Intravaginal device for sexually transmitted infection protection and treatment

Abstract

An intravaginal device configured to be deployed within a vaginal tract of a patient for treating, reducing risks associated with, and / or preventing sexually transmitted infection includes a body having a flexible biocompatible material. The intravaginal device also includes: a flexible sensor array embedded in the body having at least one of a sodium sensor or pH sensor; a reservoir embedded in the body including a therapeutic agent configured to be released by an electro-responsive electrode assembly; and a near field communication circuit configured for wireless communication with an external device for wireless charging, data transmission, and receipt of control signals. The intravaginal device also includes a device controller configured to activate the electro-responsive electrode assembly to release the therapeutic agent from the reservoir in response to signals detected by the flexible sensor array and / or control signals received from the external device via the near field communication circuit.

Description

INTRA VAGINAL DEVICE FOR SEXUALLY TRANSMITTED INFECTION PROTECTION AND TREATMENTCROSS REFERENCE TO RELATED APPLICATION

[0001] The present application claims the benefit of United States Provisional Patent Application No. 63 / 613,430 filed December 21, 2023, the disclosure of which is hereby incorporated by reference in its entirety.BACKGROUND OF THE INVENTIONField of the Invention

[0002] The present disclosure is directed to an indwelling device configured to be deployed in the vagina for on-demand release of a therapeutic agent and, in particular, to an intravaginal device configured to release an anti-sexually transmitted infection (Anti-STI) therapeutic agent in response to conditions detected by embedded sensors of the device or in response to an external activation signal.Description of Related Art

[0003] As an epidemic, sexually transmitted infection (STI) is a worldwide health concern covering a wide range of pathogens including bacteria, parasites, and viruses, which can cause significant morbidity or mortality if not treated properly in the early stage of the infection. For example, chlamydia, gonorrhea, and syphilis caused by bacteria can cause pelvic inflammatory disease, infertility, or damage to organs, including nervous system and heart, and can often become life-threatening. Although such STIs are curable, treatments cannot repair or reverse damage that has already occurred. Some STIs, such as Human Immunodeficiency Virus (HIV), hepatitis B, and human papillomavirus (HPV), are still incurable viral infections and lifethreatening. STIs can also pass to newborn babies if untreated, resulting in pneumonia, blindness, prematurity, stillbirth, or neonatal death. Currently, use of condoms is considered the gold standard for prevention of STIs. However, effectiveness of condoms varies depending on end users. It is estimated that condom effectiveness is only about 87% when used consistently and correctly. When not used properly, effectiveness of condoms can be less than 60%. As a result, even with continuous efforts on STI prevention, more than 26 million new infections occur every year in the United States. Furthermore, over 1.5 million individuals worldwide acquired HIV in 2021. These conditions result in an estimated $16 billion in direct lifetime medical costs in the United States, which does not include costs associated with lowproductivity and other non-medical costs. Current anti-STI administration pathways for antiSTI medications can include oral pathways, as well as intravenous pathways and pathways for intravaginal delivery.

[0004] Intravaginal delivery can have advantages over other delivery pathways because the vagina is the major route of the infection and the intravaginal delivery can increase the accumulation of the therapeutics at the target site with reduced off-target effects. An Intra- Vaginal Ring (IVR) is an FDA approved device, which can comprise an elastomeric polymer (e.g., silicone or polyurethane) ring configured to release drugs (contraceptive or anti-STI) in the vagina. IVRs have benefits compared to other intravaginal formulations (e.g., cream, gel, or film) in terms of higher acceptability by the end-users, provision of controlled release of drugs for longer periods, more uniform concentration of released drugs in the vagina, and protection of the loaded drugs from hydrolysis.

[0005] There are two types of IVRs, generally referred to as matrix-IVRs and reservoir- IVRs. The matrix-IVRs are configured to provide sustained drug release. Furthermore, reservoir- IVRs can be designed to control drug release based, for example, on thickness and / or physicochemical characteristics of an outer layer of the reservoir. Although topical drug delivery using an IVR is beneficial, in some instances, continuous exposure to anti-STIs may not be recommended to those who are healthy, but want to prevent potential STIs. Therefore, there is a need for IVR with other drug release capabilities. The IVR device and other therapeutic devices disclosed herein are configured to provide such additional drug release capabilities.SUMMARY OF THE INVENTION

[0006] According to an aspect of the disclosure, an intravaginal device configured to be deployed within a vaginal tract of a patient for treating, reducing risks associated with, and / or preventing sexually transmitted infection includes a body having a flexible biocompatible material. The intravaginal device also includes: a flexible sensor array embedded in the body having at least one of a sodium sensor or pH sensor; a reservoir embedded in the body including a therapeutic agent configured to be released by an electro-responsive electrode assembly; and a near field communication circuit configured for wireless communication with an external device for wireless charging, data transmission, and receipt of control signals. The intravaginal device also includes a device controller configured to activate the electro-responsive electrode assembly to release the therapeutic agent from the reservoir in response to signals detected bythe sensor array and / or control signals received from the external device via the near field communication circuit.

[0007] According to another aspect of the disclosure, a patient health monitoring system includes an intravaginal device and a controller, which can be a portable controller and / or a portable computing device (e.g., a smartphone). The intravaginal device is configured to be deployed within a vaginal tract of a patient for treating, reducing risks associated with, and / or preventing sexually transmitted infection. The intravaginal device includes: a body including a flexible biocompatible material; a flexible sensor array embedded in the body with at least one of a sodium sensor or pH sensor; a reservoir embedded in the body having a therapeutic agent configured to be released by an electro-responsive electrode assembly; and a near field communication circuit for wireless charging, data transmission, and receipt of control signals. The controller is in communication with the flexible sensor array and the electro-responsive electrode assembly via the near field communication circuit. The controller is configured to: receive and process signals from the at least one sodium sensor or pH sensor of the sensor array to determine a sodium value and / or a pH valve for the vaginal tract of the patient; compare the determined sodium and / or pH value to a sodium and / or pH threshold value; and cause the electro-responsive electrode assembly to release the therapeutic agent of the reservoir when the determined sodium value and / or pH value exceeds the threshold value.

[0008] Preferred and non-limiting examples of the present disclosure will now be described in the following numbered clauses:

[0009] Clause 1 : An intravaginal device configured to be deployed within a vaginal tract of a patient for treating, reducing risks associated with, and / or preventing sexually transmitted infection, the device comprising: a body comprising a flexible biocompatible material; a flexible sensor array embedded in the body comprising at least one of a sodium sensor or pH sensor; a reservoir embedded in the body comprising a therapeutic agent configured to be released by an electro-responsive electrode assembly; a near field communication circuit configured for wireless communication with an external device for wireless charging, data transmission, and receipt of control signals; and a device controller configured to activate the electro-responsive electrode assembly to release the therapeutic agent from the reservoir in response to signals detected by the flexible sensor array and / or control signals received from the external device via the near field communication circuit.

[0010] Clause 2: The device of clause 1, wherein the body comprise silicone or polyurethane.

[0011] Clause 3: The device of clause 1 or clause 2, wherein the therapeutic agent comprises at least one of a contraceptive, an anti-sexually transmitted infection composition, a spermicide, or an antibiotic.

[0012] Clause 4: The device of any of clauses 1-3, wherein the at least one sodium sensor or pH sensor is configured to detect seminal fluid in the vaginal tract.

[0013] Clause 5: The device of any of clauses 1-4, wherein the at least one sodium sensor or pH sensor comprises an ion-selective electrode.

[0014] Clause 6: The device of any of clauses 1-5, wherein the at least one sodium sensor is configured to detect fluids in the vaginal tract with a sodium concentration of about 0.5 mg / mL to about 5 mg / mL.

[0015] Clause 7: The device of any of clauses 1-6, wherein the near field communication circuit and the flexible sensor array are configured for real-time continuous monitoring.

[0016] Clause 8: The device of any of clauses 1-7, wherein the near field communication circuit comprises a micro-coil antenna.

[0017] Clause 9: The device of any of clauses 1-8, wherein the electro-responsive electrode assembly comprises conductive polyurethane coated electrodes.

[0018] Clause 10: The device of any of clauses 1-9, wherein the reservoir is configured for release of oleanolic acid by reduction of electro-responsive polymers.

[0019] Clause 11: The device of clause 10, wherein the electro-responsive polymers comprise at least one of polyester urethane urea (PEUU) or polypyrrole nanoparticles.

[0020] Clause 12: The device of any of clauses 1-11, wherein the therapeutic agent comprises oleanolic acid contained in the reservoir of the intravaginal device.

[0021] Clause 13: The device of any of clauses 1-12, wherein the body is fabricated by at least one of hot-melt injection molding or three-dimensional printing.

[0022] Clause 14: The device of any of clauses 1-13, wherein the device is configured to provide controlled release of the therapeutic agent from the reservoir to the vaginal tract of the patient.

[0023] Clause 15: A patient health monitoring system, comprising: an intravaginal device configured to be deployed within a vaginal tract of a patient for treating, reducing risks associated with, and / or preventing sexually transmitted infection, the device comprising: a body comprising a flexible biocompatible material; a flexible sensor array embedded in the body comprising at least one of a sodium sensor or pH sensor; a reservoir embedded in the body comprising a therapeutic agent configured to be released by an electro-responsive electrode assembly; and a near field communication circuit for wireless charging, datatransmission, and receipt of control signals; and a controller in communication with the flexible sensor array and the electro-responsive electrode assembly via the near field communication circuit, wherein the controller is configured to: receive and process signals from the at least one sodium sensor or pH sensor of the flexible sensor array to determine a sodium value and / or a pH valve for the vaginal tract of the patient; compare the determined sodium and / or pH value to a sodium and / or pH threshold value; and cause the electro-responsive electrode assembly to release the therapeutic agent of the reservoir when the determined sodium value and / or pH value exceeds the threshold value.

[0024] Clause 16: The system of clause 15, wherein therapeutic agent of the reservoir comprises at least one of a contraceptive, an anti-sexually transmitted infection composition, a spermicide, or an antibiotic.

[0025] Clause 17: The system of clause 15 or clause 16, wherein the controller is a component of the intravaginal device, which is configured to be deployed in the vaginal tract along with the intravaginal device.

[0026] Clause 18: The system of clause 15 or clause 16, wherein the controller is a component of an external portable computing device, which is in wireless communication with the intravaginal device by the near field communication circuit.

[0027] Clause 19: The system of clause 18, wherein the external portable computing device comprises a device display, and wherein the controller is configured to cause visual indicators representative of the determined sodium value and / or pH value to appear on the device display in real time.

[0028] Clause 20: The system of clause 18 or clause 19, wherein the external portable computing device is configured to receive a user input for drug release, and wherein, upon receipt of the user input for drug release, the controller is configured to cause the electro- responsive electrode assembly to release the therapeutic agent from the reservoir.BRIEF DESCRIPTION OF THE DRAWINGS

[0029] These and other features and characteristics of the present disclosure, as well as the methods of operation and functions of the related elements of structures and the combination of parts and economies of manufacture, will become more apparent upon consideration of the following description and the appended claims with reference to the accompanying drawings, all of which form a part of this specification, wherein like reference numerals designate corresponding parts in the various figures. It is to be expressly understood, however, that thedrawings are for the purpose of illustration and description only, and are not intended as a definition of the limit of the invention.

[0030] FIG. 1 is a schematic drawing of an intravaginal (IV) device according to an aspect of the present disclosure;

[0031] FIGS. 2A and 2B are schematic drawings of a patient health monitoring system showing communication between electrical components of the intravaginal (IV) device and external device(s), according to an aspect of the present disclosure;

[0032] FIG. 3 is a schematic drawing of an IV device showing a deployment location on a schematic drawing of a patient, according to an aspect of the present disclosure;

[0033] FIG. 4A is a schematic drawing of an NFC chip configuration, according to an aspect of the present disclosure;

[0034] FIG. 4B is a schematic drawing of a pH and / or sodium sensor of the IV device, according to an aspect of the present disclosure;

[0035] FIGS. 5 A and 5B are chemical equations showing features of the drug release mechanism of the present disclosure;

[0036] FIG. 6 is a schematic drawing showing features of the drug release mechanism of the present disclosure; and

[0037] FIG. 7 is a schematic drawing showing the prototype device for use in a rabbit according to an experimental example of the present disclosure.DESCRIPTION OF THE INVENTION

[0038] As used herein, the singular form of “a”, “an”, and “the” include plural referents unless the context clearly states otherwise.

[0039] As used herein, the terms “right”, “left”, “top”, “bottom”, and derivatives thereof shall relate to the invention as it is oriented in the drawing figures. However, it is to be understood that the invention can assume various alternative orientations and, accordingly, such terms are not to be considered as limiting. Also, it is to be understood that the invention can assume various alternative variations and stage sequences, except where expressly specified to the contrary. It is also to be understood that the specific devices and processes illustrated in the attached drawings, and described in the following specification, are examples. Hence, specific dimensions and other physical characteristics related to the embodiments disclosed herein are not to be considered as limiting.

[0040] For the purposes of this specification, unless otherwise indicated, all numbers expressing, for example, dimensions, physical characteristics, and so forth used in thespecification and claims are to be understood as being modified in all instances by the term “about.” Unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by the present invention. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any measured numerical value, however, may inherently contain certain errors resulting from the standard deviation found in their respective testing measurements.

[0041] As used herein, the terms “comprising,” “comprise” or “comprised,” and variations thereof, are meant to be open ended.

[0042] Also, it should be understood that any numerical range recited herein is intended to include all sub-ranges subsumed therein. For example, a range of “1 to 10” is intended to include any and all sub-ranges between and including the recited minimum value of 1 and the recited maximum value of 10, that is, all subranges beginning with a minimum value equal to or greater than 1 and ending with a maximum value equal to or less than 10, and all subranges in between, e.g., 1 to 6.3, or 5.5 to 10, or 2.7 to 6.1.

[0043] The device and method provided herein may comprise a therapeutic agent or delivery of a therapeutic agent, such as an antimicrobial or antibiotic. As used herein, the “treatment” or “treating” of an STI means administration to a patient by any suitable dosage regimen, procedure, and / or administration route of a composition, device, or structure with the object of achieving a desirable clinical / medical end-point, including but not limited to, delivery of an amount of an antimicrobial or antibiotic in amounts effective to treat or prevent an STI. An amount of any reagent or therapeutic agent, administered by the described intravaginal route, effective to treat a patient may range from 1 pg per dose to 10 g per dose, including any amount there between, such as, without limitation, 1 ng, 1 pg, 1 mg, 10 mg, 100 mg, or 1 g per dose. The therapeutic agent may be administered as a single dose, at regular or irregular intervals, in amounts and intervals as dictated by any clinical parameter of a patient, or continuously.

[0044] Active ingredients may be compounded or otherwise manufactured into a suitable composition for use as described herein, such as in the device as described herein. Suitable compositions may comprise a pharmaceutically acceptable carrier, or excipient. An excipient is an inactive substance used as a carrier for the active ingredients of a medication. Although “inactive,” excipients may facilitate and aid in increasing the delivery or bioavailability of an active ingredient in a drug product. Non-limiting examples of useful excipients include: antiadherents, binders, rheology modifiers, coatings, disintegrants, emulsifiers, oils, buffers, salts,acids, bases, fillers, diluents, solvents, flavors, colorants, glidants, lubricants, preservatives, antioxidants, sorbents, vitamins, sweeteners, etc., as are available in the pharmaceutical / compounding arts. Pharmaceutical formulations adapted for administration as described herein may contain, for example and without limitation, anti-oxidants, buffers, bacteriostats, lipids, liposomes, lipid nanoparticles, emulsifiers, suspending agents, and rheology modifiers.

[0045] A “therapeutically effective amount” refers to an amount of a drug product or active agent effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. An “amount effective” for treatment of a condition is an amount of an active agent or dosage form, such as a single dose or multiple doses, effective to achieve a determinable endpoint. The “amount effective” is preferably safe - at least to the extent the benefits of treatment outweigh the detriments, and / or the detriments are acceptable to one of ordinary skill in the art and / or to an appropriate regulatory agency, such as the U.S. Food and Drug Administration. A therapeutically effective amount of an active agent may vary according to factors, such as the disease state, age, sex, and weight of the individual, and the ability of the active agent to elicit a desired response in the individual. A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount may be less than the therapeutically effective amount.

[0046] Therapeutic agents in the context of the present disclosure may comprise any antimicrobial or antibiotic agent (e.g., compounds, drugs, active pharmaceutical ingredients, etc.), including antibacterial, anti-sexually transmitted infection composition, a spermicide an antifungal, or antiviral agents, and other bioactive agents. Non-limiting examples of suitable antimicrobial or antibiotic compounds comprise: terpenoids, e.g. triterpenoids such as oleanolic acid and ursolic acid, betulinic acid, bevirimat, acyclovir, afloxacin, ampicillin, amphotericin B, atovaquone, azithromycin, ciprofloxacin, clarithromycin, clindamycin, clofazimine, dapsone, diclazaril, doxycycline, erythromycin, ethambutol, fluconazole, fluoroquinolones, foscarnet, ganciclovir, gentamicin, iatroconazole, isoniazid, ketoconazole, levofloxacin, lincomycin, miconazole, neomycin, norfloxacin, ofloxacin, paromomycin, penicillin, pentamidine, polymixin B, pyrazinamide, pyrimethamine, rifabutin, rifampin, sparfloxacin, streptomycin, sulfadiazine, tetracycline, tobramycin, trifluorouridine, trimethoprim sulphate, Zn-pyrithione, and silver salts such as chloride, bromide, iodide and periodate. In one example, the therapeutic agent may comprise oleanoic acid and / or doxycycline. The therapeutic agent may be a contraceptive, an anti-sexually transmittedinfection composition, a spermicide, or an antibiotic. A spermicide may comprise nonoxynol 9. The therapeutic agent may comprise a contraceptive, such as: Estradiol acetate, estradiol, progesterone, and / or estropipate.

[0047] With reference to the figures, the present disclosure is directed to an intravaginal (IV) device 10 configured to be deployed in a vagina of a patient for a period of days or weeks. For example, the IV device 10 can be configured for twenty-eight (28) day deployment, which is the length of an average menstrual cycle. The IV device 10 can be configured to monitor the patient and to detect when intercourse occurs. When intercourse is detected, the IV device 10 can be configured to release a therapeutic agent, such as an anti-STI agent, in the vagina to reduce a risk of and / or to prevent infection. In some examples, as described in further detail herein, the therapeutic agent can be a contraceptive agent, spermicide, antibiotic or similar therapeutic agent into the vagina for infection treatment and / or prevention. As described in further detail herein, the IV device 10 can provide a mechanism for electro-responsive release of the therapeutic agent. In some examples, the IV device 10 can be configured for use for early detection and treatment of STIs. The IV device 10 can be configured for human use or for use by other animals (e.g., mammals, such as dogs, cats, horses, cows, etc.).

[0048] In some examples, the IV device 10 comprises ion-selective electrodes (ISEs) employed to assess pH (H+) and sodium (Na+) levels in the vagina. ISEs can provide high selectivity, wide signal range, and fast response time, but also can be fabricated as all-solid- state electrodes without any internal filling solution, which makes such ISEs easy to miniaturize and safe to use within the body. In some examples, the IV device 10 comprises a sensor, such as a wireless sensor, embedded with a reservoir-type IV device, which is configured to release drug using the electro-responsive release assembly or system. The sensor embedded IV device 10 can be designed to release cargo drugs when heterosexual intercourse occurs by detecting the change in the vagina (sodium or pH level). Alternatively or in addition, drug release can occur or can be controlled by an end user with a remote device (e.g., a smartphone) in wireless communication with the IV device 10. In particular, the IV device 10 can be configured to detect changes in a sodium level in the vaginal tract representative of introduction of seminal fluid into the vagina. Typically, a reproductive-age woman produces 1.5 grams of vaginal discharge every day and the vaginal fluid contains a low sodium concentration (1.7 mg / mL) with an acidic pH (3.5-4.5). The human seminal fluid includes 10.2 mg of sodium per average volume of seminal fluid per ejaculation (3.4 mL) with a range of pH of about 7.1-8.0. Normal acidic vaginal pH can be elevated with the introduced seminal fluid or bacterial infection, therefore, double monitoring of pH and sodium level mayincrease the chance of the prevention and maintain the user’s vaginal health.

[0049] In some examples, the IV device 10 comprises a near field communication (NFC) circuit 14 that is integrated with electrochemical sensors (e.g., the sensors for detecting ions of interest (e.g., H+and Na+)). The NFC circuit 14 can be configured to generate voltage signals through general-purpose input / output (GPIO) pins.

[0050] In some examples, the sensor embedded in the IV device 10 can be configured to provide an on-demand electro-responsive intravaginal anti-STIs releasing device that monitors vaginal health. In particular, the IV device 10 can be configured to release anti-STIs in a repeatable electro-responsive manner controlled by a portable device. This intravaginal drugreleasing device 10 can also be applied with artificial intelligence (Al) and potentially increase the chance of protection against STIs in user convenience and controllable manner.

[0051] In some implementations, the IV device 10 can provide a mechanism for electro- responsive release of the therapeutic agent. The release mechanism can comprise the following actions or steps (a) the embedded sensors of the IV device 10 monitor changes in pH and sodium levels in the vagina; (b) a portable device (e.g., a user’s smartphone) receives the signal, emits an alarm to an end user, and sends a signal to trigger the stimulus in the segment for electro-responsive drug release; (c) oleanolic acid is released by reduction of electro-responsive polymers (e.g., poly(ester urethane)urea conjugated with aniline tetramer (PEUU-AT) and polypyrrole nanoparticles (PPy-NPs)); (d) the released oleanolic acid diffuses out through an outer layer of the reservoir- segment of the IV device 10; and (e) when oleanolic acid cross over the outer layer, a coated pH-sensitive polyurethane (PU) and / or phenylhydrazono-methyl phenol (PHMP) will hinder the permeability at normal acidic vaginal pH, but allow the permeability of oleanolic acid at elevated pH near pH 7.0.Intravaginal Device

[0052] With reference to FIGS. 1 and 3, the IV device 10 can comprise a coil antenna 12, a flexible NFC circuit 14, a flexible sensor array 16 comprising, for example, the sodium and pH sensors or electrodes, and a reservoir 18 (e.g., a reservoir containing electro-responsive materials for drug release), which are embedded in a body 20, such as a ring-shaped or T- shaped flexible body. The body 20 can comprise silicone, polyurethane, or another biocompatible material suitable to be implanted in the vaginal tract for a period of days or weeks. In some examples, as shown in FIGS. 1 and 3, the body 20 is annular or ring shaped structure, similar to the intravaginal rings (IVRs) described above. The body 20 can be sized to be deployed in the vaginal tract of an average sized female patient and / or for use for patients over a reasonable size range (e.g., from a smallest 10%, 5%, or 1% of patients to a largest 90%,95%, or 99% of patients). In some examples, IV devices 10 can be made in a variety of sizes (e.g., small, medium, and large). In other examples, the body 20 can comprise various other shapes. For example, the body 20 could be partially annular, c-shaped, or u-shaped. In other examples, the body 20 can be rectangular, square, or any other convenient shape depending on the desired deployment location and / or to impart other desired functionality.

[0053] In some examples, the body 20 can be made from a variety of different biocompatible polymer materials, as are known in the art. In a specific example, to fabricate the ring or body 20, flexible medical-grade polyurethane (PU) pellets (Tecophilic® HP-60D-35, Lubrizol) can be loaded into a hot-melt twin-screw extruder operating at a temperature of, for example, about 140°C. The extruded filaments can be spooled and loaded onto an additive manufacturing three-dimensional printer, which can be customized to produce a polymer structure of selected shape and dimensions. In some examples, the IV device 10 can be designed using a computer-aided design program (e.g., Geomagic Design; 3DS Systems) and printed under varying print parameters, including a selected print pattern (e.g., triangular, rectilinear, grid, honeycomb), in-fill density, print speed, and / or melting temperature. In some examples, the IV device 10 can have an outer diameter OD (shown in FIG. 1) of about 30 mm to about 90 mm, or about 40 mm to about 60 mm, or about 50 mm, and an inner diameter ID (shown in FIG. 1) of about 20 mm to 40 mm or about 32 mm. The IV device 10 can have a cross-sectional dimension or thickness T1 (shown in FIG. 1) of about 5 mm to about 15 mm, or about 8 mm to about 10 mm, or about 9 mm. In some examples, dimensions of the IV device 10 can be similar to the commercially available intravaginal devices, such as the Estring® estradiol vaginal device manufactured by Pfizer, Inc.

[0054] As shown in FIG. 1, the drug-release reservoir 18 comprises electrodes 32 configured to generate sufficient electrical potential to trigger drug release. The reservoir 18 can have a varying wall thickness (e.g., about 0.25 mm to about 1.5 mm or about 0.5 mm to about 1.0 mm), which can be modified or evaluated to determine an impact on a rate of drug release and flexibility of the scaffold. As will be appreciated by those skilled in the art, rate of drug release and flexibility of the scaffold can be experimentally determined using, for example, a materials compression testing system (Instron 5943). Scanning Electron Microscopy (SEM) can be used to measure pore / channel size.

[0055] In some examples, mechanical properties of the body 20 of the IV device 10 can be important as the body 20 should be rigid enough to be retained in the vaginal cavity, but soft enough to be inserted and not to damage vaginal tissue. In some examples, mechanical properties (e.g., the compression and relaxation forces and tensile strength) of a prototypehuman-size IV device 10 can be measured using the Instron Testing System (Instron, MA, USA) and a packing condition of the IV device 10 and / or body 20 can be adjusted to achieve compatible mechanical properties of commercial IVRs (e.g., NuvaRing, compression and relaxation at 3 N, tensile strength at 6.5 N / mm2).

[0056] More particularly, testing of the mechanical properties of the body 20 of the IV device 10 may be performed as follows. For compression and relaxation, the IV device 10 can be placed vertically in a system loaded with a 2.5 kN cell. After descending at a rate of 2 mm / s to compress the IV device 10 by 50% of its initial diameter (e.g., 25 mm), a probe can ascend back at a rate of 2 mm / s to its original position. For tensile strength testing, the IV device 10 can be placed in a system loaded with a 50 kN cell. The IV device 10 can be oriented vertically and stretched at a rate of 1 mm / s until the point of failure. The maximum tensile stress can be calculated by an equation, <jmax=Fy2xnx2 , where <r=tensile stress, y=radius of cross-section (2.5 mm), and F=force.

[0057] In some examples, the body 20 of the IV device 10 can be made by three-dimensional printing. Benefits of utilizing three-dimensional printing can include that device components including wires can be embedded in the body 20 during the print process. In an exemplary printing method, a first portion (e.g., a first quarter, third, or half) of the IV device 10 can be printed layer-by-layer, after which the printing process can be paused. The IV device 10 components (e.g., the coil antenna 12, flexible NFC circuit 14, and flexible sensor array 16) can then be embedded into the printed layers and, once the components are properly positioned, remaining layers can be printed layer by layer until the body 20 is complete. In some examples, the IV device 10 components have been shown to be able to withstand temperatures up to 200°C, which is above the temperature required for three-dimensional printing.Near Field Communication Circuit and Antenna

[0058] As previously described, the IV device 10 comprises electronic communication and wireless charging circuitry, such as the coil antenna 12 and the flexible NFC circuit 14. A schematic drawing of the NFC circuity 14 is shown in FIG. 4A. As shown in FIG. 4A, the NFC circuitry 14 comprises an NFC chip 22 that is connected to the coil antenna 12 via coil antenna ports 24. As described in further detail herein, the NFC chip 22 is configured to receive power from the coil antenna 12 and / or transmit data via the coil antenna 12 to external devices, such as a smart phone or another portable computing device. The NFC circuitry 14 can also comprise other common electronic components, such as an analog-to-digital converter 26 and / or input / output interface(s) or pins 28, as are known in the art, connecting the NFC circuitry 14 to other electronic components of the IV device 10.

[0059] In some examples, the coil antenna 12 and NFC circuitry 14 are configured to provide battery-free wireless communication. While active wireless communication systems can offer long-range access points, such active systems may not be suitable to use in implantable or indwelling medical devices because active systems require a battery to operate. The battery can be bulky and needs to be periodically replaced. Hence, in some examples, the IV device 10 utilizes the near-field communication technology to provide a wireless, battery-free system, which facilitates device miniaturization and real-time continuous monitoring.

[0060] In some examples, the communication micro-coil (e.g., the coil antenna 12) can comprise a deformable micro-coil antenna configured to achieve up to, for example, about 1 cm to about 10 cm, about 4 cm to about 6 cm, or about 5 cm of wireless access points. In addition to reliable wireless communication, the NFC circuitry 14 can be configured to transmit sensor data from the miniaturized sensor array 16 to an external device and to generate voltage signals for electro-responsive drug release from the reservoir 18.

[0061] In some examples, the fabrication process for an NFC circuit 14 can comprise use of ultrathin Cu film preparation, microfabrication, material transfer printing, and / or chip mounting techniques, as are known in the art. In some examples, ultrathin Cu films, such as MT18FL 2 pm by Mitsui Kinzoku USA Inc., can be utilized to fabricate the flexible circuit 14 instead of thin film deposition techniques. It is believed that such deposition techniques can make the device fabrication process cost-effective and time efficient. In particular examples, the thickness of the fabricated circuit 14 can be maintained at less than about 50 pm, less than about 25 pm, or less than about 15 pm to demonstrate a high level of flexibility.

[0062] In some examples, an overall bending radius of the IV device 10 can be less than about 1 mm to about 10 mm, or about 2 mm to about 6 mm, or about 4 mm in the presence of rigid electronic components. Desirably, the size of the flexible NFC circuit 14 can be less than 10 mm x 10 mm x 1 mm to be embedded within the inner diameter of the IV device 10 as shown, for example, in FIG. 3. In a particular example, the NFC chip 22 of the NFC circuit 14 can comprise a 13.56 MHz transponder chip (RF430FRL152H, Texas Instruments), which contains multiple 14-bit analog-to-digital converters (ADCs) and multiple GPIO pins 28. For example, the NFC circuit 14 can comprise three ADCs 26 and seven GPIO pins 28. In some examples, the H+and Na+working electrodes of the sensor array 16 can be connected to one of ADCs 26 to read pH and sodium concentrations, and one of the GPIO pins 28 can be connected to the reservoir 18 to apply an electric potential (e.g., -I V) for controlled drug release upon demand. Based on the NFC chip 22 specifications, the input voltage range of the ADCs is 0V - 0.9V. It is believed that potentials of our H+and Na+sensors with no gain canbe about 0.6V to about 0.3V. Voltage can be about 0.7 V to about 0.4V for pH4 to pH6 and 100 M - 10'2M of sodium concentrations, which are aligned with ion concentration ranges utilized by the IV device 10.

[0063] As discussed above, the NFC circuit 14 comprises the coil antenna 12 for communication and for wireless charging. There are different ways to design such coil antennas 12, which can be adapted for use with the IV device 10. In some examples, the IV device 10 can comprise a micro-coil antenna due to its small size. In some examples, the transponder or NFC chip 22 requires antenna inductance of, for example, about 2.66 pH for 51.8 pF of resonance capacitance to operate at 13.56 MHz. Wheeler’s equation for a length (L) of a single-layer helical coil antenna defines that L=D2N218D+4Ql, where L at low frequencies of a single layer circular winding ( / and D are in inches). Using the equation, a required coil lengths ( / ) and a number of turns (TV) for different coil diameters (D) at 0.2 mm of the wire diameter can be calculated to meet the required antenna inductance. Various micro coil antennas based on different coil diameters can be explored to maximize the reading distance. Three-dimensional printed molds can be utilized to produce flexible elastomeric rods for different coil diameters. Resonant frequency can be confirmed using computational models (e.g., Altair Feko), and experimental measurements using an oscilloscope and function generator to see if they meet the required antenna inductance.Sensor Array and Ion Selective Electrodes

[0064] The IV device 10 further comprises the sensor array 16 for detection of saline and / or pH measurements indicative of intercourse, which will now be described in detail. As previously described, it is believed that a vagina of healthy reproductive women maintains acidic pH (about 3.5 to about 4.5) and low sodium levels (about 1.7 mg / mL). The presence of certain STIs can elevate the pH level (e.g., >4.5), so clinical laboratory testing often includes a vaginal pH test to diagnose vaginal symptoms. However, current vaginal pH tests rely on disposable pH papers, which have poor reliability. Since the human seminal fluid includes 10.2 mg of sodium per average volume of seminal fluid per ejaculation (3.4 mL) with a range of about pH 7.1-8.0 with a high buffering capacity, the elevation of pH and sodium levels after intercourse using a condom can be a good indicator of incorrect use of condom or condom leakage.

[0065] In some examples, the sensor array 16 of the IV device 10 comprises a microstructurebased flexible sensor array embedded within the IV device 10. For example, the IV device 10 can comprise a miniaturized fully flexible sensor array, which can be embedded into a true IV format as shown in FIGS. 1 and 3. In some examples, the flexible sensor array 16 comprises amechanically compliant electronic system for the wireless monitoring of sensing data. Due to its small form factor and mechanical compliance, the electronic system can be configured to ensure the continuous operation of the IV device 10 after being inserted into the vagina. The micro- structured flexible sensor array 16 can be fabricated as all- solid- state electrodes, such that it can reliably operate without any internal filling solution. In order to provide long-term stability of the sensor array 16, the IV device 10 can be configured to minimize the phase boundary potential by utilizing a thin, soft conductive polymer in the working electrode. In addition, the IV device 10 can comprise a salt- saturated membrane for the reference electrode to prevent any reference potential change due to interference by other ions, as shown for example, in FIG. 4B, which is an exploded view of our micro-structured flexible sensor array 16 configured for use with the IV device 10.

[0066] In some examples, the electronics (e.g., the saline and / or pH sensors) can comprise an ultrathin, low-profile, soft electronic platform along with wireless telemetry for health monitoring, such as wireless telemetry using the NFC circuit 14 and coil antenna 12 described previously. More specifically, the electronics can comprise a biocompatible, stretchable hybrid electronic system incorporating chip-scale electronic components and miniaturized electrochemical sensors with stretchable interconnects, together in an ultrasoft, breathable membrane. The electronics can be made by material transfer printing and integration. In some examples, the sensor array 16 can comprise a miniaturized flexible sensor based on sodium ion-selective electrodes (Na+ISE). The sensor electrode can be prepared by drop casting sodium ion selective electrode (ISE) membrane cocktails, which detect the presence of sodium ions, on a palladium coated pad. The reference electrode can be made, for example, by electroplating silver and Cl on a Cu pad.

[0067] In some examples, the sensors of the array 16 can be configured to provide a high selectivity, wide signal range, and fast response time. For example, the ISEs can be fabricated as all-solid-state electrodes without any internal filling solution, which makes the sensor array 16 easy to miniaturize and safe to use within the body. In one particular example, the sensor array 16 comprises two working electrodes, such as an H+and an Na+ISE, and the reference electrode can be a solid-state Ag / AgCl electrode coated by a salt- saturated polymer membrane. An exemplary arrangement of the ISE and reference electrodes for use with the IV device 10 disclosed herein is shown in FIG. 4B. In particular, as shown in FIG. 4B, the sensor array 16 comprises a porous membrane 30 covering an Na+ ion-selective membrane (ISM) of the Na+ ISE and a H+ ISM of the H+ ISE. The sensor array 16 further comprises layers of a conductive polymer, the Ag / AgCL solid-state electrode, and a base or lower layer comprising Ag.

[0068] In some examples, the fabrication process for H+and Na+ISEs can be identical except for ion-selective membrane (ISMs) used, which is configured to capture a particular ion of interest. For example, the fabrication of the sensors can start with depositing three Ag electrodes (500 nm in thickness) on a thin polyimide (PI) film (4 pm in thickness) using microfabrication techniques, as shown in FIG. 4B. Pd and Ag / AgCl layers can then be electroplated on the Ag electrode for the working and reference electrodes, respectively. For the working electrodes, the conductive polymer (e.g., a mixture of carbon black and elastomer) can be cast and dried as an intermediate layer between the Ag electrode and a thin ISM to stabilize the phase boundary potential across the interface.

[0069] In a particular example, the Na+ISM shown in FIG. 4B can be composed of sodium ionophore X, bis(2-ethylhexyl) sebacate, potassium tetrakis(p-chlorophenyl)borate, and polyvinyl chloride (PVC) in 2 mF of anhydrous tetrahydrofuran. The H+ISM can be composed of hydrogen ionophore I, 2-nitrophenyl octyl ether, and PVC in 5 mF of anhydrous tetrahydrofuran. For the reference electrode, a thin salt- saturated polymer membrane can be cast to cover the entire Ag / AgCl electrode to stabilize the reference electrode, which may prevent undesired changes of the reference potential due to chloride ion concentration.

[0070] In some examples, the sensor array 16 can be applied to the body 20 of the IV device 10 during manufacture according to the following manufacturing process or method. Initially, once all polymeric membranes are completely dried, the sensor array 16 can be carefully laminated on the surface of the IV device 10 via material transfer printing and glued using a liquid form of an elastomeric membrane. Next, the entire sensor array 16 can be encapsulated with a thin, porous polymer (e.g., Soma Foama™, Smooth-On, Inc) to protect the electrode(s) from physical damage and prevent possible delamination of the sensor components. Once the sensor array 16 is integrated into the surface of the IV device 10, sensitivity, selectivity (e.g., K+, Ca2+, Mg2+, Cl’), and long-term stability (e.g., 30 days) of each sensor can be characterized. Based on preliminary data, sensitivity of ISM sensors can be affected by other ions at high concentrations, concentrations of K+, Ca2+, and Mg2+ions (e.g., approx. 5 mM, 1 mM, and 1 mM, respectively), which, at the human vagina, are significantly lower compared to the sodium concentration (e.g., 100 mM). In some examples, long-term stability of the sensor array 16 is especially important because the sensors cannot be recalibrated once the IV device 10 is inserted into the vagina. Therefore, it is important that, once calibrated, sensors remain stable for an entire useful life of the IV device 10, which as previously described, can be at least twenty-eight (28) days, which is an average menstrual cycle.Drug Reservoir and Release Mechanism

[0071] The IV device 10 further comprises the reservoir 18 containing the therapeutic agent to be released within the vagina in response to detected changes in sodium and / or pH, which, as previously described, are indicators of a presence of semen within the vagina from sexual intercourse. The reservoir 18 can be provided in a variety of shapes, sizes, and configurations depending on the amount and type of therapeutic agent to be released. Characteristics of the reservoir 18 can be optimized for the specific therapeutic agent and / or release conditions of the IV device 10. In particular, the reservoir 18 can be configured for rapid release of anti-STI therapeutic agents when heterosexual intercourse occurs or as controlled by a device user (e.g., the patient).

[0072] The IV device 10 also includes components, such as the electrodes 32, for controlling delivery of the therapeutic agent from the reservoir 18 to the vaginal tract in response to detected changes in sodium content and / or pH. In some examples, the stimuli-responsive release mechanism can comprise one or more of the following stimuli-responsive polymers: PEUU-AT; PPy-NPs; and PHMP. Desirably, polymers can be selected accounting for release kinetics for the polymers in order to achieve up to, for example, 10 repeatable triggered releases over EC50 of 22.7 pM for 28 days without unnecessary burst release.

[0073] More specifically, in some examples, the IV device 10 can be configured to provide an electro-responsive repeatable on-demand intravaginal release of the therapeutic agent. In order to provide such on-demand release, the IV device 10 can comprise a responsive drug release assembly or system using new polymers including polyurethane (PU) and polypyrrole (PPy) derivatives. PPy is an intrinsically conducting polymer, used in electronics, optical, and biological and medical fields. PPy has been studied for electro-responsive drug release systems such as film, nanoparticle, or hydrogel. In some examples, as an electro-responsive anti-STI release system, betulinic acid (antiretroviral, antimalarial, and anti-inflammatory drug) loaded PPy nanoparticles can be designed to be incorporated in semisolid (hydroxypropyl methylcellulose) to be injected into the reservoir 18 of IV device 10 between the embedded conductive PU coated electrodes 32 for the electro-responsive on-demand release.

[0074] As preliminary data, the present inventors successfully synthesized a conductive PU elastomer, which showed potential use in coating electrodes and electro-responsive release of cargo drug with a repeatable on-demand functionality. It is believed that oleanolic acid (anionic with pKa 4.74) loaded PPy nanoparticles can also be incorporated in hydroxypropyl methylcellulose (HPMC) semisolid to be injected into the reservoir of IV device 10 between embedded conductive PU coated electrodes for the electro-responsive on-demand release. Insome examples, a pH-sensitive-PU can be coated onto the outer layer of the segment comprising the reservoir 18 for electro-responsive drug release of the IV device 10 to avoid unnecessary leakage of oleanolic acid at normal acidic vaginal pH. The combination of the three stimuli-responsive polymers (e.g., PEUU-AT, PPy-NPs, and / or PHMP) can be configured to ensure close-to-zero release at idle, while achieving target release kinetic when an electric stimulus is given.

[0075] Elastomeric conductive materials have also been studied for deformable electronics by implanting conductive fillers in elastomers, filling microchannels with liquid metals, infiltrating elastomers in conductive-filler networks, blending conductive fillers with elastic polymers, and synthesizing metal fillers within elastomers. Such elastomeric conductive materials can also be used with the IV device 10 and reservoir 18 of the present disclosure. These conductive elastomers have been used for the development of electronic skins, stretchable transistors and antennas, stretchable displays, and stretchable energy devices. Polyurethane (PU) elastomer is used for the preparation of conductive elastomer by composition with conductive filers including, for example, polyaniline (PANI), polypyrrole (PPy), poly thiophene (PTh), poly (3, 4-ethylenedioxy thiophene) (PEDOT), graphene, graphene oxide, and carbon nanotube. Polyurethane elastomer can be expected to provide excellent mechanical properties, good processability, and high conductivity. Recently aniline trimer conjugated elastomeric PUs were synthesized. Conductivity, processability, and cytocompatibility of such material has been demonstrated.

[0076] In some examples, the release agent can comprise a conductive polyester urethane urea conjugated with aniline tetramer (PEUU-AT). In some examples, the PEUU-AT can be synthesized and its chemical structure can be confirmed by1H-nuclear magnetic resonance. The conjugated AT can have a reversible redox behavior, which can be used for the electro responsive release of anti-STI drugs, especially anionic drugs, which can be incorporated in the PEUU-AT matrix and can be released when reduction status of the AT occurs as shown in FIG. 5B. In some examples, the PEUU-AT can be subsequently doped with (lS)-(+)- 10- camphor sulfonic acid (CSA), which can increase conductivity and the root- mean- square value. Experimental testing has shown that the doped PEUU-AT showed good flexibility and comparable cytocompatibility to tissue culture plastics (TCPs) when an amount of CSA doping is minimum (PCL: AT: CSA= 1: 1: 2 mole). A model anti-inflammatory drug dexamethasone release test demonstrated electro-responsive release with a pulse signal, generated by an arbitrary wave generator (Rigol DG1022), at four predetermined times. Overall, the PEUU-ATshowed its potential use in the electro-responsive release of the cargo drug by coating the electrodes.

[0077] In other examples, a PPy nanoparticle (PPy-NP) can be selected for encapsulating the drug and controlling release in an electro- responsive fashion. Previous studies have shown that PPy nanoparticles suspended in hydrogel demonstrated electro-responsive release of anionic model drug fluorescein in vitro and in vivo. The mechanism of the electro-responsive release of fluorescein may be explained as, upon reduction or oxidation, the release of encapsulated drug is directly related to the change of the overall net charge within the PPy- NPs. Upon reduction, the positive charge within the PPy-NPs is decreased, expelling anionic drugs from the PPy-NPs. After being released from the PPy-NPs, the migration of the drug mainly depends on the electric field resulting in the movement of the drug to an electrode bearing an opposite charge. Without an electric field, released fluorescein crosses the outer layer of a reservoir 18 of IV device 10 by diffusion.

[0078] In some examples, fluorescein-loaded PPy-NPs (FP- NPs) can be synthesized by an emulsion polymerization technique. In one experimental example, an average size of the FP- NPs was found to be 178±41nm. This size of the FP-NPs may be suitable to form a uniform suspension of the FP-NPs in a semi-solid hydrogel and a rapid release of the cargo drug upon the electric trigger. However, this size of FP-PPy may not allow for permeation through an outer layer of the reservoir 18 of the IV device 10.

[0079] A schematic drawing showing an experimental arrangement for testing permeation for the reservoir 18 is shown in FIG. 6. As shown in FIG. 6, in order to test permeation of the reservoir 18, a segment of an exemplary IV device 10 was fabricated by injection of FP-NPs dispersed in hydroxypropyl methylcellulose (HPMC) semisolid, followed by sealing both ends with polyurethane flexible foam. The segment filled with FP-NPs suspension was immersed in phosphate buffer saline (PBS), which was linked with an arbitrary wave generator and then an electric signal (-1 V, 1 Hz, 1 ms, 15 sec) was given at certain time points. The release profile showed a close-to-zero release for 18 hours, without the electric signal, but, after giving an electric signal, the cargo drug showed a rapid release for 1 hour and then sustained release for another 28 hours. By optimizing the electric signal, it is believed that multiple electro- responsive releases can be achieved. In order to confirm device safety of the release profile, the cytotoxic effect of the segment of the IV device 10 was evaluated by indirect contacting method using VK2 / E6E7. The test showed that the prepared segment of the IV device 10 does not induce a significant cytotoxic effect compared with the negative control (N, normal cell media without samples).

[0080] In other examples, a pH- sensitive poly ether- PUs (PHHP and PHMP) can be synthesized from polyethylene glycol, l,4-Bis(2-hydroxyethyl) piperazine, and propylene glycol. The synthesized pH-sensitive PUs demonstrated pH-triggered reversible changes in surface charge, swelling ratio, and morphology. Close-to-zero release of an anionic model drug (diclofenac, NaDF), through the pH-sensitive-PUs, was found at pH 4.5, whereas rapid release of NaDF occurred at pH 7.0 resulting the switchable on-demand off-and-on. The pH- sensitive PUs showed non-cytotoxicity and non-proinflammatory cytokines expression toward VK2 / E6E7 and T-cell line SupTl. These pH-sensitive PUs can be used as a surface coating material for the reservoir of the IV device 10.Patient Health Monitoring System

[0081] As previously described, the IV device 10 can be used with a patient health monitoring system 110 for health monitoring and controlled drug release, features of which are shown in FIGS. 2A and 2B. As shown in FIGS. 2A, the patient health monitoring system 110 comprises the IV device 10 configured to be deployed within a vaginal tract of a patient for treating, reducing risks associated with, and / or preventing sexually transmitted infection. The IV device 10 comprises the sensor array 16, which can comprise both the H+ and Na+ sensors for H+ and Na+ detection, and an integrated wireless device, such as the NFC circuitry 14 for providing communication and power for device components. As previously described, the IV device 10 further comprises the reservoir 18 containing the therapeutic agent, which can be configured to release the therapeutic agent in response to voltage applied to reservoir electrodes. As shown in FIG. 2A, the IV device 10 is in wireless communication with a controller or processor. In some examples, the controller or processor can be a processor of an external medical or non-medical device, such as a processor of a portable computing device 112, such as a smart phone, tablet, or personal computer. In other examples, the controller can be a component of the IV device 10 or of another implanted or indwelling medical device in wired or wireless communication with the IV device 10.

[0082] In some examples, the system 110 can comprise a software application (e.g., an android application configured to be executed on the portable device 112). Actions performed by the software application are shown schematically in FIG. 2B. Specifically, as shown in FIG. 2B, H+ / Na+ readings detected by the sensor array 16 are wirelessly transmitted to the portable computing device 112 via the NFC circuit 14. Measurement values for H+ / Na+ concentrations can be displayed on the user interface or visual display of the portable computing device 112. Also, the software application executed on the portable computing device 112 can be configured to analyze the received measurement values by, for example,applying a simple threshold algorithm based on H+and Na+ concentrations. Based on such threshold analysis, the portable computing device 112 can be configured to wirelessly transmit instructions to the IV device 10 via the NFC circuitry 14 for drug release. In response, the IV device 10 can be configured turn on or off the reservoir electrodes 32 in order to, for example, provide an electric potential sufficient to initiate the drug release mechanism, as previously described. In some examples, the controller of the portable computing device 112 can be configured to wirelessly provide instructions for drug release in real-time or substantially realtime (e.g., within 10 seconds, 30 seconds, 1 minute, or 5 minutes of receiving the signals from the IV device 10) in order to provide effective therapy.

[0083] More particularly, in some examples, a controller or computer processor, such as a processor of the portable computing device 112, can be configured to receive and process signals from, for example, the sodium (Na+) sensor or pH (H+) sensor of the flexible sensor array 16 to determine a sodium value and / or a pH valve for the vaginal tract of the patient. The controller can also be configured to cause the portable computing device 112 to display the determined measurement values. For example, the controller can be configured to cause visual indicators, such as alphanumeric characters, graphs, or icons (e.g., a speedometer or fuel gauge icon), representative of the determined sodium value and / or pH value to appear on a visual display of the portable computing device 112. In some examples, measurement values can be displayed in real time. Alternatively or in addition to display of real information, the controller can be configured to cause historical information for measurement values to be displayed when, for example, such historical information is requested by the user. Once measurement values are received, the controller can also be configured to compare the determined sodium and / or pH value to a sodium and / or pH threshold value(s) and, in response to the comparison, cause an electro-responsive electrode assembly of the drug containing reservoir 18 to release the therapeutic agent from the reservoir 18 when the determined sodium value and / or pH value exceeds the threshold value. As previously discussed, in some examples, the therapeutic agent released by the patient health monitoring system 110 can be a contraceptive, an anti-sexually transmitted infection composition, a spermicide, or an antibiotic.

[0084] Although the invention has been described in detail for the purpose of illustration based on what is currently considered to be the most practical and preferred embodiments, it is to be understood that such detail is solely for that purpose and that the invention is not limited to the disclosed embodiments, but, on the contrary, is intended to cover modifications and equivalent arrangements. Furthermore, it is to be understood that the present inventioncontemplates that, to the extent possible, one or more features of any embodiment can be combined with one or more features of any other embodiment.EXAMPLES

[0085] The following proposed and experimental examples are presented to demonstrate the general principles of the invention. The invention should not be considered as limited to the specific examples presented.Proposed Example 1

[0086] A cytocompatibility and pro-inflammatory cytokines sensor array of an IV device 10 will be evaluated against human vaginal epithelial cell line VK2 / E6E7 cells (ISO 10993). To assess the cytotoxicity, the elution method will be used, and MTS assay will be conducted for the quantification of different time points, such as 1, 7, 15, and 30 hours. For the pro- inflammatory cytokines array, pro-inflammatory markers of samples including negative control (normal cell medium) and positive control (lipopolysaccharide, nonoxynol-9) will be evaluated by a downstream ELISA assay.

[0087] Hemocompatibility of the IV device 10 will be evaluated following the Standard Practice for Assessment of Hemolytic Properties of Materials from the American Society for Testing and Materials (ASTM F756-17). The % hemolysis will be calculated using the equation A x 100) / B, where A is a supernatant hemoglobin concentration and B is a total hemoglobin concentration in a tube. The sample will be considered as non-hemolytic if the % hemolysis above the negative control is lower than 2%, slightly hemolytic if between 2% and 5%, and hemolytic if higher than 5%. Non-sample contacted blood will be used as a negative control.

[0088] Monitoring changes in pH and sodium levels and communicating with a portable device in the tissue will be performed. The fabricated human-size IV device will be placed under a 3 cm thick (10x10 cm2) pork or beef steak. The pH of the steak will be pre-adjusted at 4.0 by soaking in 0.1N HC1 solution. At a certain timepoint(s), such as 1, 3, 6, and 12 hours, 5 mL of 0.01N NaOH solution will be spread to the IV device under the steak to monitor changes in pH and sodium level by the portable device.Proposed Example 2

[0089] An initial animal study will be used to evaluate the functionality of embedded sensors, the NFC circuit, and antenna, which are provided for detecting pH and sodium levels and to communicate with a wireless portable device, such as a smart phone. For the animal study, a “T” shaped IV device (shown in FIG. 7) will be fabricated. The “T” shaped device is used forin vivo study to validate features of the IV device 10. For animal studies, a different design of the IV device (“T” shape) is used, but with exactly the same components, such as the flexible NFC circuit, coil antenna, sensor array, and reservoir. The dimension of the “T” shaped IV device 10 will be 13 mm in diameter and 60 mm in length so that all components are properly embedded, while the device is insertable to the rabbit’ s vagina.

[0090] In vivo implantation of “T” shape IV device will be performed using a rabbit model. It is believed that rabbits are an excellent model for studying the IV device because the urovagina (distal section of the vagina) of a rabbit is composed of squamous epithelium, which is similar to that of the human vagina. The cervicovagina (proximal section of the vagina) of a rabbit is composed of mono-stratified columnar epithelium, which is also similar to that of humans. In addition, the relatively larger size of the rabbit (in comparison to other rodents), allows for researchers to study an actual human-sized IV device.

[0091] The inventors anticipate using hollow cylindrical tubing (5 / 16” outer diameter) made of medical grade PU to insert and place the “T” shaped IV device towards the urovagina. A metal rod will then be inserted within the hollow cylinder to push and release the “T” shape IV device within the urovagina. The hollow PU rod and the metal rod will be sterilized with 70% isopropanol prior to the procedure. The exterior of the IVR / capsule segments will also be gently wiped with alcohol. The “T” shaped IV device will be specially designed to contain “arms” or “protrusions” which are flexible and can non-invasively hold the segment in place within the vaginal tract. With this model, we can determine whether the system is biocompatible in vivo over a 28-day period.

[0092] In some examples, 5 to 8 month-old New Zealand white rabbits (Charles River Laboratories International, Inc.) will be anesthetized and the lubricated PU hollow rod containing the “T” shape IV device will be inserted gently into the vaginal tract. There will be a total of four implant groups i) non-implanted control, ii) placebo “T” shaped IVR-only group, iii) “T” shaped IV device releasing fluorescein, and iv) “T” shaped IV device releasing oleanolic acid. Because the rabbit vagina ranges from about 14 cm to about 19 cm in length and the urethrovaginal sphincter is located midway, we will need to bypass this sphincter in order to release the rod segments into the urovagina. To do this, the PU hollow tubing will be marked to indicate the appropriate distance for insertion. This will prevent insertion that is too deep into the vaginal tract or too short. Throughout the entire 28-day study period, the animal will be observed for signs of distress (e.g., changes in animal weight, signs of vulval irritation, and vaginal discharge or bleeding) and involuntary expulsion of the device.

[0093] In this study, an electric trigger may not be provided to the reservoir of the IV devices to ensure that the proposed IV device will not release encapsulated drugs without the signal. At various time points (0, 1, 3, 7, 14, 21, 28 days) post-insertion, pH and sodium levels in the vagina tract will be adjusted by applying vaginal fluid or seminal fluid simulants, and the changes will be monitored. After 30 min from the pH and sodium level monitoring, blood and cervico vaginal lavage (CVL) samples will be collected to determine the release of oleanolic acid by UHPLC and pro-inflammatory cytokine expression by ELISA. Blood will be collected via ear vessels and CVL will be collected by gently washing the cervicovaginal area using a flexible polyethylene catheter tubing containing sterile saline. The samples will then be centrifuged, separated and stored in a freezer at -80 °C prior to analysis. The concentration of oleanolic acid will be recorded and compared to electro-responsive release. The cytokine levels will be measured using standard ELISA kits (R&D Systems®). Upon termination of the animals (day 30), vaginal tissue (urovagina and cervicovagina) will be collected and analyzed for changes in tissue health / architecture (immunohistochemistry including H&E) and barrier function (Transepithelial electrical resistance, TEER).Proposed Example 3

[0094] Preliminary studies for the drug release mechanism have been conducted. In one study, oleanolic acid (OA, EC of 22.7 pM) was selected as a model drug (representing hydroxyl pentacyclic triterpenoid acids including betulinic acid, ursolic acid, and their derivatives) because of its antimicrobial and anti-HIV activities, pKa (4.74), and similarity to other model drugs. Other model drugs can include fluoresceine, diclofenac, and dexamethasone (anionic, a molecular structure consisting of a hydrophobic six-membered ring structure fused cyclohexane or benzene ring, molar mass around 400g / mol). From the preliminary study, it was found that the dopant CSA may potentially be deprotonated and diffused out from the PEUU-AT resulting in decreasing conductivity and increased risk of cytotoxicity in high concentration. It is believed that this may be overcome by other dopants such as phytic acid. Phytic acid is a natural organic compound, and a phytic-acid-doped polyaniline hydrogel showed an electronic conductivity without cytotoxicity. Also, phytic acid has been used for anti-corrosive coating because of its strong chelating ability to metals. The amount of cargo oleanolic acid in coated PEUU-AT matrix on the electrode might be insufficient for repeatable release over 28 days. Oleanolic acid-loaded PPy nanoparticles (OP-NPs) suspended in the semisolid support the release for a longer period. To avoid an unnecessary leakage of drugs at normal acidic vaginal pH (3.5-4.5), pH-sensitive PU, PHMP, will be coated onto the outer layer of the reservoir of IV device as shown in FIG. 6.

[0095] Oleanolic acid, PEUU-AT, and dopant (e.g., phytic acid) will be dissolved in hexafluoro-2-propanol (HFIP) and coated to the electrodes by dip-coating. Electro-responsive release of loaded oleanolic acid will be evaluated in 5 mL of vaginal fluid simulant (VFS) at pH 4.0 or 7.4 (pH will be adjusted by adding 0.1N HC1 or NaOH solutions) with or without an electric trigger. The coated electrodes will then be immersed in 5 mL VFS at 37°C. At the predetermined times points, 200 pL of the VFS will be taken after 10 min from the electric trigger (every 24 hours for 28 days) for High-performance liquid chromatography (HPLC) analysis and replenished with fresh VFS.

[0096] In vitro cell viability of the electrode with an electric trigger will be evaluated using vaginal epithelial cell VK2 / E6E7 by the indirect contacting method. The cell viability will be evaluated by CellTiter 96® AQueous One Solution Cell Proliferation Assay (MTS assay), Live / Dead assay, and SEM imaging after 6 hours from the trigger. The cell viability will be compared with non-electro trigger given and non-electrode immersed controls. These drugreleasing and cell viability studies will be repeated by different loading concertation of oleanolic acid or applied voltages to achieve repeatable release without significant toxic effects.

[0097] For the oleanolic acid-loaded PPy nanoparticle (OP-NPs) system, oleanolic acid will be encapsulated in PPy by emulsion polymerization technique and suspended in HPMC semisolid to be injected into the reservoir of IV device. The particle size and zeta potential of the OP-NPs will be confirmed and compared with oleanolic acid- free PPy-NPs using a dynamic light scattering, zeta potential analyzer, and SEM images. The OP-NPs will be suspended in HPMC semisolid and injected into a segment of reservoir-SWIR. After injection, the open ends of the segment will be capped with custom-fabricated plastic lids and sealed with a flexible foam (SMOOTH-ON, Lower Macungie, PA, USA).

[0098] The electro-responsive release of oleanolic acid from the segmented IV device will be studied in VFS. Briefly, the end capped segmented IV device will then be immersed in 5 mL of VFS at pH 7.4 at 37°C, and then the electric trigger will be applied by electrodes every 24 hours for 28 days. After 10 min from each electric trigger, 200 pL of release medium will be taken for quantification of released oleanolic acid by HPLC and the medium will be replenished with fresh VFS. In vitro cell viability of the segments with electric trigger will be evaluated following an indirect contact method described above section. These drug-releasing and cell viability studies will be repeated using various concertation of OP-NPs in the segment (50- lOOmg of OP-NPs / 1 mL of HPMC) or applied voltages to achieve repeatable release for 28 d without significant toxic effects.

[0099] The pH-sensitive-PU (PHMP) will be coated onto the outer layer of the segment of IV device (e.g., the reservoir for electro-responsive drug release) to avoid unnecessary leakage of oleanolic acid at normal acidic vaginal pH. The PHMP will be synthesized by referring to procedures in published articles, and it will be coated onto the segment of the IV device by the dip-coating method. The coating of the PHMP-coated surface will be evaluated by SEM imaging and Attenuated Total Reflectance-Fourier Transform Infrared Spectroscopy. The electro-responsive release and cell viability test will be executed for comparison with non- PHMP coated segment of SWIR following the procedure described in the above paragraphs.

Claims

THE INVENTION CLAIMED IS:

1. An intravaginal device configured to be deployed within a vaginal tract of a patient for treating, reducing risks associated with, and / or preventing sexually transmitted infection, the device comprising: a body comprising a flexible biocompatible material; a flexible sensor array embedded in the body comprising at least one of a sodium sensor or pH sensor; a reservoir embedded in the body comprising a therapeutic agent configured to be released by an electro-responsive electrode assembly; a near field communication circuit configured for wireless communication with an external device for wireless charging, data transmission, and receipt of control signals; and a device controller configured to activate the electro-responsive electrode assembly to release the therapeutic agent from the reservoir in response to signals detected by the flexible sensor array and / or control signals received from the external device via the near field communication circuit.

2. The device of claim 1, wherein the body comprises silicone or polyurethane.

3. The device of claim 1, wherein the therapeutic agent comprises at least one of a contraceptive, an anti-sexually transmitted infection composition, a spermicide, or an antibiotic.

4. The device of claim 1, wherein the at least one sodium sensor or pH sensor is configured to detect seminal fluid in the vaginal tract.

5. The device of claim 1, wherein the at least one sodium sensor or pH sensor comprises an ion-selective electrode.

6. The device of claim 1, wherein the at least one sodium sensor is configured to detect fluids in the vaginal tract with a sodium concentration of about 0.5 mg / mL to about 5 mg / mL.

7. The device of claim 1, wherein the near field communication circuit and the flexible sensor array are configured for real-time continuous monitoring.

8. The device of claim 1, wherein the near field communication circuit comprises a micro-coil antenna.

9. The device of claim 1, wherein the electro-responsive electrode assembly comprises conductive polyurethane coated electrodes.

10. The device of claim 1, wherein the reservoir is configured for release of oleanolic acid by reduction of electro-responsive polymers.

11. The device of claim 10, wherein the electro-responsive polymers comprise at least one of polyester urethane urea (PEUU) or polypyrrole nanoparticles.

12. The device of claim 1, wherein the therapeutic agent comprises oleanolic acid contained in the reservoir of the intravaginal device.

13. The device of claim 1, wherein the body is fabricated by at least one of hot-melt injection molding or three-dimensional printing.

14. The device of claim 1, wherein the device is configured to provide controlled release of the therapeutic agent from the reservoir to the vaginal tract of the patient.

15. A patient health monitoring system, comprising: an intravaginal device configured to be deployed within a vaginal tract of a patient for treating, reducing risks associated with, and / or preventing sexually transmitted infection, the device comprising: a body comprising a flexible biocompatible material; a flexible sensor array embedded in the body comprising at least one of a sodium sensor or pH sensor; a reservoir embedded in the body comprising a therapeutic agent configured to be released by an electro-responsive electrode assembly; anda near field communication circuit for wireless charging, data transmission, and receipt of control signals; and a controller in communication with the flexible sensor array and the electro- responsive electrode assembly via the near field communication circuit, wherein the controller is configured to: receive and process signals from the at least one sodium sensor or pH sensor of the flexible sensor array to determine a sodium value and / or a pH valve for the vaginal tract of the patient; compare the determined sodium and / or pH value to a sodium and / or pH threshold value; and cause the electro-responsive electrode assembly to release the therapeutic agent of the reservoir when the determined sodium value and / or pH value exceeds the threshold value.

16. The system of claim 15, wherein therapeutic agent of the reservoir comprises at least one of a contraceptive, an anti-sexually transmitted infection composition, a spermicide, or an antibiotic.

17. The system of claim 15, wherein the controller is a component of the intravaginal device, which is configured to be deployed in the vaginal tract along with the intravaginal device.

18. The system of claim 15, wherein the controller is a component of an external portable computing device, which is in wireless communication with the intravaginal device by the near field communication circuit.

19. The system of claim 18, wherein the external portable computing device comprises a device display, and wherein the controller is configured to cause visual indicators representative of the determined sodium value and / or pH value to appear on the device display in real time.

20. The system of claim 18, wherein the external portable computing device is configured to receive a user input for drug release, and wherein, upon receipt of the userinput for drug release, the controller is configured to cause the electro-responsive electrode assembly to release the therapeutic agent from the reservoir.

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