tract with pulsed electric fields

Abstract

Devices, systems, and methods for treating reproductive tract conditions are provided. Many conditions can affect linings and cell layers deep within the anatomical structure. For example, cervical intraepithelial neoplasia (CIN), also known as cervical dysplasia, is a condition involving abnormal growth of cells on the surface of the cervix that may lead to cervical cancer in situ (CIS). Other conditions include cervical diseases associated with human papillomavirus (HPV), various endometrial diseases, acute and chronic cervicitis, and various infections (e.g., trichomoniasis). In some embodiments, treatment eliminates diseased, damaged, abnormal, or otherwise undesirable cells, leaving behind an intact tissue framework. This allows the tissue to regenerate in a normal manner, avoiding the formation of scar tissue. When the tissue framework remains intact, the framework structure repopulates with healthy cells, thereby regenerating normal tissue without changing the structural properties.

Description

[0001] Cross-references

[0002] This application claims priority to and the benefit of U.S. Patent Application No. 62 / 874,605, filed on July 16, 2019, and entitled “Treatment of the Reproductive Tract with Pulsed Electric Fields,” the disclosure of which is incorporated herein by reference in its entirety. Background Art

[0003] The reproductive tract (or birth canal) is a biological system consisting of the anatomical organs involved in sexual reproduction. The human female reproductive system consists of a series of organs located primarily within the female body and pelvic region that facilitate the reproductive process. The internal portion of the female reproductive system can be considered a single lumen, beginning with a single passage through the vagina, extending through the opening of the cervix, and dividing in the uterus into two lumens, each of which extends through the fallopian tubes. The vagina is a fibromuscular tube that leads from the outside of the body to the cervix. The cervix, the neck of the uterus, is the lower, narrower part connecting to the upper part of the vagina. It has a cylindrical or conical shape and protrudes through the upper anterior vaginal wall. Approximately half of its length is visible, while the remainder lies above the vagina, out of view. The uterus is the primary female reproductive organ. It provides mechanical protection, nutritional support, and waste removal for the developing embryo and fetus. Furthermore, contractions of the uterine muscle wall are crucial for fetal delivery. The fallopian tubes are two tubes that lead from the ovaries into the uterus. When the egg matures, the follicle and ovarian wall rupture, allowing the egg to escape and enter the fallopian tubes. The egg moves toward the uterus, propelled by the movement of hairs called cilia lining the fallopian tubes. If the egg is fertilized in the fallopian tubes, it usually implants in the uterine lining when it reaches the uterus, signaling the start of pregnancy.

[0004] Epithelial cells line the fallopian tubes, uterus, cervix, and vagina. Epithelial cells provide a first line of defense that provides continuous protection by providing a physical barrier and secretions containing microbicides and virucides. In addition to maintaining a constant protective state, these cells have evolved to respond to pathogens, in part through toll-like receptors (TLRs) that serve to enhance innate immune protection and, when necessary, promote the initiation of adaptive immune responses. Within this context, the innate and adaptive immune functions of epithelial cells are regulated to meet reproductive constraints.

[0005] However, many conditions affect the epithelial cell lining and, in some cases, cell layers deeper within the anatomy. For example, cervical intraepithelial neoplasia (CIN), also known as cervical dysplasia, is a condition involving abnormal growth of cells on the surface of the cervix that may lead to cervical cancer. More specifically, CIN refers to the potentially precancerous transformation of cervical cells. CIN most commonly occurs at the squamocolumnar junction of the cervix, which is the transition zone between the squamous epithelium of the vagina and the columnar epithelium of the endocervix. CIN can also occur in the vaginal wall and vulvar epithelium. CIN is graded from 1 to 3, with grade 3 being the most abnormal. The cause of CIN is chronic infection of the cervix with the human papillomavirus (HPV), particularly high-risk HPV types 16 or 18. High-risk HPV infection is thought to have the ability to inactivate tumor suppressor genes, such as the p53 and RB genes, allowing infected cells to grow unchecked and accumulate continuous mutations, ultimately leading to cancer.

[0006] Figure 1A shows the reproductive tract of a female patient. As shown, the reproductive tract includes the vagina (V), cervix (C), uterus (U), and fallopian tubes (F). Figure 1B is a close-up view of a portion of the cervix (C), showing the normal endocervical epithelium (EC) lining the cervix (C). Figure 1C shows the progression of mild epithelial dysplasia. Epithelial dysplasia involves an expansion of immature cells with a corresponding decrease in the number and location of mature cells. Dysplasia often heralds the development of an early neoplasm. The term "dysplasia" is generally used when the cellular abnormalities are limited to the primary tissue, such as an early in situ neoplasm. Mild dysplasia is typically limited to the anterior (most superficial) third of the epithelium. Figure 1D shows the progression of moderate to severe dysplasia. Moderate dysplasia is limited to the upper two-thirds of the epithelium and appears as a mixture of low-grade and high-grade lesions that are poorly differentiated histologically. Severe dysplasia involves undifferentiated neoplastic cells spanning more than two-thirds of the epithelium. Abnormal cells seen on a Pap test may require further testing for a definitive diagnosis. This diagnosis can be made by loop electrosurgical excision procedure (LEEP) / large loop excision of the transformation zone (LLETZ) or cone biopsy / cold knife conization. Conditions beyond severe dysplasia are often referred to as cervical cancer in situ (CIS).

[0007] Stage O categorizes CIS as the earliest form of cervical cancer, but doctors generally consider it a precancerous stage. This is because the cancer cells are only growing in the surface layer of the cervix and have not grown into the deeper cell layers. These cells often show up on a Pap test, and further testing may be needed to confirm the diagnosis. Again, this diagnosis can be achieved through a loop electrosurgical excision procedure (LEEP) / large loop excision of the transformation zone (LLETZ) or a cone biopsy / cold knife conization. Typically, for stage O, these surgical procedures are effective treatments due to the removal of cells.

[0008] After stage O, CIS is divided into different cancer stages. In some early stages, cryosurgery and laser surgery can be used for treatment. Later stages generally include surgery, radiotherapy, or radiotherapy plus chemotherapy (concurrent chemoradiotherapy). Figures 2A-2C show stage IB1 and stage IB2 cervical cancer. As shown, the malignant MCs have invaded the deeper tissues of the cervix, exceeding the epithelial cells (ECs). For patients who wish to preserve their fertility, radical trachelectomy plus pelvic lymph node dissection can be used.

[0009] Possible complications in the diagnosis and treatment of CIN and CIS include infection, bleeding, changes, or scarring of the cervix following tissue removal. Even in procedures that only remove epithelial cells, deeper tissue layers can be affected, leading to scarring. Scarring prevents normal cellular regeneration of decellularized tissue and is associated with necrosis and coagulative necrosis patterns of extracellular matrix (ECM) proteins in response to heat and cold. These suboptimal responses and lesion regression patterns are associated with persistent bleeding, potential loss of tissue elasticity, and the risk of cervical lumen obliteration. In some cases, cervical stenosis can affect fertility and may lead to premature birth.

[0010] A case-control study found an association between surgical treatment of CIN and a higher risk of infertility or subfertility, with an odds ratio of approximately 2. A cohort study found that women whose interval from LEEP to pregnancy was less than 12 months had a significantly increased risk of spontaneous abortion compared with those whose interval was 12 months or longer, with an 18% and 4.6% risk, respectively. On the other hand, no increased risk of preterm birth was found after LEEP. However, a large meta-analysis concluded that women with CIN have a higher baseline risk of preterm birth than the general population, and that LEEP as a treatment for CIN may further increase this risk. Furthermore, the risk of preterm birth appears to increase with the number of treatments and the amount of tissue removed. Cervical conization carries risks for subsequent pregnancies, resulting in an average of 30% preterm birth due to cervical insufficiency.

[0011] Improved diagnostic and treatment procedures are needed. These treatments should be safe, effective, and reduce complications, including impacts on future fertility. Summary of the Invention

[0012] Described herein are embodiments of devices, systems, and methods for treating target tissue.

[0013] In a first aspect, a catheter for treating a tissue region within a patient's reproductive system is provided, the catheter comprising an elongated shaft and an energy delivery body disposed near a distal end of the elongated shaft, wherein the elongated shaft is configured to be advanced into the reproductive system to position the energy delivery body proximate to or against the tissue region within the reproductive system, and wherein the catheter is couplable to a generator in a manner such that energy can be transmitted through the energy delivery body to treat the tissue region.

[0014] In some embodiments, the energy delivery body has a shape configured to match the contour of the patient's cervix. For example, in some embodiments, the energy delivery body has a cup shape, wherein the cup shape has a concave surface configured to match the contour of the patient's cervix. In some embodiments, the energy delivery body comprises a wireform. In some embodiments, the energy delivery body comprises a flexible expandable member configured to be compressed against the cervix to conform to the contour of the cervix. In some embodiments, the flexible expandable member comprises one or more flexible electrodes. Optionally, the flexible expandable member comprises a non-conductive material and the one or more flexible electrodes comprise one or more pad electrodes.

[0015] In some embodiments, the catheter further comprises a stabilizing element configured to be advanced into the patient's uterus to stabilize the catheter while the energy delivery body resides in the patient's vagina to deliver energy to the cervix. In some embodiments, the stabilizing element is mounted on a shaft configured to pass through a lumen in the elongated shaft of the catheter. In some embodiments, the stabilizing element is mounted on a shaft configured to be advanced within the endocervical canal. In some embodiments, the stabilizing element comprises an expandable member having a collapsed configuration that allows passage through the endocervical canal and an expanded configuration that prevents passage through the endocervical canal.

[0016] In some embodiments, the catheter further comprises a second energy delivery body. Optionally, the energy delivery body and the second energy delivery body function as a bipolar pair. In some embodiments, the energy delivery body and the second energy delivery body are configured to receive energy of different waveforms from the generator.

[0017] In some embodiments, the second energy delivery body is configured to be advanced into the patient's uterus to treat a tissue region within the uterus while the energy delivery body resides in the patient's vagina to treat a tissue region within the vagina. In some embodiments, the energy delivery body and the second energy delivery body function as a bipolar pair that delivers an electric field configured to cause destruction of cells along and / or within the cervix. In some embodiments, the second energy delivery body has a funnel shape. In some embodiments, the energy delivery body has a cup shape. In some embodiments, the first and second energy delivery bodies are shaped to nest together, retaining cervical tissue therebetween. In some embodiments, the second energy delivery body is mounted on a second elongated shaft that telescopes within the elongated shaft of the energy delivery body. In some embodiments, the second energy delivery body is configured to be advanced into the endocervical canal to treat a tissue region within the endocervical canal while the energy delivery body resides in the patient's vagina to treat a tissue region within the vagina, or the energy delivery body resides in the patient's uterus to treat a tissue region within the uterus. In some embodiments, the second energy delivery body is mounted on a second elongated shaft that telescopes within the elongated shaft of the energy delivery body.

[0018] In some embodiments, the catheter further comprises a third energy delivery body configured to be advanced into the patient's uterus while the second energy delivery body resides in the endocervical canal and the energy delivery body resides in the patient's vagina. In some embodiments, the second energy delivery body is mounted on a second elongated shaft that telescopes within the elongated shaft of the energy delivery body, and the third energy delivery body is mounted on a third elongated shaft that telescopes within the second elongated shaft.

[0019] In some embodiments, the tissue region comprises multiple interior surfaces of a luminal structure of the reproductive tract, and wherein the energy delivery body comprises an expandable member configured to expand so as to be simultaneously positionable against the multiple interior surfaces. In some embodiments, the expandable member is configured to expand to substantially fill the patient's uterus. In some embodiments, the expandable member comprises a flexible, non-conductive material and one or more flexible pad electrodes.

[0020] In some embodiments, the energy delivery body includes a probe configured to penetrate the wall of a luminal structure within the reproductive system and deliver energy to a tissue region. In some embodiments, the probe is capable of being advanced from the distal end of the elongated shaft. In some embodiments, the probe includes a probe tip, wherein the probe tip is capable of being advanced up to 8 cm from the distal end of the elongated shaft. In some embodiments, the distal end of the elongated shaft is configured to be advanced up to 20 cm beyond the wall of the luminal structure. In some embodiments, the probe includes multiple probe elements, at least one of which is capable of delivering energy to a tissue region. In some embodiments, at least two probe elements are capable of delivering energy, and at least one of the at least two probe elements is capable of being independently selected to receive energy for delivery. In some embodiments, each of the at least two probe elements is capable of simultaneously delivering a different amount of energy. In some embodiments, the probe includes multiple probe elements, wherein each probe element is capable of delivering energy to a tissue region. In some embodiments, wherein the probe includes multiple probe elements, at least one of which is capable of being individually advanced from the shaft.

[0021] In some embodiments, the probe comprises a conductive tube extending from the proximal end of the elongated shaft to the distal end of the elongated shaft. In some embodiments, the probe further comprises an energy plug configured to electrically connect the probe to the generator, wherein the energy plug comprises a conductive wire configured to engage the conductive tube. In some embodiments, the probe comprises: a probe tip disposed near the distal end of the elongated shaft; and a conductive wire extending from the proximal end of the elongated shaft to the probe tip. In some embodiments, the probe comprises a probe tip and a conductive element configured to extend beyond the probe tip, wherein the conductive element is configured to deliver energy to the tissue region.

[0022] In some embodiments, the energy delivery body comprises an electrode having a disk shape. In some embodiments, the disk shape is configured such that its diameter is substantially perpendicular to the longitudinal axis of the elongated shaft. In some embodiments, the energy delivery body comprises a probe tip that is substantially concentric with the electrode having a disk shape. In some embodiments, the catheter is configured such that the electrode having a disk shape delivers different energy than the probe tip.

[0023] In some embodiments, the energy delivery body comprises a basket electrode. In other embodiments, the energy delivery body comprises a paddle configured to be positioned adjacent to a tissue region such that the paddle can deliver energy to the tissue region.

[0024] In some embodiments, the elongated shaft further comprises a delivery lumen configured to deliver a fluid to the tissue region.

[0025] In a second aspect, a system for treating a tissue region within a patient's reproductive system is provided, the system comprising a catheter as described herein; and a generator coupleable to the catheter, wherein the generator comprises at least one energy delivery algorithm configured to provide an electrical signal for energy, wherein the energy is delivered by an energy delivery body to treat the tissue region.

[0026] In some embodiments, the energy comprises non-thermal energy, and treating the tissue region comprises destroying at least a portion of the cells within the tissue region while preserving the collagen structure of the tissue region. In some embodiments, the tissue region comprises epithelial cells along the inner surface of the reproductive system, and wherein the non-thermal energy deliverable by the energy delivery device causes destruction of at least a portion of the epithelial cells. In some embodiments, the epithelial cells reside along the cervix of the reproductive system. In some embodiments, the tissue region resides within the wall of a luminal structure of the reproductive system. In some embodiments, the tissue region comprises a fibroid. In some embodiments, the tissue region resides within the wall of a fallopian tube. In some embodiments, at least one energy delivery algorithm is configured to provide an electrical signal for delivering energy to the tissue region, thereby destroying at least a portion of the tissue region while maintaining the patency of the luminal structure. In some embodiments, the tissue region comprises an undesirable mass of tissue cells, and treating the tissue region comprises destroying at least a portion of the undesirable mass of tissue cells. In some embodiments, the undesirable mass of tissue cells comprises a tumor, a benign tumor, a malignant tumor, a fibroid, a cyst, or a diseased tissue region.

[0027] In some embodiments, the tissue region is located outside a wall of a luminal structure of the reproductive system. In some embodiments, at least one energy delivery algorithm is configured to provide non-thermal energy that can be delivered from the energy delivery body to a depth of up to 3 cm from outside a wall of the luminal structure within the reproductive tract when the energy delivery body is positioned within the luminal structure.

[0028] In some embodiments, at least one energy delivery algorithm is configured to provide non-thermal energy that can be delivered from the energy delivery body to a depth of up to but not exceeding 2 mm into the wall of the luminal structure within the reproductive tract when the energy delivery body is positioned within the luminal structure.

[0029] In some embodiments, at least one energy delivery algorithm is configured to provide non-thermal energy that can be delivered from the energy delivery body to, but not beyond, the epithelial layer of a luminal structure within the reproductive tract. In some embodiments, the luminal structure comprises the cervix, vagina, uterus, or endocervical canal. In some embodiments, the electrical signal comprises a series of biphasic pulses delivered in packets to provide the non-thermal energy. In some embodiments, the voltage of each biphasic pulse is approximately between 100V and 10kV. In some embodiments, the voltage of each biphasic pulse is approximately between 500-4000V. In some embodiments, the frequency range of the electrical signal is approximately 100-1000kHz. In some embodiments, the system further comprises a return electrode that can be positioned at a distance from the energy delivery body so that the energy delivery body acts in a monopolar manner.

[0030] In some embodiments, the catheter includes a second energy delivery body, wherein the energy delivery body and the second energy delivery body function as a bipolar pair, and wherein at least one energy delivery algorithm includes: a first energy delivery algorithm configured to provide a first energy electrical signal deliverable by the energy delivery body; and a second energy delivery algorithm configured to provide a second energy electrical signal deliverable by the second energy delivery body.

[0031] In some embodiments, the system further comprises a liquid transportable by the catheter. Optionally, the liquid comprises a conductive solution. Optionally, the liquid comprises an auxiliary material, and wherein the energy promotes absorption of the auxiliary material. In some embodiments, the auxiliary material comprises a molecule, a macromolecule, or a plasmid.

[0032] Likewise, the present invention relates to the following numbered clauses:

[0033] 1. A method of treating a tissue region within the reproductive system of a patient, comprising:

[0034] inserting a distal end of a catheter having an energy delivery body into a lumen structure of the reproductive system;

[0035] positioning the energy delivery body adjacent to the tissue region; and

[0036] Energy is provided to the catheter so that the energy delivery body delivers the energy to the tissue region, thereby treating the tissue region.

[0037] 2. The method of claim 1, wherein the energy comprises non-thermal energy that causes destruction of at least a portion of cells within the tissue region while preserving collagen structure within the tissue region.

[0038] 3. The method of claim 2, wherein the at least a portion of the cells comprises epithelial cells or squamous cells.

[0039] 4. The method of claim 2, wherein at least a portion of the cells suffer from dysplasia.

[0040] 5. The method of claim 2, wherein the energy causes destruction of at least a portion of cells in the tissue region.

[0041] 6. The method of claim 5, wherein the at least a portion of the cells suffer from cancer.

[0042] 7. The method of claim 1 , wherein the energy delivery body has a shape configured to match the contour of the patient's cervix, and wherein positioning the energy delivery body near the tissue region comprises matching the energy delivery body to the contour of the cervix.

[0043] 8. The method of claim 7, wherein the energy delivery body has a cup shape, and wherein matching comprises positioning a concave surface of the cup shape against the contour of the cervix.

[0044] 9. The method of claim 1, wherein the energy delivery body is comprised of a flexible material, and wherein positioning the energy delivery body comprises pressing the energy delivery body against an inner surface of a luminal structure of the reproductive system.

[0045] 10. The method of claim 9, wherein the energy delivery body comprises a flexible expandable member, the method further comprising expanding the flexible expandable member so as to compress against the inner surface of the luminal structure of the reproductive system.

[0046] 11. The method of claim 10, wherein expanding the flexible expandable member comprises expanding the flexible expandable member to substantially fully fill the patient's uterus.

[0047] 12. The method of claim 9, wherein the flexible expandable member comprises one or more flexible electrodes and wherein pressing the energy delivery body against the inner surface of the luminal structure comprises pressing at least one of the one or more flexible electrodes against the inner surface of the luminal structure.

[0048] 13. The method of claim 1, wherein the catheter further comprises a stabilization element, the method further comprising positioning the stabilization element in a manner to stabilize the position of the energy delivery body adjacent the tissue region.

[0049] 14. The method of claim 13, wherein positioning the stabilization element comprises positioning the stabilization element within the patient's uterus, and wherein positioning the energy delivery body comprises positioning the energy delivery body within the patient's vagina.

[0050] 15. A method as claimed in claim 14, wherein the stabilizing element includes an expandable member, the method further comprising passing the expandable member through the endocervical canal when the expandable member is in a collapsed configuration and expanding the expandable member within the uterus such that such expansion prevents the expandable member from returning through the endocervical canal.

[0051] 16. The method of claim 1 , wherein the catheter further comprises a second energy delivery device, the method further comprising positioning the second energy delivery device near a second tissue region and providing energy to the catheter such that the second energy delivery device delivers energy to the second tissue region, thereby treating the second tissue region.

[0052] 17. The method of claim 16, wherein the first tissue region resides within the patient's vagina and the second tissue region resides within the patient's uterus.

[0053] 18. The method of claim 16, wherein providing energy to the catheter comprises providing energy to the catheter such that the energy delivery body delivers energy to a depth of up to but not exceeding 2 mm into the wall of the luminal structure of the tissue region.

[0054] 19. The method of claim 16, wherein providing energy to the catheter comprises providing energy to the catheter such that the energy delivery body delivers energy to the tissue region to a depth of at most 3 cm from an exterior of a wall of the luminal structure.

[0055] 20. The method of claim 16, wherein providing energy to the catheter comprises providing energy to, but not beyond, an epithelial layer of the luminal structure within the reproductive tract.

[0056] 21. The method of claim 1, wherein the luminal structure comprises a cervix, vagina, uterus, or endocervical canal.

[0057] 22. The method of claim 1, wherein the energy is generated by an electrical signal comprising a series of biphasic pulses delivered in packets.

[0058] 23. The method of claim 22, wherein each of the biphasic pulses has a voltage between approximately 100 V and 10 kV.

[0059] 24. The method of claim 23, wherein each of said biphasic pulses has a voltage of approximately between 500-4000V.

[0060] 25. The method of claim 22, wherein the electrical signal has a frequency in the range of approximately 100-1000 kHz.

[0061] 26. The method of claim 1, further comprising positioning a return electrode at a distance from the energy delivery body such that the energy delivery body functions in a monopolar manner.

[0062] 27. The method of claim 1, further comprising delivering a fluid to the tissue region.

[0063] 28. The method of claim 27, wherein the liquid comprises a conductive solution.

[0064] 29. The method of claim 27, wherein the liquid comprises a secondary material, and wherein the energy promotes absorption of the secondary material.

[0065] 30. The method of claim 29, wherein the auxiliary material comprises a molecule, a macromolecule, or a plasmid.

[0066] 31. A method of treating a cervix of a patient, comprising:

[0067] inserting a distal end of a catheter having an energy delivery body into the patient's vagina;

[0068] positioning the energy delivery body near the cervix;

[0069] Energy is provided to the catheter so that the energy delivery body delivers the energy toward the cervix, thereby causing destruction of a portion of the epithelial cells.

[0070] 32. The method of claim 31 , wherein providing energy comprises providing energy to a depth of up to but not exceeding 2 mm into the wall of the cervix.

[0071] 33. The method of claim 32, wherein providing energy comprises providing energy to a depth of up to but not exceeding 1 mm into the wall of the cervix.

[0072] 34. The method of claim 31, wherein providing energy results in destruction of the portion of epithelial cells without producing scar tissue.

[0073] 35. The method of claim 31, wherein the epithelial cells are dysplastic.

[0074] 36. The method of claim 31, wherein the energy comprises non-thermal energy, and wherein the non-thermal energy causes disruption of the portion of the epithelial cells while preserving the collagen structure of the cervix.

[0075] 37. A method of treating the vagina of a patient, comprising:

[0076] inserting a distal end of a catheter having an energy delivery body into the patient's vagina;

[0077] positioning the energy delivery body adjacent to a wall of the vagina;

[0078] Energy is provided to the catheter such that the energy delivery body delivers the energy toward the vaginal wall, thereby causing rejuvenation of at least a portion of the vaginal wall.

[0079] 38. The method of claim 37, wherein the energy comprises non-thermal energy.

[0080] 39. The method of claim 37, wherein rejuvenating comprises increasing blood flow.

[0081] 40. The method of claim 37, wherein rejuvenating comprises increasing lubricity.

[0082] 41. The method of claim 37, wherein the energy delivery element comprises a wire basket, and positioning the energy delivery element comprises expanding the wire basket so as to contact at least a portion of the vaginal wall.

[0083] 42. The method of claim 41, wherein positioning the energy delivery body comprises expanding the wire basket to circumferentially contact the vaginal canal with the vaginal wall.

[0084] 43. A catheter for treating a tissue region of a patient, comprising:

[0085] an elongated shaft; and

[0086] an energy delivery body disposed near the distal end of the elongated shaft,

[0087] wherein the elongated shaft is configured to be advanced to position the energy delivery body proximate to or against the tissue region, and

[0088] The catheter is coupled to a generator in such a manner that energy can be delivered through the energy delivery body to treat the tissue region.

[0089] 44. The catheter of claim 43, wherein the distal end of the shaft is configured to pass through a percutaneous needle.

[0090] 45. The catheter of claim 43, wherein the shaft is configured to be advanced percutaneously through the patient's skin.

[0091] 46. A system for treating a tissue region in a patient, comprising:

[0092] The catheter of any one of claims 43-45; and

[0093] A generator is coupleable to the catheter, wherein the generator includes at least one energy delivery algorithm configured to provide an electrical signal of energy, wherein the energy is deliverable by the energy delivery body to treat the tissue region.

[0094] These and other embodiments are described in further detail in the following description taken in conjunction with the accompanying drawings.

[0095] Incorporation by reference

[0096] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS

[0097] The accompanying drawings are not necessarily drawn to scale, in which like numerals may describe similar components in different views. Like numerals with different letter suffixes may represent different instances of similar components. These drawings generally illustrate various embodiments discussed herein by way of example and not limitation.

[0098] FIG1A illustrates the reproductive tract of a female patient.

[0099] FIG. 1B provides a close-up view of a portion of the cervix, depicting the normal cervical epithelium lining the cervix.

[0100] Figure 1C depicts the progression of mild epithelial dysplasia.

[0101] Figure 1D depicts the progression of moderate to severe dysplasia.

[0102] 2A-2C illustrate stage IB1 and stage IB2 cervical cancer.

[0103] FIG3A illustrates a basic embodiment of a therapeutic energy delivery catheter.

[0104] FIG. 3B shows an energy delivery body having a paddle shape.

[0105] Figure 4A-4B An embodiment of a therapeutic energy delivery catheter for delivering energy to the surface of the cervix is depicted.

[0106] Figure 5A An embodiment of a waveform of a signal dictated by an energy delivery algorithm is depicted.

[0107] Figure 5B Various examples of biphasic pulses with switching times in between are depicted.

[0108] Figure 5C The relationship between the effective electric field threshold and the pulse length is plotted.

[0109] Figure 5D Example waveforms prescribed by another energy delivery algorithm are depicted, where the waveforms have a voltage imbalance.

[0110] Figure 5E Other examples of waveforms with unequal voltages are depicted.

[0111] Figure 5F Other examples of waveforms with unequal pulse widths are depicted.

[0112] Figure 5G An example waveform prescribed by another energy delivery algorithm is depicted, where the waveform is single-phase.

[0113] Figure 5H Other examples of waveforms with monophasic pulses are depicted.

[0114] Figure 5I Other examples of waveforms with such phase imbalance are depicted.

[0115] Figure 5J An example of a waveform where both the positive and negative voltages are unbalanced is depicted.

[0116] Figure 5K Depicted is an example waveform prescribed by another energy delivery algorithm in which the pulses are sinusoidal in shape rather than square.

[0117] Figures 6A-6D An embodiment of a therapeutic energy delivery catheter for delivering energy to the surface of a cervix is depicted, wherein the catheter has an energy delivery body comprising a flexible expandable member (eg, a balloon) having one or more flexible electrodes mounted thereon.

[0118] Figure 7A-7B An embodiment of a therapeutic energy delivery catheter for delivering energy to a surface of the cervix is depicted, wherein the catheter includes an energy delivery body and a stabilizing element.

[0119] Figure 8A-8B Another embodiment of a therapeutic energy delivery catheter for delivering energy to a portion of the reproductive tract is depicted, wherein the catheter includes a first energy delivery body and a second energy delivery body, wherein the second energy delivery body also serves as a stabilizing element.

[0120] Figure 9A-9BAn embodiment of a therapeutic energy delivery catheter for delivering energy to a portion of reproductive anatomy is depicted, wherein the catheter is configured to deliver energy to the endocervical canal.

[0121] Figures 10A-10B Another embodiment of a therapeutic energy delivery catheter for delivering energy to a portion of the reproductive tract is depicted, wherein the catheter incorporates Figure 8A and Figure 9A Various features of the energy delivery catheter are described.

[0122] Figures 11A-11B Depicted is an embodiment of a therapeutic energy delivery catheter configured to deliver energy to the uterus.

[0123] Figures 12A-12B Depicted are embodiments of therapeutic energy delivery catheters that deliver energy to selected locations within the reproductive anatomy.

[0124] Figures 13A-13B An embodiment of a therapeutic system for extraluminal energy delivery is depicted.

[0125] Figures 14A-14C An example of a connection between an energy plug and a handle is depicted.

[0126] Figures 15A-15C An example method of extraluminal treatment is depicted.

[0127] Figures 16A-16B Depicted is a shaft of a probe having a pattern incorporated into the shaft to provide the desired flexibility and maneuverability, wherein the pattern has a continuous or discontinuous helical pitch along its length.

[0128] Figures 17A-17B Depicted are shafts of probes having a braid incorporated into the shaft, where the braid has either a consistent or variable PIC count along its length.

[0129] Figures 18A-18B A cross-section of an embodiment of a probe shaft 106 having a lumen for fluid transport is depicted.

[0130] Figure 18C A probe shaft is depicted having multiple ports for fluid delivery or aspiration.

[0131] Figure 18D A probe tip is depicted having multiple ports for fluid delivery or aspiration.

[0132] Figure 19A An embodiment of a probe is depicted having three probe elements, each probe element having a corresponding probe tip.

[0133] Figure 19BEmbodiments of probes are depicted that have probe elements extending different distances from the axis and having different curvatures.

[0134] Figure 19C An embodiment of a probe is depicted having probe elements that curve radially outward in a flower or umbrella shape.

[0135] Figure 19D An embodiment of a probe is depicted that includes two probe elements extending from a shaft, wherein each probe element is at least partially covered by a respective insulating sheath, leaving the tip exposed.

[0136] Figure 20 An embodiment of a probe is depicted that includes a plurality of wires or ribbons to form a basket.

[0137] Figure 21 A side view illustration of a probe including a basket having a disc shape is provided.

[0138] Figure 22A An embodiment of a probe is depicted positioned within a target tissue region forming a first ablation zone around the probe tip.

[0139] Figure 22B A probe is depicted in which a disc-shaped basket is added to form a second ablation zone larger than the first ablation zone Figure 22A implementation method.

[0140] Figure 23 An energy delivery body comprising a conductive element passing through and extending from a probe is depicted.

[0141] Figure 24 Flowchart providing example care pathway options for cancer patients. DETAILED DESCRIPTION

[0142] Devices, systems, and methods are provided for treating conditions of the reproductive tract, which, in some cases, are associated with the lining of the reproductive tract. Many conditions can affect the endometrium and cell layers deep within the anatomical structure. For example, cervical intraepithelial neoplasia (CIN), also known as cervical dysplasia, is a condition involving abnormal cell growth on the surface of the cervix that can lead to cervical cancer in situ (CIS). Other conditions include cervical disease related to human papillomavirus (HPV), various endometrial diseases, acute and chronic cervicitis, and various infections (e.g., trichomoniasis). Such conditions can affect various parts of the reproductive tract, such as the vagina, cervix, endocervix, and uterus. Conditions specific to the uterus can include those that cause abnormal uterine bleeding, such as menorrhagia or metrorrhagia. Such non-malignant conditions include polyps, secretory endometrium, and endometritis. Malignant causes include simple and complex hyperplasias that lead to endometrial cancer. Other causes of abnormal uterine bleeding include fibroids or leiomyomata. The devices, systems, and methods described herein are particularly suitable for treating such conditions and other conditions.

[0143] The devices, systems and methods described herein eliminate diseased, damaged, abnormal or otherwise undesirable cells, leaving behind an intact tissue framework. This allows tissue to regenerate in a normal manner, avoiding the formation of scar tissue. Scars occur when the tissue framework is damaged or removed. In this case, the repair of the tissue framework involves the introduction of the same protein (collagen) that it replaced, but the protein's fiber composition and arrangement are different from those of normal tissue. Unlike the random basket-weave form of collagen fibers found in normal tissue, in fibrotic tissue, the collagen is cross-linked and forms a distinct arrangement in a single direction. The functional quality of this collagen scar tissue arrangement is generally lower than that of randomly arranged normal collagen. The result is scar tissue. In contrast, when the tissue framework remains intact, the framework structure is repopulated with healthy cells, regenerating normal tissue without changing its structural properties.

[0144] This treatment, which preserves the tissue framework and thus reduces or eliminates complications such as scarring, is achieved using specialized energy delivery devices that deliver pulsed electric fields (PEFs) under specific parameter settings. PEFs are delivered via at least one electrode placed on or near the target tissue area. These PEFs destabilize the affected cells, leading to subsequent cell death. In some cases, this directly treats the condition. In other cases, it can reduce the severity of the condition, such as downstaging a cancer, potentially allowing other treatments to successfully eliminate the cancer.

[0145] Typically, an electrode or electrode array is placed near or in contact with a target tissue, such as the lining of the reproductive tract, optionally the epithelial cells (EC) lining the cervix C. It will be appreciated that in some embodiments, the electrodes are positioned in contact with a conductive substance that is also in contact with the target tissue. Such solutions may include isotonic or hypertonic solutions. These solutions may also include adjuvants, such as chemotherapy or calcium, to further enhance the effectiveness of treatment for focal lesions and potential regional infiltration of the target tissue type. In a monopolar arrangement, dispersed electrodes are placed externally, such as on the patient's skin. High-voltage, short-duration biphasic electrical pulses are then delivered through the electrodes near the target tissue. The induced electric field is strongest at the tissue-electrode interface and gradually decays until it falls below a lethal field threshold, which is based on secondary parameters such as packet duration, number of packets / packet count, frequency, and packet timing. Cells within the tissue region where the electric field is greater than the lethal field threshold die. Thus, therapies are designed such that target cells (e.g., potentially abnormal / neoplastic / dysplastic cells) are either killed directly or rendered more sensitive to the effects of the therapy or by absorption of adjuvant materials, while surrounding tissues are preserved to maintain their function and reduce the likelihood of any adverse events or concurrent morbidity.

[0146] Overview of Example Implementations

[0147] Typically, the electrodes or electrode arrays that deliver PET are placed on a therapeutic energy delivery catheter configured to be advanced to the target tissue site. Access to various portions of the reproductive tract is typically through the vagina V. FIG3A illustrates a basic embodiment of a therapeutic energy delivery catheter 102. In this embodiment, the catheter 102 has an elongated shaft 106 with at least one energy delivery element 108 near its distal end and a handle 110 at its proximal end. The catheter 102 can be connected to a generator 104 as part of the treatment system 100. The connection between the catheter 102 and the generator 104 provides electrical energy to the energy delivery element 108, as well as other features. In this embodiment, the energy delivery element 108 comprises a plurality of wires or ribbons 120, which are constrained by proximal and distal end restraints 122 and 124 and form a helical basket that serves as the electrode. In alternative embodiments, the wires or ribbons are straight rather than helically shaped (i.e., configured to form a straight basket). In yet another embodiment, the energy delivery element 108 is laser cut from the tube. It will be appreciated that a variety of other designs may be used. For example, FIG3B depicts an energy delivery body 108 having a paddle-like shape. In this embodiment, the energy delivery body 108 is composed of a plurality of wires or ribbons 120 arranged to form a flat pad or paddle. Such an energy delivery body 108 is flexible so as to be retracted into the shaft 106. Referring back to FIG3A , in some embodiments, the energy delivery body 108 is self-expandable and delivered to the target area in a collapsed configuration. For example, this collapsed configuration may be achieved by placing a sheath 126 over the energy delivery body 108. The catheter shaft 106 (within the sheath 126) terminates in a proximal end restraint 122, leaving the distal end restraint 124 substantially unconstrained axially and free to move relative to the shaft 106 of the catheter 102. Advancing the sheath 126 over the energy delivery body 108 allows the distal end restraint 124 to move forward, thereby extending / contracting and restraining the energy delivery body 108.

[0148] As shown in this example, the catheter 102 includes a handle 110 at its proximal end. In some embodiments, the handle 110 is removable, such as by pressing a handle removal button 130. In this embodiment, the handle 110 includes an energy delivery body manipulation knob 132, wherein movement of the knob 132 causes the basket electrode to expand or retract / collapse. In this example, the handle 110 also includes: a working port clip 134, which is used to optionally connect to an endoscope, hysteroscope, or other type of visualization device; and a cable insertion port 136, which is used to connect to the generator 104. It will be appreciated that various types of visualization can be used. Typically, the reproductive tract is entered through the use of a speculum, and direct visualization or direct video visualization is employed. In some embodiments, particularly when accessing portions of the reproductive tract distal to the vagina, other types of visualization can be used, including angiography (optionally including markers), computed tomography, optical coherence tomography, and ultrasound, to name a few.

[0149] In this embodiment, the therapeutic energy delivery catheter 102 can be connected to a generator 104 and a dispersive (return) electrode 140 applied externally to the skin of the patient P. Thus, in this embodiment, monopolar energy delivery is achieved by supplying energy between an energy delivery body 108 disposed near the distal end of the catheter 102 and the return electrode 140. However, it should be understood that bipolar energy delivery and other arrangements may be used instead. When bipolar energy delivery is used, the therapeutic energy delivery catheter 102 may differ in overall design, such as including multiple energy delivery bodies 108, or may appear similar in overall design, such as including a single energy delivery body 108 configured to function in a bipolar manner (e.g., the energy delivery body 108 includes multiple electrodes functioning in a bipolar manner). In some cases, bipolar energy delivery allows for the use of lower voltages to achieve a therapeutic effect compared to monopolar energy delivery. In some bipolar configurations, the positive and negative electrodes are close enough together to provide a therapeutic effect both at the electrode poles and between the electrode poles. This allows the therapeutic effect to be spread over a larger, more superficial surface area than with monopolar therapy, thus requiring a lower voltage to achieve a therapeutic effect. Likewise, this lower voltage can be used to reduce penetration depth.

[0150] In this embodiment, the generator 104 includes a user interface 150, one or more energy delivery algorithms 152, a processor 154, a data storage / retrieval unit 156 (such as a memory and / or database), and an energy storage subsystem 158 for generating and storing energy to be delivered. In some embodiments, one or more capacitors are used for energy storage / delivery, however, any other suitable energy storage element may be used. In addition, one or more communication ports are included.

[0151] In some embodiments, the generator 104 includes three subsystems: 1) a high energy storage system; 2) a high voltage intermediate frequency switching amplifier; and 3) a system controller, firmware, and a user interface. Although unlikely to be required when treating the reproductive tract, in some embodiments, the system controller includes a cardiac synchronization trigger monitor that allows the pulse energy output to be synchronized with the patient's heart rhythm. The generator receives an alternating current (AC) power source to power multiple direct current (DC) power supplies. Before energy delivery is initiated, the generator's controller can cause the DC power supply to charge the high energy capacitor storage device group. When therapeutic energy delivery is initiated, the generator's controller, high energy storage reservoir, and biphasic pulse amplifier can operate simultaneously to form a high voltage, intermediate frequency output.

[0152] It should be understood that a variety of generator electrical configurations can be employed to implement energy delivery algorithms. In particular, in some embodiments, advanced switching systems are used that can separate the pulsed electric field circuitry from the same energy storage and high-voltage delivery system to direct the energy delivery electrodes. In addition, generators employed in advanced energy delivery algorithms that employ rapidly changing pulse parameters (e.g., voltage, frequency, etc.) or multiple energy delivery electrodes can utilize modular energy storage and / or high-voltage systems to facilitate highly customizable waveforms and geographic pulse delivery paradigms. It should also be understood that the electrical configurations described above are merely examples, and that systems delivering pulsed electric fields may or may not include other switching amplifier components.

[0153] The user interface 150 may include a touch screen and / or more traditional buttons to allow an operator to enter patient data, select a treatment algorithm (e.g., energy delivery algorithm 152), initiate energy delivery, view records stored on the storage / retrieval unit 156, and / or otherwise communicate with the generator 104.

[0154] In some embodiments, the user interface 150 is configured to receive operator-defined inputs. The operator-defined inputs can include the duration of energy delivery, one or more other timing aspects of energy delivery pulses, power and / or operating modes, or combinations thereof. Example modes of operation can include (but are not limited to): system startup and self-test, operator input, algorithm selection, pre-treatment system status and feedback, energy delivery, post-energy delivery display or feedback, treatment data review and / or download, software update, or any combination or subcombination thereof.

[0155] Because the reproductive system is located at a considerable distance from the heart, treatment of the reproductive system is unlikely to require cardiac synchronization. However, in some embodiments, the system 100 also includes a mechanism for obtaining an electrocardiogram (ECG) in the event cardiac synchronization is required, such as an external cardiac monitor 170. An example cardiac monitor is available from AccuSync Medical Research Corporation. In some embodiments, the external cardiac monitor 170 is operably connected to the generator 104. The cardiac monitor 170 can be used to continuously obtain ECG signals. External electrodes 172 can be applied to the patient P to obtain the ECG. The generator 104 analyzes one or more cardiac cycles and identifies the beginning of a time period when it is safe to apply energy to the patient P, thereby providing the ability to synchronize energy delivery with the cardiac cycle. In some embodiments, this time period is within milliseconds of the R wave (of the ECG QRS complex) to avoid inducing arrhythmias, which may occur if the energy pulse is delivered on the T wave. It should be understood that this type of cardiac synchronization is typically utilized when using unipolar energy delivery, but it can be used as part of other energy delivery methods.

[0156] In some embodiments, the processor 154 modifies and / or switches between energy delivery algorithms, monitors energy delivery and any sensor data, and reacts to the monitored data via a feedback loop, among other activities. In some embodiments, the processor 154 is configured to execute one or more algorithms to operate a feedback control loop based on one or more measured system parameters (e.g., current), one or more measured tissue parameters (e.g., impedance), and / or a combination thereof.

[0157] The data storage / retrieval unit 156 stores data, such as data related to the delivered therapy, and can be optionally downloaded by connecting a device (e.g., a laptop or thumb drive) to the communication port. In some embodiments, the device has local software for directing the download of information, such as, for example, instructions stored on the data storage / retrieval unit 156 and executable by the processor 154. In some embodiments, the user interface 150 allows the operator to select to download data to a device and / or system, such as, but not limited to, a computer device, a tablet computer, a mobile device, a server, a workstation, a cloud computing device / system, etc. As just described, the communication port, which can permit wired and / or wireless connections, can permit data downloads, but can also allow data uploads, such as uploading customized algorithms or providing software updates.

[0158] As described herein, a variety of energy delivery algorithms 152 can be programmed or pre-programmed into the generator 104, such as stored in a memory or data storage / retrieval unit 156. Alternatively, the energy delivery algorithms can be added to the data storage / retrieval unit for execution by the processor 154. Each of these algorithms 152 can be executed by the processor 154. In some embodiments, the catheter 102 includes one or more sensors 160 that can be used to determine temperature, impedance, resistance, capacitance, conductivity, dielectric constant, and / or conductance, among other things. The sensor data can be used to plan treatment, monitor treatment, and / or provide direct feedback via the processor 154, which can then make changes to the energy delivery algorithm 152. For example, impedance measurements can be used not only to determine the initial dose to be applied, but also to determine whether additional treatment is needed.

[0159] It should be understood that system 100 may include an automated therapy delivery algorithm that can dynamically respond and adjust and / or terminate therapy in response to inputs such as temperature, impedance at various voltages or AC frequencies, therapy duration or other timing aspects of energy delivery pulses, therapy power, and / or system status.

[0160] In some embodiments, imaging is achieved using a commercially available system, such as an endoscope or hysteroscope, coupled to a separate imaging screen 180, as shown in FIG3. It should be understood that the imaging modality can be incorporated into, used with, or in conjunction with the catheter 102. The imaging modality can be mechanically, operatively, and / or communicatively coupled to the catheter 102 using any suitable mechanism.

[0161] As previously described, one or more energy delivery algorithms 152 are programmable or can be pre-programmed into the generator 104 for delivery to the patient P. The one or more energy delivery algorithms 152 specify electrical signals that provide non-thermal energy delivered to the reproductive tract wall (e.g., below the threshold for thermal ablation; below the threshold for inducing coagulative thermal damage), reduce or avoid inflammation, and / or prevent denaturation of matrix proteins in the luminal structure. Generally speaking, the algorithms 152 are tailored to affect tissue to a predetermined depth or volume and / or to target the response of a specific type of cell to the delivered energy.

[0162] Figures 4A-4B An embodiment of a therapeutic energy delivery catheter 102 delivering energy to the surface of the cervix C is depicted. Figure 4A The catheter 102 is shown advanced into the vagina V and positioned so that the energy delivery body 108 is proximate to or against a portion of the cervix C. Figure 4B Provided Figure 4A, in which the energy delivery bodies 108 are shown positioned against the epithelial cells EC lining the cervix C. It will be appreciated that the epithelial cells EC along the ectocervix (the portion of the cervix C outside the endocervical canal ECC) are composed of squamous cells. Such squamous cells transform into glandular cells near or within the endocervical canal, with soft columnar glandular cells lining the endocervix. Thus, in this example, the energy delivery bodies 108 are positioned against the squamous cells of the ectocervix. Energy is delivered to the squamous cells as indicated by the wavy arrows. It will be appreciated that depth and / or cell targeting can be affected by the parameters of the energy signal dictated by the one or more energy delivery algorithms 152, the design of the catheter 102 (particularly the one or more energy delivery bodies 108), and / or the choice of monopolar or bipolar energy delivery.

[0163] In some embodiments, energy penetrates the epithelial cell EC layer to different depths (e.g., up to 1 mm, up to 2 mm), for example, for the treatment of CIN. This can destroy abnormal epithelial cell EC without affecting cells outside the epithelial cell layer. In other embodiments, energy penetrates beyond the epithelial cell EC layer (e.g., up to 1 cm), for example, for the treatment of CIS. In such embodiments, energy penetration can be increased to treat tumors of various sizes and various degrees of disease. It will be appreciated that due to the nature of the energy delivered, penetration beyond the epithelial cell layer avoids many complications associated with conventional treatments of these tissue layers, particularly the formation of scar tissue. As previously described, the energy delivered eliminates diseased, damaged, abnormal or otherwise undesirable cells, leaving behind an intact tissue framework. This allows tissue to regenerate in a normal manner, avoiding the formation of scar tissue.

[0164] In some embodiments, a penetration depth of at most 0.01 cm, at most 0.02 cm, 0.01-0.02 cm, at most 0.03 cm, 0.03-0.05 cm, at most 0.05 cm, at most 0.08 cm, at most 0.09 cm, at most 0.1 cm, at most 0.2 cm, at most 0.5 cm, at most 0.7 cm, at most 1.0 cm, at most 1.5 cm, at most 2.0 cm, at most 2.5 cm, at most 3.0 cm, at most 3.5 cm, at most 4.0 cm, at most 4.5 cm, or up to 5.0 cm can be achieved, to name a few. It will be appreciated that in some embodiments, energy is delivered to the target tissue from within the cavity wall rather than from the surface of the cavity wall. This can be achieved using various devices, including, for example, needle electrodes. This can be particularly useful in treating tumors or fibroids. Fibroids can vary greatly in size. Typically, fibroids are at least 0.5 cm in diameter at diagnosis and up to 20 cm or more in diameter. Therefore, fibroids can be treated with a single treatment or with multiple overlapping treatments. For example, the volume treatment area can be 0.05 cm 3 to 4000cm3 Or even bigger.

[0165] As described above, the treatment energy is typically characterized by high-voltage pulses that allow for the removal of targeted tissue with little or no damage to critical anatomical structures, such as tissue-level structural proteins in the extracellular matrix. This can prevent dangerous complications such as stenosis (e.g., when treating the endocervical canal), thrombosis, or fistula formation, and also allows for the regeneration of healthy new luminal tissue within a few days after the procedure. The treatment can use 1) a circumferentially distributed pulsed electric field current or 2) a locally directed pulsed electric field current. Examples of systems that provide similar types of treatment methods include lung tissue modification systems (e.g., energy delivery catheter systems) described in the following commonly assigned patent applications: International Patent Application No. PCT / US2017 / 039527, entitled “GENERATOR AND A CATHETER WITH AN ELECTRODE AND A METHOD FOR TREATING A LUNGPASSAGEWAY,” which claims priority to U.S. Provisional Application Nos. 62 / 355,164 and 62 / 489,753; International Patent Application No. PCT / US2018 / 067501, entitled “METHODS, APPARATUSES, AND SYSTEMS FOR THE TREATMENT OF DISORDERS,” which claims priority to U.S. Provisional Application No. 62 / 610,430; and International Patent Application No. PCT / US2018 / 067504, entitled “OPTIMIZATION OF ENERGY DELIVERY FOR VARIOUS APPLICATIONS,” which claims priority to Provisional Patent Application No. 62 / 610,430, filed December 26, 2017, and Provisional Patent Application No. 62 / 693,622, filed July 3, 2018, all of which are incorporated herein by reference for all purposes.

[0166] Energy delivery algorithm

[0167] It will be appreciated that various energy delivery algorithms 152 may be used. In some embodiments, the algorithm 152 provides for a signal having a waveform comprising a series of energy packets, wherein each energy packet comprises a series of high voltage pulses. In such embodiments, the algorithm 152 specifies parameters of the signal, such as the energy amplitude (e.g., voltage) and the duration of energy application, including the number of packets, the number of pulses within a packet, and the fundamental frequency of the pulse train, to name a few. Additional parameters may include the switching time between polarities in biphasic pulses, the dead time between biphasic cycles, and the rest time between packets, which will be described in more detail in later sections. There may be a fixed rest period between packets, or packets may be gated into the cardiac cycle, thereby varying with the patient's heart rate. There may be an intentional, variable rest period algorithm, or no rest period may be applied between packets. Feedback loops based on sensor information and automatic shut-off specifications, etc. may be included.

[0168] Figure 5A An embodiment of a waveform 400 of a signal specified by the energy delivery algorithm 152 is depicted. Here, two packets are shown, a first packet 402 and a second packet 404, wherein packets 402, 404 are separated by a rest period 406. In this embodiment, each packet 402, 404 includes a first biphasic period (including a first positive pulse peak 408 and a first negative pulse peak 410) and a second biphasic period (including a second positive pulse peak 408' and a second negative pulse peak 410'). The first biphasic pulse and the second biphasic pulse are separated by a dead time 412 (i.e., a pause) between each pulse. In this embodiment, the biphasic pulses are symmetrical, such that the set voltage 416 of the positive and negative peaks is the same. Here, the biphasic symmetrical wave is also a square wave, such that the amplitude and duration of the positive voltage wave are approximately equal to the amplitude and duration of the negative voltage wave. When using a bipolar configuration, portions of the luminal cells facing the negative voltage wave experience cellular depolarization in these regions, wherein normally negatively charged cell membrane regions briefly become positive. Conversely, the portion of the luminal cell facing the positive voltage wave experiences hyperpolarization, where the potential of the cell membrane region becomes extremely negative. It will be appreciated that during each positive or negative phase of the biphasic pulse, portions of the luminal cell will experience opposing effects. For example, the portion of the cell membrane facing the negative voltage will experience depolarization, while the portion 180° away from this portion will experience hyperpolarization. In some embodiments, the hyperpolarized portion faces the dispersive or return electrode 140.

[0169] A. Voltage

[0170] The voltage used and considered can be the top of a square wave, can be the peak of a sine wave or sawtooth wave, or can be the RMS voltage of a sine wave or sawtooth wave. In some embodiments, energy is delivered in a unipolar manner, and each high voltage pulse or set voltage 416 is between about 500V and 10,000V, particularly about 500V to 2500V, 2500V to 3000V, 500V to 3500V, 3500V to 4000V, about 3500V to 5000V, about 3500V to 6000V, including all values and subranges therebetween, including about 1500V, 2000V, 2500V, 3000V, 3500V, 4000V, 4500V, 5000V, 5500V, 6000V, etc.

[0171] As will be appreciated, the set voltage 416 can vary depending on whether the energy is delivered in a monopolar or bipolar manner. In bipolar delivery, lower voltages can be used due to the smaller, more directional electric field. The bipolar voltage selected for treatment depends on the separation distance of the electrodes, while a monopolar electrode configuration using one or more remote dispersive pad electrodes allows for delivery without requiring greater consideration of the precise placement of the catheter electrode and the dispersive electrode placed on the body. In monopolar electrode embodiments, higher voltages are typically used due to the dispersive behavior of the delivered energy through the body to the dispersive electrodes, with an effective separation distance of approximately 10 cm to 100 cm. In contrast, in a bipolar electrode configuration, the relatively close active areas of the electrodes, approximately 0.5 mm to 10 cm (including 1 mm to 1 cm), result in a greater impact on the electrical energy concentration and active dose delivered to the tissue from the separation distance. For example, if the target voltage-to-distance ratio is 3000 V / cm to evoke the desired clinical effect at the appropriate tissue depth (1.3 mm), if the separation distance is changed from 1 mm to 1.2 mm, this will result in an increase in the treatment voltage from 300 V to approximately 360 V, a change of 20%.

[0172] In some embodiments, energy is delivered in a bipolar manner and utilizes a voltage-to-distance ratio. Depending on the distance between the poles in the bipolar arrangement, the voltage can be varied to achieve the same voltage-to-distance ratio. For example, voltage-to-distance ratios in a bipolar arrangement include 200 V / cm, 250 V / cm, 500 V / cm, 500-3000 V / cm, 1000 V / cm, 1500 V / cm, 250-1500 V / cm, 2000 V / cm, 2500 V / cm, 3000 V / cm, etc.

[0173] B. Frequency

[0174] It will be appreciated that the number of biphasic cycles per second is the frequency of the signal if it were continuous. In some embodiments, biphasic pulses are used, for example, to reduce undesirable muscle stimulation. In other embodiments, the pulse waveform is monophasic and has no well-defined natural frequency. Instead, the fundamental frequency can be taken into account by doubling the monophasic pulse length to derive the frequency.

[0175] In some embodiments, the signal has a frequency in the range of 100kHz to 1MHz (more specifically 100kHz to 1000kHz). Typically, the frequency is selected based on the target depth and the type of disease. In some embodiments, the signal has a frequency in the range of approximately 100kHz to 800kHz, which typically penetrates the cavity wall by at most 10mm, depending on the combined parameters. When using a unipolar biphasic waveform, example base frequencies include 300kHz, 400kHz, 500kHz, 300-600kHz, 400-800kHz, 500-800kHz, 550kHz, 600kHz, 650kHz, 700kHz, 750kHz, 300-800kHz, and 800kHz, including all subranges. It will be understood that at some voltages, frequencies of 100kHz to 250kHz or below may cause undesirable muscle stimulation. It will be understood that higher frequencies can also be used with components that minimize signal artifacts.

[0176] C. Voltage-frequency balance

[0177] The delivered waveform frequency can be varied synchronously with the treatment voltage to maintain adequate therapeutic effect. Such synergistic variations would include a decrease in frequency, resulting in a stronger effect, along with a decrease in voltage, resulting in a weaker effect. For example, in some cases, treatment may be delivered monopolarly at 3000V with a waveform frequency of 800kHz, while in other cases, treatment may be delivered at 2000V with a waveform frequency of 400kHz.

[0178] When used in the opposite direction, the treatment parameters may be manipulated in a way that makes it too effective, which may increase the likelihood of muscle contraction or risk effects on undesirable tissue (such as cartilage for airway treatment). For example, if the frequency is increased and the voltage is decreased, such as using 2000V at 800kHz, the treatment may not have sufficient clinical therapeutic benefit. Conversely, if the voltage is increased to 3000V and the frequency is decreased to 400kHz, an undesirable degree of therapeutic effect may be achieved on collateral sensitive tissues. In some cases, overtreatment of these undesirable tissues may lead to patient morbidity or safety issues, such as destruction of cartilage tissue in the airway sufficient to cause airway collapse, or destruction of smooth muscle in the gastrointestinal tract sufficient to cause disruption of normal peristalsis. In other cases, overtreatment of non-targeted or undesirable tissues may have benign clinical outcomes and not affect patient response or morbidity if they are overtreated.

[0179] D. Packet

[0180] As described above, the algorithm 152 provides for a signal having a waveform comprising a series of energy packets, wherein each energy packet comprises a series of high voltage pulses. The cycle count 420 is half the number of pulses in each biphasic packet. Figure 5A , the first packet 402 has a cycle count 420 of two (i.e., four biphasic pulses). In some embodiments, the cycle count 420 is set between 1 and 100 per packet, including all values and subranges therebetween. In some embodiments, the cycle count 420 is at most 5 pulses, at most 10 pulses, at most 25 pulses, at most 40 pulses, at most 60 pulses, at most 80 pulses, at most 100 pulses, at most 1,000 pulses, or at most 2,000 pulses, including all values and subranges therebetween.

[0181] The packet duration is determined by the cycle count and frequency, among other factors. When other variables remain constant, the higher the cycle count, the longer the packet duration and the greater the amount of energy delivered. In some embodiments, the packet duration is in the range of approximately 20 μs to 1000 μs, such as 20 μs, 30 μs, 40 μs, 50 μs, 50 μs-250 μs, 60 μs, 70 μs, 80 μs, 90 μs, 100 μs, 125 μs, 150 μs, 175 μs, 200 μs, 250 μs, 100 μs to 250 μs, 150 μs to 250 μs, 200 μs to 250 μs, 500 μs to 1000 μs, and the like. In other embodiments, the packet duration is in the range of approximately 100 microseconds to 1000 microseconds, such as 150 μs, 200 μs, 250 μs, 500 μs, or 1000 μs. In other embodiments, the packet duration is in the range of approximately 2 ms, 3 ms, 5 ms, or 10 ms.

[0182] The number of packets delivered during treatment, or packet count, can include 1 packet, 2 packets, 3 packets, 4 packets, 5 packets, 10 packets, 15 packets, 20 packets, 25 packets, 30 packets, 40 packets, 1 to 5 packets, 1 to 10 packets, 1 to 15 packets, 1 to 20 packets, 1 to 100 packets, or 1 to 1000 packets, including all values and subranges therein. In some embodiments, when using a monopolar arrangement with a biphasic waveform, 1-15 packets are delivered, where each packet has a packet duration of 100 μs, a set voltage of 2500 V, and a fundamental frequency of 600 kHz. This can achieve a target depth of 0.1-1 mm. Increasing the packet count to 15-40 can increase the target depth to 1-2 mm. Similarly, increasing the packet count to 40-100 and using a set voltage of 3000V, a fundamental frequency of 500kHz, and a packet duration of 100μs can increase the target depth to 2-5mm. In addition, using a packet count of 20-200 and using a set voltage of 4000V, a frequency of 400kHz, and a packet duration of 200μs can increase the target depth to 5-10mm. In some embodiments, when using a bipolar arrangement with a biphasic waveform, 1-100 packets are delivered, each with a packet duration of 100μs, a voltage-to-distance ratio of 2000V / cm, and a fundamental frequency of 600kHz are used. This can achieve a target depth of 0.1-1mm. Increasing the packet count to 40-100, each with a packet duration of 100μs, a voltage-to-distance ratio of 2500V / cm, and a fundamental frequency of 500kHz can increase the target depth to 2-5mm.

[0183] E. Rest period

[0184] In some embodiments, the time between packets, referred to as rest period 406, is set between about 0.1 seconds and about 5 seconds, including all values and subranges therebetween. In other embodiments, rest period 406 ranges from about 0.001 seconds to about 10 seconds, including all values and subranges therebetween. In some embodiments, rest period 406 is approximately 1 second.

[0185] F. Switching time and dead time

[0186] like Figures 5B to 5C As shown, the switching time is the delay or period of no energy delivered between the positive and negative peaks of the biphasic pulse. Figure 5B Various examples of biphasic pulses (including positive peak 408 and negative peak 410) are depicted with a switching time 403 therebetween (however, it does not occur when the switching time 403 is zero). In some embodiments, the switching time ranges from about 0 microseconds to about 1 microsecond, including all values and subranges therebetween. In other embodiments, the switching time ranges from 1 microsecond to 20 microseconds, including all values and subranges therebetween. In other embodiments, the switching time ranges from about 2 microseconds to about 8 microseconds, including all values and subranges therebetween. Figure 5C The relationship between the effective electric field threshold and the switching time is plotted.

[0187] A delay, referred to as "dead time," may also be inserted between each cycle of the biphasic pulses. Dead time occurs within a packet, but between biphasic pulses. This is in contrast to the rest period that occurs between packets. In other embodiments, dead time 412 is in the range of approximately 0 microseconds to 0.5 microseconds, 0 microseconds to 10 microseconds, 2 microseconds to 5 microseconds, 0 microseconds to 20 microseconds, approximately 0 microseconds to approximately 100 microseconds, or approximately 0 microseconds to approximately 100 milliseconds, including all values and subranges therebetween. In some embodiments, dead time 412 microseconds is in the range of 0.2 microseconds to 0.3 microseconds. Dead time may also be used to define the period between individual monophasic pulses within a packet.

[0188] Delays (such as switching times and dead times) are introduced into the package to reduce the effects of biphasic cancellation within the waveform. Biphasic cancellation is a term used to refer to the reduced induction of cellular modulation in response to a biphasic waveform relative to a monophasic waveform, particularly when the switching time and dead time are small (such as, less than 10 μs). An explanation for this phenomenon is provided here, although it is understood that there may be other biological, physical or electrical properties or changes that lead to reduced modulation of the biphasic waveform. When cells are exposed to an electromotive force induced by the presence of an electric field, there is electrokinetic movement of ions and solutes in the intracellular and extracellular fluids. These charges accumulate at dielectric boundaries such as cell and organelle membranes, thereby changing the resting transmembrane potential (TMP). When the electric field is removed, the driving force that generates the manipulated TMP is also eliminated, and normal biological transport and ion dynamics operated by concentration gradients begin to restore the normal distribution of solutes. This results in a logarithmic decay of the TMP manipulated on the membrane. However, if, rather than eliminating the electric field, the field polarity is maintained but with an opposite polarity, a new electromotive force is generated that actively cancels the existing TMP induced, subsequently accumulating a TMP of the opposite polarity. This active depletion of the initially manipulated TMP significantly limits the cascade of downstream effects that can occur in the cell, weakening the therapeutic effect of the initial electric field exposure. Furthermore, the subsequent electric field of opposite polarity must first "undo" the original TMP manipulation generated before beginning to accumulate its own TMP of the opposite polarity; assuming the duration of each phase of the cycle is the same, the final TMP achieved during the second phase of the field is less intense than the original TMP. This reduces the therapeutic effect generated by each phase of the waveform, resulting in a lower therapeutic effect than that generated by any pulse in the cycle alone. This phenomenon is known as biphasic cancellation. For packets with many cycles, this pattern repeats across the entire collection of cycles, with the phase varying within the packet. This significantly limits the therapeutic effect. When pulsed electric fields modulate cellular behavior through mechanisms other than pure transmembrane potential manipulation, the effects of biphasic cancellation are understandably less pronounced, and thus the impact of switching time and dead time on therapeutic outcomes is reduced.

[0189] Therefore, in some embodiments, the effect of dual-phase cancellation is reduced by introducing a switching time delay and a dead time. In some cases, both the switching time and the dead time are increased together to enhance the effect. In other cases, only the switching time or only the dead time is increased to induce this effect.

[0190] It will be appreciated that, generally, appropriate timing is to complete relaxation of the TMP after 5 times the charging time constant τ. For most cells, the time constant can be on the order of 1 μs. Therefore, in some embodiments, both the switching time and the dead time are set to at least 5 μs to eliminate biphasic cancellation. In other embodiments, reduction in biphasic cancellation may not require complete cell relaxation before reversing polarity, so both the switching time and the dead time are set to 0.5 μs to 2 μs. In other embodiments, the switching time and the dead time are set to the same length as the length of a single pulse, as further increases in these delays may only provide diminishing returns in terms of increased therapeutic effect and incidental increases in muscle contraction. In this way, a combination of longer pulse durations (>500 ns) and stacked pulse periods with substantial switching time and dead time delays makes it possible to use biphasic waveforms without experiencing a significant reduction in therapeutic effect due to biphasic cancellation. In some cases, these parameters can be adjusted to induce a stronger therapeutic effect without a correspondingly proportional increase in muscle contraction. For example, using a 600 kHz waveform with switching time = dead time = 1.66 us (twice the pulse duration) can be used to maintain a reduction in muscle contraction relative to a monophasic pulse waveform, but maintain a stronger therapeutic effect.

[0191] In some embodiments, the switching duration is adjusted so that the extent of the therapeutic effect relative to the distant cellular effect is optimized for the targeting of the therapy. In some embodiments, the switching duration or dead time duration is minimized to reduce distant muscle cell contraction, with a smaller local therapeutic effect. In other embodiments, the switching duration is extended to increase the local therapeutic effect, with the potential for additional distal end muscle cell contraction. In some embodiments, the switching time or dead time duration is extended to increase the local therapeutic effect, and a neuromuscular paralytic agent is used to control the eventual increase in muscle contraction. In some embodiments, the switching duration is 10 ns to 2 μs, while in other embodiments, the switching duration is 2 μs to 20 μs. In some cases, when targeting cellular modulation in a manner where transmembrane potential manipulation is not the primary mechanism required to elicit the targeted therapeutic effect, the switching time and dead time delays are minimized to less than 0.1 μs or 0 μs. Elimination of such delays minimizes peripheral non-targeted therapeutic effects, such as skeletal or smooth muscle contraction.

[0192] Another benefit of utilizing switching and dead-time delays to enhance the therapeutic effect of biphasic waveforms is reduced generator requirements, as the introduction of pauses allows for a stronger therapeutic effect without the need for asymmetric / unbalanced pulse waveforms. In this context, an unbalanced waveform is described as a monophasic waveform, or one with an unbalanced duration, voltage, or combination of polarity relative to another. In some cases, unbalance means that the integral of the positive portion of the waveform is not equal to the integral of the negative portion. Generators capable of providing unbalanced waveforms have a separate set of design considerations, potentially increasing generator complexity.

[0193] G. Waveform

[0194] Figure 5A An embodiment of the waveform 400 is depicted having symmetrical pulses, such that the voltage and duration of the pulse in one direction (ie, positive or negative) are equal to the voltage and duration of the pulse in the other direction. Figure 5D An example waveform 400 prescribed by another energy delivery algorithm 152 is depicted, wherein the waveform 400 has a voltage imbalance. Here, two packets are shown, a first packet 402 and a second packet 404, where packets 402, 404 are separated by a rest period 406. In this embodiment, each packet 402, 404 includes a first biphasic period (including a first positive pulse peak 408 having a first voltage V1 and a first negative pulse peak 410 having a second voltage V2) and a second biphasic period (including a second positive pulse peak 408' having the first voltage V1 and a second negative pulse peak 410' having the second voltage V2). Here, the first voltage V1 is greater than the second voltage V2. The first and second biphasic periods are separated by a dead time 412 between each pulse. Therefore, the voltage in one direction (i.e., positive or negative) is greater than the voltage in the other direction, resulting in the area under the positive portion of the curve not being equal to the area under the negative portion of the curve. This unbalanced waveform may result in a more pronounced therapeutic effect because the dominant positive or negative amplitude results in a longer duration of the cell membrane charge potential of the same charge. In this embodiment, the first positive peak 408 has a set voltage 416 ( V1 ) that is greater than the set voltage 416 ′ ( V2 ) of the first negative peak 410 . Figure 5EOther examples of waveforms with unequal voltages are shown. Four different types of packets are shown in a single figure for simplified explanation. A first packet 402 includes pulses with unequal voltages but equal pulse widths, and without switching time or dead time. Thus, the first packet 402 consists of four biphasic pulses, each including a positive peak 408 with a first voltage V1 and a negative peak 410 with a second voltage V2. Here, the first voltage V1 is greater than the second voltage V2. A second packet 404 consists of pulses with unequal voltages but symmetrical pulse widths (as in the first pulse 402), where the switching time is equal to the dead time. A third packet 405 consists of pulses with unequal voltages but symmetrical pulse widths (as in the first pulse 402), where the switching time is shorter than the dead time. A fourth packet 407 consists of pulses with unequal voltages but symmetrical pulse widths (as in the first pulse 402), where the switching time is greater than the dead time. It will be appreciated that in some embodiments, the positive and negative phases of the biphasic waveform are not identical, but are balanced, where the voltage in one direction (i.e., positive or negative) is greater than the voltage in the other direction, but the length of the pulse is calculated such that the area under the positive phase curve is equal to the area under the negative phase curve.

[0195] In some embodiments, the imbalance comprises pulses having pulse widths of unequal durations. In some embodiments, the biphasic waveform is unbalanced such that the voltage in one direction is equal to the voltage in the other direction, but the duration of one direction (i.e., positive or negative) is greater than the duration of the other direction such that the area under the curve of the positive portion of the waveform is not equal to the area under the negative portion of the waveform.

[0196] Figure 5F Other examples of waveforms with unequal pulse widths are depicted. Four different types of packets are shown here in a single figure for simplified explanation. First packet 402 includes pulses with equal voltage but unequal pulse widths, and there is no switching time or dead time. Thus, first packet 402 consists of four biphasic pulses, each pulse including a positive peak 408 with a first pulse width PW1 and a negative peak 410 with a second pulse width PW2. Here, first pulse width PW1 is greater than second pulse width PW2. Second packet 404 consists of pulses with equal voltage but unequal pulse widths (as in first pulse 402), where the switching time is equal to the dead time. Third packet 405 consists of pulses with equal voltage but unequal pulse widths (as in first pulse 402), where the switching time is shorter than the dead time. Fourth packet 407 consists of pulses with equal voltage but unequal pulse widths (as in first pulse 402), where the switching time is greater than the dead time.

[0197] Figure 5GAn example waveform 400 prescribed by another energy delivery algorithm 152 is depicted, wherein the waveform is monophasic, which is a special case of unbalanced energy, whereby only positive or negative portions of the waveform exist. Here, two packets are shown, a first packet 402 and a second packet 404, where the packets 402, 404 are separated by a rest period 406. In this embodiment, each packet 402, 404 consists of a first monophasic pulse 430 and a second monophasic pulse 432. The first monophasic pulse 430 and the second monophasic pulse 432 are separated by a dead time 412 between each pulse. This monophasic waveform can result in a more desirable therapeutic effect because the same charge cell membrane potential is maintained for a longer duration. However, compared to a biphasic waveform, a monophasic waveform provides greater stimulation of adjacent muscle groups.

[0198] Figure 5H Other examples of waveforms with single-phase pulses are depicted. Four different types of packets are shown here in a single figure for simplified illustration. A first packet 402 consists of pulses of equal voltage and pulse width, with no switching time (because the pulses are single-phase) and a dead time equal to the active time. In some cases, the dead time duration may be shorter than the active time of a given pulse. Thus, the first packet 402 consists of three single-phase pulses 430, each including a positive peak. With the dead time equal to the active time, the waveform can be considered unbalanced, with the fundamental frequency representing a period of twice the active time and no dead time. A second packet 404 consists of single-phase pulses 430 with the same voltage and pulse width (as in the first packet 402), but with a larger dead time. A third packet 405 consists of single-phase pulses 430 with the same voltage and pulse width (as in the first packet 402), but with an even larger dead time. The fourth packet 407 consists of single-phase pulses 430 of equal voltage and pulse width (as the first packet 402), with an even greater dead time.

[0199] In some embodiments, a target depth of 0.1 mm to 5 mm can be achieved by monopolar, monophasic (coincident or alternating) delivery, for example, at a voltage of 2000 V, a packet duration of 100 μs, and a packet count of 1 to 100. Similarly, the voltage can be 500 to 1500 V, a packet duration of 100 μs, and a packet count of 40, or a voltage of 2000 V, a packet duration of 10 to 200 μs, and a packet count of 40, to name a few. Alternatively, in some embodiments, a target depth of 0.1 mm to 2 mm can be achieved by bipolar, monophasic (coincident or alternating) delivery, for example, at a voltage-to-distance ratio of 1000 V / cm, a packet duration of 100 μs, and a packet count of 1 to 60. Likewise, the voltage-to-distance ratio may be 250-1500 V / cm, the packet duration may be 100 μs, and the packet count may be 30; or the voltage-to-distance ratio may be 1000 V / cm, the packet duration may be 20-1000 μs, and the packet count may be 30.

[0200] In some embodiments, an unbalanced waveform is achieved by delivering more than one pulse of one polarity before reversing to an unequal number of pulses of the opposite polarity. Figure 5I Other examples of waveforms with this type of phase imbalance are shown. Here, four different types of packets are shown in a single figure for simplified explanation. The first packet 402 consists of four cycles of equal voltage and pulse width, however, pulses of opposite polarity are intermixed with the monophasic pulses. Thus, the first cycle includes a positive peak 408 and a negative peak 410. The second cycle is monophasic, consisting of a single positive pulse without a subsequent negative pulse 430. This then repeats. The second packet 404 consists of a mixture of biphasic and monophasic cycles (as in the first packet 402), however, the pulses have unequal voltages. The third packet 405 consists of a mixture of biphasic and monophasic cycles (as in the first packet 402), however, the pulses have unequal pulse widths. The fourth packet 407 consists of a mixture of biphasic and monophasic pulses (as in the first packet 402), however, the pulses have unequal voltages and unequal pulse widths. Thus, numerous combinations and permutations are possible. Figure 5J An example of a waveform with unbalanced positive and negative voltages is depicted. Here, a packet is shown with a first positive pulse peak 408 and a first negative pulse peak 410, where the voltage of the first negative pulse peak 410 is greater than the voltage of the second positive pulse peak 408' and the second negative pulse peak 410'. These different cycles repeat throughout the packet.

[0201] Regarding the effectiveness of unequal waveforms, unbalanced TMP manipulation reduces the effects of biphasic cancellation. There is a correlation between the degree of imbalance (approaching a fully unbalanced unipolar waveform) and the intensity of the TMP manipulation. This will result in a proportional relationship between the degree of therapeutic effect and the degree of muscle contraction. Therefore, a waveform approaching a more unbalanced waveform will enable a stronger therapeutic effect to be produced with a biphasic waveform at the same voltage and frequency (if applicable) than that produced by a purely balanced biphasic waveform. For example, a therapeutic effect caused by a pulse length sequence of 830ns-415ns-830ns within an envelope will result in the pulses constituting the second half of the cycle being half the duration of the original phase. This will limit the induction of TMP manipulation in the second phase of the cycle, but will also generate fewer reverse TMPs, thereby enabling a stronger effect from the original polarity to be generated at the original length in subsequent cycles. In another example, the "positive" portion of the waveform could be 2500V, while the "negative" portion could be 1500V (2500-1250-2500-equal V), which would induce an effect on TMP polarization comparable to that described for pulse duration imbalance. In both cases, manipulation of the opposite polarity intensities would result in a stronger TMP manipulation of the accumulation of positive pulses in the cycle. This would therefore reduce the effects of biphasic cancellation and produce a stronger therapeutic effect than the 830-830-830ns or 2500-2500-2500V schemes, despite less total energy deposition delivered to the tissue. In this way, when TMP manipulation is an integral part of the therapeutic mechanism of action, it is possible to deliver less total energy to the tissue while still inducing the desired therapeutic effect.

[0202] Expanding further, a fully unbalanced waveform would not include any opposite polarity components, but could still include brief portions of pulses delivered only during the positive phase. An example of this would be a packet containing 830ns of positive polarity, followed by an 830ns pause with no energy delivered, followed by another 830ns packet of positive polarity, and so on. The same approach holds true whether considering pulse length imbalance or voltage imbalance, as the absence of a negative pulse is equivalent to setting either of these parameters to zero for the "negative" portion.

[0203] However, proper therapeutic delivery, taking into account the advantages provided by a biphasic waveform, namely the reduction in muscle contraction due to biphasic cancellation, will also be reduced. Therefore, the appropriate degree of therapeutic effect is balanced with an acceptable degree of muscle contraction. For example, an ideal voltage imbalance could be 2500-1000-2500-...V, or 2500-2000-2500-...V; or 830-100-830-...ns, or 830-500-830-...ns.

[0204] H. Waveform shape

[0205] Figure 5K An example waveform 400 dictated by another energy delivery algorithm 152 is depicted, wherein the pulses are sinusoidal in shape rather than square. Again, two packets are shown, a first packet 402 and a second packet 404, wherein the packets 402, 404 are separated by a rest period 406. In this embodiment, each packet 402, 404 includes three biphasic pulses 440, 442, 444. Furthermore, these pulses 440, 442, 444 are not square waves, but rather sinusoidal in shape. One benefit of a sinusoidal shape is that it is balanced or symmetrical, so the shape of each phase is equal. This balance can help reduce undesirable muscle stimulation. It will be appreciated that in other embodiments, the pulses have a decaying shaped waveform.

[0206] Energy delivery can be actuated by a variety of mechanisms, such as using a button 164 on the catheter 102 or a foot switch 168 operably connected to the generator 104. Such actuation generally provides a single energy dose. The energy dose is limited by the number of packets delivered and the voltage of the packets. Each energy dose delivered to the wall W maintains the temperature at or in the wall W below the thermal ablation threshold, particularly below the thermal ablation threshold of the basement membrane BM, and the thermal ablation of the basement membrane BM includes the denaturation of matrix proteins in the basement membrane or the deeper submucosal extracellular protein matrix. In addition, the dose can be titrated or adjusted over time to further reduce or eliminate heat accumulation during treatment. The energy dose is not to induce thermal damage (defined as protein coagulation at the treatment risk site), but to provide a certain level of energy to treat diseases (such as cancer) without damaging sensitive tissues.

[0207] It will be appreciated that other surfaces along the reproductive tract or other surfaces or lumens within the body can be treated in a similar manner. In some embodiments, a target depth of 0.1-1 mm can be achieved using a monopolar arrangement and a biphasic waveform with a voltage of 500-2500 V, a fundamental frequency of 500 kHz, a packet duration of 100 μs, and a packet count of 10. Similarly, a target depth of 1-2 mm can be achieved using a monopolar arrangement and a biphasic waveform with a voltage of 2500-3000 V, a fundamental frequency of 500 kHz, a packet duration of 100 μs, and a packet count of 15. Similarly, a target depth of 2-5 mm can be achieved using a monopolar arrangement and a biphasic waveform with a voltage of 2500-3500 V, a fundamental frequency of 500 kHz, a packet duration of 100 μs, and a packet count of 40. Furthermore, a target depth of 5–10 mm was achieved using a monopolar arrangement and a biphasic waveform with a voltage of 3000–6000 V, a fundamental frequency of 400 kHz, a packet duration of 200 μs, and a packet count of 20.

[0208] Other implementation methods

[0209] Figures 6A-6D Another embodiment of a therapeutic energy delivery catheter 102 for delivering energy to the surface of the cervix C is illustrated. In this embodiment, the catheter 102 has an energy delivery body 108 comprising a flexible expandable member 500 (e.g., a balloon) onto which one or more flexible electrodes 502 are mounted. In this embodiment, the electrodes 502 are in the form of pads with a relatively wide surface area and a thin cross-section. While the pad shape provides a greater surface area than other shapes (e.g., wires), wires can also be used. Each electrode 502 is connected to a conductive wire 504, which electrically connects the electrode 502 to a generator. As can be seen, each electrode 502 can be energized individually or in conjunction or coordination with one or more other electrodes 502. The electrodes 502 can be composed of flexible circuit pads or other materials, attached to or formed within the expandable member 500. The electrodes 502 can have various shapes, sizes, and patterns, and can be present in varying numbers, and can operate in a monopolar or bipolar manner. Typically, the electrodes 502 are sized, shaped, and arranged to cover the surface of the expandable member 500, which is configured to mate with the cervix C. Figure 6A In an embodiment, electrodes 502 have a pedal shape and are arranged around a point 506 on a distal end 508 of the expandable member 500 . Figure 6B A similar embodiment is shown in which a catheter 102 has an energy delivery body 108 comprising a flexible expandable member 500 (e.g., a balloon) on which one or more flexible electrodes 502 are mounted. However, in this embodiment, the shaft 126 to which the energy delivery body 108 is mounted extends through the catheter beyond the distal end 508 of the expandable member 500. This extension allows the shaft 126 to enter the endocervical canal ECC. This helps guide the energy delivery body 108 into position and stabilizes its orientation relative to the cervix C. Figure 6C Provided Figure 6B FIG. 5 is a top view of the distal end 508 of the energy delivery body 108 of FIG. As shown, the electrodes 502 each have a pedal shape and are arranged around the shaft 126 on the distal end 508 of the expandable member 500. Figure 6D Draws Figures 6B-6C The following illustrates the use of catheter 102. As shown, catheter 102 is introduced through vagina V, and shaft 126 is advanced into the endocervical canal. Energy delivery body 108 is advanced so that its distal end 508 contacts the surface of the cervix C. The flexibility of expandable member 500 and electrodes 502 allows electrodes 502 to conform to the contours of the surface of the cervix C, maximizing contact. One or more electrodes 502 are then energized, delivering PET to the cervix C.

[0210] In some embodiments, the energy penetrates to different depths (e.g., up to 2 mm) within the epithelial cell EC layer, such as for the treatment of CIN. This can destroy abnormal epithelial cell ECs without affecting cells outside the epithelial cell layer. In other embodiments, the energy penetrates beyond the epithelial cell EC layer (e.g., up to 1 cm), such as for the treatment of CIS. In such embodiments, energy penetration can be increased to treat tumors of various sizes and various degrees of disease. It will be appreciated that due to the nature of the energy delivered, penetration beyond the epithelial cell layer avoids many complications associated with conventional treatments of these tissue layers, particularly the formation of scar tissue. As previously described, the energy delivered eliminates diseased, damaged, abnormal, or otherwise undesirable cells, leaving behind an intact tissue framework. This allows the tissue to regenerate in a normal manner, avoiding the formation of scar tissue.

[0211] Figures 7A-7B Another embodiment of a therapeutic energy delivery catheter 102 is depicted, which delivers energy to the surface of the cervix C. In this embodiment, the catheter 102 includes an energy delivery body 108 and a stabilizing element 520. The stabilizing element 520 is configured to be advanced into the uterus U to stabilize the catheter 102, while the energy delivery body 108 resides in the vagina V to deliver energy to the cervix C. In this embodiment, the stabilizing element 520 includes an expandable member 522 (e.g., a balloon) mounted on a shaft 524. The shaft 524 is sized and configured to concentrically pass through the lumen in the shaft 126 of the catheter 102. The energy delivery body 108 is mounted on the shaft 126. Thus, the shaft 524 and the stabilizing element 520 are movable relative to the energy delivery body 108, thereby allowing the distance between the stabilizing element 520 and the energy delivery body 108 to be adjustable. In this embodiment, the energy delivery body 108 includes a wireform 526 shaped to match the contours of the cervix C. Thus, in this embodiment, the wireform 526 has a modified cup shape facing the stabilization element 520. Likewise, the shaft 126 is positioned so that the stabilization element 520 and its shaft 524 pass through the center of the wireform 526, centering the cup shape around, for example, the endocervical canal EEC.

[0212] In some embodiments, the wireform 526 is composed of multiple wires that together act as a single electrode. In these embodiments, the wireform 526 delivers PEF in a monopolar manner. In other embodiments, the wireform 526 is composed of multiple wires that can be energized individually or in groups. In these embodiments, the wireform 526 delivers PEF in a bipolar manner, but can also optionally operate in a monopolar manner. Furthermore, these functions may change over time.

[0213] Figure 7BThe catheter 102 is depicted positioned within the patient's reproductive tract. As shown, the catheter 102 is introduced through the vagina V, and the shaft 524 is advanced into the endocervical canal EEC. The stabilizing element 520 is expanded so that the shaft 524 can no longer be retracted through the endocervical canal EEC. The energy delivery body 108 is advanced so that the wireform 526 contacts the surface of the cervix C. In this embodiment, the wireform 526 is shaped so that the wireform 526 matches the circumferential portion of the surface of the cervix C. The electrodes of the wireform 526 are then energized to deliver PEF to the cervix C.

[0214] In some embodiments, the energy penetrates to varying depths within the epithelial cell EC layer (e.g., up to 2 mm), such as for the treatment of CIN. This can destroy abnormal epithelial cell ECs without affecting cells outside the epithelial cell layer. In other embodiments, the energy penetrates beyond the epithelial cell EC layer (e.g., up to 1 cm), such as for the treatment of CIS. In such embodiments, energy penetration can be increased to treat tumors of various sizes and various degrees of disease. It will be appreciated that due to the nature of the energy delivered, penetration beyond the epithelial cell layer avoids many complications associated with conventional treatments of these tissue layers, particularly the formation of scar tissue. As previously described, the energy delivered eliminates diseased, damaged, abnormal, or otherwise undesirable cells, leaving behind an intact tissue framework. This allows the tissue to regenerate in a normal manner, avoiding the formation of scar tissue.

[0215] Figures 8A-8BAnother embodiment of a therapeutic energy delivery catheter 102 is depicted, which delivers energy to a portion of the reproductive tract. In this embodiment, the catheter 102 includes a first energy delivery body 108a and a second energy delivery body 108b, wherein the second energy delivery body 108b also serves as a stabilizing element. The second energy delivery body 108b is configured to be advanced into the uterus U to stabilize the catheter 102 and deliver energy to the uterus U, while the first energy delivery body 108a resides in the vagina V to deliver energy to the cervix C. In this embodiment, the second energy delivery body 108b includes a second wireform 540 having a funnel shape and mounted on a shaft 524. In this embodiment, the opening of the funnel shape faces distally to more closely mimic the internal shape of the uterus U near the cervix C. The shaft 524 is sized and configured to concentrically pass through the lumen of the shaft 126 of the catheter 102. The first energy delivery body 108a is mounted on the shaft 126. Thus, the shaft 524 and the second energy delivery body 108b are movable relative to the first energy delivery body 108a, thereby allowing the distance between the second energy delivery body 108b and the first energy delivery body 108a to be adjustable. In this embodiment, the first energy delivery body 108a includes a first wireform 526 shaped to match the contour of the cervix C. Thus, in this embodiment, the first wireform 526 has a modified cup shape facing the second energy delivery body 108b. Similarly, the shaft 126 is configured so that the second energy delivery body 108b and its shaft 524 pass through the center of the first wireform 526, centered around, for example, the endocervical canal EEC.

[0216] In some embodiments, the first wireform 526 and / or the second wireform 540 are comprised of multiple wires that collectively function as a single electrode. In these embodiments, each wireform 526, 540 delivers PEF in a monopolar manner. In other embodiments, the first wireform 526 and the second wireform 540 function as a bipolar pair, transmitting energy between them. This may be particularly useful when treating conditions and diseases that extend deep into the cervix or involve areas with multiple anatomical structures. In other embodiments, the first wireform 526 and / or the second wireform 540 are comprised of multiple wires, wherein the wires can be energized individually or in groups. In these embodiments, each wireform 526, 540 delivers PEF in a bipolar manner, but may also optionally function in a monopolar manner. Therefore, it can be understood that in some embodiments, the first wireform 526 functions in a monopolar manner while the second wireform 540 functions in a bipolar manner, or vice versa. Furthermore, these functions may change over time.

[0217] Figure 8BThe catheter 102 is depicted positioned within a patient's reproductive tract. As shown, the catheter 102 is introduced through the vagina V, and the shaft 524 is advanced into the endocervical canal EEC. The second energy delivery body 540 expands within the uterus U, preventing the shaft 524 from being retracted through the endocervical canal EEC. The funnel shape of the second energy delivery body 108b conforms to the inner surface of the uterus U above the cervix C, causing the second wireform 540 to contact at least a portion of the lining of the uterus U. The first energy delivery body 108 is advanced so that the first wireform 526 contacts the surface of the cervix C. In this embodiment, the first wireform 526 is shaped so that the first wireform 526 matches the circumferential portion of the surface of the cervix C. The electrodes of the first wireform 526 and the second wireform 540 are then energized to deliver PEF to the cervix C and the uterus U, respectively.

[0218] In some embodiments, the energy from the first filamentous member 526 penetrates to different depths (e.g., up to 1 mm, up to 2 mm) into the epithelial cell EC layer of the cervix C, such as for the treatment of CIN. This can destroy abnormal epithelial cells EC without affecting cells outside the epithelial cell layer. In other embodiments, the energy penetrates beyond the epithelial cell EC layer of the cervix C (e.g., up to 1 cm), such as for the treatment of CIS. In such embodiments, energy penetration can be increased to treat tumors of various sizes and various degrees of disease. It will be appreciated that due to the nature of the energy delivered, penetration beyond the epithelial cell layer avoids many complications associated with conventional treatments of these tissue layers, particularly the formation of scar tissue. As previously described, the delivered energy eliminates diseased, damaged, abnormal or other undesirable cells, leaving behind an intact tissue framework. This allows the tissue to regenerate in a normal manner, avoiding the formation of scar tissue.

[0219] Similarly, the energy from the second filamentous member 540 penetrates to different depths (e.g., up to 1 mm, up to 2 mm, or up to 3 mm) within the epithelial cell EC layer of the uterus U. This can destroy abnormal epithelial cell ECs without affecting cells outside the epithelial cell layer. In other embodiments, the energy penetrates beyond the epithelial cell EC layer of the uterus U (e.g., up to 1 cm or up to 2 cm). The normal thickness of the uterus is 1-2 cm, but this thickness may vary greatly. In such an embodiment, energy penetration can be increased to treat tumors of various sizes and various degrees of disease. It will be understood that due to the nature of the energy delivered, penetration beyond the epithelial cell layer avoids many complications associated with conventional treatments of these tissue layers, particularly the formation of scar tissue. As previously described, the delivered energy eliminates diseased, damaged, abnormal, or other undesirable cells, leaving behind an intact tissue framework. This allows the tissue to regenerate in a normal manner, avoiding the formation of scar tissue.

[0220] Figures 9A-9BAnother embodiment of a therapeutic energy delivery catheter 102 is depicted, which delivers energy to portions of reproductive anatomy. In this embodiment, the catheter is configured to deliver energy to the endocervical canal EEC, which is typically 2.5-4 cm in length. In this embodiment, the catheter 102 includes an energy delivery body 108 mounted on a shaft 552, wherein the energy delivery body 108 includes an elongated wireform 550 having an elongated, tubular, or elliptical shape for passage through the endocervical canal EEC. In some embodiments, the elongated wireform 550 is of sufficient length to extend to the length of the endocervical canal, extend beyond the length of the endocervical canal, or extend along a portion of the endocervical canal. Thus, in some embodiments, the length of the wireform 550 ranges from 0.1 cm to 5 cm, 0.1 cm to 4 cm, 0.1 cm to 2 cm, and all subranges therebetween. Typically, the elongated wireform 550 has a diameter sufficient to contact the wall of the endocervical canal. In some embodiments, the diameter of the wireform 550 ranges from 0.5 cm to 1 cm.

[0221] In some embodiments, the elongated filament 550 is composed of multiple filaments that together act as a single electrode. In these embodiments, the filament 550 delivers PEF in a monopolar manner. In other embodiments, the elongated filament 550 is composed of multiple filaments that can be energized individually or in groups. In these embodiments, the filament 550 delivers PEF in a bipolar manner, but can also be operated in a monopolar manner. Furthermore, these functions may change over time.

[0222] Figure 9B The catheter 102 is depicted positioned within the patient's reproductive tract. As shown, the catheter 102 is introduced through the vagina V, and the shaft 552 is advanced into the endocervical EEC, such that the energy delivery device 108 is positioned within the endocervical EEC. The electrodes of the energy delivery device 108 are then energized to deliver PEF to the endocervical EEC. It will be appreciated that in some embodiments, the energy delivery device 108 is sized and / or positioned to selectively deliver energy to portions of the cervix C and / or portions of the uterus U.

[0223] In some embodiments, energy from the energy delivery body 108 penetrates to varying depths within the epithelial EC layer of the endocervical EEC (e.g., up to 1 mm, up to 2 mm). This can destroy abnormal epithelial EC cells without affecting cells outside the epithelial layer. In other embodiments, energy penetrates beyond the epithelial EC layer of the endocervical EEC (e.g., up to 1 cm). In such embodiments, energy penetration can be increased to treat tumors of various sizes and various degrees of disease. It will be appreciated that due to the nature of the energy delivered, penetration beyond the epithelial layer avoids many complications associated with conventional treatments of these tissue layers, particularly the formation of scar tissue. As previously described, the delivered energy eliminates diseased, damaged, abnormal, or otherwise undesirable cells, leaving behind an intact tissue framework. This allows the tissue to regenerate in a normal manner, avoiding the formation of scar tissue.

[0224] Figures 10A-10B Another embodiment of a therapeutic energy delivery catheter 102 is shown that delivers energy to a portion of the reproductive tract. Figure 8A and Figure 9A Various characteristics of the energy delivery catheter 102. In this embodiment, the catheter 102 includes Figure 8A The first energy transporter 108a and the second energy transporter 108b, and Figure 8B The embodiment of the present invention further comprises an elongated filament 550, which serves as a third energy delivery body. Thus, the first energy delivery body 108a is composed of a filament 526 having a cup shape and is mounted on the shaft 126. The filament 526 is shaped and configured to engage the surface of the cervix C from within the vagina V. The elongated filament 550 is mounted on a shaft 552. The shaft 552 is sized and configured to concentrically pass through the lumen in the shaft 126. Thus, the elongated filament 550 and the first energy delivery body 108a are movable relative to each other, thereby making the distance between them adjustable. As previously described, the elongated filament 550 is configured to deliver energy to the endocervical canal EEC and, optionally, to portions of the cervix C and uterus U. In this embodiment, the second energy delivery body 108b comprises a filament 540 having a funnel shape and is mounted on the shaft 524. In this embodiment, the shaft 524 is sized and configured to concentrically pass through the lumen in the shaft 552. Thus, the elongated filament 550 and the second energy delivery body 108b are able to move relative to each other, thereby making the distance therebetween adjustable.

[0225] In some embodiments, the first filament 526 and / or the second filament 540 and / or the elongated filament 550 are composed of multiple filaments that together act as a single electrode. In these embodiments, each filament 526, 540, 550 delivers PEF in a monopolar manner. In other embodiments, any pair of the first filament 526, the second filament 540, and the elongated filament 550 functions as a bipolar pair, transmitting energy between them. In other embodiments, the first filament 526, the second filament 540, and the elongated filament 550 function as a tripolar configuration, transmitting energy between them. This may be particularly useful when treating conditions and diseases that extend deep into the cervix or involve sites with multiple anatomical structures. In other embodiments, the first filament 526 and / or the second filament 540 and / or the elongated filament 550 are composed of multiple filaments, wherein the filaments can be energized individually or in groups. In these embodiments, each wireform 526, 540, 550 delivers PEF in a bipolar manner, but may also optionally operate in a monopolar manner. Therefore, it will be appreciated that in some implementations, each wireform 526, 540, 550 operates in a different manner and may change over time.

[0226] Figure 10B The diagram depicts a catheter 102 positioned within a patient's reproductive tract. As shown, the catheter 102 is introduced through the vagina V, and the second energy delivery element 108b is passed through the endocervical canal EEC and into the uterus U. The second energy delivery element 108b expands within the uterus U so that it can no longer be retracted through the endocervical canal EEC. The funnel shape of the second energy delivery element 108b conforms to the inner surface of the uterus U above the cervix C, causing the second wireform 540 to contact at least a portion of the lining of the uterus U. The elongated wireform 550 is advanced into the endocervical canal EEC. Furthermore, the first energy delivery element 108 is advanced so that the first wireform 526 contacts the surface of the cervix C. In this embodiment, the first wireform 526 is shaped so that it matches a circumferential portion of the surface of the cervix C. The electrodes of the first wireform 526, the elongated wireform 550, and the second wireform 540 are energized to deliver PEF to the cervix C, the endocervical canal EEC, and the uterus U, respectively.

[0227] In some embodiments, the energy from the first filamentous member 526 penetrates to different depths (e.g., up to 1 mm, up to 2 mm) into the epithelial cell EC layer of the cervix C, such as for the treatment of CIN. This can destroy abnormal epithelial cells EC without affecting cells outside the epithelial cell layer. In other embodiments, the energy penetrates beyond the epithelial cell EC layer of the cervix C (e.g., up to 1 cm), such as for the treatment of CIS. In such embodiments, energy penetration can be increased to treat tumors of various sizes and various degrees of disease. It will be appreciated that due to the nature of the energy delivered, penetration beyond the epithelial cell layer avoids many complications associated with conventional treatments of these tissue layers, particularly the formation of scar tissue. As previously described, the delivered energy eliminates diseased, damaged, abnormal or other undesirable cells, leaving behind an intact tissue framework. This allows the tissue to regenerate in a normal manner, avoiding the formation of scar tissue.

[0228] In some embodiments, energy from the energy delivery body 108 penetrates to varying depths within the epithelial EC layer of the endocervical EEC (e.g., up to 1 mm, up to 2 mm). This can destroy abnormal epithelial EC cells without affecting cells outside the epithelial layer. In other embodiments, energy penetrates beyond the epithelial EC layer of the endocervical EEC (e.g., up to 1 cm). In such embodiments, energy penetration can be increased to treat tumors of various sizes and various degrees of disease. It will be appreciated that due to the nature of the energy delivered, penetration beyond the epithelial layer avoids many complications associated with conventional treatments of these tissue layers, particularly the formation of scar tissue. As previously described, the delivered energy eliminates diseased, damaged, abnormal, or otherwise undesirable cells, leaving behind an intact tissue framework. This allows the tissue to regenerate in a normal manner, avoiding the formation of scar tissue.

[0229] In addition, the energy from the second filamentous member 540 penetrates to different depths (e.g., up to 1 mm, up to 2 mm) within the epithelial cell EC layer of the uterus U. This can destroy abnormal epithelial cell ECs without affecting cells outside the epithelial cell layer. In other embodiments, the energy penetrates outside the epithelial cell EC layer of the uterus U (e.g., up to 1 cm). In such an embodiment, energy penetration can be increased to treat tumors of various sizes and various degrees of disease. It will be appreciated that due to the nature of the energy delivered, penetration outside the epithelial cell layer avoids many complications associated with conventional treatments of these tissue layers, particularly the formation of scar tissue. As previously described, the energy delivered eliminates diseased, damaged, abnormal or other undesirable cells, leaving behind an intact tissue framework. This allows the tissue to regenerate in a normal manner, avoiding the formation of scar tissue.

[0230] It will be appreciated that in some embodiments, one or more of the first energy delivery body 108a, the second energy delivery body 108b, and the third energy delivery body / filament 550 may be formed together as a single unit. Such an embodiment may allow for faster delivery but may reduce variability in the positioning of some or more components within the reproductive anatomy.

[0231] It will also be appreciated that the first energy delivery body 108a, the second energy delivery body 108b, and the third energy delivery body / slender filament 550 can take various forms and are not limited to the embodiments described herein. For example, the first energy delivery body 108a, the second energy delivery body 108b, and / or the third energy delivery body / slender filament 550 may have a circular or oval shape, such as a basket shape. Similarly, the first energy delivery body 108a, the second energy delivery body 108b, and / or the third energy delivery body / slender filament 550 can be expanded by any suitable mechanism, such as self-expansion or the use of an expandable member (e.g., a balloon).

[0232] Figures 11A-11B Another embodiment of a therapeutic energy delivery catheter 102 is depicted, which delivers energy to a portion of a reproductive anatomy. In this embodiment, the catheter 102 is configured to deliver energy to the uterus U. In this embodiment, the catheter 102 includes an energy delivery body 108 mounted on a shaft 126, wherein the energy delivery body 108 is configured to expand within the uterus U, thereby contacting one or more inner surfaces or walls of the uterus U. Therefore, in some embodiments, the energy delivery body 108 includes a flexible expandable member 600 (such as a balloon) having one or more flexible electrodes 602 mounted thereon. In this embodiment, each electrode 602 has a pad form having a relatively wide surface area and a thin cross-section. Compared to other shapes (such as a wire shape), the pad shape provides a larger surface area, but wire can also be used. Each electrode 602 is connected to a conductive wire 604, which electrically connects the electrode 602 to a generator. It can be seen that each electrode 602 can be energized individually or in conjunction with or in conjunction with one or more other electrodes 602. The electrodes 602 can be made of flexible circuit pads or other materials that are attached to or formed in the expandable member 600. The electrodes 602 can have various shapes, can have various sizes, can be distributed in various patterns, can have different numbers, and can operate in a monopolar or bipolar manner. Generally, the size, shape, and arrangement of the electrodes 602 are configured to cover the surface of the expandable member 600, and the expandable member is configured to match the uterus U, so that Figure 11A In this embodiment, the electrodes 602 each have an elongated shape, extending from the distal end to the proximal end of the energy delivery body 108. Furthermore, in this embodiment, the electrodes 602 are arranged around the circumference of the expandable member 500.

[0233] Figure 11B Draws Figure 11A 1. The catheter 102 is introduced through the vagina V, and the shaft 126 is advanced into the endocervical canal EEC. The energy delivery body 108 is advanced into the uterus U, where it expands to allow one electrode 602 to contact the inner surface of the uterus U. The flexibility of the expandable member 600 and the electrodes allows the electrodes 602 to conform to the shape of the uterus U, thereby maximizing contact. One or more electrodes 602 are then energized, delivering PEF to the lining of the uterus U and, optionally, deep into the uterus U itself.

[0234] In some embodiments, the energy from the energized electrode 602 penetrates to different depths within the epithelial cell EC layer of the uterus U (e.g., up to 1 mm, up to 2 mm). This can destroy abnormal epithelial cell ECs without affecting cells outside the epithelial cell layer. In other embodiments, the energy penetrates outside the epithelial cell EC layer of the uterus U (e.g., up to 1 cm). In such an embodiment, energy penetration can be increased to treat tumors of various sizes and various degrees of disease. It will be appreciated that due to the nature of the energy delivered, penetration outside the epithelial cell layer avoids many complications associated with conventional treatments of these tissue layers, particularly the formation of scar tissue. As previously described, the delivered energy eliminates diseased, damaged, abnormal, or other undesirable cells, leaving behind an intact tissue framework. This allows the tissue to regenerate in a normal manner, avoiding the formation of scar tissue.

[0235] Figures 12A-12B Another embodiment of a therapeutic energy delivery catheter 102 is depicted that delivers energy to a portion of the reproductive anatomy. In this embodiment, the catheter 102 is configured to provide energy to a selected location within the reproductive tract, such as within the vagina V, along the cervix C, within the endocervical canal EEC, or within the uterus U. In this embodiment, the catheter 102 includes an energy delivery body 108 mounted on a shaft 126. In this embodiment, the shaft 126 can be moved by a steerable guide 650, such as a catheter, sheath, or scope. However, it will be appreciated that in some embodiments, the shaft 126 itself is steerable. In some embodiments, the energy delivery body 108 can be retracted into the steerable guide 650 during entry and positioning, while in other embodiments, the energy delivery body 108 resides near the distal end of the guide 650 to create a tip.

[0236] In this embodiment, the energy delivery body 108 comprises a wire basket that acts as one or more electrodes. However, it will be appreciated that in other embodiments, the energy delivery body 108 comprises a balloon with an electrode cover or a finger probe. In some embodiments, the energy delivery body 108 is blunt or atraumatic, while in other embodiments, it is sharp or has a penetrating shape.

[0237] Figure 12B The catheter 102 of FIG12 is depicted as being used to treat one or more locations within the uterus U. As shown, the catheter 102 is introduced through the vagina V so that the energy delivery body 108 passes through the endocervical canal EEC and enters the uterus U. In this embodiment, the energy delivery body 108 is directed to a target location on the inner wall of the uterus U by manipulation using a steerable guide 650. Thus, the guide 650 is laterally curved away from the endocervical canal EEC and toward the side wall within the uterus U. The catheter 102 is advanced so that the energy delivery body 108 contacts the side wall (or the fluid / substance on the side wall) to deliver energy thereto. The energy delivery body 108 is then energized to deliver PEF to the target location on the lining of the uterus U and, optionally, deep into the uterus U itself.

[0238] In some embodiments, the energy from the energy delivery body 108 penetrates to different depths within the epithelial cell EC layer of the uterus U (e.g., up to 1 mm, up to 2 mm). This can destroy abnormal epithelial cell ECs without affecting cells outside the epithelial cell layer. In other embodiments, the energy penetrates outside the epithelial cell EC layer of the uterus U (e.g., up to 1 cm). In such an embodiment, energy penetration can be increased to treat tumors of various sizes and various degrees of disease. It will be appreciated that due to the nature of the energy delivered, penetration outside the epithelial cell layer avoids many complications associated with conventional treatments of these tissue layers, particularly the formation of scar tissue. As previously described, the delivered energy eliminates diseased, damaged, abnormal or other unwanted cells, leaving behind an intact tissue framework. This allows the tissue to regenerate in a normal manner, avoiding the formation of scar tissue.

[0239] It will be appreciated that the catheter 102 can be repositioned to treat a new target location within the uterus U or elsewhere within the reproductive tract. It will be appreciated that in some embodiments, the energy delivery body 108 is manipulated and / or positioned with the assistance of a balloon or other expandable member.

[0240] As previously described, in some embodiments, biphasic pulses are utilized, for example, to reduce unwanted muscle stimulation. In other embodiments, the pulse waveform is monophasic and has no clear natural frequency. Alternatively, the frequency can be derived by taking into account the fundamental frequency by doubling the monophasic pulse length. In some embodiments, a treatment depth of 2-5 mm can be achieved by monopolar, monophasic (consistent or alternating) delivery, for example, with a voltage of 1500 V, a packet duration of 100 μs, and a packet count of 40-100. In some embodiments, a treatment depth of 5-10 mm can be achieved by monopolar, monophasic (consistent or alternating) delivery, for example, with a voltage of 3000 V, a packet duration of 100 μs, and a packet count of 40-100. In some embodiments, a treatment depth of 2-10 mm can be achieved by bipolar, monophasic (consistent or alternating) delivery, for example, with a voltage-to-distance ratio of 1500 V / cm, a packet duration of 100 μs, and a packet count of 20-100.

[0241] It will be appreciated that in each embodiment, the catheter 102 may include markers or markings to aid visualization. For example, the catheter 102 may include one or more radiopaque marker bands. This may be particularly useful when targeting a specific location, such as a specific fibroid. In other embodiments, the catheter 102 may have one or more markers visible by ultrasound. This may include a roughened surface or markers attached thereto.

[0242] It will be appreciated that in each embodiment, energy can be transferred directly to the cell or tissue, or to a substance or other entity along the surface of the cell or tissue, such as saline, blood, mucus, etc., which is capable of conducting or otherwise transferring energy to the cell or tissue. These substances can be naturally occurring or can be delivered to the area as liquid electrodes.

[0243] In some embodiments, the liquid electrode is composed of a conductive solution that is delivered to the luminal structure, particularly the target area. For example, in some embodiments, the uterus U, the endocervical canal ECC, and / or the vagina V are filled or at least partially filled with a conductive solution to act as a liquid electrode. Typically, this conductive solution includes hypertonic saline, calcium, or other components. The treatment is then delivered through the catheter 102 having one or more energy delivery bodies 108 as described above, or a catheter having a simple electrode configured to activate the conductive solution (e.g., a blunt probe). In some embodiments, the conductive solution is then removed, and in other embodiments, the conductive solution is left for reabsorption. It will be understood that in some embodiments, the conductive solution is composed of a hypertonic solution, an isotonic solution, or a special conductive solution (e.g., calcium, silver, etc.) that affects the therapeutic effect.

[0244] In some embodiments, the liquid electrode is composed of a conductive solution disposed within one or more energy delivery bodies 108. For example, in some embodiments, the energy delivery body 108 includes a braided wire electrode formed into a basket shape and a porous expandable member (e.g., a balloon with laser-drilled holes) disposed within the braided wire electrode basket. Expansion of the expandable member unfolds the braided wire electrode basket and allows the conductive solution to seep out of the porous expandable member. In a blood-filled environment, the blood will interact with the conductive solution seeping from the porous expandable member, creating a virtual electrode. Thus, in some embodiments, the conductive solution forms the second pole of the circuit to create a bipolar electrode configuration. In another embodiment, a second pole electrode is added to the distal tip of the catheter to serve as the return pole of the bipolar circuit. The second pole electrode can be composed of any suitable conductive material, such as a platinum metal tip. In a blood-filled environment, the surrounding blood will interact with the second pole electrode, thereby transforming the local blood into a virtual electrode to complete the circuit. These embodiments allow for localized bipolar energy delivery for tissue treatment while reducing the impact on the integrity of adjacent structures.

[0245] The energy delivered is suitably treated abnormal or diseased tissue. In the case of cancer, cancer cells are destroyed, eliminated, killed, removed, etc., while maintaining non-cancerous, non-cellular components, such as collagen, elastin and matrix proteins. These non-cellular components maintain the structure of the wall of the luminal structure (such as the vagina, endocervical canal, uterus, fallopian tube, etc.), while allowing and promoting normal cell regeneration. Therefore, while fully eliminating abnormal or diseased cells and tissues, the integrity and mechanical properties of the luminal structure are maintained. It is understood that in some cases, energy directly kills cells, such as via the irreversible destruction of accumulated systemic cell damage and cell homeostasis. In other cases, energy promotes the macromolecular absorption of target cells for gene, drug or other bioactive compound transfection. This treatment can also utilize a combination of these effects, such as directly killing the most superficial cells, while making deeper target cells more susceptible to the treatment or influence of certain auxiliary substances absorption.

[0246] After treatment, the catheter 102 is removed from the reproductive tract. In some cases, the patient will not need subsequent treatment. In other cases, the treatment can be repeated or other types of treatments can be used, such as tumor resection (for example, surgery can now be performed due to this treatment).

[0247] It will be appreciated that the methods and devices described herein can be used or modified to achieve various therapeutic purposes. Such treatments can be used to restore the function of tissue, with or without the removal of tissue. Such treatments can be used to alleviate or eliminate pain. Such treatments can be the only treatment or can be used in combination with other treatments such as surgery, other energy forms, pharmacologically based treatments and other methods (such as treating the remaining tissue area). For example, such treatments can be performed before resection or ablation therapy (such as 2 hours before, 1 day before, 3 days before, 7 days before, 14 days before, 28 days before, 60 days before, 90 days before or longer). Alternatively, such treatments can be performed during the same surgery as resection or ablation therapy, or after surgical resection and / or removal of tumors. It will be appreciated that such treatments can be performed during a single session, or can be achieved in a series of multiple treatment deliveries.

[0248] Therefore, the method is minimally invasive, fast and easy to perform, and has a relatively low sensitivity to electrode placement (e.g., when using a monopolar arrangement), thereby allowing technicians of various skill levels to achieve a high level of consistency and successful results. In some embodiments, due to the waveform characteristics of the energy used, a monopolar arrangement is possible without the need for muscle paralysis. This can reduce the muscle contraction caused by motor neuron and skeletal muscle depolarization to an acceptable level, regardless of whether there is neuromuscular paralysis. It will be appreciated that paralytic agents can be selectively used, depending on the desired energy type and penetration depth.

[0249] In some embodiments, the energy delivery catheter 102 is configured to provide focused therapy, such as according to International Patent Application No. PCT / US2018 / 067504, entitled "Optimization of Energy Delivery for Various Applications," which claims priority to Provisional Patent Application No. 62 / 610,430, filed December 26, 2017, and U.S. Provisional Patent Application No. 62 / 693622, filed July 3, 2018, all of which are incorporated herein by reference. This may be specifically with reference to Figures 6A-6D and Figures 11A-11B Examples of implementation methods.

[0250] It will be appreciated that in some embodiments, focused therapy is used to treat tissue that is not localized but that already surrounds most or all of the tissue surrounding the electrodes. In such cases, energy can be delivered circumferentially or longitudinally in segmented sections throughout the affected area, such as by energizing the various electrodes in a predetermined pattern and / or with predetermined patterned energy parameters. It will also be appreciated that in some embodiments, the various electrodes are energized at varying voltage levels relative to the dispersive (return) electrode 140 applied externally to the skin of the patient P. Manipulation of the voltage levels manipulates the electric field distribution, thereby shaping the treatment area.

[0251] Extraluminal placement and energy delivery

[0252] Figures 13A-13B Another embodiment of a treatment system 100 is depicted. Here, the system 100 is configured to treat target tissue located at least partially outside of a body cavity (e.g., near the vagina V, cervix C, uterus U, and fallopian tubes F), where the treatment may benefit from generating therapeutic energy within the body cavity. This may be particularly suitable for treating cervical cancer in situ (CIS) or various tumors, masses, growths, fibroids, abnormal tissue, undesirable tissue, etc. within or accessible from the reproductive tract. Likewise, this may be particularly suitable for treating tissue that is beyond the penetration depth of the above-described delivery methods and / or that would benefit from generating at least some energy beyond the lumen.

[0253] Figures 13A-13B The illustrated system 100 includes an energy delivery catheter 102 that is connectable to a generator 104. It will be appreciated that many of the aforementioned system components, such as specific aspects of the catheter 102, generator 104, and other accessories, are utilized in this embodiment of the system 100. Therefore, the descriptions provided above apply to the system 100 described below. The primary differences relate to the energy delivery body 108.

[0254] Here, catheter 102 includes a shaft 106 having a distal end 103, a proximal end 107, and at least one lumen 105 extending at least partially therethrough. Likewise, catheter 102 also includes at least one energy delivery body 108. In this embodiment, energy delivery body 108 is in the form of a probe 700 disposed within lumen 105 of shaft 106. Probe 700 has a probe tip 702 that is advanceable through lumen 105 and that extends from distal end 103 of shaft 106 (at a position substantially parallel to the distal end). Figure 13A(The figure is enlarged to show details). In this embodiment, the tip 702 has a pointed shape that is configured to penetrate tissue, such as similar to a needle. Therefore, in this embodiment, the probe tip 702 is used to penetrate the cavity wall W and surrounding tissue so that it can be inserted into the target tissue outside the body cavity. Therefore, the probe 700 has sufficient flexibility to be delivered intraluminally and sufficient column strength to penetrate the cavity wall W and the target tissue. In some embodiments, the catheter 102 has markings to indicate to the user the distance the probe tip 702 has been advanced, thereby ensuring the desired placement.

[0255] In some embodiments, the probe extends approximately less than 0.5 cm, 0.5 cm, 1 cm, 2 cm, 3 cm, 4 cm, 5 cm, 6 cm, 7 cm, 8 cm, or greater than 8 cm from the distal end 103 of the shaft 106. In some embodiments, the probe extends 1 cm to 3 cm or 2 cm to 3 cm from the distal end of the shaft 106. In some embodiments, the probe is 18, 19, 20, 21, 22, 23, 24, or 25 gauge. In some embodiments, the probe 700 is composed of a conductive material to function as an electrode. Thus, the electrode will have the dimensions of an exposed probe. Example materials include stainless steel, nitinol, cobalt-chromium alloy, copper, and gold. Thus, in these embodiments, PEF energy can be transmitted through the probe 700 to the probe tip 702. Therefore, the shaft 106 is composed of an insulating material or is covered by an insulating sheath. Example insulating materials include polyimide, silicone, polytetrafluoroethylene, and polyether block amide. The insulating material can be consistent or varied along the length of the shaft 106 or sheath. Likewise, in either case, the insulating material typically comprises complete electrical insulation. However, in some embodiments, the insulating material allows some leakage current to penetrate.

[0256] When the probe 700 is energized, the insulating shaft 106 protects the surrounding tissue from the therapeutic energy and directs the energy to the probe tip 702 (and any exposed portion of the probe 700), which is capable of delivering the therapeutic energy to the surrounding tissue. Thus, the tip 702 serves as a delivery electrode, and its size can be selected based on the amount of the probe 700 that is exposed. By exposing a greater amount of the probe 700, a larger electrode can be formed, and by exposing less, a smaller electrode can be formed. In some embodiments, the length of the tip 702 exposed during energy delivery (measured from its distal end to the distal end edge of the insulating shaft) is 0.1 cm, 0.2 cm, 0.3 cm, 0.4 cm, 0.5 cm, 0.6 cm, 0.7 cm, 0.8 cm, 0.9 cm, 1 cm, 2 cm, 3 cm, greater than 3 cm, up to 8 cm, less than or equal to 0.1 cm, less than or equal to 0.3 cm, less than or equal to 0.5 cm, less than or equal to 1 cm, 0.2 cm to 0.3 cm, 0.1 cm to 0.5 cm, 0.1 cm to 1 cm, and all ranges and subranges therebetween. In addition to changing the size of the electrode, the tip 702 can be retracted into the shaft 106 to allow for atraumatic endoscopic delivery and then advanced as desired to reach the target tissue. In this embodiment, advancement and retraction are controlled by an actuator 732 (e.g., a knob, button, lever, slider, or other mechanism) on the handle 110 attached to the proximal end 107 of the shaft 106. It will be appreciated that the shaft 106 itself can be advanced toward the target tissue, with or without advancing the probe from the distal end 103 of the shaft 106. In some embodiments, the distal end of the shaft 106 is advanced up to 20 cm into tissue, such as from the outer surface of a luminal structure or from the outer surface of a patient's body.

[0257] The handle 110 is connected to the generator 104 using a dedicated energy plug 510. The energy plug 510 has a first end 512 that is connected to the handle 110 and a second end 514 that is connected to the generator 104. Figure 16B FIG2 is an enlarged detail of the connection of the first end 512 to the handle 110. In this embodiment, the first end 712 has an adapter 716 that includes a connecting wire 718 extending therefrom. The connecting wire 718 is pluggable into the proximal end of the probe 700 within the handle 110. This allows energy to be transferred from the generator 104 to the probe 700 through the connecting wire 718. Thus, the probe 700 can be powered along its entire length, however, due to the presence of the insulating shaft 106, only the exposed tip 702 delivers energy to the tissue.

[0258] Figures 14A-14CAn example of a connection between the energy plug 510 and the handle 110 is depicted. As previously described, in this embodiment, the first end 712 of the energy plug 710 has an adapter 716 that includes a connecting wire 718 extending therefrom. The connecting wire 718 is electrically conductive and is typically composed of copper, aluminum, stainless steel, or nitinol. Thus, energy from the generator 104 can be transferred from the generator 104 through the plug 710 and to the connecting wire 718. In this embodiment, the adapter 716 can be engaged with the handle 110 so that the connecting wire 718 is inserted into the handle 110. FIG. 14A to FIG. 14B As shown, the handle 110 has a cavity 730 into which the connecting wire 718 can be inserted. The cavity 730 guides the connecting wire 718 into the proximal end of the probe 700, wherein the probe 700 has a hollow configuration at least near its proximal end to receive the connecting wire 718. When the connecting wire 718 is advanced into the probe 700, the adapter 716 engages with the handle 110. In this embodiment, the adapter 716 has threads 732 to retain the handle 110 engaged, as shown in FIG. Figure 14C In this embodiment, the connecting wire 718 includes at least one bend or kink 734. Thus, when the connecting wire 718 is coaxially positioned within the probe 700, the kink 734 pulls the connecting wire away from the coaxial axis and into contact with the probe 700. It is this contact that allows energy to be transferred from the connecting wire 718 to the probe 700.

[0259] Figures 15A-15C Example methods of treatment are depicted. Figure 15A Abnormal or diseased tissue D, such as a tumor, is depicted near a luminal structure LS. In this example, the diseased tissue D is near the luminal structure LS, but is spaced a distance from the lumen wall W. This luminal structure LS is used to access the diseased tissue D and perform extraluminal treatment on the diseased tissue D near the luminal structure LS. In this embodiment, the elongated insertion tube 14 of the endoscope 10 is advanced into the luminal structure LS, and its distal end 16 is turned toward the lumen wall W, with the diseased tissue D positioned outside the lumen wall W. Once ideally positioned, the treatment catheter 102 is advanced through the lumen in the insertion tube 14 so that the distal end 103 of the shaft 106 extends beyond the tip 16 of the endoscope 10, as shown in FIG. Figure 15B In this embodiment, the probe tip 702 assists in penetrating the wall W, and the shaft 106 is advanced through the wall W until the probe tip 702 is ideally positioned within the diseased tissue D. Figure 15C In this embodiment, the probe tip 702 is then advanced from the shaft 106 to form the desired delivery electrode size. Energy is then delivered to the diseased tissue D via the probe 700 according to one or more energy delivery algorithms 152, such as Figure 15C702. As shown by the wavy arrows extending radially outward from the probe tip 702 in FIG. 703. It will be appreciated that the distance into the diseased tissue may vary based on parameter values, treatment time, and tissue type, to name a few. It will also be appreciated that a greater or lesser treatment depth than shown herein may be achieved.

[0260] The energy delivered is suitably used to treat the diseased tissue D. In the case of cancer, cancer cells are destroyed, eliminated, killed, removed, etc., while maintaining non-cancerous, non-cellular components, such as collagen, elastin, and matrix proteins. These non-cellular components maintain the structure of the tissue, allowing and promoting normal cell regeneration. Similarly, any energy that reaches the wall W of the nearby luminal structure LS maintains the integrity and mechanical properties of the luminal structure LS. It will be appreciated that in some cases, energy directly kills the cells in the diseased tissue D, such as via the irreversible destruction of accumulated systemic cell damage and cell homeostasis. Then, any remaining diseased tissue can be removed by surgery or by other methods that are usually unable to safely treat tissue near the luminal structure.

[0261] Alternative probe designs

[0262] It will be appreciated that probe 700 can have a variety of forms and structures. In some embodiments, probe 700 is hollow, such as having a tubular shape. In such embodiments, probe 700 can be formed from a hypotube or metal tube. Probe 700 can be provided in a variety of sizes, including 16 to 25 gauge. Probe 700 can be optimized for desired thrust and torque capabilities, kink resistance, compression resistance, and flexibility to ensure consistent and reliable steerability to the targeted treatment site. Similarly, such tubes can include custom-designed transitions, such as laser cutting and cutting features, as well as optional coatings to optimize product performance.

[0263] Figures 16A-16B 17A-17B depict an embodiment of a probe 700 having a shaft 106 customized to meet the desired flexibility and maneuverability while maintaining the desired thrust and torque capabilities. Figure 16A A shaft 106 is shown that includes a tube having a pattern 707 incorporated therein to provide such handling properties. In some embodiments, the tube is comprised of metal and the pattern 707 is laser cut or etched. In this embodiment, the pattern 707 includes a spiral wound around the circumference of the tube. Likewise, in this embodiment, the pitch of the spiral is uniform throughout the length of the pattern 707.

[0264] Figure 16BThe illustrated shaft 106 has a pattern 707 that varies along its length. In this embodiment, pattern 707 also comprises a spiral wound around the circumference of the tube. However, in this embodiment, the pitch of the spiral varies throughout the length of pattern 707. Specifically, in this embodiment, pattern 707 is composed of three sections, each with a different pitch. First section 709 has a first pitch, second section 711 has a second pitch, and third section 713 has a third pitch. Here, second section 711 has a larger pitch than first section 709, while third section 713 has a larger pitch than second section 709. Similarly, in this embodiment, sections 709, 711, and 713 are adjacent to each other, allowing pattern 707 to consist of a continuous spiral. However, it will be appreciated that two or more sections can be separated so that the pattern consists of more than one spiral cut. Similarly, the pitch can vary in different combinations, including repeated intervals between non-adjacent sections.

[0265] It will be appreciated that in some embodiments, the shaft 106 is at least partially covered by the insulating layer 715 . Figures 16A-16B An insulating layer 715 is depicted, comprising a heat-shrinkable polymer tube disposed around the shaft 106, exposing the probe tip 702 for energy delivery. The insulating layer 715 seals against the laser-cut pattern and acts as electrical insulation. By varying the insulating layer 715, the size of the exposed tip 702 can be varied to achieve the desired electrode size for energy delivery.

[0266] In some embodiments, the shaft 106 includes a tube having a braid 721 that is incorporated into the shaft 106 to provide the desired handling properties. Typically, the braid material is composed of stainless steel. The braid material can be composed of round wire or flat wire. The PIC count provides the number of crosses per inch (PIC) of the braid. A higher PIC count improves flexibility, while a lower PIC count increases longitudinal stiffness. The PIC count can be varied within a specific length to provide variable flexibility. This can also be achieved by selectively removing different layers of the tube, such as a polymer layer. In some embodiments, the tube is composed of various layers, such as a polytetrafluoroethylene (PTFE) inner layer, an adjacent polyimide layer, an adjacent braided layer, another polyimide layer, and an outer Pebax sheath.

[0267] Figure 17A Depicted is a shaft 106 comprising a tube having such a braid 721 incorporated into the shaft 106. The braid 721 here is uniform along its length, with a consistent PIC count. Figure 17BA shaft 106 is depicted having a braid 721 that varies along its length. In this embodiment, the PIC count varies along three sections, each with a different spacing. A first section 723 has a first PIC count, a second section 725 has a second PIC count, and a third section 727 has a third PIC count. Here, the second section 725 has a greater PIC count than the first section 723, and the third section 729 has a greater PIC count than the second section 725. Also, in this embodiment, sections 723, 725, and 727 are adjacent to one another, making the braiding continuous. However, it will be appreciated that two or more sections may be spaced apart, such that non-braided sections are interspersed between braided sections. Similarly, the PICs may vary in different combinations, including repeating PIC types in non-adjacent sections.

[0268] It will be appreciated that the probe tip 702 may have a variety of shapes and styles, including lancet, Chiba (a two-part hollow needle with a 30-degree angled tip), or pencil tip (atraumatic) designs. In certain embodiments, the probe shaft has a sharp point with multiple cutting edges to form the probe tip 702. In other embodiments, the tube has a blunt atraumatic tip. In some embodiments, the probe 700 is solid, such as having a rod shape. These probes can also be optimized and customized like hypotubes. In some embodiments, the solid probe 700 has a sharp point with symmetrical or asymmetrical cuts to form the probe tip 702. In other embodiments, the solid probe tip 702 has a blunt atraumatic tip.

[0269] It will be appreciated that the probe 700 may include a lumen for delivering fluids or medications. Such a lumen may be internal or external to the probe. Figures 18A-18B A cross-section of an embodiment of the probe shaft 106 is depicted. Figure 18A A probe 700 is depicted having a shaft 106 that includes a single lumen 730 for delivering fluid. Such delivery can be delivery and / or aspiration. A conductive filament 732 is also shown. Figure 18B A probe 800 is depicted having a shaft 106 that includes two lumens 730a and 730b for delivering fluids. Thus, two different fluids can be delivered through different lumens. Alternatively, one lumen can be used for delivery while the other lumen is used for aspiration. It will be appreciated that various combinations can be employed. A conductive filament 732 is also shown. Fluids or agents can be delivered directly from the shaft 106, for example, through an internal lumen and output from one or more ports 734 located along the shaft 106, or output from the probe tip 702. In some embodiments, such as Figure 18D As shown, the probe tip 702 includes a plurality of ports 734, such as microports, that allow fluid to be delivered in a uniform and prevalent radial pattern.

[0270] In some embodiments, stylet 700 is comprised of multiple stylet elements, each of which has similar features and functions as the single stylet 700 described above. Thus, in some embodiments, they can be considered separate stylets, however, for simplicity, they will be described as stylet elements comprising a single stylet 700 because they pass through the same shaft 106 of catheter 102. Figure 19A An embodiment is depicted having three probe elements 700a, 700b, and 700c, each having a corresponding probe tip 702a, 702b, and 702c. Probe elements 700a, 700b, and 700c extend from shaft 106 in different directions from a central axis 750, for example, radially curving along axis 750 and away from axis 750 in opposite directions. This allows tips 702a, 702b, and 702c to be positioned in an array of positions across the entire area of lesion D. Thus, a larger ablation zone can be formed. This may be desirable when the area of lesion D is large, when treating multiple targets, or when the targets have imprecise location information. It will be appreciated that probe elements 700a, 700b, and 700c can be deployed independently or simultaneously. Similarly, tips 702a, 702b, and 702c can be energized independently or simultaneously. The energy delivered by the tips 702a, 702b, 702c can be provided by the same energy delivery algorithm 152 or different energy delivery algorithms 152, thereby delivering the same or different energies. The probe elements 700a, 700b, 700c can function in a monopolar manner or in a bipolar manner between the probe element pairs. Similarly, it will be understood that the probe elements 700a, 700b, 700c can function in a combination of monopolar and bipolar modes.

[0271] It will be appreciated that there may be any number of probe elements, including one, two, three, four, five, six, seven, eight, nine, ten, or more. Likewise, the probe elements may extend the same or different distances from the axis 106 and may have the same or different curvatures. Figure 19BIn FIG, three probe elements 700a, 700b, and 700c are depicted extending different distances from shaft 106, with one probe element 700a extending the shortest distance, another probe element 700b extending the farthest distance, and another probe element 700c extending in between. These probe elements 700a, 700b, and 700c, also depicted as having different curvatures, extend radially outward from central axis 750. Here, one probe element 700a has the greatest curvature, another probe element 700b has no curvature, and yet another probe element 700c has an intermediate curvature. In another embodiment, the probe elements have no curvature and withdraw from shaft 106 in a linear manner. Typically, the probe elements are pre-curved so that advancement of the probe tip from shaft 106 allows the probe element to assume its pre-curved shape. Therefore, in some embodiments, a variety of curvatures can be utilized by advancing the probe tip from shaft 106 by different amounts.

[0272] In some embodiments, the probe element is curved radially outward into a flower or umbrella shape, such as Figure 19C Here, multiple probe elements 700a, 700b, 700c, 700d, 700e, 700f extend radially outward from a central axis 750 in a flower shape and are curved around so that their respective tips are ultimately oriented in a proximal direction. In some embodiments, elements 700a, 700b, 700c, 700d, 700e, 700f have equal lengths and are equally spaced to form a symmetrical arrangement. In other embodiments, elements 700a, 700b, 700c, 700d, 700e, 700f have different lengths and / or different spacings to form a myriad of arrangements.

[0273] It will be appreciated that the size of the probe tip 702 capable of transmitting energy can be further adjusted by using an insulating sheath 752 that extends at least partially over the probe. As previously described, the size of the active portion of the probe tip 702 can be adjusted based on its extension from the shaft 106. However, this can be further improved, particularly when multiple probe elements are present, by using an insulating sheath 752 to cover portions of each probe element. Figure 19DAn embodiment of a probe is depicted that includes two probe elements 700a, 700b extending from a shaft 106. Here, each probe element 700a, 700b is at least partially covered by a corresponding insulating sheath 752a, 752b, leaving the tip 702a, 702b exposed. In some embodiments, the sheaths 752a, 752b can be advanced individually, allowing the size of each probe tip 702a, 702b to be individually selected. This can be beneficial when the tips 702a, 702b are deployed to different portions of target tissue where different energy delivery amounts are desired. This can also be beneficial when focusing energy delivery to a location at an angular distance from the central axis of the shaft 106. In summary, the ability to vary the number of probe elements, the shape and length of the probe elements, the arrangement of the probe elements, and the size of the delivery area on the probe tip allows for the creation of a wide variety of lesion shapes, sizes, and intensities.

[0274] It will be appreciated that any probe element described herein can have the same structure and features as any probe described herein. For example, the probe element can be made of the same material, have the same function, and have a sharp or non-damaged tip. Equally, it will be appreciated that any probe element can be deployed independently or simultaneously and can be powered on independently or simultaneously. The energy delivered can be provided by the same energy delivery algorithm 152 or different energy delivery algorithms 152, thereby delivering the same or different energies. Any probe element can act in a monopolar or bipolar manner between probe element pairs. Equally, it will be appreciated that the probe element can act in a monopolar and bipolar combination.

[0275] As previously described, in many of these extraluminal delivery embodiments, the energy delivery body 108 is in the form of a probe 700 disposed within the lumen 105 of the shaft 106. In some embodiments, the probe 700 includes a plurality of wires or ribbons 120 and forms a basket 755 that acts as an electrode, such as Figure 20 As shown. It will be appreciated that, alternatively, the basket 755 can be laser cut from a tube. It will be appreciated that a variety of other designs can be used. Typically, the basket 755 is delivered to the target area in a collapsed configuration and then expanded for use. Such expansion can form the basket 755 into a rectangular, oval or elliptical shape, a circle, or a disk, to name a few. In some embodiments, the basket 755 is configured to form a disk, such as Figure 21 (side view). In this embodiment, the probe 700 includes a disc-shaped basket 755 and a pointed probe tip 702, wherein the probe tip 702 is concentric with the disc-shaped basket 755. Such an arrangement may help to form a larger lesion. For example, Figure 22AAn embodiment of a probe tip 702 is depicted positioned within a target tissue region A. Energy transmitted from the probe tip 702 forms a first ablation zone Z1 surrounding the tip 702. In this example, the first ablation zone Z1 is smaller than the target tissue region A. However, as Figure 22B As shown, by adding the disc-shaped basket 755, energy is also delivered from the basket 755, forming a second ablation zone Z2 that is larger than the first ablation zone Z1. In some embodiments, the first ablation zone Z1 and the second ablation zone Z2 overlap, such that the first ablation zone Z1 resides entirely within the second ablation zone Z2. This provides a superimposed effect of two ablations within the first ablation zone Z1. In other embodiments, the disc-shaped basket 755 delivers energy only or primarily from its periphery or edge (e.g., by isolating or shielding the central area of the basket 755). In such embodiments, the first ablation zone Z1 and the second ablation zone Z2 do not substantially overlap. When the energy provided by the basket 755 and the probe tip 702 is the same, this arrangement can allow the first ablation zone Z1 to uniformly expand to the size of the second ablation zone Z1 (i.e., form a uniform lesion). When the energy provided by the basket 755 and the probe tip 702 is different, this can allow different types of lesions to be formed in the first ablation zone Z1 and the second ablation zone Z2.

[0276] It will be appreciated that in some embodiments, the probe 700 can include two or more baskets 755 that are spaced apart to allow target tissue to be positioned therebetween. In such instances, energy can be delivered from the two or more baskets 755 in a monopolar manner or in a bipolar manner, wherein the two baskets have opposite polarity such that energy is transferred therebetween, thereby treating tissue therebetween.

[0277] It will be appreciated that in some embodiments, the stylet 700 is fixed relative to the shaft 106. Likewise, in some embodiments, the stylet 700 does not extend the entire length of the shaft 106. For example, in some embodiments, the stylet 700 is shortened and resides near the distal end 103 of the shaft 106, where the stylet tip 702 extends from the shaft 106. In such embodiments, energy is transmitted to the shortened stylet 700 via a conductive wire or other device that extends through the shaft 106 to the shortened stylet 700. In some cases, this can allow the shaft 106 to have altered physical properties, such as increased flexibility.

[0278] It will be appreciated that in some embodiments, the energy delivery body 108 includes a conductive element 760 (such as a conductive wire or filament) that passes through and extends from the probe 700, such as Figure 23As shown. In this embodiment, the probe 700 is non-conductive and simply provides a tip 702 to assist in penetrating tissue and delivering a conductive element 760. It will be appreciated that the conductive element 760 has suitable strength to advance beyond the probe tip 702 for insertion into the target tissue. Energy is delivered from the generator 104 to the conductive element 760, which delivers the energy to the tissue. In some embodiments, the conductive element 760 has a length of 0.5 cm, 0.5 cm, 1 cm, 2 cm, 3 cm, 1 cm to 3 cm, 2 cm to 3 cm, or greater than 3 cm from the probe tip. In some embodiments, the conductive element 760 has a diameter of 0.010 inches, 0.011 inches, 0.012 inches, 0.013 inches, 0.014 inches, or 0.015 inches. When it is desired to deliver a higher concentration of energy at a specific tissue location, the use of such a conductive element 760 may be beneficial.

[0279] It will be appreciated that in some embodiments, the catheter 102 does not include the stylet 700, and the one or more electrode bodies 108 are mounted on or integral with the shaft 106. In such embodiments, the one or more electrode bodies 108 can be in the form of ribbon electrodes, basket electrodes, or any other suitable electrode shape. In such embodiments, the shaft 106 is advanced into the target tissue, and energy is delivered from the one or more electrode bodies 108.

[0280] Catheter manipulation and visualization

[0281] As described above, the catheter 102 is typically delivered through an endoscope 10 or other delivery device that is steered through a luminal structure by conventional methods. This can ultimately result in positioning one or more energy delivery bodies 108 within a body cavity (intraluminal placement) or positioning one or more energy delivery bodies 108 outside a body cavity (extraluminal placement). In either case, the shaft 106 of the catheter 102 is advanced from the endoscope or delivery device to its desired position. Such positioning can be achieved manually, such as by manually manipulating the handle 110 (such as with one or two hands), and / or positioning can be controlled or assisted by a variety of mechanisms, such as electromechanical servo-based control (e.g., robotic) actuated by the handle 110 or the user interface 150.

[0282] In some embodiments, the distal end 103 of the shaft 106 can be turned in one or more planes. This includes left-right movement, up-down movement, or angular movement relative to the central longitudinal axis of the shaft 106 when the shaft 106 leaves the endoscope or conveying device. In some embodiments, the distal end 103 of the shaft 106 can rotate relative to the endoscope or conveying device. As described above, such steering can be achieved manually or with electromechanical control via the handle 110 and / or user interface 150. Similarly, in an embodiment with a probe and / or probe element, the probe / probe element can be independently or relative to each other and / or relative to the shaft 106 simultaneously in a similar manner, advanced, steered, manipulated, or positioned.

[0283] The steering and positioning of shaft 106 can be assisted by a variety of design features. For example, in some embodiments, the flexibility of shaft 106 is enhanced by a series of design cuts along its length. Such cuts can vary along the length, thereby causing a change in flexibility, such as increasing flexibility along the distal end 103 of shaft 106. Similarly, probe 700 itself can enhance flexibility, such as having notches processed along its length to impart additional steerability or flexibility. This is especially true when using a solid probe 700.

[0284] Typically, during placement, the catheter 102 is visualized in vivo using one or more visualization systems, including but not limited to white light visualization from an endoscope, ultrasound visualization from an endoscope or external ultrasound system, fluoroscopy, cone beam computed tomography, or any other X-ray visualization system. In some embodiments, the catheter 102 has an integrated or embedded electromagnetic (EM) sensor that provides tracking in an electromagnetic field. In other embodiments, the catheter 102 has an integrated or embedded sensing system that measures changes in shaft shape, such as a fiber Bragg grating sensor. In other embodiments, the catheter 102 and / or the energy delivery body 108 is coated with an echogenic coating that allows for enhanced visualization in an ultrasound field. In other embodiments, the catheter 102 has a surface preparation or treatment that allows for enhanced visualization in an ultrasound field. In other embodiments, the catheter 102 has one or more designs imprinted onto its surface that allow for enhanced visualization in an ultrasound field. In other embodiments, the catheter 102 is enhanced with integrated ultrasound. For example, in some embodiments, the shaft 106 includes one or more piezoelectric micromachined ultrasonic transducers (PMUTs), capacitive micromachined ultrasonic transducers (CMUTs), or lead zirconate titanate (PZT)-based ultrasonic transducers, such as in an array positioned circumferentially around the shaft 106. In other embodiments, the catheter 102 is at least partially composed of a metal that is radiopaque and visible under X-ray, fluoroscopy, cone beam computed tomography (CBCT), and / or magnetic resonance imaging (MRI). In other embodiments, the shaft is partially composed of a fluorescent visible material (such as tungsten powder or solder paste). In other embodiments, a combination of these sensors, coatings, surface treatments, imprints, or materials enhances visualization.

[0285] Useful methods associated with imaging include: (a) detecting diseased target tissue; (b) identifying an area to be treated; (c) evaluating the treated area to identify the effectiveness of energy delivery; (d) evaluating the target area to identify whether an area was missed or undertreated; (e) using pre-procedural or intra-procedural imaging to measure the depth of targeted treatment, and using the depth to select a specific energy delivery algorithm to achieve a tissue effect at the depth; (f) using pre-procedural or intra-procedural imaging to identify a targeted cell type or cell interface, and using the location or depth to select a specific energy delivery algorithm to achieve a tissue effect on the targeted cell type or cell interface; and / or (g) using pre-procedural, intra-procedural, or post-procedural imaging to identify the presence or absence of pathogens, and the presence or absence of inflammatory tissue.

[0286] In some embodiments, confocal laser microendoscopy (CLE), optical coherence tomography (OCT), ultrasound, static or dynamic CT imaging, X-ray, magnetic resonance imaging (MRI), and / or other imaging modalities can be used as separate devices / systems or combined / integrated (functionally and / or structurally) into the treatment system 100 by being incorporated into the instrument 102 or a separate device. The imaging modality (or multiple modalities) can be used to locate and / or access various sections of the target tissue. In some embodiments, the targeted treatment depth can be measured and used to select a treatment algorithm 152 that is sufficient to treat to the targeted depth. Then, at least one energy delivery body can be deployed at the target tissue site and deliver energy to affect the target tissue. The imaging modality (or multiple modalities) can be used before, during, between, and / or after treatment to determine where treatment has or has not been delivered, or whether the energy has adequately affected the airway wall. If it is determined that an area has been missed or an area has not been adequately affected, the energy delivery can be repeated, followed by the imaging modality (or multiple modalities), until adequate treatment is achieved. Furthermore, imaging information can be used to determine whether specific cell types should be applied and / or the desired treatment depth. This can allow for customization of energy delivery algorithms for treating various patient anatomies.

[0287] In some embodiments, a pathway through a body cavity is visualized by one or more instruments inserted into the body. Likewise, in some embodiments, one or more of a plurality of imaging modes (e.g., CLE, OCT) are used in conjunction with direct visualization, or in place of direct visualization. As an example, a bronchoscope can be delivered via the mouth to allow direct visualization and delivery of the instrument 102, while an alternative imaging mode can be delivered via another working channel of the bronchoscope, via the nose, or adjacent to the bronchoscope via the mouth. In some embodiments, an imaging modality (e.g., direct visualization, CLE, and / or OCT) is incorporated into the instrument 102 by an appropriate mechanism to connect the imaging modality to a system generator 104 or a commercially available console.

[0288] Sensing

[0289] In some embodiments, one or more sensors for measuring one or more system or tissue parameters are included in the system 100. Example sensors include temperature sensors, impedance sensors, resistance sensors, surface conductivity sensors, membrane potential sensors, capacitance sensors, and / or force / pressure sensors, or combinations thereof. Thus, the parameters measured by the sensors can include impedance, membrane potential or capacitance, and / or temperature, to name a few. The sensors can be used to (a) obtain baseline measurements, (b) measure parameters during energy delivery, and / or (c) measure parameters after energy delivery, among others.

[0290] As a non-limiting example, sensor information can be used as feedback to the system 100 to determine the appropriate deployment of the energy delivery body 108, drive the therapy algorithm 152, and / or stop energy delivery for safety reasons. Sensors can also be used to sense when appropriate treatment has been achieved. The algorithm 152 within the generator 104 can also use the sensed data to automatically titrate the therapy algorithm 152 so that target tissue treatment is achieved. In other words, one or more parameters and / or aspects of the therapy algorithm can be iteratively modified based on the sensor data. For example, in some embodiments, the power and / or energy duration can be increased or decreased based on the sensor data. Therefore, in some embodiments, the system 100 includes one or more sensors that can optionally provide real-time information that can be used to modify the treatment during treatment. It will be understood that in some embodiments, the energy delivery body 108 having or serving as an electrode can be used as a sensor. These include some probes 700 and probe elements.

[0291] In some embodiments, the catheter 102 includes one or more sensors for providing force feedback to the user during positioning of the catheter 102. Example sensors include force sensors based on fiber Bragg gratings (FBGs). FBGs are microstructures, typically several millimeters long, that can be photoetched into the core of a single-mode optical fiber. As sensors, FBGs have unique properties. For example, when the fiber is stretched or compressed, the FBG will measure strain. This occurs because deformation of the optical fiber causes a change in the period and Bragg wavelength of the microstructure. Such force sensors can be configured to measure force in one dimension, two dimensions, or three dimensions. It will be appreciated that other types of force sensors can be used. Such force sensors can be used to sense the curvature of the shaft 106 and / or probe 700 during delivery. Alternatively, such force sensors can be used to provide various force feedback to assist in advancing or redirecting the catheter during placement of one or more energy delivery bodies 108.

[0292] In some embodiments, the system 100 includes one or more sensors for measuring tissue impedance. In some embodiments, such tissue impedance information is used to generate an approximate map of the tissue treatment area before, during, and after treatment. In other embodiments, such tissue impedance information is provided as feedback to the generator 104 during treatment. Accordingly, the energy delivery algorithm 152 can be modified, or a different algorithm 152 can be selected based on the feedback information, in order to alter the energy delivered. In other embodiments, an alert is provided to the user. In either case, this can be triggered when tissue impedance exceeds a predetermined threshold, optionally for a predetermined period of time.

[0293] In some embodiments, impedance measurements can be taken before, during, or after energy application to define which energy delivery algorithm 152 to apply and / or whether additional energy needs to be applied to the target location. In some embodiments, pre-processing impedance measurements can be used to determine the settings of various signal parameters. In other embodiments, sensors can be used to determine whether the energy delivery algorithm should be adjusted.

[0294] In some embodiments, impedance measurement is performed as follows. Once the target area within the lung passage is positioned, a low-pressure signal of short duration is delivered to the energy delivery body 108 via a generator (e.g., generator 104). Based on the measured current feedback received by the generator 104, the generator 104 performs a calculation using the set voltage and actual current to calculate the impedance. The calculated impedance is compared with an impedance value that is considered acceptable for the measured impedance. The energy delivery algorithm 152 is then modified or customized based on the measured impedance. Parameters that can be adjusted include, but are not limited to, voltage, frequency, rest period, cycle count, dead time, packet count or number of packets, or a combination thereof. Thus, the feedback control loop can be configured to modify the parameters of energy delivery based on one or more measured system or tissue parameters.

[0295] In some embodiments, one or more impedance sensors are used to monitor the electrical properties of tissue. The impedance value can be considered an indicator of tissue state. In some embodiments, impedance is measured at different frequencies to provide an impedance spectrum. This spectrum characterizes the frequency-dependent or reactive component of the impedance. Tissue has both a resistive component and a reactive component; these are components of the complex impedance. Reactance is the frequency-dependent component of impedance, which includes tissue capacitance and inductance. Changes in tissue state can result in changes in the total impedance as well as changes in the resistive or reactive components of the complex impedance. Measuring complex impedance involves conducting a low-voltage sensing signal between two electrodes. The signal can include, but is not limited to, a sine wave. Changes in complex impedance, including changes in resistance or reactance, can reflect the state of the treated tissue and, therefore, serve as an indicator that the treatment is affecting the tissue, is not affecting the tissue, and / or that the treatment is complete. The impedance value can also vary depending on the contact between the sensor and the airway tissue. In this way, the sensor can also be used to determine the contact state between the electrodes and the tissue.

[0296] In some cases, the generator 104 indicates to the user that no further energy delivery is required at the targeted location. Alternatively, the generator 104 displays a specific message and / or emits a specific sound to alert the operator which energy delivery algorithm 154 has been selected or that treatment is complete at the targeted location. Thus, the generator 104 can be configured to automatically select the appropriate algorithm for a particular measured impedance or to shut off the delivery of the energy signal if treatment is determined to be complete. Additionally, impedance or other sensors can be used to determine that treatment should be automatically stopped for safety reasons.

[0297] In some embodiments, the system 100 includes one or more sensors for measuring temperature. An example sensor includes a fiber Bragg grating (FBG)-based temperature sensor. Sensitivity to temperature is an inherent property of FBGs. In this case, the primary cause of the change in Bragg wavelength is changes in the refractive index of silica induced by thermo-optical effects. Thermal expansion also has a smaller impact on the microstructure. It will be appreciated that other types of temperature sensors can be used. In some embodiments, potential thermal damage can be calculated based on feedback from one or more temperature sensors and aspects of the energy being used, such as waveform parameters. Therefore, in some embodiments, the system 100 includes software for calculating such potential thermal damage, and such information is provided as feedback to the generator 104 during treatment. Accordingly, the energy delivery algorithm 152 can be modified, or a different algorithm 152 can be selected based on the feedback information, in order to alter the delivered energy. In other embodiments, an alert is provided to the user. In other embodiments, the approximate local perfusion of the treatment site can be calculated based on feedback from one or more temperature sensors measuring the temperature of the treatment site, combined with the patient's core temperature (measured by the system 100's temperature sensors or other mechanisms). Thus, in some embodiments, the system 100 includes software that calculates such local perfusion at the treatment site, and such information is provided as feedback during treatment to the generator 104. Thus, the energy delivery algorithm 152 can be modified, or a different algorithm 152 can be selected based on the feedback information, in order to vary the energy delivered.

[0298] In some embodiments, one or more temperature sensors are positioned along the surface of one or more energy delivery bodies 108 so as to contact the tissue and ensure that the tissue is not heated above a predefined safety threshold. Thus, one or more temperature sensors can be used to monitor the temperature of the tissue during treatment. In one embodiment, a temperature change that meets a pre-specified criteria, such as an increase in temperature above a threshold value (e.g., 40°C, 45°C, 50°C, 60°C, 65°C), can result in a change in the energy delivery parameters (e.g., modifying the algorithm) in an effort to lower the measured temperature or to lower the temperature below a preset threshold. Adjustments can include, but are not limited to, increasing the rest period or dead time, or reducing the packet count. Such adjustments occur in a predefined stepwise approach, as a percentage of a parameter, or by other methods.

[0299] In other embodiments, one or more temperature sensors monitor the temperature of the tissue and / or electrodes, and if a predefined threshold temperature (e.g., 65° C.) is exceeded, the generator 104 changes the algorithm to automatically stop energy delivery. For example, if the safety threshold is set to 65° C. and the generator 104 receives feedback from one or more temperature sensors that the temperature safety threshold has been exceeded, treatment can be automatically stopped.

[0300] In some embodiments, the system 100 includes one or more sensors for measuring pH. In some embodiments, such pH information is used to provide information about the microenvironment of the targeted treatment area, such as before, during, and after treatment. When used during treatment, the pH information can be provided as feedback to the generator 104 so that the energy delivery algorithm 152 can be modified, or a different algorithm 152 can be selected based on the feedback information. In other embodiments, an alert is provided to the user. Thus, the energy delivered can be changed in real time. In either case, this can be triggered when the information exceeds a predetermined threshold, optionally for a predetermined period of time.

[0301] It will be appreciated that sensors can be located in various locations throughout the system 100. For example, one or more sensors can be attached to or embedded in the shaft 106 of the catheter 102. Additionally or alternatively, one or more sensors can be attached to or embedded in the stylet 700 or various stylet elements. Similarly, if other accessories are used, one or more sensors can be located on the accessory and in communication with the system 100.

[0302] Alternative delivery methods

[0303] As previously mentioned, in most embodiments, access is minimally invasive and relies on an endoluminal approach. However, it will be appreciated that other approaches, such as percutaneous, laparoscopic, or open surgical approaches, may be used in some cases.

[0304] In some embodiments, when accessing percutaneously, the shaft 106 of the catheter 102 passes through a delivery device that penetrates the skin layer and enters the underlying tissue. In some embodiments, the delivery device includes a needle that is inserted through the skin and directed toward the target tissue. The shaft 106 is then advanced through the needle. In some embodiments, the probe tip 702 is shaped to facilitate tissue penetration, such as a pointed shape. Thus, the shaft 106 can be advanced through the tissue to a desired location therein. Once ideally positioned, energy is delivered through the probe tip 702 to treat the target tissue. It will be appreciated that the probe tip 702 can also be advanced from the shaft 106 into the tissue, and / or the conductive element 760 can be advanced into the tissue, with energy being delivered from the conductive element 760.

[0305] In other embodiments, when percutaneously accessing, the shaft 106 of the catheter 102 is rigid, thereby being able to penetrate the skin layer without the use of a delivery device. In such embodiments, the probe tip 702 is typically shaped to facilitate penetration of tissue, such as a pointed shape. Thus, the shaft 106 itself is advanced into the tissue to a desired location therein. Once ideally positioned, energy is delivered through the probe tip 702 to treat the target tissue. It will be appreciated that the probe tip 702 may also be advanced into the tissue from the shaft 106, and / or the conductive element 760 may be advanced into the tissue, with energy being delivered from the conductive element 760.

[0306] In a laparoscopic approach, the shaft 106 of the catheter 102 passes through a laparoscope that has been inserted through small incisions. Compared to open surgery, these small incisions reduce pain, reduce bleeding, and shorten recovery time. In some embodiments, the probe tip 702 is shaped to facilitate penetration of tissue, such as a pointed shape. Therefore, the shaft 106 can be advanced through the tissue to the desired position therein. Once ideally positioned, energy is delivered through the probe tip 702 to treat the target tissue.

[0307] In an open surgical approach, the shaft 106 of the catheter 102 may also be passed through the delivery device, or the catheter 102 may penetrate the tissue directly. In either case, once ideally positioned, energy is delivered through the probe tip 702 to treat the target tissue.

[0308] Treatment Examples

[0309] As previously mentioned, devices, systems and methods described herein treat damaged, diseased, abnormal, obstructed, cancerous or undesirable tissue by delivering special pulsed electric field (PEF) energy to target tissue area. Such therapy can be used alone, wherein undesirable cells are destroyed, eliminated, killed, removed, etc., while maintaining non-cellular components, such as collagen, elastin and matrix proteins. These non-cellular components maintain the structure of tissue, allow and promote normal cell regeneration. Therefore, while fully eliminating abnormal or diseased cells and tissue, the integrity and mechanical properties of the luminal structure of tissue and any vicinity are maintained. In such cases, treatment can solve the problem in a single treatment, or can relate to subsequent treatment.

[0310] However, in some cases, the medical problem involves multiple treatment options, where the treatment provided by the system 100 described herein is used in combination with other treatments. This may be particularly the case when treating cancer. Figure 24A flow chart is provided showing example care pathway options for a cancer patient. Cancer is typically discovered through symptoms or through unrelated tests in which the cancer is identified (step 800). Once discovered, a diagnosis is made regarding the type of cancer and its stage (step 802). Staging refers to the extent of the cancer, such as how large the tumor is and whether it has spread. The FIGO (International Federation of Gynecology and Obstetrics) staging system is most commonly used for cancers of the female reproductive organs, including cervical cancer. The following explains what the letters and numbers mean:

[0311] FIGO Stage I: Cancer has grown from the surface of the cervix into the deeper tissues of the cervix. The cancer has not spread to nearby lymph nodes. The cancer has not spread to distant sites.

[0312] IA: The amount of cancer is so small it can only be seen under a microscope. It has not spread to nearby lymph nodes. It has not spread to distant sites.

[0313] IA1: The area of cancer can be seen only under a microscope and is less than 3 mm (about 1 / 8 inch) deep. It has not spread to nearby lymph nodes. It has not spread to distant sites.

[0314] IA2: The area of cancer can only be seen under a microscope and is between 3-5mm (about 1 / 5 of an inch) deep. It has not spread to nearby lymph nodes. It has not spread to distant sites. IB: This includes stage I cancers that have spread deeper than 5mm (about 1 / 5 of an inch) but are still confined to the cervix. It has not spread to nearby lymph nodes. It has not spread to distant sites. IB1: The cancer is more than 5mm (about 1 / 5 of an inch) deep but no larger than 2cm (about 4 / 5 of an inch) in size. It has not spread to nearby lymph nodes. It has not spread to distant sites. IB2: The cancer is at least 2cm in size but no larger than 4cm in size. It has not spread to nearby lymph nodes. It has not spread to distant sites.

[0315] IB3: The cancer is at least 4 centimeters in size and is confined to the cervix. It has not spread to nearby lymph nodes. It has not spread to distant sites.

[0316] FIGO Stage II: The cancer has grown beyond the cervix and uterus but has not spread to the pelvic wall or lower part of the vagina. It has not spread to nearby lymph nodes. It has not spread to distant sites. IIA: The cancer has grown beyond the cervix and uterus but has not spread to tissue near the cervix (called parametrial tissue). It has not spread to nearby lymph nodes. It has not spread to distant sites.

[0317] IIA1: The cancer is no larger than 4 centimeters (about 1 3 / 5 inches). It has not spread to nearby lymph nodes. It has not spread to distant sites.

[0318] IIA2: The cancer is larger than or equal to 4 centimeters. It has not spread to nearby lymph nodes. It has not spread to distant sites.

[0319] IIB: The cancer has grown outside the cervix and uterus and has spread to tissue near the cervix (parametrial tissue). It has not spread to nearby lymph nodes. It has not spread to distant sites.

[0320] FIGO Stage III: The cancer has spread to the lower vagina or pelvic wall. The cancer may block the ureters (the tubes that carry urine from the kidneys to the bladder). It may or may not have spread to nearby lymph nodes. It has not spread to distant sites.

[0321] IIIA: The cancer has spread to the lower part of the vagina but not to the pelvic wall. It has not spread to nearby lymph nodes. It has not spread to distant sites.

[0322] IIIB: The cancer has grown into the pelvic wall and / or blocked one or both ureters, causing kidney problems (called hydronephrosis). It has not spread to nearby lymph nodes. It has not spread to distant sites.

[0323] IIIC: The cancer can be any size. Imaging tests or a biopsy show that the cancer has spread to nearby pelvic lymph nodes (IIIC1) or para-aortic lymph nodes (IIIC2). It has not spread to distant sites.

[0324] FIGO Stage IV: Cancer has spread to the bladder or rectum or to distant organs, such as the lungs or bones.

[0325] IVA: The cancer has spread to the bladder or rectum, or has grown outside the pelvis.

[0326] IVB: Cancer has spread beyond the pelvic area to distant organs, such as distant lymph nodes, lungs, or bones.

[0327] Diagnosis and staging are used to plan the best treatment for the patient. Typically, there are two main treatment pathways for cancer patients: surgical treatment (the left branch of the flowchart) and non-surgical treatment (the right branch of the flowchart).

[0328] Surgery (step 900) can be used as a treatment option on its own. However, it is often provided as primary treatment in conjunction with neoadjuvant therapy (step 804) and / or adjuvant therapy (step 902). Neoadjuvant therapy is given before primary therapy to help shrink the tumor or kill cancer cells that have already spread. Adjuvant therapy is delivered after primary therapy to destroy remaining cancer cells. Neoadjuvant and adjuvant therapies benefit many, but not all, cancer patients. The type and stage of a patient's cancer often determine whether they are candidates for additional treatment. For example, if surgery determines that cancer is found in a large number of lymph nodes, the risk of cancer cells remaining increases, and adjuvant therapy may be helpful. Additionally, because some cancers are caused by specific mutations that carry a high risk of recurrence, adjuvant therapy may benefit these cancer patients more than patients with a lower risk of recurrence. In some cases, neoadjuvant therapy may be more helpful than adjuvant therapy. For example, if neoadjuvant therapy is given before surgery, doctors can assess the response to see if the tumor is actually shrinking. Treatment can then be adjusted accordingly, which may mean fewer treatments. Neoadjuvant therapy can also be used as a tool to determine a patient's response to treatment. If the tumor responds to neoadjuvant therapy before surgery, you know the patient is likely to get better. Often, both neoadjuvant and adjuvant therapies are prescribed.

[0329] Figure 24 Several different types of neoadjuvant therapies are depicted: radiation therapy (step 806), chemotherapy (step 808), targeted therapy / immunotherapy (step 810), and focused therapy (step 820). Example focused therapies include microwave ablation, radiofrequency ablation, cryoablation, high-intensity focused ultrasound (HIFU), and pulsed electric field ablation, such as described herein.

[0330] Radiation therapy or radiotherapy (step 806), often abbreviated as RT, RTx, XRT or SBRT (also known as CyberKnife), is a type of therapy that uses ionizing radiation, normally delivered by a linear accelerator. Radiation therapy is often applied to cancerous tumors because it can control cell growth. The ionizing radiation acts by damaging the DNA of cancerous tissue, causing cell death. To protect normal tissue (such as the skin or organs through which radiation must pass to treat the tumor), a shaped radiation beam is aimed from several angles to intersect the tumor, providing a much greater absorbed dose there than to surrounding healthy tissue.

[0331] It is understood that because radiation therapy relies on DNA damage to kill cells, cells do not die immediately. Over time, the damage can lead to cell death, leaving scar tissue. In some cases, pulsed electric field ablation provided by the system 100 described herein is used in combination with radiation therapy to provide improved results. For example, in some cases, the target tissue is treated with PEF energy provided by the system 100 described herein before, during, and / or after radiation therapy. This type of treatment disrupts the homeostasis of the cells, which may trigger effects similar to apoptosis, resulting in permanent cell death or causing cells to be more effectively damaged by radiation therapy. Since cell death is delayed during radiation therapy, applying PEF energy after radiation therapy can also increase cell death rate. Therefore, this type of combined treatment can lead to more effective treatment and better results.

[0332] Chemotherapy (step 808) is generally a systemic therapy introduced into the bloodstream, so in principle it can treat cancer at any anatomical location in the body. Traditional chemotherapy agents are cytotoxic by virtue of interfering with cell division, but cancer cells vary greatly in their sensitivity to these agents. To a large extent, chemotherapy can be considered a way to damage or stress cells, which may lead to cell death if apoptosis is initiated. Many of the side effects of chemotherapy can be traced back to damage to normal cells that divide rapidly and are therefore sensitive to anti-mitotic drugs, particularly cells in the bone marrow, digestive tract, and hair follicles. Chemotherapy can also be administered locally to tumor tissue.

[0333] In some cases, pulsed electric field ablation provided by the system 100 described herein is used in conjunction with chemotherapy to provide improved results. For example, in some cases, target tissue is treated with PEF energy provided by the system 100 described herein before, during, and / or after chemotherapy. Such treatment disrupts cellular homeostasis, which can trigger effects similar to apoptosis, leading to permanent cell death or causing cells to be more effectively damaged by chemotherapy. Such activation provides synergy between PEF treatment and chemotherapy, resulting in results that exceed those of either treatment alone. Thus, such combined treatments can result in more effective treatment and significantly improved responses.

[0334] Targeted therapy / immunotherapy (step 810) is a type of targeted cancer therapy. Targeted therapy is a drug or other substance that blocks cancer growth and spread by interfering with specific molecules or molecular targeting involved in cancer growth, progression and spread. Targeted therapy is different from standard chemotherapy in several aspects. For example, targeted therapy acts on specific molecular targeting associated with cancer, while most standard chemotherapy acts on all rapidly dividing normal cells and cancer cells. Targeted therapy is deliberately selected or designed to interact with its target, but many standard chemotherapy are identified because they kill cells. Targeted therapy usually inhibits cell growth (i.e., stops tumor cell proliferation), while standard chemotherapy agents have cytotoxicity (i.e., kills tumor cells). Targeted therapy is the cornerstone of precision medicine, which is a form of medicine that uses information about people's genes and proteins to prevent, diagnose and treat diseases.

[0335] Immunotherapy is a type of biological therapy. A biological therapy is a treatment that uses substances made from living organisms to treat cancer. Several types of immunotherapy are used to treat cancer. One example is immune checkpoint inhibitors. Checkpoints are a normal part of the immune system and prevent an overly strong immune response. Therefore, by blocking or inhibiting them, these drugs allow immune cells to respond more strongly to cancer. In T-cell transfer therapy, immune cells are removed from the tumor. Those most active against cancer are selected or engineered to better attack cancer cells, grown in large numbers, and returned to the patient via intravenous injection. This treatment enhances the natural cancer-fighting ability of T cells. In this treatment, immune cells are removed from your tumor. In another type of immunotherapy, monoclonal antibodies are designed to bind to specific targets on cancer cells. Some monoclonal antibodies mark cancer cells so that they can be better seen and destroyed by the immune system. Monoclonal antibodies are also called therapeutic antibodies. In addition, immune system modulators have been developed to enhance the body's immune response to cancer. Some of these agents affect specific parts of the immune system, while others affect the immune system more generally.

[0336] In some cases, pulsed electric field ablation provided by the system 100 described herein is used in combination with targeted therapies and immunotherapies to provide improved results. For example, in some cases, PEF energy provided by the system 100 described herein is used to treat target tissues before or during these therapies. When PEF energy causes cell death, the cell membrane ruptures, and internal cellular components are released. This exposes DNA and other cellular components, making them more easily recognized by the immune system, targeted therapies, and immunotherapies. Therefore, such combined therapies can lead to more effective treatments and better outcomes.

[0337] Focused therapy (step 812) is also used as a neoadjuvant therapy. Focused therapy relies heavily on focused delivery of energy to kill cells. As mentioned above, example focused therapies include radiofrequency ablation (RFA), microwave ablation (MWA), high-intensity focused ultrasound (HIFU), cryoablation, and pulsed electric field ablation, such as described herein. MWA, RFA, and HIFU are conventional therapies that rely on thermal energy. RFA and MWA are treatments that use image guidance to place a needle through the skin into the tumor (such as in the chest cavity to treat lung cancer). In RFA, a high-frequency current is passed through an electrode, creating a small area of heat. In MWA, microwaves are generated by the needle to create a small heated area. HIFU uses an ultrasonic transducer, similar to the transducers used for diagnostic imaging, but with much higher energy. The transducer focuses the sound waves to generate heat at a single point in the body and destroy the target tissue. Tissue can rise to 150°F in as little as 20 seconds. This process is repeated as many times as needed until the target tissue is destroyed. HIFU can also operate in a non-thermal manner.

[0338] In each case, heat is intended to destroy cancer cells. As is well known, thermal energy not only destroys cells by coagulation necrosis, but also destroys collagen support structures. Therefore, thermal energy cannot be used near sensitive or critical structures (such as body cavities). Similarly, thermal energy is limited in its scope, effectiveness and repeatability. For example, once tissue is thermally ablated, it is difficult or undesirable to overlap or re-treat tissue because the tissue is already necrotic and difficult to penetrate. For all these reasons, the pulsed electric field ablation provided by the system 100 described herein can be used in combination with RFA, MWA and HIFU therapy to treat tissue areas that cannot reach or are contraindicated for thermal therapy and / or to improve the effectiveness of these conventional therapies. Therefore, in some cases, before, during or after these conventional thermal therapies, the PEF energy treatment tissue provided by the system 100 described herein is used.

[0339] Other focused therapies do not rely on heat to kill cancer cells. For example, cryoablation uses extremely cold temperatures to kill cancer cells. During cryoablation, a thin needle (cryoprobe) is inserted through the skin and directly into the cancerous tumor. Gas is pumped into the cryoprobe to freeze the tissue. The tissue is then allowed to thaw. The freezing and thawing process is repeated several times during the same treatment session. The intracellular and / or extracellular ice crystals formed during this process cause the cells to rupture. Like thermal energy, cryotherapy has limitations. First, the size of the lesion is limited and the treatment time is prolonged. In addition, the therapy is limited to the locations where it can be applied. For example, current technology cannot reach some locations, such as lymph nodes. Similarly, although the luminal structure is preserved, cryotherapy is not suitable for use near many luminal structures because it interferes with the cooling process, rendering the therapy ineffective. For all of these reasons, the pulsed electric field ablation provided by the system 100 described herein can be used in combination with cryotherapy to treat tissue areas that are inaccessible or contraindicated for treatment and / or to improve the effectiveness of these conventional therapies.

[0340] Likewise, non-thermal energy has been used to treat tumors by mechanisms other than heating. Specifically, irreversible electroporation (IRE) has been used to treat cancerous tumors. A system for performing percutaneous IRE, called The system uses a probe inserted into the skin to deliver energy to tumor cells. This technology uses non-thermal energy to create permanent nanopores in the cell membrane. After a sufficient number of high-voltage pulses are delivered, the cells within the electric field are irreversibly damaged and die. Like other such therapies, transcutaneous IRE has limitations. As in other cases, the treatment is limited to the location where it can be applied. Some locations are not accessible or suitable for percutaneous approaches. Thus, the pulsed electric field ablation provided by the system 100 described herein can be used in conjunction with other non-thermal therapies to treat tissue areas that are inaccessible or contraindicated for such therapies and / or to enhance the effectiveness of such therapies.

[0341] It will be appreciated that the pulsed electric field ablation provided by the system 100 described herein can be used alone as a non-adjuvant therapy. This type of PEF ablation can result in sufficient tissue destruction and cell death to treat the cancer and cure the patient. In addition, the immune system activation induced by the presence of highly genetically resistant tumor cell components generated by the deposition of such PEF energy in the target tissue can induce abscopal effects. The abscopal effect is the theory that using local treatment in one area can lead to the shrinkage of cancer in untreated areas. This is particularly beneficial in treating metastatic cancer. When PEF energy causes cell death, the cell membrane ruptures and internal cellular components are released. This exposes DNA and other cellular components, making them more easily recognized by the immune system. These components are carried to the lymphatic system, which also aids in recognition. Therefore, the treatment acts in some ways as a vaccine, generating a systemic immune response.

[0342] Likewise, it will be understood that any of the neoadjuvant therapies can be used in any combination, including combinations of two or more therapies.

[0343] Reference again Figure 24 Once neoadjuvant therapy is offered, surgery is offered to those patients on the surgical care pathway (step 900). It will be appreciated that some patients will undergo surgery (step 900) directly after diagnosis and staging (step 802), skipping neoadjuvant therapy entirely. After surgery, some patients may be considered cured and will be monitored (step 904) to monitor the patient for signs of cancer recurrence. Other patients will receive adjuvant therapy (step 902) to destroy any remaining cancer cells. Adjuvant therapy can include any of the therapies described above in connection with neoadjuvant therapy, such as radiation therapy, chemotherapy, targeted therapy / immunotherapy, alone or in combination with pulsed electric field ablation provided by the system 100 described herein. Similarly, adjuvant therapy can include any of the treatments described above with respect to focused therapy, such as radiofrequency ablation (RFA), microwave ablation (MWA), high-intensity focused ultrasound (HIFU), cryoablation, pulsed electric field ablation provided by the system 100 described herein, and other pulsed electric field ablation, or any combination of these. It will be appreciated that any adjuvant therapy can be used in any combination, including combinations of two or more therapies. After adjuvant therapy, the patient will be monitored (step 804) to monitor for signs of recurrence of the patient's cancer. Some patients will not relapse and will be considered cured (step 806).

[0344] Unfortunately, some patients will experience a recurrence of their cancer (step 908). Typically, these patients will be offered non-surgical treatment options. Figure 24, non-surgical therapy (step 820) is provided as a first-line therapy for patients who are not suitable for or contraindicated for surgery or for patients with cancer recurrence. As shown in the flowchart, non-surgical therapy can include any of the therapies described above for neoadjuvant therapy, such as radiation therapy (step 826), chemotherapy (step 828), targeted therapy / immunotherapy (step 830), alone or in combination with the pulsed electric field ablation provided by the system 100 described herein. Similarly, non-surgical therapy can include any of the therapies described above for focused therapy (step 832), such as radiofrequency ablation (RFA), microwave ablation (MWA), high-intensity focused ultrasound (HIFU), cryoablation, pulsed electric field ablation and other pulsed electric field ablations provided by the system 100 described herein, or any combination of these. It will be understood that any non-surgical therapy can be used in any combination, including a combination of two or more therapies. After such treatment, the patient will typically undergo maintenance surgery (step 840) to suppress the cancer.

[0345] Some of these patients will not relapse or progress and will eventually be considered cured (step 906). Those who relapse may receive additional non-surgical treatments. Others will be given salvage therapy (step 910), which is treatment given after the cancer has not responded to other treatments. And, eventually, some patients will die from the cancer (step 912).

[0346] It will be appreciated that the pulsed electric field ablation therapy provided by the system 100 described herein, whether alone or optionally in combination with other therapies, offers additional benefits beyond the immediate success of the therapy. For example, in some cases, the PEF ablation therapy provided by the system 100 induces abscopal effects. This is the theory that localized treatment in one area leads to shrinkage of cancer in untreated areas. This is particularly beneficial when treating metastatic cancer. When PEF energy causes cell death, the cell membrane ruptures, releasing internal cellular components. This exposes DNA and other cellular components, making them more easily recognized by the immune system. These components are carried to the lymphatic system, which also aids recognition. Thus, the treatment acts in some ways as a vaccine, generating a systemic immune response. This can be further exacerbated when using targeted therapies and immunotherapies.

[0347] adjust

[0348] In some embodiments, cells targeted for treatment are regulated so as to change the behavior of the cells in response to the delivery of an energy signal. Such regulation can occur before, during, or after the delivery of the energy signal. In some embodiments, regulation before energy delivery is considered pre-regulation, while regulation after energy delivery is considered post-regulation. Such differentiation is based solely on time, rather than how the regulation therapy affects the cells. In other embodiments, pre-regulation involves influencing what happens to the cells during energy delivery, such as how the cells take up energy, and post-regulation involves influencing what happens to the cells after energy delivery, such as how the cells behave after receiving energy. Such differences may not have much to do with time, because in some cases, regulation may occur before energy delivery, but only affects the cellular response after energy delivery. Therefore, it will be understood that, unless otherwise stated, "regulation" can be considered to apply to each of these situations.

[0349] Typically, regulation is achieved by delivering a regulating solution. In some embodiments, the regulating solution is delivered by direct fluid injection of the regulating solution into the target area. In some embodiments, the regulating solution selectively changes the electrical properties of the target cells, such as affecting the distribution pattern of pulsed energy delivery. In other embodiments, the regulating solution affects the activity of the target cells. In other embodiments, the regulating solution increases the possibility of death of the target cells after pulsed energy delivery. In other embodiments, the regulating solution changes the response of non-targeted cells to the pulsed electric field. In alternative embodiments, regulation is performed via non-solution-based exposure of the tissue. This includes radiotherapy, radiation therapy, proton beam therapy. In some embodiments, regulation will affect the enzymes and energy-generating components of the cellular infrastructure.

[0350] The conditioning solution can be composed of a variety of agents, such as drugs, genetic materials, bioactive compounds, and antimicrobial agents, to name a few. For embodiments in which the conditioning solution increases the likelihood that targeted cells will die after pulsed energy delivery, the conditioning solution can include chemotherapy drugs (e.g., doxorubicin, paclitaxel, bleomycin, carboplatin, etc.), calcium, antibiotics, or toxins, to name a few. For embodiments in which the conditioning solution alters the response of non-targeted cells to pulsed electric fields, the conditioning solution can include cytokines (e.g., immunostimulants such as interleukins), genes, VEGF (e.g., to promote the growth of more blood vessels into an area), and / or cell differentiation factors.

[0351] In some embodiments, the conditioning solution includes cells, such as stem cells, autologous transplant cells, allogeneic transplant cells or other cell types. In these embodiments, cells can be used to change the response of tissue to pulsed electric fields. In other embodiments, cells can be used to refill the affected area with healthy or desired cells. For example, once the targeted cells are weakened or killed by the pulsed energy treatment delivered, the cells from the conditioning solution can move into a vacancy (such as a decellularized extracellular matrix). In some embodiments, before delivering the conditioning solution comprising new cells, the area is washed away to remove dead cells, such as with mild detergents, surfactants or other solutions. In other embodiments, before delivering the conditioning solution comprising new cells, mechanical stimulation is used, such as suction, debridement or ultrasonic water separation to physically remove dead cells.

[0352] In some embodiments, the regulation provided can trigger a targeted immune response. Immune response may result in a plurality of factors that change the therapeutic effect. This may result in an increase in the systemic immune upregulation using specific markers associated with some target tissues (such as tumors or bacteria or viruses associated with infection). It can also result in the upregulation of innate immunity, which widely affects immune system function, to detect the usual abnormal cells, bacteria or other infectious organisms resident in the body, which may occur locally, regionally or systemically.

[0353] In some embodiments, the conditioning solution is heated or cooled to change how the targeted cells respond. Generally, warm solutions promote to increase therapeutic effects (such as increasing the susceptibility of cell death), and cooled solutions can reduce the degree of therapeutic effects or increase cell survival after being exposed to the scheme of reversible design. In some embodiments, the freezing conditioning solution composed of gene and / or drug is used for pre-treatment cells to survive in energy delivery therapy, increases the quantity of cells that survive in treatment. In some embodiments, the impact of warm / freezing conditioning solution and other medicaments in the solution (such as warm calcium solution, the solution comprising freezing gene) cause the usual effect compound. In other embodiments, the heating / cooling conditioning solution does not provide the impact except that temperature changes. In such embodiments, conditioning solution is generally composed of isotonic saline, phosphate buffered solution or other benign solutions.

[0354] It will be appreciated that such heating or cooling can also be achieved by other methods that do not involve the delivery of a conditioning solution. For example, the target tissue can be heated or cooled by contacting the tissue with a heating / cooling device, intentionally heating / cooling a pulsed electric field delivery catheter, delivering mild cryotherapy, or delivering mild radiofrequency or microwave energy. As previously discussed, this can enhance the lethal or permeabilizing effect on the tissue, or it can provide a protective aspect to the cells, allowing them to survive the process and emit the desired changes to them as a result of the treatment.

[0355] In some embodiments, the conditioning solution is delivered systemically, such as by intravenous injection, ingestion, or other systemic methods. In other embodiments, the conditioning solution is delivered locally in the area of the targeted cells, such as by a delivery device or the energy delivery catheter 102 itself.

[0356] Vulvovaginal rejuvenation

[0357] Vulvovaginal rejuvenation can address both aesthetic and functional issues related to the female genitalia and urinary tract. Female genital aesthetics has become an area of interest for women, with an increasing number choosing to modify their genital anatomy to achieve greater self-esteem, reduce functional discomfort, and enhance sexual pleasure. Others are interested in correcting functional issues arising from physiological changes in women's lives, such as childbirth, weight fluctuations, genetics, and even trauma. Vaginal laxity, often attributed to vaginal childbirth, is associated with stretching and dilation of the vaginal opening. Reduced vaginal muscle firmness can lead to orgasmic dysfunction, altered genital sensation, and even urinary incontinence. Similarly, hormonal changes associated with aging and menopause can alter the laxity of the vaginal canal, compromise the pelvic floor, and reduce the firmness of the vaginal mucosa. These events often lead to the development of genitourinary disorders such as stress urinary incontinence, vaginal atrophy, dryness, and other physical distress that can impact a woman's quality of life, self-confidence, and sexual desire. This myriad of symptoms is collectively referred to as the genitourinary syndrome of menopause. Many patients with vaginal laxity or the genitourinary syndrome of menopause also experience stress urinary incontinence, recurrent urinary tract infections, and painful urination. Therefore, women seek rejuvenation or rejuvenating of the vagina and / or related structures for both cosmetic and medical reasons. Vaginal or vulvovaginal rejuvenation are marketing rather than medical terms, but these terms can be used to describe a range of aesthetic and functional procedures to correct and restore optimal or standard aesthetics and function of these organs and tissues.

[0358] The vaginal wall is composed of a superficial layer of non-keratinized squamous epithelial cells, while the deeper layers contain dense connective tissue, smooth muscle, collagen, and elastin, which provide the vaginal wall with strength and elasticity. The vaginal mucosa is estrogen-dependent and responds to cyclical changes associated with the menstrual cycle. With menopause, estrogen secretion decreases, leading to changes in the reproductive tract that reduce vaginal elasticity and thin the vaginal wall. Due to the decrease in estrogen levels, vaginal blood flow and secretions also decrease.

[0359] The vaginal wall can be treated using certain devices, systems, and methods described herein to reduce or reverse at least some of these anatomical changes. In some embodiments, as shown in FIG3A or FIG3B , a therapeutic energy delivery catheter 102 is inserted into the vagina to apply energy to a portion of the vaginal wall. Catheter 102 has an elongated shaft 106 with at least one energy delivery element 108 near its distal end and a handle 110 elongated at its proximal end. Catheter 102 can be connected to a generator 104 as part of the treatment system 100. The connection between catheter 102 and generator 104 provides electrical energy to energy delivery element 108, as well as other features. The embodiment shown in FIG3A includes an energy delivery element 108 comprising a plurality of filaments or ribbons 120, which are constrained by proximal end restraints 122 and distal end restraints 124 and form a basket that serves as an electrode. Energy delivery element 108 can be expanded within the vagina so that the basket circumferentially or partially circumferentially contacts the vaginal wall. Pulsed electric field energy is delivered to the vaginal wall in a manner that treats epithelial cells. In some embodiments, epithelial cells are destroyed so that new, healthy epithelial cells can regenerate in their place. In other embodiments, epithelial cells are treated to improve blood flow and lubrication in the area.

[0360] It will be appreciated that a variety of other designs may be used. For example, FIG3B depicts an energy delivery body 108 having a paddle shape. In this embodiment, the energy delivery body 108 is comprised of a plurality of wires or ribbons 120 arranged to form a flat pad or paddle. In these embodiments, the paddle can be positioned against the vaginal wall for treatment. In other embodiments, the energy delivery body comprises a flexible material having surface electrodes, such as flexible pad electrodes. Such electrodes can be used to provide energy to the vaginal canal circumferentially or partially circumferentially. Alternatively, the electrodes can be used individually or in groups to provide localized treatment as described above.

[0361] In some embodiments, energy is provided in conjunction with an agent, such as a pharmacological agent (e.g., growth factors, hormones, estrogens, etc.). In some embodiments, the energy causes epithelial cells to preferentially absorb the agent to achieve a beneficial therapeutic effect, such as correcting and restoring optimal or standard aesthetics and function of vaginal tissue.

[0362] It will be appreciated that the devices, systems, and methods described herein for treating conditions and illnesses of the reproductive system can be used for other parts of the body, including other lumens, cavities, and tissue surfaces. Similarly, the various parameter values and parameter value combinations for achieving the various treatment depths described herein can be utilized to treat tissue at the treatment depth in other areas of the body outside the reproductive tract. Examples of luminal structures include blood vessels, airways, esophagus, stomach, small and large intestines, colon, bladder, urethra, ureteral collecting ducts, uterus, vagina, fallopian tubes, ureters, kidneys, renal tubules, spinal canal, spinal cord, and other luminal structures in the body, as well as structures within organs such as the lungs, heart, and kidneys.

[0363] It will be appreciated that although devices, systems, and methods utilizing pulsed electric fields are described herein, it will be appreciated that other types of energy may be used in place of or in combination with pulsed electric fields in certain circumstances. Other types of energy include microwaves, radiofrequency (RF), and high-intensity focused ultrasound (HIFU), among others.

[0364] The above detailed description includes reference to the accompanying drawings, which form a part of the detailed description. These drawings show, by way of illustration, specific embodiments in which the present invention may be implemented. These embodiments are also referred to herein as "examples." Such examples may include other elements in addition to those shown or described. However, the present inventors also contemplate examples that only provide those elements shown or described. In addition, the present inventors also contemplate examples of any combination or arrangement of these elements shown or described (or one or more aspects thereof) relative to a specific example (or one or more aspects thereof) or relative to other examples shown or described (or one or more aspects thereof).

[0365] In the event of an inconsistency in usage between this document and any document incorporated by reference, the usage in this document controls.

[0366] Throughout this document, the terms "a" or "an" are used to include one or more, as is common in patent documents, independent of any other examples or uses of "at least one" or "one or more." Throughout this document, unless otherwise stated, the term "or" is used to refer to a non-exclusive or, so that "A or B" includes "A without B," "B without A," and "A and B." Throughout this document, the terms "including" and "in which" are the plain English equivalents of the respective terms "comprising" and "wherein." In addition, in the following claims, the terms "including" and "comprising" are open-ended, that is, systems, devices, articles, compositions, formulations, or methods that include elements in addition to the elements listed after the term in the claim are still considered to fall within the scope of the claim. In addition, in the following claims, the terms "first," "second," and "third," etc., are used merely as labels and are not intended to impose numerical requirements on their objects.

[0367] The purpose of the above description is to illustrate, not to limit. For example, the examples described above (or one or more aspects thereof) may be used in combination with each other. For example, a person of ordinary skill in the art may use other embodiments after reviewing the above description. The abstract is provided to comply with 37 CFR § 1.72 (b) so that the reader can quickly determine the nature of the technical disclosure. It should be understood that this submission shall not be used to interpret or limit the scope or meaning of the claims. In addition, in the above detailed description, various features may be combined together to simplify the disclosure. This should not be interpreted as meaning that unclaimed disclosed features are essential to any claim. On the contrary, the subject matter of the invention may lie in less than all the features of a particular disclosed embodiment. Therefore, the following claims are incorporated into the detailed description as examples or embodiments, each claim existing independently as a separate embodiment, and it is envisaged that these embodiments may be combined with each other in various combinations or arrangements. The scope of the invention should be determined with reference to the appended claims and the full scope of equivalents to which such claims are entitled.

Claims

1. A system for treating a tissue region within the reproductive system of a patient, the system comprising: A catheter for treating a tissue region within a patient's reproductive system, the catheter comprising: an elongated shaft; and an energy delivery body disposed near a distal end of the elongated shaft, wherein the elongated shaft is configured to be advanced into a luminal structure of the reproductive system to position the energy delivery body proximate to or against the tissue region within the reproductive system suffering from dysplasia or cancer; and a generator coupleable to the catheter, wherein the generator comprises at least one energy delivery algorithm configured to provide an energy electrical signal, wherein the energy is deliverable by the energy delivery body to treat the tissue region having dysplasia or cancer at a depth of up to 2 mm, wherein the energy comprises a biphasic pulse packet, and treating the tissue region comprises destroying at least a portion of cells having dysplasia or cancer in the tissue region while preserving collagen structure in the tissue region.

2. The system of claim 1 , wherein the energy delivery body has a shape configured to match the contour of the patient's cervix.

3. The system of claim 2, wherein the energy delivery body has a cup shape, wherein the cup shape has a concave surface configured to match the contour of the patient's cervix.

4. The system of claim 1, wherein the energy delivery body comprises a wireform.

5. The system of claim 2, wherein the energy delivery body comprises a flexible expandable member configured to be compressed against the cervix to conform to the contours of the cervix.

6. The system of claim 5, wherein the flexible expandable member comprises one or more flexible electrodes.

7. The system of claim 5, wherein the flexible expandable member comprises a non-conductive material and the one or more flexible electrodes comprise one or more pad electrodes.

8. The system of claim 2, further comprising a stabilization element configured to be advanced into the patient's uterus to stabilize the catheter while the energy delivery body resides in the patient's vagina to deliver energy to the cervix.

9. The system of claim 8, wherein the stabilization element is mounted on a shaft configured to pass through a lumen in the elongated shaft of the catheter.

10. The system of claim 8, wherein the stabilization element is mounted on a shaft configured to be advanced into the endocervical canal.

11. The system of claim 10, wherein the stabilization element comprises an expandable member having a collapsed configuration that permits passage through the endocervical canal and an expanded configuration that prevents passage through the endocervical canal.

12. The system of claim 1, further comprising a second energy delivery entity.

13. The system of claim 12, wherein the energy delivery body and the second energy delivery body function as a bipolar pair.

14. The system of claim 12, wherein the energy delivery body and the second energy delivery body are configured to receive energy of different waveforms from the generator.

15. The system of claim 12, wherein the second energy delivery device is configured to be advanced into the patient's uterus to treat a tissue region within the uterus while the energy delivery device resides in the patient's vagina to treat a tissue region within the vagina.

16. The system of claim 15, wherein the energy delivery body and the second energy delivery body function as a bipolar pair that delivers an electric field configured to cause destruction of cells along and / or within the patient's cervix.

17. The system of claim 15, wherein the second energy delivery body has a funnel shape.

18. The system of claim 15, wherein the energy delivery body has a cup shape.

19. The system of claim 15, wherein the first energy delivery body and the second energy delivery body are configured to nest together to retain cervical tissue therebetween.

20. The system of claim 15, wherein the second energy delivery body is mounted on a second elongated shaft, the second elongated shaft telescoping within the elongated shaft of the energy delivery body.

21. The system of claim 12, wherein the second energy delivery device is configured to be advanced into the endocervical canal to treat a tissue region within the endocervical canal while the energy delivery device resides in the patient's vagina to treat a tissue region within the vagina, or resides in the patient's uterus to treat a tissue region within the uterus.

22. The system of claim 21, wherein the second energy delivery body is mounted on a second elongated shaft, the second elongated shaft telescoping within the elongated shaft of the energy delivery body.

23. The system of claim 21 , further comprising a third energy delivery body configured to be advanced into the patient's uterus while the second energy delivery body resides in the endocervical canal and the energy delivery body resides in the patient's vagina.

24. The system of claim 23, wherein the second energy delivery body is mounted on a second elongated shaft that telescopes within the elongated shaft of the energy delivery body, and the third energy delivery body is mounted on a third elongated shaft that telescopes within the second elongated shaft.

25. The system of claim 1, wherein the tissue region comprises a plurality of interior surfaces of the luminal structures of the reproductive system, and wherein the energy delivery body comprises an expandable member configured to expand so as to be simultaneously positionable against the plurality of interior surfaces.

26. The system of claim 25, wherein the expandable member is configured to expand so as to substantially fill the patient's uterus.

27. The system of claim 25, wherein the expandable member comprises a flexible non-conductive material and one or more flexible pad electrodes.

28. The system of claim 1, wherein the energy delivery body comprises a probe configured to penetrate a wall of the luminal structure of the reproductive system and deliver the energy to the tissue region.

29. The system of claim 28, wherein the probe is advanceable from the distal end of the elongated shaft.

30. The system of claim 28, wherein the probe comprises a probe tip, wherein the probe tip is advanceable up to 8 cm from the distal end of the elongated shaft.

31. The system of claim 28, wherein the distal end of the elongated shaft is configured to be advanced up to 20 cm beyond the wall of the luminal structure.

32. The system of claim 28, wherein the probe comprises a plurality of probe elements, wherein at least one of the probe elements is capable of delivering the energy to the tissue region.

33. The system of claim 32, wherein at least two probe elements are capable of delivering the energy, and at least one of the at least two probe elements is independently selectable for receiving the energy for delivery.

34. The system of claim 33, wherein each of the at least two probe elements is capable of simultaneously delivering a different amount of the energy.

35. The system of claim 28, wherein the probe comprises a plurality of probe elements, wherein each probe element is capable of delivering the energy to the tissue region.

36. The system of claim 28, wherein the stylet comprises a plurality of stylet elements, wherein at least one stylet element is individually advanceable from the shaft.

37. The system of claim 28, wherein the stylet comprises a conductive tube extending from the proximal end of the elongated shaft to the distal end of the elongated shaft.

38. The system of claim 37, further comprising an energy plug configured to electrically connect the probe to the generator, wherein the energy plug includes a conductive wire configured to engage the conductive tube.

39. The system of claim 28, wherein the probe comprises: a probe tip disposed proximate the distal end of the elongated shaft; and a conductive wire extending from the proximal end of the elongated shaft to the probe tip.

40. The system of claim 28, wherein the probe comprises a probe tip and a conductive element configured to extend beyond the probe tip, wherein the conductive element is configured to deliver the energy to the tissue region.

41. The system of claim 28, wherein the energy delivery body comprises an electrode having a disk shape.

42. The system of claim 41, wherein the disk is shaped such that its diameter is substantially perpendicular to the longitudinal axis of the elongated shaft.

43. The system of claim 41, wherein the energy delivery body comprises a probe tip that is substantially concentric with the electrode having the disk shape.

44. The system of claim 43, wherein the catheter is configured such that the electrode having the disc shape delivers different energies than the probe tip.

45. The system of claim 1, wherein the energy delivery body comprises a basket electrode.

46. The system of claim 1, wherein the energy delivery body comprises a paddle configured to be positioned adjacent the tissue region such that the paddle can deliver the energy to the tissue region.

47. The system of claim 1, wherein the elongated shaft further comprises a delivery lumen configured to deliver a fluid to the tissue region.

48. The system of claim 1, wherein the energy comprises non-thermal energy.

49. The system of claim 48, wherein the tissue region comprises epithelial cells along an inner surface of the reproductive system, and wherein the non-thermal energy deliverable by the energy delivery entity causes at least a portion of the epithelial cells to be destroyed.

50. The system of claim 49, wherein the epithelial cells reside along a cervix of the reproductive system.

51. The system of claim 48, wherein the tissue region resides within a wall of the luminal structure of the reproductive system.

52. The system of claim 51, wherein the tissue region comprises a fibroid.

53. The system of claim 51, wherein the tissue region resides within the wall of a fallopian tube.

54. The system of claim 51 , wherein the at least one energy delivery algorithm is configured to provide the energy electrical signal deliverable to the tissue region to destroy at least a portion of the tissue region while maintaining patency of the luminal structure.

55. The system of claim 1, wherein the tissue region comprises an undesirable mass of tissue cells, and treating the tissue region comprises destroying at least a portion of the undesirable mass of tissue cells.

56. The system of claim 55, wherein the undesirable mass of tissue cells comprises a tumor, a benign tumor, a malignant tumor, a fibroid, a cyst, or an area of diseased tissue.

57. The system of claim 1, wherein the tissue region is located outside of a wall of the luminal structure of the reproductive system.

58. The system of claim 1, wherein the at least one energy delivery algorithm is configured to provide non-thermal energy that is deliverable from the energy delivery body to, but not beyond, an epithelial layer of the luminal structure of the reproductive system.

59. The system of claim 58, wherein the luminal structure comprises a cervix, vagina, uterus, or endocervical canal.

60. The system of claim 1, wherein each of the biphasic pulses has a voltage between approximately 100 V and 10 kV.

61. The system of claim 60, wherein each of said biphasic pulses has a voltage between approximately 500-4000 V.

62. The system of claim 1, wherein the electrical signal has a frequency in the range of approximately 100-1000 kHz.

63. The system of claim 1 further comprising a return electrode positionable at a distance from the energy delivery entity such that the energy delivery entity functions in a monopolar manner.

64. The system of claim 1, wherein the catheter comprises a second energy delivery entity, wherein the energy delivery entity and the second energy delivery entity function as a bipolar pair, and wherein the at least one energy delivery algorithm comprises: a first energy delivery algorithm configured to provide a first electrical energy signal delivered by the energy delivery entity; and a second energy delivery algorithm configured to provide a second electrical energy signal delivered by the second energy delivery entity.

65. The system of claim 1, further comprising a fluid deliverable by the catheter.

66. The system of claim 65, wherein the liquid comprises a conductive solution.

67. The system of claim 65, wherein the liquid comprises a secondary material, and wherein the energy promotes absorption of the secondary material.

68. The system of claim 67, wherein the auxiliary material comprises a molecule, a macromolecule, or a plasmid.

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