METHOD AND APPARATUS FOR DIRECT IN-VIVO, ELECTRICAL AND CHEMICAL MONITORING AND STIMULATION OF THE ENDOMETRIAL CAVITY

Abstract

Devices, systems and related methods for direct and in-vivo monitoring and stimulation of the endometrial cavity include a plurality of sensing modalities incorporated on a set of flexible conductive filaments that allows its insertion in an endometrial cavity through the vagina. The flexible set of conductive filaments is in direct contact with the endometrium to maximize recording sensitivity and acquire direct readings, which correspond to the functionality of the endometrium and/or electrically stimulate endometrial peristalsis in a controlled manner. The same electrodes can be used for a controlled stimulation to strengthen weakened muscle tissue before and after medical and surgical interventions on the uterus, to reset to normal contractility. The methods and systems disclosed herein can be used to improve the chances of success for artificial insemination, including in-vitro fertilization, embryo transfer, and intrauterine insemination, diagnostic tests, and may further improve the overall understanding of endometrial functionality.

Claims

1. A system for in-vivo direct monitoring of an endometrial cavity comprising: a flexible set of insulated conductive filaments, wherein a first end of the flexible set of insulated conductive filaments includes a plurality of connections, wherein at least one of the plurality of connections is connected to an external electrical sensing/stimulation device that includes a data transmitter, wherein a second end of the flexible set of insulated conductive filaments includes at least one sensing/stimulation module along its length, wherein the flexible set of insulated conductive filaments has a width such that it will not cause pain to a subject, and wherein the at least one sensing/stimulation module includes a sensing array disposed along a length of the flexible set of insulated conductive filaments.

2. The system of claim 1, wherein the sensing/stimulation module is configured to monitor one of the chemical and biochemical content of the endometrial cavity.

3. The system of claim 1, wherein the sensing/stimulation module is configured to monitor environmental conditions of the endometrial cavity.

4. The system of claim 1, wherein the sensing/stimulation module is configured to monitor electrical activity of the endometrial cavity.

5. The system of claim 1, wherein the sensing/stimulation module is fabricated using one of thin film and thick film fabrication techniques.

6. The system of claim 1, wherein the first end the flexible set of insulated conductive filaments is fabricated using one of classical rigid or flex PCB fabrication techniques.

7. The system of claim 1, wherein the flexible set of insulated conductive filaments has a width less than 5 mm.

8. The system of claim 1, wherein the external electrical sensing/stimulation device transmits data via one of tethered or untethered transmission.

9. The system of claim 1, wherein the sensing/stimulation module includes one of a semipermeable membrane that is specific to particular ions and a solid chemical that is gradually release with an electrical stimulus.

10. The system of claim 1, wherein the sensing/stimulation module includes one of a micro thermocouple semiconductor junction and a temperature dependent voltage sensor.

11. A method for in-vivo monitoring of an endometrial cavity comprising: positioning a flexible set of insulated conductive filaments within a subject, wherein at least a portion of the flexible set of insulated conductive filaments contacts a wall of an endometrial cavity of the subject; receiving an electrical signal equivalent to a sensing parameter with at least one sensing/stimulation module attached to the flexible set of insulated conductive filaments; processing the electrical signal to translate the electrical signal into the sensing parameter; transmitting an electrical stimulus to the endometrial cavity; receiving a subsequent electrical signal equivalent to a subsequent sensing parameter with the sensing/stimulation module; and processing the subsequent electrical signal to translate the subsequent electrical signal into the subsequent sensing parameter.

12. The method of claim 11, wherein the sensing parameter and the subsequent sensing parameter are used for subsequent fertility analysis.

13. The method of claim 11, wherein the sensing parameter and the subsequent sensing parameter are used to derive mechanisms that control uterus functionality.

14. The method of claim 13, wherein uterus functionality can be used to improve fertility of the subject.

15. The method of claim 13, wherein uterus functionality can be used to determine an appropriate treatment course for various uterine pathologies.

16. A method for identifying artificial insemination viability associated with a woman's optimal implantation window and menstrual cycle: positioning a flexible set of conductive filaments within a subject, wherein at least a portion of the flexible set of conductive filaments contacts one of an endometrial wall and an endometrial cavity of the subject; receiving an electrical signal equivalent to a sensing parameter of interest of one of the endometrial wall and endometrial cavity using a sensing array attached to a structural component associated with the flexible set of conductive filaments; processing the electrical signal to translate the electrical signal into the sensing parameter; and identifying a time in the subject's menstrual cycle associated with the highest likelihood of artificial insemination success.

17. The method according to claim 16, wherein the sensing array monitors one of a chemical content and a biochemical content of the endometrium or endometrial cavity.

18. The method according to claim 16, wherein the sensing array monitors environmental conditions of the endometrium or endometrial cavity.

19. The method according to claim 16, wherein the sensing array monitors electrical activity of the endometrium or endometrial cavity.

20. The method according to claim 19, wherein the sensing array monitors a velocity vector associated with electrical activity of the endometrium or endometrial cavity.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0040] Understanding that the figures depict only typical embodiments and are not to be considered to be limiting the scope of the present disclosure, the present disclosure is described and explained with additional specificity and detail through the use of the accompanying figures. The figures are listed below.

[0041] FIG. 1 illustrates the complete design of a flexible set of conductive filaments configured for insertion into a woman's endometrial cavity for monitoring and/or for stimulation, according to an example embodiment of the present disclosure.

[0042] FIG. 2A and FIG. 2B illustrate a connector, including a single pin extending from the opposite side of the connector, which may be connected to another external electrode or sensor to be used as a baseline/reference for the readings or an electrical stimulation circuit, according to an example embodiment of the present disclosure.

[0043] FIG. 3A and FIG. 3B illustrate a rigid section of the flexible set of conductive filaments with via holes that enable connection to the connector that will further connect to the data acquisition/stimulation system, according to an example embodiment of the present disclosure.

[0044] FIG. 3C illustrates one possible configuration, consisting of exposed conductive filaments coated with gold as electrodes to sense/stimulate the electrical activity in the endometrial cavity, according to an example embodiment of the present disclosure.

[0045] FIG. 4 illustrates the uterus and the endometrial cavity, for subsequent device insertion and sensing/stimulation, according to an example embodiment of the present disclosure.

[0046] FIG. 5 illustrates an external view of the female reproductive organs with a speculum in place, the electrodes inserted into the uterus for electro-utero-graph recording and connected to a flexible ribbon cable leading to a recording device, according to an example embodiment of the present disclosure

[0047] FIG. 6 illustrates a possible portable electro-utero-graph recording/stimulation device that stores the data on a micro-SD card, according to an example embodiment of the present disclosure.

[0048] FIG. 7 illustrates a laptop computer displaying the signals recorded by the recording/stimulation device, according to an example embodiment of the present disclosure.

[0049] FIG. 8 illustrates an ultrasound image obtained with the flexible set of insulated conductive filaments in place, and with openings at various sites of interest, according to an example embodiment of the present disclosure.

[0050] FIG. 9 illustrates some sample signals illustrating how the electro-utero-graph activity changes in the same patient, depending on the phase of the menstrual cycle, according to an example embodiment of the present disclosure.

[0051] FIG. 10 illustrates some sample signals illustrating how the electro-utero-graph activity changes between different patients, depending on whether they are menopausal or of reproductive age, according to an example embodiment of the present disclosure.

[0052] FIG. 11 illustrates some sample signals coming from a perimenopausal subject and a menopausal subject undergoing hormone replacement therapy, according to an example embodiment of the present disclosure.

DETAILED DESCRIPTION OF EXAMPLE EMBODIMENTS

[0053] The device used along with the inventive methods herein, is described briefly as follows. FIGS. 1, 2A, 2B, 3A, 3B and 3C show the arrangement of sensing/stimulation modalities for in-vivo monitoring of the endometrial cavity. Specifically, the device 100 includes a flexible set of conductive filaments 103, encapsulated in an insulator material, having two ends. A first end includes the connection board 101 with multiple via holes 107, 108 (or a related surface mount footprint), for related coupling with an electrical connector 102 via pins 106. Connector 102 may further include single pin 105 extending from the opposite side of the connector 102, which may be configured for connection to another external electrode (or sensor) to be used as a baseline/reference for the readings or an electrical stimulation circuit. Furthermore, at least one of said via holes 107, 108 is designated for connection to at least one external sensing/stimulation device 600 (described in greater detail herein with respect to FIG. 6).

[0054] The flexible set of conductive filaments 103 includes one or more sensing/stimulation modalities 104 along its length at a second end. For example, with reference to FIG. 3C, the conductive filaments may be coated in gold or, alternatively, an other conductive material. In an embodiment, the flexible set of conductive filaments 103 and related sensing/stimulation modalities 104 have a width of less than 5 mm. By having a reduced width, such as less than 5 mm, the device 100 ensures that subsequent insertion into the endometrial cavity is safe, painless, and harmless to the patient.

[0055] In an embodiment, the sensing/stimulation modalities 104 are disposed in the form of sensing/stimulation array of conductive openings 109, 110 in an insulator along a portion of the length of the second end. In an embodiment, the conductive openings 109, 110 may be coated with a semipermeable membrane or a solid chemical that may be released gradually with the application of electric pulses.

[0056] FIG. 4 shows a schematic of a uterus 400 of a woman. The schematic shows the vagina 407, cervix 406, cervical canal 404, external orifice of the cervix 405, internal orifice of the cervix 403, myometrium 408, endometrium and endometrial walls 402, endometrial cavity 401 and the fundus 409. Once inserted (as descried in greater detail below), the flexible set of conductive filaments 103 are configured to pass electrical charge to and from the sensing/stimulation modalities 104; when inserted, the sensing/stimulation modalities 104 are configured to be disposed within a subject's endometrium 402, such that the sensing/stimulation modalities 104 are in direct and electrical contact with the endometrial walls 402 and/or endometrial cavity 401. The sensing/stimulation modalities 104 relay electrical signals to and from the connector board 101, which in turn relays information to the external sensing/stimulation device 600.

[0057] Via this system, the flexible set of insulated conductive filaments 103 are configured to record a multichannel electrical recording from within the uterus, particularly at the endometrium and/or endometrial walls 402. This multichannel electrical recording is referred to herein is an electro-utero-graph (EUG). This EUG can be used to determine uterus functionality, including an appropriate treatment course for various uterine pathologies including fibroids, adenomyosis, sub-endometrial adenomyotic cysts, and other related pathologies. The EUG can identify the magnitude of the abnormal contractility, indicating the need of myomectomy or adenomyomectomy, and related timing for said procedures.

[0058] An example of the procedure, with reference to FIGS. 5 and 8, to insert the sensing/stimulation modalities 104 in the endometrium 402 of the subject includes insertion of the speculum 504 and use transvaginal ultrasound to visualize 800 the vaginal walls and the external orifice of the cervix 405. The clinician will then insert an embryo transfer catheter 503, up to 3 mm from the fundus 409. Once the catheter 503 is inserted, the clinician will, insert the flexible set of insulated conductive filaments 103 including the sensing/stimulation modalities 104 and sensing/stimulation array into the embryo transfer catheter 503 until the tip of the sensing/stimulation modalities 104 reach the tip of the catheter, with a fundal sensor/stimulators being in proximity to the fundus 801, Mid Endometrial point 802, Low Endometrial point 803, cervical points 804, 805. The clinician then retracts the catheter 503 out of the endometrium 402, to expose the sensing/stimulation modalities 104 of the sensing/stimulation array to be in direct contact with the endometrial walls 402. The clinician connects electrical connector 102 to the inputs of the external sensing/stimulation device 600, via cable 502. Once the sensing/stimulation modalities 104 are exposed to the relevant anatomical features, the sensing/stimulation modalities 104 may advantageously take required readings using a data acquisition system, such as the external sensing/stimulation device 600, apply stimulation to the relevant anatomical features, or a combination of both for diagnosis, treatment, and the like. While ultrasonic guidance is described above, it should be appreciated that ultrasonic guidance is not required for the devices and methods disclosed herein.

[0059] For example, sensing/stimulation modalities 104 may measure electrical signals on or near at least one of the endometrium and endometrial walls 402; these electrical signals are provided to external sensing/stimulation device 600, for subsequent analysis and processing, to associate the electrical signals with one or more physiological parameters and/or physiological phenomena. Analysis include, for example, identification of the intensity, frequency, and direction of the various signals. Directional analysis can include, for example, whether the intensity is more directed in a cephalad direction or a caudal direction at the measurement site. Alternatively, for example, sensing/stimulation modalities 104 may apply stimulation, such as electrical stimulation, to at least one of the endometrium and the endometrial walls 402. Alternatively, for example, sensing/stimulation modalities 104 may both measure electrical signals and apply stimulation, such as measuring electrical signals on or near at least one of the endometrium and endometrial walls 402 both before and after electrical stimulation. Again, parameter detection and stimulation signal control are provided, for example, by the external sensing/stimulation device 600.

[0060] Once procedures are completed, with the use of the ultrasound for visualization, the clinician can reinsert the catheter 503 to completely cover the sensing/stimulation modalities 104, and then subsequently remove the sensing/stimulation modalities 104 out of the subject and remove the catheter 503 out of the subject.

[0061] While the embodiment above describes that the device 100 may take readings, and subsequently store these readings on the data acquisition system, such as the external sensing/stimulation device 600, it should be appreciated that additional data storage capabilities are contemplated herein. For example, the external device 600, which is a data storage device, may advantageously include a wireless transmitter, such as Bluetooth, ZigBee, Wi-Fi, or the like, for wireless transmission from external device 600 to a handheld device, such as a cell phone. Data may also be wirelessly transmitted from external device 600 to the cloud, for additional processing and/or data aggregation. Clinicians may access data on the cloud, for patient diagnosis and related data analysis; patients may access data on the cloud, for personal medical history, symptom tracking, and the like.

[0062] Advantageously, the sensing/stimulation modalities 104 are disposed along the length of the flexible set of insulated conductive filaments 103, such that the sensing/stimulation modalities 104 are configured to monitor sensing parameters with respect to a longitudinal dimension of the endometrial cavity, providing an overall high density network of sensors/stimulators and related direction-based measurement.

[0063] In the primary embodiment described above, the sensing/stimulation modalities 104 take required readings, apply stimulation to the relevant anatomical features, or a combination of both. Once readings/stimulation occur, the catheter 503 is reinserted and the entire device 100 is removed from the subject. In a different embodiment, the catheter 503 is not required to be reinserted. Rather, the device 100 remains inside the subject for 24-hour continuous monitoring. For example, after catheter 503 is initially removed, external sensing/stimulation device 600 is attachable to the first end of the flexible set of insulated conductive filaments 103 via a low or zero insertion force connector and related flexible cable. For example, a flex connector such as the SFVL Series connectors by Amphenol is used to connect device 600 to the flexible set of insulated conductive filaments 103.

[0064] Continuous data measured by the sensing/stimulation modalities 104 are stored in the external sensing/stimulation device 600. In an embodiment, device 600 is clipped onto the user's apparel, such as the user's underwear in close proximity to the insertion point, during continuous monitoring. After a particular monitoring period is completed, device 600 can wirelessly transmit data associated with the monitoring period, such as a day's worth of data, to an external device such as a cell phone. While a 24-hour monitoring period is disclosed herein, it should be appreciated that other (potentially longer) monitoring periods are contemplated. For example, device 600 could include an external power source, such as a battery, such that monitoring periods could run for indefinite lengths of time.

[0065] In a particular embodiment of the medical device 100 used with the methods of the present invention, the other side of the flexible set of conductive filaments 103 is inserted into the subject's endometrium 401 comprising: positioning a medical device within the subject, wherein the sensing/stimulation modalities 104 with the sensing array designed to be in contact with the endometrial walls 402 and/or endometrial cavity 401 of the subject; receiving an electrical activity of said endometrial walls 402 and/or cavity 401 using at least an electrode array of the said other side of the flexible set of conductive filaments 103, wherein said electrode array is in electrical contact with said endometrial walls 402 and/or cavity 401, receiving/transmitting an electrical activity, as otherwise called in the literature electrohysterography (EHG), of the endometrium 402 and/or endometrial cavity 403.

[0066] In accordance with another embodiment of the medical device used with the methods of the present invention, the flexible set of conductive filaments 103 is inserted into the subject's endometrium 401 comprising: positioning a medical device within the subject, wherein the sensing modalities 104 with the sensing array designed to be in contact with the endometrial walls 402 and/or endometrial cavity 401 of the subject; receiving an electrical signal equivalent to the sensing parameter of interest of said endometrial walls 402 (in the case of semi-permeable membrane coatings of the conductor) and/or cavity 401 using the chemical and/or biochemical sensing array of the sensing modalities 104, wherein said sensing array of chemical/biochemical sensing modalities 104 are in physical direct contact with said endometrial walls 402 and/or cavity 401, receiving an electrical signal equivalent to the sensing parameter of interest of said endometrium 402 and/or endometrial cavity 401. The levels of the sensing parameters such as pH, progesterone, luteinizing hormone, progesterone and other concentration levels of several ionic substances, together with the period in the menstrual cycle of the subject can be used to generate correlations between healthy and non-healthy subjects in terms of pathogenic diseases or even early cancer detection.

[0067] In accordance with another embodiment of the medical device used with the methods of the present invention, the other side of the flexible set of conductive filaments 103 is inserted into the subject's endometrium 401 comprising: positioning a medical device within the subject, wherein the sensing modalities 104 with the sensing array designed to be in contact with the endometrial walls 402 and/or endometrial cavity 401 of the subject; receiving an electrical signal equivalent to the sensing parameter of interest such as temperature, moisture levels, surface roughness, and the like, of said endometrial walls 402 and/or cavity 401 using the physical sensing array of the sensing modalities 104, wherein said sensing array of physical sensing modalities 104 are in electrical/direct contact with said endometrial walls 402 and/or cavity 401, receiving an electrical signal equivalent to the sensing parameter of interest of said endometrium 402 and/or endometrial cavity 401.

[0068] In accordance with a further embodiment of the medical device used with the methods of the present invention, identification of the time when the chances for embryo transfer after an in-vitro fertilization (IVF) or the timing of an intrauterine insemination are at the maximum in a subject is achieved by: a) positioning one side of a flexible set of insulated conductive filaments 103 within the subject, wherein the sensing modalities 104 with the sensing array of the device is designed to be in contact with the endometrial walls 402 and/or endometrial cavity 401 of the subject; b) receiving an electrical signal equivalent to the sensing parameter of interest of said endometrial walls 402 and/or cavity 401 using the sensing modalities 104 of chemical and/or physical and/or biochemical and/or electrical sensing array, wherein said sensing array of chemical and/or physical and/or biochemical and/or electrical sensing modalities 104 is in electrical/direct contact with said endometrial walls 402 and/or cavity 401; c) receiving an electrical signal equivalent to the sensing parameter of interest of said endometrium 402 and/or endometrial cavity 401; d) processing the electrical signals of said endometrium 402 and/or endometrial cavity 401 using signal processing techniques to translate the signal into values of the sensing parameters, e) determining the correlations of the sensed parameters of said endometrium 402 and/or endometrial cavity 401; and f) identifying the time during the subject's menstrual cycle with the highest likelihood of IVF success when the said sensed parameters show positive correlations. Other patents (US2015/0216472A1) have claimed to be able to generate correlations between the likelihood of success of IVF by monitoring only the electrical activity of the myometrium 408. This invention monitors chemical and/or physical and/or electrical parameters directly within the endometrial cavity 401 allowing for a much higher sensitivity and more reliable correlations.

[0069] In accordance with a further embodiment of the medical device used with the methods of the present invention, understanding of the functionality of the endometrium and the endometrial cavity is achieved by: a) positioning a side of a flexible set of conductive filaments 103 within the subject, wherein the sensing modalities 104 with the sensing array of the device is designed to be in contact with the endometrial walls 402 and/or endometrial cavity 401 of the subject; b) receiving an electrical signal equivalent to the sensing parameter of interest of said endometrial walls 402 and/or cavity 401 using the sensing modalities 104 of chemical and/or physical and/or biochemical and/or electrical sensing array, wherein said sensing array of chemical and/or physical and/or biochemical and/or electrical sensing modalities 104 is in electrical/direct contact with said endometrial walls 402 and/or cavity 401; c) receiving an electrical signal equivalent to the sensing parameter of interest of said endometrium 402 and/or endometrial cavity 401; d) processing the electrical signals of said endometrium 402 and/or endometrial cavity 401 using signal processing techniques to translate the signal into values of the sensing parameters, e) determining the correlations of the sensed parameters of said endometrium 402 and/or endometrial cavity 401; f) identifying the mechanisms controlling the said endometrium functionality and understand how the said functionality is related to the fertility of the subject. Although the way the endometrium 402 functions is understood by speculation and how that functionality affects the fertility of the uterus 400, there are currently no experimental, in-vivo results to prove it and moreover the mechanisms by which that functionality is controlled are yet unknown. This invention can be used to derive all the required in-vivo, experimental data to fully model and understand those mechanisms.

[0070] In accordance with a further embodiment of the medical device used with the methods of the present invention, monitoring other biological parameters of the subject is achieved by: a) positioning a side of a flexible set of conductive filaments 103 within the subject, wherein the sensing modalities 104 with the sensing array of the device is designed to be in contact with the endometrial walls 402 and/or endometrial cavity 401 of the subject; b) receiving an electrical signal equivalent to the sensing parameter of interest of said endometrial walls 402 and/or cavity 401 using the sensing modalities 104 of chemical and/or physical and/or biochemical and/or electrical sensing array, wherein said sensing array of chemical and/or physical and/or biochemical and/or electrical sensing modalities 104 is in electrical/direct contact with said endometrial walls 402 and/or cavity 401; c) receiving an electrical signal equivalent to the sensing parameter of interest of said endometrium 402 and/or endometrial cavity 401; d) processing the electrical signals of said endometrium 402 and/or endometrial cavity 401 using signal processing techniques to translate the signal into values of the sensing parameters, e) determining the correlations of the sensed parameters of said endometrium 402 and/or endometrial cavity 401 with other biological parameters of the subject; f) identifying the mechanisms associated with the correlations of the biological parameter of interest and the sensing parameter within the endometrium. Due to the fact that, the endometrium 402 and the endometrial cavity 401 have a plurality of blood vessels, several biological parameters can be monitored through the blood providing vital information on the subject's health. This information can be used to optimize the doses of Hormone Replacement Therapy (HRT) since lower doses can prevent the development of heart diseases or breast cancer.

[0071] Specifically, for example, the sensing modalities 104 disclosed herein may advantageously identify and characterize uterine peristalsis, and related physiological phenomena, including but not limited to menstrual blood clearance, endometrial rejuvenation, fertilization, implantation, early pregnancy preservation, and the like. Identification and characterization may involve both sensing of information, stimulation of pertinent anatomical features, and both sensing and stimulation; identification and characterization will typically involve additional analysis at a third party source, such as a cell phone or the cloud, once data is provided by the external device 600, for example.

[0072] Use of the verb comprise and its associations do not exclude the presence of elements or steps other than those stated in a claim. The article a or an preceding an element does not exclude the presence of a plurality of such elements. The invention may be implemented by means of hardware comprising several distinct elements, and by means of a suitably programmed data acquisition and signal processing hardware as well as by means of a suitably programmed computer. Moreover, any combination of the above-described elements in all possible variation thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0073] As used in this specification, including the claims, the term and/or is a conjunction that is either inclusive or exclusive. Accordingly, the term and/or either signifies the presence of two or more things in a group or signifies that one selection may be made from a group of alternatives.

[0074] The many features and advantages of the present disclosure are apparent from the written description, and thus, the appended claims are intended to cover all such features and advantages of the disclosure. Further, since numerous modifications and changes will readily occur to those skilled in the art, the present disclosure is not limited to the exact construction and operation as illustrated and described. Therefore, the described embodiments should be taken as illustrative and not restrictive, and the disclosure should not be limited to the details given herein but should be defined by the following claims and their full scope of equivalents, whether foreseeable or unforeseeable now or in the future.