Transcervical access systems for intrauterine fluid exchange, e.g., placement of hydrogels formed in situ.

Abstract

This invention provides a transcervical access system for moving fluids transcervically. [Solution] The transcervical access system 100 is effective in transferring a wide range of fluids into the uterine cavity, including the delivery of a hydrogel precursor, saline solution, and imaging fluid. The transcervical access system 100 is also effective in removing fluids, such as residual bodily fluids, residual fluids from procedures, or tissue from the uterine cavity. The transcervical access system 100 includes a flow limiter, such as an outflow limiter 106 and / or a cervical plug. A method of using the transcervical access system 100 involves using the transcervical access system 100 to transcervically access the uterine cavity and to install the hydrogel. The transcervical access system 100 and related methods are useful in preventing adhesions after intrauterine procedures by providing a biodegradable hydrogel within the uterine cavity, including the cervix.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 113,013, filed November 12, 2020, to Bassett et al. (「Placement of Hydrogels Formed In Situ, Composition Design and Delivery Tools for Intrauterine Use」), and claims priority to co - pending U.S. Patent Application No. 17 / 494,752, to Bassett et al., and incorporates both by reference herein.

[0002] Aspects of the present invention relate to methods of applying materials delivered to the uterine cavity, such as in situ - formed hydrogels, and to arrangements of these materials, instrumentation using tools, and tools useful for delivery.

Background Art

[0003] Undesirable adhesions of scar tissue that can occur after intrauterine procedures, known as uterine cavity adhesions, generally occur when two injured tissue surfaces are in close proximity to each other. This complication can cause painful and debilitating medical problems, including but not limited to postoperative adverse events, failure of medical interventions, and infertility. Surgical dissection and adhesiolysis often lead to a high rate of adhesion re - formation. Current methods for preventing adhesions, including but not limited to uterine cavity adhesions, are of limited effectiveness.

Summary of the Invention

Means for Solving the Problems

[0004] In some embodiments, methods and apparatus for delivering or removing fluids into or from the uterine cavity, including in situ-forming hydrogels, are presented herein to prevent the formation of uterine adhesions. In situ-forming hydrogel technology can also be used as tamponade to stop unwanted postoperative bleeding and to mechanically support uterine tissue. The material can be introduced into the surgical site to reduce or prevent contact between damaged tissues or between multiple parts of tissue. Fluid components can be used to facilitate the introduction and formation of the material. For example, a fluid polymer precursor can be introduced transcervically and, after introduction, activated to form a material in the uterus. Examples of precursors include polymerizable, crosslinkable, and thermosetting polymers that form a material, such as a hydrogel, in the uterus. In some embodiments, other fluids for therapeutic, imaging, or other purposes can be delivered using the improved catheter systems described herein. The catheter system can also be used to remove fluids from the uterine cavity, for example, to prepare the patient for further treatment or to collect material for biopsy. The fluid can be broadly considered a material that can flow into and / or from the catheter of the device and may contain tissue elements suitable for tissue biopsy.

[0005] Some embodiments relate to methods for preventing adhesion of damaged tissue surfaces in potential spaces, such as the uterus. The methods include introducing a fluid material into the uterus to tamponade the surface within the uterus. Tamponade can be effective in reducing bleeding from damaged tissue after surgical procedures. The material may be, for example, a hydrogel and may function as a stent or splint. Some embodiments relate to preventing adhesion within the uterus by crosslinking a material to at least one precursor to form a hydrogel within the uterus, for example, to coat the surface of damaged tissue, or to tamponade the surface of the uterine cavity, or to prevent collapse and adhesion of the uterine cavity wall to each other. Additional embodiments relate to premixing hydrogel components into one precursor and activating the crosslinking while performing the procedure with a second precursor. Embodiments relating to the design of the application device include the use of a soft, flexible, and non-traumatic catheter, the addition of one or more side ports for improved application to the uterine surface, and a low catheter profile for reduced insertion trajectory remaining after removal. The incorporation of rounded, non-traumatic features on the outside of the catheter body, in the form of an external plug or balloon feature, can be adjusted along the length of the catheter to be retained at the cervix in order to control the outflow of excess hydrogel from the target tissue.

[0006] In one embodiment, the present invention relates to a crosslinked hydrogel composition comprising a multi-arm polyethylene glycol molecule crosslinked with a multifunctional crosslinking agent having a molecular weight of about 2 kDa or less by biodegradable crosslinking, with a swelling of about 125% by weight or less 24 hours after placement in a neutral buffered saline solution. In some embodiments, the hydrogel may have an in vivo intrauterine degradation time of about 3 hours to about 29 days. For in vivo use, to provide stability without causing discomfort to the patient, the hydrogel may have a Young's modulus value of 5 kPa to 300 kPa. In some embodiments, the crosslinking molecule incorporated into the hydrogel is a polyamine, such as polylysine, which may be trilysine. In some embodiments, the crosslinking functional group is an N-hydroxysuccinimide ester and a primary amine that react to form an amide bond by nucleophilic substitution.

[0007] In further embodiments, the present invention relates to a method for providing an in situ-forming tamponer or adhesion inhibitor into the uterine cavity, the method of delivering a crosslinked hydrogel precursor solution through an applicator catheter in a manner that facilitates uniform delivery of the precursor solution into the cavity, wherein the hydrogel swells by 125% or less after in vivo formation and decomposes in about 3 hours to about 21 days. In some embodiments, a hydrogel polymer composition comprising a multi-arm polyethylene glycol polymer core (PEG precursor) is crosslinked with a multifunctional crosslinking agent (crosslinking agent precursor) having a molecular weight of about 2 kD or less, and the precursor solution is formed by mixing the PEO precursor, the crosslinking agent precursor, and a promoting compound in a flow directed towards the applicator catheter to initiate the crosslinking reaction. Delivery from the catheter is carried out rapidly so that the precursor solution entering the cavity is sufficiently low viscosity to fill the space, while crosslinking quickly enough to prevent excessive loss of the precursor from the uterine cavity, so that the procedure can be completed within a desired timeframe. The applicator may include or be associated with a flow limiter, which helps to maintain the hydrogel precursor within the uterine cavity, thereby ensuring that separation of the uterine wall is achieved by completely filling the uterine cavity.

[0008] In another embodiment, the present invention relates to a hydrogel applicator comprising two reservoirs, the outlets of which are connected to a Y-type connector, and a section of a tube connected to a catheter having a size of 9Fr or less, with the outlet port on the side of the catheter body having a non-traumatic tip, which mixes the respective solutions from the reservoirs. The reservoirs may be syringe tubes mounted on a holder, and the plungers may be connected to plunger caps to allow for convenient simultaneous deployment of two syringe plungers. A static mixer may provide more rapid mixing of the combined solutions from the reservoirs. The catheter may be formed from a polymer with a sufficiently low durometer value, thus reducing the likelihood of causing injury to patient tissue. In some embodiments, one reservoir may hold a blend of hydrogel precursors, provided that the crosslinking is sufficiently slow, and the other reservoir may contain an accelerator, such as a basic buffer.

[0009] In one embodiment, the present invention relates to a transcervical access system for moving a fluid by simple operation, wherein the transcervical access system is: A graspable structure comprising one or more fluid reservoirs and one or more actuators that direct flow from or into the one or more fluid reservoirs; A catheter comprising a tubular element having a lumen, an outer diameter, an average wall thickness, and one or more distal ports, wherein when an actuator is activated, a structure that can be grasped engages in such a manner that it brings fluid flow through the tubular element of the catheter; and An egress limiter comprising a tubular member and a cap element fixedly attached to or near the end of the tubular member, wherein the tubular member has an inner lumen with an inner diameter larger than the outer diameter of the tubular element of the catheter, allowing the egress limiter to slide over the catheter and be removable from the catheter, the length of the tubular member is shorter than the length of the tubular element of the catheter, the position of the tubular member allows for adjustment of the distal catheter length, and the distal catheter length includes the length from the distal end of the catheter to the distal end of the cap element. This includes. In some embodiments, the system is suitable for one-handed operation.

[0010] In some embodiments, the present invention relates to a transcervical access system for moving fluid within the uterus with simple operation, wherein the transcervical access system is: A graspable structure comprising one or more reservoirs and one or more actuators that direct flow from or into the one or more fluid reservoirs; A catheter comprising a tubular element having a lumen, an outer diameter, and one or more distal ports, wherein a structure that can be grasped engages in a manner that brings fluid flow through the tubular element of the catheter; and A cervical plug having an inner lumen with an inner diameter larger than the outer diameter of the tubular element of a catheter, wherein the cervical plug can slide over the upper side of the catheter and can be removed from the catheter, and the cervical plug has an outer diameter suitable for placement within the cervix. Includes.

[0011] In an additional aspect, the present invention relates to a method for moving a fluid transcervically into or out of a patient's uterine cavity, the method being: The transfer of fluid into or from the patient's uterine cavity using a catheter system, the catheter system being: A graspable structure comprising a hydrogel precursor reservoir and an actuator. A catheter comprising a tubular element with a lumen, an outer diameter, and one or more distal outlets, wherein the catheter is connected to a reservoir in a manner that provides fluid flow through the tubular element of the catheter, and the tubular element has a length suitable for transcervical intrauterine delivery, and A blocking structure comprising a lumen with an inner diameter larger than the outer diameter of the tubular element of the catheter, wherein the blocking structure is slidable over the catheter, and the blocking structure is positioned to adjust the distal catheter length, the distal catheter length including the length from the distal end of the catheter to the distal end of the blocking structure. Including; and The catheter is removed from the patient, while a blocking structure is left in place to prevent fluid from leaking out of the neck. Includes. [Brief explanation of the drawing]

[0012] [Figure 1A] This is a diagram of a transcervical access system equipped with an outflow limiter and a single syringe. [Figure 1B] This is a diagram of a transcervical access system, which includes a flow limiter and dual syringes connected to a catheter via a Y-type connector. [Figure 2] Figure 1B shows a transcervical access system equipped with an optional T-branch connector and syringe. [Figure 3] This is a basic cross-section of the mounting tip. [Figure 4] This diagram shows the geometric shapes of various placement tips, each featuring an opening positioned radially along the circumference of the catheter. [Figure 5] This is a diagram of a transcervical access system used to deliver fluid components to the uterus through the cervix, with a cap element used to control catheter placement and the outflow of material from the external cervical os. [Figure 6] This is a diagram illustrating various cap element designs. [Figure 7]It is a diagram of the assembled form (A) of the catheter and the outflow limiter and the separated form (B) of the catheter and the outflow limiter. [Figure 8A] It is a diagram of a catheter assembly including an outflow limiter and a connector. [Figure 8B] It is an enlarged cross-section of a part of the catheter assembly of FIG. 8A and the outflow limiter. [Figure 8C] It is an exploded view of the catheter assembly, the outflow limiter, and the connector of FIG. 8A. [Figure 9] It is a diagram of a catheter assembly including a luer connector and an outflow limiter having an inflatable / contractable adjustable cap element connected to an internal balloon lumen in an inflatable / suppressible port. [Figure 10] It is a diagram of a catheter assembly including a cervical plug and a connector. [Figure 11] It is a diagram of a catheter assembly including a cervical plug, an outflow limiter, and a connector. [Figure 12] It is a diagram of various cervical plug shapes. [Figure 13] It is a diagram of a transcervical access system including a cap element used to deliver a fluid component to the uterus trans-cervically. [Figure 14] It is a diagram of a transcervical procedure using a transcervical access system including an outflow limiter. [Figure 15] It is a diagram of a transcervical procedure using a transcervical access system including a cervical plug. [Figure 16] It is a diagram of a transcervical procedure using a transcervical access system including a cervical plug and an outflow limiter. [Figure 17] It is a diagram of a transcervical procedure using a transcervical access system including a cervical plug having a tapered tether or a grip end. [Figure 18] It is a photograph taken after using a standard Cook Goldstein Sonohysterography Catheter to place a hydrogel into the human uterus. [Figure 19] These are a series of photographs of the post-perihysterectomy lesion taken after uterine ablation and the use of a delivery system to place the hydrogel. The photographs show the removed uterus, the removed uterus cut open to show the placed hydrogel, and the cut and opened uterus together with the removed hydrogel implant. [Modes for carrying out the invention]

[0013] Catheter systems are described for facilitating fluid movement into and out of the patient's uterine cavity. In embodiments of particular interest, an effective approach is presented for reducing or eliminating uterine adhesions resulting from surgical procedures by delivery of a well-designed hydrogel precursor using an improved applicator designed to ensure stable hydrogel delivery to all relevant locations in the uterus. Effective hydrogel precursors can be designed for one or more of the following: gelation time, viscosity of the precursor solution, degree of swelling after crosslinking, or biodegradation time. Improvements in these parameters can overcome the shortcomings of previous attempts to deliver hydrogel-based products useful for adhesion prevention. Improved catheter systems that can function as applicators are designed for more effective delivery into cavities such as the uterine space by preventing outflow from the cervix, and, in some embodiments, for proper mixing of precursors to control the placement of the hydrogel based on gelation time. The improved applicator is also designed to avoid accidental removal of the hydrogel from the cervix when the applicator is withdrawn, so adhesions can be suppressed in locations near the cervix. The improved applicator may include a temporary cervical cap that remains in place when the catheter is withdrawn from the cervix and / or a cervical plug that remains in place after the procedure, in order to stabilize the hydrogel in the uterus and prevent involuntary discharge of the hydrogel from the uterus due to spontaneous contractions. The blocking structure may refer to an outflow limiter including a cervical cap, a cervical plug, or both. Corresponding methods based on the use of the improved applicator are described. By using one or more of these improved features, an effective therapeutic approach may be provided to reduce common causes of post-procedure complications.

[0014] Some embodiments of improved applicators relate to devices for delivering either a single solution or two or more crosslinkable solutions to form hydrogel implants in situ. Based on the applicator design, the corresponding methods can be effectively carried out by a medical professional with simple operation. This specification includes single-component, two-component, and multi-component hydrogel systems for such use, as well as delivery systems for depositing such hydrogel systems. Some embodiments involve forming a gel or hydrogel from a precursor, which is a material that will be incorporated into a gel or hydrogel structure. Monomers or macromers used to form a gel or hydrogel are generally considered precursors, while polymerization accelerators are not generally considered precursors, although their presence is directly involved in the formation of the hydrogel.

[0015] The catheter system can be particularly effective as an applicator for the delivery of hydrogel precursors, and the device can also be effective for the delivery of other fluids used for intrauterine imaging, such as, but not limited to, saline, contrast agents, and sterile gel formulations. Furthermore, the catheter system can also be effective for removing fluids from the uterine cavity. For example, fluids can be removed before hydrogel infusion to reduce dilution effects. Fluids can also be removed to capture released tissue cells for biopsy.

[0016] Uterine cavity adhesions Intrauterine adhesions (IUAs) appear as adhesive bands with distinct or irregular edges, causing distortion of the natural physiological function of the uterus and eventually obstructing the uterine cavity (1). Partial or complete obstruction of the uterine cavity due to adhesions can result in abnormal bleeding, infertility, and recurrent miscarriage (2). For any of these reasons, avoiding intrauterine adhesions is desirable. IUAs are commonly found in patients after gynecological procedures requiring the placement of instruments in the uterus for either diagnostic or therapeutic purposes, or in patients who have suffered trauma within the uterine cavity (3). The incidence of intrauterine adhesion formation after such events can reach 60% (4). Adhesions are a result of surgical hysteroscopy, and their incidence varies depending on the type of procedure involved, and is particularly high in hysteroplasty, myomectomy, and endometrial ablation (5, 6). These conditions, while treating the primary cause of low fertility, increase the risk of adhesions, which represent a more latent risk to fertility. The association between the presence of adhesions and infertility has been reported to reach 43% (3). Furthermore, evidence suggests that the severity of adhesions can progress from mild, thin-membrane adhesions to fibromuscular adhesions and eventually to dense connective tissue (8). Various factors have been associated with the formation of intrauterine adhesions (6, 9, 10, 11, 12).

[0017] Over the past few years, the use of reabsorbable barriers to prevent IUA has shown some clinical success. These barriers include hyaluronic acid solutions, cross-linked hyaluronic acid solutions, and viscoelastic solutions containing hydrophilic polymers. While hyaluronic acid and cross-linked solutions, such as Sepracoat, are prophylactically effective, they remain ineffective or lack sufficient data to support a reduction in IUA when applied after tissue damage has occurred (17). Viscoelastic forms have shown promising clinical outcomes in the overall reduction of IUA, but remain subject to the effects of premature dilution and require extension of the overall duration. To date, no single modality has proven satisfactorily effective in preventing postoperative adhesion formation in hysteroscopic use (18).

[0018] In situ-formed hydrogels offer several advantages for use as adhesion barriers. The liquid nature of the precursors allows for ease of use, minimal invasiveness, and thorough application throughout the uterine cavity. After crosslinking and gel formation, the barrier is more resistant to discharge from the uterine cavity and premature dilution. Hydrogel formulations are generally described as being able to achieve durations designed to prevent intrauterine adhesions (IUA). Previous efforts to apply hydrogels to prevent uterine adhesions are described in U.S. Patent Application Publication No. 2005 / 0266086 to Sawhney (hereinafter referred to as Application 086) ("Intrauterine Applications of Materials Formed In Situ") (incorporated herein). An example uses a material called SPRAYGEL, which was developed and demonstrated to be useful for preventing intraperitoneal adhesion formation (5, 6, 7) (see Mettler et al., "Prospective Clinical Trial of SprayGel as a Barrier to Adhesion Formation: An Interim Analysis," Journal of the American Association of Gynecological Laparoscopists, (August 2003) 10(3), 339-344, incorporated herein by reference). SPRAYGEL consists of two liquids (one clear and one blue), each containing chemically different polymer precursors, which, when mixed, rapidly crosslink to form a biocompatible, absorbable hydrogel in situ. Further details regarding SPRAYGEL are provided in U.S. Patent No. 7,009,034 to Pathak et al., "Biocompatible Crosslinked Polymers" (incorporated herein by reference). While the concept of hydrogel materials for preventing uterine adhesions is known, access to this information is limited because evaluations have been conducted using compositions and devices designed for intraperitoneal applications (19, 20).The intrauterine environment presents unique challenges compared to the intraperitoneal environment, including limited space, uterine muscle contractions, exit pathways from the body, different healing mechanisms after injury, and other differences. Therefore, specific compositions and delivery devices are desirable to achieve the desired outcome for preventing uterine adhesions.

[0019] Hydrogels for medical applications Hydrogels are generally considered insoluble materials that absorb water and swell to form an elastic three-dimensional network structure. See, for example, Park, et al., Biodegradable Hydrogels for Drug Delivery, Technomic Pub. Co., Lancaster, PA (1993). Network structures crosslinked by covalent bonds of hydrophilic polymers are traditionally represented as hydrogels in the hydrated state. Hydrogel precursors are generally water-soluble polymers that become insoluble when preferably crosslinked. As described below, hydrogels are known based on a variety of chemical properties using suitable hydrophilic polymers. In some situations, swelling may refer to a continuous change in volume or weight following the initial formation of a crosslinked insoluble structure, in which case the timing is appropriately specified. The transition from a dry state to a hydrated state results in a weight increase and generally some volume increase, while the change from the initial state formed in aqueous solution to the state over time may or may not involve an increase in weight or volume over time, and may result in a decrease in some time windows.

[0020] The crosslinkable solutions for use in the methods described herein may include precursor solutions that can be used to form a hydrogel structure in situ within the lumen or cavity of a patient and that form physical crosslinks, chemical crosslinks, or both. Physical crosslinking may result from complex formation, hydrogen bonding, physical entanglement, van der Waals interactions, ionic bonding, and other interactions, and may be initiated by mixing two physically separated components until they are combined in situ by radiation irradiated to the site, or as a result of dominant conditions in the physiological environment, such as temperature, pH, ionic strength, other environmental conditions, or a combination thereof. Chemical crosslinking may be achieved by any of several mechanisms, including free radical polymerization, condensation polymerization, anionic or cationic polymerization, stepwise polymerization, or other types of chemical reactions. When two solutions are used, each solution contains one component of a co-initiation system and can crosslink immediately upon mixing. The solutions may be stored separately and mixed when delivered to the tissue lumen. Suitable applicators for precursors based on one or more precursor solutions are described in detail herein.

[0021] Hydrogels can be spontaneously crosslinked from at least one precursor without the need for a separate energy source. Such systems allow for control of the crosslinking process, for example, because a large increase in the viscosity of the material flowing through the delivery device does not occur until after the precursor comes into contact with the environment outside the applicator. In the case of a two-component system, the mixing of the two solutions is carried out so that the solutions remain fluid while passing through the device. If necessary, one or both of the crosslinkable precursor solutions may contain a contrast agent or other means for visualizing the hydrogel implant. The crosslinkable solution may contain a bioactive drug or other therapeutic compound, which is trapped in the resulting implant, so that the hydrogel implant performs a drug delivery function with gradual drug elution.

[0022] Further properties of the hydrogel system may be selected according to the intended application. For example, when a hydrogel implant is used to temporarily block the reproductive organs, such as the uterine cavity, the hydrogel system may be desirable to swell moderately to conform to irregular geometric shapes and to be biodegradable within the time frame of a single menstrual cycle. The hydrogel is preferably soft, and its modulus or rigidity is lower than that of uterine tissue in a non-pregnant uterus. More generally, the material should be selected based on its indicated biocompatibility and lack of toxicity.

[0023] Furthermore, hydrogel system solutions can be prepared without the use of harmful or toxic solvents. Generally, the solutions are substantially water-soluble and can be used in physiologically compatible solutions, such as buffered isotonic saline. Since the hydrogels can be biodegradable, the hydrogel implants do not need to be recovered from the body. Biodegradability as used herein refers to the predictable breakdown of the hydrogel into molecules small enough to be metabolized, purged, or excreted under normal physiological conditions. Biodegradability can occur, for example, by hydrolysis, enzymatic action, reversal of physical crosslinking by instilled active ingredients, or cell-mediated disruption.

[0024] Monomers and macromers for chemical crosslinking Monomers that can be crosslinked to form biocompatible implants may be used. Monomers may be small molecules, such as acrylic acid or vinyl caprolactam; larger molecules containing polymerizable groups, such as acrylate-capped polyethylene glycol (PEG-diacrylate); or other polymers containing ethylenically unsaturated groups, such as those described in U.S. Patent No. 4,826,945 to Cohn et al. ("Biodegradable Polymeric Materials Based on Polyether Glycols, Processes for Preparation Thereof and Surgical Articles Made Therefrom"), U.S. Patent No. 5,160,745 to De Luca et al. ("Biodegradable Microspheres as a Carrier for Macromolecules"), or U.S. Patent No. 5,410,016 to Hubbell et al. (hereinafter referred to as Patent No. 016) ("Photopolymerizable, Biodegradable Hydrogels as Tissue Contacting Materials and Controlled-Release Carriers"), all of which are incorporated herein by reference.

[0025] A water-soluble, polymerizable monomer having an overall functionality > 2 (i.e., forming a crosslinked network structure immediately upon polymerization) and forming a hydrogel may be referred to herein as a macromer.

[0026] Several functional groups can be used to facilitate chemical crosslinking reactions. When these functional groups are self-polymerizable, for example, ethylenically unsaturated functional groups, the macromer alone is sufficient to produce hydrogel formation when polymerization is initiated with a suitable active agent. If two solutions are used, each solution preferably contains one component of the co-initiation system and crosslinks upon contact. The solutions are stored in separate compartments of the delivery system and mixed when deposited either on or within the tissue.

[0027] A suitable initiation system for use in forming hydrogels is a combination of a peroxygen compound in one solution and a reactive ion, such as a transition metal, in another solution. Other initiation systems, such as those initiated by pH, thermally, or photochemically, may also be used. To form hydrogel implants in situ, other means of crosslinking macromers containing functionally active groups, such as amines, imines, thiols, carboxyls, isocyanates, urethanes, amides, thiocyanates, and hydroxyls, which may naturally exist in, on, or around tissues, may also be conveniently used. Alternatively, such functional groups may be provided in a second compositional component, which may be a small molecule, or in a second macromer as part of the hydrogel system.

[0028] Suitable hydrogel systems are biocompatible single-component or multi-component systems that spontaneously crosslink when activated by an initiator, a change in the environment, or by mixing two components, although when two or more components are used, they may be individually stable. Such systems include, for example, macromers, which are difunctional or polyfunctional amines in one component and difunctional or polyfunctional oxirane-containing portions in the other component. Components of other initiator systems, such as redox initiators, may also be used. Mixing two or more solutions results in either addition or condensation polymerization, which further leads to implant formation. Free radical-driven crosslinking systems that rely on thermal or photoinitiation may also be used to trigger polymerization of ethylenically unsaturated monomers or macromers to form hydrogels.

[0029] The monomers may include biodegradable, water-soluble macromers as described in Patent No. 016. These monomers are characterized by having at least two polymerizable groups separated by at least one degradable region. When polymerized in water, they form a coherent gel that persists until it is destroyed by autodegradation. In one embodiment, the macromer is formed by a water-soluble and biocompatible polymer core, such as polyalkylene oxide polyethylene glycol, which may be adjacent to hydroxy acids such as lactic acid, to which acrylate groups are bonded. Generally, the monomers are also biodegradable, biocompatible, and non-toxic, and are at least to some extent elastic after crosslinking or curing.

[0030] For some crosslinked polymers, it has been found that using monomers with longer crosslink distances generally forms hydrogels that are softer, more compliant, and more elastic. Therefore, polymers such as those in patent '016', where the length of the water-soluble segment is increased, such as polyethylene glycol, tend to have increased elasticity. Polyethylene glycol with molecular weights in the range of 10,000 to 35,000 g / mol offers particularly useful properties for such applications, but molecular weight ranges of 1,000 to 500,000 g / mol can also be useful.

[0031] Crosslinking reaction and initiation system Crosslinking reactions can occur through nucleophilic-electrophilic substitution, free radical reactions, oxidation / reduction reactions, etc. These reactions can be initiated by mixing, heat, pH changes, radiation, and / or pressure. In the one-component system described herein, body temperature or pH changes associated with tissue contact can be used as initiators, but radiation may be more effective for faster crosslinking. In the two-component systems described herein, mixing can be used to initiate well-controlled hydrogel delivery, but other initiators may be used.

[0032] Metal ions may be used as either oxidizing or reducing agents in redox initiation systems. For example, ferrous ions may be used in combination with peroxides or hydroperoxides to initiate polymerization or as part of a polymerization system. In this case, the ferrous ion functions as a reducing agent. In other previously known initiation systems, metal ions function as oxidizing agents. For example, cerium ions (cerium in its 4+ valence state) interact with various organic groups, such as carboxylic acids and urethanes, to remove electrons from the metal ion and leave an initiation radical on the organic group. In such systems, the metal ion acts as an oxidizing agent.

[0033] A thermal initiation system may be used instead of the redox system described herein. Several commercially available low-temperature free radical initiators, such as V-044 available from Wako Chemicals USA, Inc. (Richmond, VA), may be used to initiate the free radical crosslinking reaction at body temperature to form a hydrogel implant with the monomers described above. Initiators, such as potassium and sodium persulfates, and various peroxy and hydroperoxyl compounds may be used. Photopolymerization initiation systems containing UV initiators, such as Irgacure 651 (Ciba Geigy), may also be used.

[0034] In the applications described herein, crosslinking reactions are generally designed to occur in aqueous solutions under physiological conditions. Therefore, crosslinking reactions occur "in situ," that is, in localized areas such as the bodies of living animals or organs or tissues of the human body. Due to the in situ nature of the reaction, crosslinking reactions can be designed to avoid releasing undesirable amounts of heat during polymerization. Crosslinking times for the desired treatment can be set as appropriate. Some functional groups, such as alcohols or carboxylic acids, do not typically react with other functional groups, such as amines, under physiological pH (e.g., pH 7.2–11.0, 37°C). However, such functional groups can be made more reactive by using activating groups, such as N-hydroxysuccinimide. Several methods for activating such functional groups are known in the art. Suitable activating groups include, for example, carbonyldiimidazole, sulfonyl chloride, aryl halide, sulfosuccinimidyl ester, N-hydroxysuccinimidyl ester, succinimidyl ester, epoxide, aldehyde, maleimide, and imide ester. N-hydroxysuccinimide esters or N-hydroxysulfosuccinimide groups are particularly desirable for crosslinking proteins or amine-functionalized polymers, such as amino-terminated polyethylene glycol ("APEG").

[0035] Aqueous solutions of NHS-based crosslinking agents and functional polymers are preferably prepared immediately before the crosslinking reaction, due to the reaction of NHS groups with water. A longer "pot life" can be obtained by maintaining these solutions at a lower pH (pH 4-5).

[0036] The resulting crosslink density of biocompatible crosslinked polymers is controlled by the total molecular weight of the crosslinking agent and functional polymer, as well as the number of functional groups available per molecule. Lower molecular weights between crosslinks, such as 600 Da, can yield a much higher crosslink density compared to higher molecular weights such as 10,000 Da. Higher molecular weight functional polymers can generally be used to obtain more elastic gels.

[0037] The crosslinking density can also be controlled by the total solids percentage of the solution of the crosslinking agent and functional polymer. Increasing the solids percentage increases the probability that electrophilic functional groups will bond with nucleophilic functional groups before being inactivated by hydrolysis. Yet another way to control the crosslinking density is by adjusting the stoichiometry of nucleophilic functional groups to electrophilic functional groups. A 1:1 ratio yields the highest crosslinking density.

[0038] Hydrogels formed by nucleophilic / electrophilic crosslinking Hydrogels particularly suitable for the applications described herein can be delivered by less invasive means, such as small-diameter catheters. Therefore, the hydrogel itself can be thixotropic or fully formed in situ after delivery. Hydrogels of particular interest generally begin as precursors, which, when crosslinked by nucleophilic substitution, can react to form a gel. In some embodiments, the crosslinking reaction occurs more slowly under neutral conditions, but can be accelerated by adding an accelerator, such as a basic buffer. With respect to the hydrogels of particular interest herein, suitable buffers are near-neutral pH and include, for example, borates, phosphates, citrates, bicarbonates, CHES, TAPS, bicine, tris, tricine, etc. A selected hydrogel precursor may be initially mixed to have a pH different from neutral, resulting in slow crosslinking until mixed with the accelerator buffer. Other methods to trigger the polymerization reaction, such as heat or light, can also be conveniently used, provided that a suitable polymerization system and precursor are selected. For example, polyethylene glycol diacrylate or multiacrylate polymers may be used to form hydrogels using a single precursor, which can be polymerized using a thermal initiator or a photoinitiator for free radical polymerization. Generally, a two-component-based system is preferred to allow for rapid crosslinking without relying on any external energy source and without concerns about shadowing or thermal conditions or generation. Conditions can be controlled to obtain crosslinking and gel formation suitable for the delivery process using the applicators described above in relation to the delivery system. Generally, crosslinking begins within the catheter of the delivery system but does not complete sufficiently to restrict flow from the catheter into the patient's body. The hydrogel can be sufficiently crosslinked and solidified to remain in place for an appropriate period and can be sufficiently crosslinked after the completion of the delivery procedure.

[0039] Sometimes, it is useful to impart color to the hydrogel precursor by adding a coloring and visualizing agent before crosslinking. The visualizing agent can help visualize the arrangement of the hydrogel. For example, when filling a uterus, the visualizing agent helps distinguish the hydrogel from other fluids. Furthermore, the hue of a colored hydrogel can provide information about the concentration of the precursor in the hydrogel or the degree of mixing of physiological fluids into the hydrogel. Darker hydrogels may indicate a higher concentration of the precursor compared to lighter-colored hydrogels made from the same precursor solution. The coloring agent may be present in a premixed amount already selected for the application. Colors such as blue and green provide a suitable contrast to blood. Embodiments of hydrogels utilize biocompatible crosslinked polymers formed from the reaction of an electrophilic precursor with a nucleophilic precursor. The precursors are generally water-soluble, non-toxic, and bioacceptable.

[0040] Precursors can be multifunctional and increase the polymerization rate. Depending on the chemical properties of polymerization and the selected end groups, precursors may be self-reactive (e.g., with acrylate and methacrylate-based systems) or have complementary end groups that react with each other. For example, in electrophilic-nucleophilic reaction systems, precursors may contain two or more electrophilic or nucleophilic functional groups, such that a nucleophilic functional group of one precursor can react with an electrophilic functional group of another precursor to form a covalent bond. If a precursor has three or more functional groups, the precursor molecule may participate in crosslinking reactions, and generally, the hydrogel is crosslinked to a relatively high degree.

[0041] Hydrogels for use in patient tissue may contain water, a biocompatible visualization agent, and a cross-linked hydrophilic polymer that forms a hydrogel after delivery into the uterine cavity. The visualization agent may reflect light or emit light at wavelengths detectable by the human eye, so that the user applying the hydrogel can observe the gel and also estimate its volume.

[0042] The hydrogel for placement in the uterus swells moderately, to the extent that it swells enough to facilitate space filling, but not excessively so as to create uncomfortable pressure on the patient. In some embodiments, the swelling of the hydrogel can be less than 300 wt%, in further embodiments about 10 wt% to about 200 wt%, and in even further embodiments about 20 wt% to about 100 wt%. In alternative embodiments, the hydrogel may experience syneresis after initial formation, i.e., it may become smaller on a weight basis and generally smaller on a volume basis, which is conveniently referred to as negative swelling. Thus, the overall swelling can be about -25 wt% to about 300 wt%, in further embodiments about -15 wt% to 200 wt%, and in other embodiments about -10 wt% to about 100 wt%. Swelling (positive or negative) can generally be determined by the weight of the polymer after 24 hours of contact with an aqueous environment, with the aqueous solution of buffered saline absorbed by the polymer, relative to the weight of the polymer and the absorbed aqueous solution after crosslinking to an insoluble mass that forms after a few seconds. Since the hydrogel can be biodegradable, the uterine space will be cleaned after a suitable period, and the healing process will not release the hydrogel material itself. In some embodiments, the hydrogel is completely biodegraded in about 3 hours to about 21 days, in further embodiments in about 3 days to about 14 days, and in further embodiments in about 5 days to about 8 days. In some applications, such as drug delivery, it may be desirable for the hydrogel to biodegrade over a longer period, e.g., 30 days or more. Also, the hydrogel may be selected to be soft enough to be gentle on tissues, but not soft enough to be extruded from the uterus, and its persistence in the cavity is unpredictable. Specifically, the Young's modulus of the hydrogel may be approximately 1 kPa to approximately 300 kPa, in a further embodiment approximately 5 kPa to approximately 250 kPa, and in a further embodiment approximately 5 kPa to approximately 200 kPa. Those skilled in the art will recognize that additional ranges of swelling, decomposition rates and Young's moduli beyond those specified above are conceivable and within the scope of this disclosure.

[0043] Natural polymers, such as proteins or glycosaminoglycans, such as collagen, fibrinogen, albumin, and fibrin, can be crosslinked using reactive precursor species having electrophilic functional groups. Natural polymers are proteolytically broken down by proteases present in the body. The precursors may have a biologically inert and water-soluble core. When the core is a water-soluble polymer region, suitable polymers that can be used include: polyethers, such as polyalkylene oxides, such as polyethylene glycol ("PEG"), polyethylene oxide ("PEO"), polyethylene oxide-co-polypropylene oxide ("PPO"), co-polyethylene oxide blocks or random copolymers, and polyvinyl alcohol ("PVA"); poly(vinylpyrrolidinone) ("PVP"); poly(amino acids); dextran, and proteins, such as albumin. Polyethers and more specifically poly(oxyalkylene) or poly(ethylene glycol) or polyethylene glycol can provide desired properties to hydrogels.

[0044] Synthetic polymers and reactive precursor species may have electrophilic functional groups, which are, for example, carbodiimidazole, sulfonyl chloride, chlorocarbonate, n-hydroxysuccinimidyl ester, succinimidyl ester, or sulfasuccinimidyl esters. In some embodiments of particular interest, the electrophilic functional group includes N-hydroxysuccinimidyl succinate (SS) esters, which provide a desired crosslinking rate for hydrogel formation and a hydrogel degradation rate after the hydrogel is formed in vivo. The term "synthesis" means molecules not found in nature, such as polyethylene glycol. Nucleophilic functional groups may be, for example, amines, such as primary amines, hydroxyl, carboxyl, and thiol. Primary amines can be desired reactants with NHS electrophiles. The polymers may have a polyalkylene glycol moiety and may be polyethylene glycol-based in embodiments of particular interest. Polyethylene glycol-based polymer precursors may have a branched core and provide a selected number of arms, which provide multiple crosslinking functional groups. Polymers may also generally have hydrolytically biodegradable moieties or bonds, such as esters, carbonates, or enzymatically biodegradable amide bonds. Some such bonds are well known in the art and are produced by α-hydroxy acids, their cyclic dimers, or other chemical species and are used to synthesize biodegradable products, such as glycosides, dl-lactides, l-lactides, caprolactones, dioxanones, trimethylene carbonates, or copolymers thereof. In some embodiments, the reactive precursor species may each have 2 to 10 nucleophilic functional groups, and the corresponding reactive precursor species may each have 2 to 10 electrophilic functional groups.

[0045] In some embodiments, the process of mixing a mixture, or hydrophilic reactive precursor species, involves having nucleophilic functional groups and electrophilic functional groups having hydrophilic reactive precursor species, so that they form a crosslinking mixture. If the mixture reacts relatively slowly under neutral conditions, the precursors may be mixed and placed in a syringe or similar reservoir of the delivery system shortly before administration. Accelerators may be placed in another syringe or similar fluid reservoir. During delivery, the accelerator may be mixed with the precursor blend to initiate more rapid crosslinking thanks to a pH change or other favorable properties of the blend. Since the precursors can be thoroughly mixed before administration, the mixing process may be more complete in the delivery system, ensuring that a well-mixed composition is delivered into the catheter for intrauterine delivery. The hydrophilic reactive precursor species may be dissolved in buffer water so that they result in a low-viscosity solution that mixes and flows readily upon contact with tissue and is effective in casting out and filling the uterine cavity completely. The use of small molecule crosslinkers for a single precursor results in a relatively low-viscosity blend precursor before extensive crosslinking, allowing the blended hydrogel precursor to be delivered through a thin catheter while crosslinking begins and the fluid conforms to the shape of the uterine cavity, after which relatively rapid crosslinking leads to stabilization of the hydrogel in the uterus for an appropriate period.

[0046] As the precursor blend flows across the tissue, the hydrogel formed during the crosslinking process will match some deviation from the shape of small tissue features, such as ridges, gaps, and surface smoothness, although a perfect match is not required. While not limited to a specific operating theory, it is thought that reactive precursor species that crosslink appropriately and rapidly after contact with the tissue surface form a three-dimensional structure that fills the space into which they are delivered. This three-dimensional structure also works to hold the uterine wall apart to resist expulsion from the uterine cavity and prevent the formation of scar bridges, or adhesions. Over time, the hydrogel breaks down and is expelled naturally from the uterine cavity by absorption into the body or, mostly, as release through the cervix and vagina.

[0047] The preferred crosslinking time varies depending on the application. In most applications, the crosslinking reaction resulting in gelation occurs within approximately 5 minutes from the start of delivery, within approximately 1 minute in some embodiments, and within approximately 2 to 30 seconds in further embodiments. Those skilled in the art will recognize that additional ranges of gelation times beyond those specified above are conceivable and within the scope of this disclosure. These gelation times do not necessarily correspond to sufficient crosslinking that may occur over a longer period, and the gelation time corresponds to the point at which the hydrogel reaches a crosslinking point where it is no longer fluid. The crosslinking time of an in-situ system is a combination of several factors, including the relative concentration of the reactive precursor, the molar ratio of the reactive ends, the temperature, and the resulting pH after mixing. The gelation time may be altered, if present, by one or more changes in the pH, temperature, or strength of the buffer salt of the “accelerator” portion of the in-situ system.

[0048] biodegradable bond If it is desired that the biocompatible crosslinked polymer be biodegradable or absorbable, one or more precursors having biodegradable bonds may be used. The biodegradable bonds may also optionally function as one or more water-soluble cores of the precursors. Alternatively, or in addition to, the functional groups of the precursors may be selected such that the reaction products between them produce biodegradable bonds. With respect to each approach, the biodegradable bonds may be selected such that the resulting biodegradable biocompatible crosslinked polymer degrades or is absorbed over a desired period of time. Generally, the biodegradable bonds are selected so that they degrade into non-toxic products under physiological conditions.

[0049] Biodegradable bonds can be chemically or enzymatically hydrolyzable or absorbable. Enzymatically hydrolyzable biodegradable bonds, which are helpful in explanation, include peptide bonds that can be cleaved by metalloproteinases and collagenases. Biodegradable bonds, which are helpful in further explanation, include polymers and copolymers of poly(hydroxy acid), poly(orthocarbonate), poly(anhydride), poly(lactone), poly(amino acid), poly(carbonate), and poly(phosphonate).

[0050] Visualizing agent Where advantageous, biocompatible cross-linked hydrogel polymers may contain a visualizing agent to enhance their visibility during surgical procedures. Visualizing agents are particularly useful when used in minimally invasive surgical procedures (MIS) for reasons including their high visibility on color monitors.

[0051] The visualization agent can be selected from a variety of non-toxic colorants suitable for use in medical implantable devices, such as FD&C BLUE dyes 1, 2, 3, and 6, indocyanine green, or colored dyes commonly found in synthetic surgical sutures. In some embodiments, green or blue is preferred because it has good visibility in the presence of blood or against a pink or white tissue background.

[0052] The visualization agent may be present together with one or more precursors or accelerators for delivery. The selected coloring substance may or may not be chemically bonded to the hydrogel. Additional visualization agents, such as fluorescent compounds (e.g., green or yellow fluorescence under visible light) (e.g., fluorescein or eosin), X-ray contrast agents for visibility under X-ray imaging equipment (e.g., iodine compounds), ultrasound contrast agents, or MRI contrast agents (e.g., gadolinium-containing compounds), may be used. The visualization agent may also be a bioactive agent suspended or dissolved in the hydrogel matrix, or a material used to encapsulate the bioactive agent.

[0053] As mentioned above, visually observable visualization agents can be conveniently used in several embodiments. Light wavelengths of approximately 400-750 nm are observable as color to humans (RKHobbie, Intermediate Physics for Medicine and Biology, 2 nd(Ed., pages 371-373). Users may use the visualizer, for example, with a video camera used during surgical hysteroscopy, with an imaging device that detects a visually observable visualizer, or to view the hydrogel with the human eye. A visually observable visualizer is an active substance that has a color detectable by the human eye. The feature of providing an image to an X-ray or MRI machine is not sufficient to establish its function as a visually observable visualizer. An alternative embodiment is a visualizer that may not normally be visible to the human eye, but which, when used in combination with a suitable imaging device, such as a properly equipped video camera, is detectable at different wavelengths, such as infrared or ultraviolet light.

[0054] In some embodiments, the visualization agent is present in the hydrogel system while it is being applied into a cavity such as the uterus by the delivery system described herein. In such applications, the target tissue on the uterine surface is not visualized or cannot be visualized. The presence of the visualization agent during application may allow the user to detect when the cavity is sufficiently filled with material due to the presence of excess material leaving the target cavity. In the case of intrauterine applications after surgical intervention, the presence of a blue or green visualization aid allows for differentiation from excess bodily blood and fluids resulting from the surgery, as well as confirmation that application and hydrogel crosslinking have occurred.

[0055] Suitable biocompatible visualizers are FD&C BLUE #1 and FD&C BLUE #2 indocyanine green. Methylene blue is less preferred because, although it offers suitable visualization potential, it has been reported to cause allergies in gynecological procedures, or because other medically acceptable colorants and dyes provide a contrasting color to red serous blood-like fluids. One or both of these visualizers may be present in the final electrophilic-nucleophilic reactive precursor species mixture at concentrations greater than 0.05 mg / ml, and in some embodiments at least 0.1 to about 12 mg / ml, and in further embodiments in the range of 0.1 to 4.0 mg / ml, although higher concentrations up to the limit of the solubility of the visualizer may be used. These concentration ranges have been found to impart the desired color to the hydrogel (as measured by the time it takes for the reactive precursor species to gel) without interfering with the crosslinking time, and to be more radioactively stable than other visualizers such as methylene blue. The visualizer may also be a fluorescent molecule. The visualizer is generally not covalently bonded to the hydrogel. Those skilled in the art will recognize that additional ranges of visualization agent concentrations beyond those specified above are conceivable and fall within the scope of this disclosure.

[0056] In some embodiments, a hydrogel is selected and delivered to at least partially fill the uterus, and in embodiments of particular interest, the hydrogel substantially fills the uterus. Therefore, upon sufficient crosslinking, the hydrogel takes on a shape similar to the interior of the uterus. While filling the uterus, the hydrogel can form a coating on at least a portion of the intrauterine tissue. In some embodiments, the hydrogel substantially fills the uterus and comes into contact with substantially all of the tissue exposed within the uterus and cervix. The introduction of one or more fluid precursors or precursor solutions into the uterus, which may be adjusted to some extent based on swelling, to form a hydrogel with a volume essentially equal to the volume of one or more fluid precursors or precursor solutions, can come into contact with substantially all of the tissue exposed within the uterus, as the fluid conforms to the shape of the tissue. Nevertheless, it is recognized by those skilled in the art that even substantially complete contact can suffer from imperfections.

[0057] In some embodiments, the method is used to form a hydrogel on tissue until the color of the hydrogel indicates that a predetermined volume of hydrogel has been deposited on or within the tissue. The precursor is continuously introduced into the space until a suitable volume is deemed to have been achieved by the color of the material entering and flowing out of the space, as indicated by observing a visualizer placed in the flowing material. For example, two fluid precursors associated with a blue dye are introduced into and delivered into the uterus until the color of the material leaving the uterus indicates that unwanted fluid has been flushed out of the uterus and the uterus is substantially full of precursors.

[0058] Catheter system for in-situ formation of hydrogel implants The catheter systems taught herein provide desired functionality for the delivery of polymers or other fluids and for the removal of fluids for corresponding applications. In particular, the catheter systems provide desired placement of fluids such as hydrogels within the uterus and their maintenance in appropriate locations to suppress adhesion formation, but the catheter systems are also suitable for other purposes, including the movement of fluids into or out of the uterine cavity. For the average physician in the industry, the catheter systems provide a graspable structure, thereby enabling placement and operation with one hand, leaving the other hand free for other functions, but physicians with disabilities can have the catheter systems appropriately adapted to the needs of such physicians. In some embodiments, the catheter system used as an applicator incorporates a design in which compositions from separate syringes are more actively mixed and then directed into a thin tube or catheter. Improved catheter system designs may include a cervical cap fixed to a tubular element of a size suitable for placement into a catheter extending proximal (towards the physician), such that the cervical cap can be positioned adjacent to the cervix in a position that allows the catheter to extend a desired distance into the patient's uterus. The cervical cap may be left in place when the catheter is removed to avoid interfering with the hydrogel when the catheter is removed, and thereafter the cervical cap is removed leaving the filler material in the cervix to prevent adhesion formation, which can be particularly problematic at the internal os. In further or alternative embodiments, a cervical plug may be used to provide additional stabilization of the hydrogel within the uterus.

[0059] Regarding transcervical access systems useful for explanation, Figures 1A and 1B show applicators suitable for single-component hydrogel precursors or two-component hydrogel precursors, respectively. When delivering three or more components, e.g., three, four or more components, the drawings can be generalized by those skilled in the art based on these teachings. Since two-component systems are exemplified and of particular interest as commercial products, most of the following description focuses on the two-component applicator in Figure 1B, although the description can be readily generalized to other embodiments. Similarly, other fluids can be delivered in the same manner as hydrogel precursors. Furthermore, a catheter system may be used to take in fluid using the compartment of an empty syringe, which can be any composition that can be drawn into the catheter.

[0060] Referring to Figure 1A, a transcervical access system is illustrated to aid in the explanation of a protocol configured according to the principles of this specification. The transcervical access system 100 includes a single-lumen catheter 108 having a proximal end 110 and a distal end 102. The distal end 102 generally includes one or more delivery ports, as will be described in detail below. The proximal end 110 is attached to the extension element 112 through a fitting 111 such as a standard Luer lock fitting that attaches male and female elements to the single-lumen catheter 108 and the extension element 112, respectively. Generally, the transcervical access system 100 has an outflow limiter 106 along the catheter 108. The outflow limiter 106 sets the insertion depth of the catheter into the patient's body and stops outflow from the cervix while the hydrogel is being dispensed into the uterus. In some embodiments, the outflow limiter 106 is adjustable, for example, slidable, along the catheter 108, and adjusts the length of the distal catheter segment 104 relative to the adjustable outflow limiter 106. Thus, the physician can adjust the outflow limiter 106 to a desired insertion depth into the patient's body, helping to ensure uniform delivery of the hydrogel, as will be further described below. In embodiments of particular interest, the outflow limiter 106 includes a support sheath 103 and a cap element 109, as will be described in detail below, where the support sheath 103 provides a reinforcing function and can facilitate handling of the cap element 109.

[0061] As shown in Figure 1A, the distal length of the catheter 108, from the distal end of the mounting tip 102 to the proximal end of the cap element 109, can be approximately 5 cm to approximately 15 cm. In some embodiments, the distal length can be approximately 7 cm to approximately 10 cm. Similarly, as shown in Figure 1A, the proximal length of the catheter, from the proximal end of the cap element 109 to the proximal end of the attachment 111, can be approximately 4 cm to approximately 20 cm. In some embodiments, the proximal length can be approximately 7 cm to approximately 9 cm. Those skilled in the art will recognize that the selected length of the catheter and the position of the reference marker depend on various factors, such as the patient's anatomical structure, application conditions, and physician's preference, and that additional ranges beyond those specified above are possible and within the scope of this disclosure. For example, a physician may choose a longer catheter for transcervical assisted laparoscopic procedures than for transvaginal intrauterine procedures, and this preference may be accommodated by using a longer catheter length, while maintaining independently a catheter segment 104 of medically appropriate length, which may be adapted from more specific teachings on cervical approaches by those skilled in the art. With regard to commercially available devices, various catheter lengths that can be connected to the attachment 111 are generally available for selection by healthcare providers, but in some embodiments described below, the length is adjustable so that the same components may be used to provide different lengths from the closure to the distal end. The cap element 109, having a conical shape as shown or other shapes, functions as a backstop or flow limiter to prevent excess material from flowing out during hydrogel application, to fill and lightly pressurize with hydrogel like a tamponade, and to guide the healthcare professional to position it in the desired location.

[0062] The extension element 112 generally has a larger diameter and is more rigid than the catheter 108. The extension element 112 allows for easier manipulation of the catheter 108 for insertion into the patient's body and allows the physician to better position the catheter for the procedure while limiting the length of the catheter 108, which can be more difficult to manipulate if it is too long. The extension element 112 has a connector 121, for example a Luer connector, at its proximal end, which connects to the syringe 114 with a connector 123 on the syringe. The syringe 114 may be a conventional syringe with a reservoir 125 containing a hydrogel precursor and any other additives, such as one or more additives as described above. The hydrogel precursor may be delivered by pushing the plunger 127, delivering the hydrogel precursor into the catheter 108 through the extension element 112 and into the patient's body from the distal end 102.

[0063] An alternative embodiment for the simultaneous delivery of two fluids is shown in Figure 1B. The catheter 108 and the outflow limiter 106 may be the same as those in Figure 1A. The catheter 108 is connected to the Y-connector 112b at a fitting 111, such as a Luer fitting. The Y-connector 112b may include a static mixing element, such as within a tube segment 113. Alternatively, the static mixing element may be replaced by a simple tube in which mixing occurs more progressively. In either case, the mixing of the first solution 114 and the second solution 116 occurs or begins within the Y-connector 112b. The Y-connector 112b may include a mixing element in its outflow channel or in a separate section of a tube connected to the Y-structure, and the static mixing element may include a flow-changing baffle, such as a helical, plate-type or other flow divider known in the art, which induces turbulence within the tubular channel to facilitate proper mixing of the solutions. The Y-type connector 112b has a fitting 111 for attaching the catheter 108, such as a Luer connector, and connections to syringes 115 and 117, which may be retractable or not. The first solution 114 may be a first precursor or a mixture of the first and second precursors, provided that the reaction occurs without an accelerator or catalyst and not to undesirable amounts, respectively, during the relevant time scale, and the second solution may be the second precursor or an accelerator / catalyst. Syringes 115 and 117 are generally held by a molded syringe holder 118, etc., so that they can be conveniently handled by a healthcare professional during use. An optional plunger cap 120 may maintain an optional fixed ratio of solution delivery ratio. If the inner diameters of syringes 115 and 117 are the same, the movement of the plunger cap 120 delivers volumes in a 1:1 ratio, but the inner diameters may be selected to result in different volume ratios if necessary. The outer diameter of syringes 115 and 117 can be determined by tracing the inner diameter or not, depending on the thickness of the syringe wall.

[0064] An alternative embodiment of the transcervical access system 100 is shown in Figure 2. In this embodiment, the T-branch connector 122 is located proximal to the tubular segment 113 within the Y-connector 112. In some embodiments, the T-branch connector 122 may be fixed to a connector, for example, a Luer connector at each end of the three branches, while in some embodiments, the T-branch connector 122 may be molded to be integral with one or more adjacent components. Similarly, another Y-branch or other connector design may be used instead of the T-branch connector. The T-branch connector 122 may be connected to a syringe 124 or other fluid source which can provide an inert flushing fluid, such as buffered saline, to clean the catheter or to assist in the delivery of therapeutic or other desired fluids.

[0065] The transcervical access system 100 and its components may be made from a wide variety of materials that are sufficiently flexible and biocompatible, and different components may be assembled from materials suitable for that component. Some components may be readily fitted from commercially available parts. For example, silicone rubber, natural rubber, polyisoprene, butyl rubber, polyethylene, polypropylene, nylon, polyvinyl chloride, polyether block amide, polyester (such as polyethylene terephthalate-PET), polycarbonate, polyurethane, polyolefin, polysiloxane, copolymers thereof, mixtures thereof, and other similar materials are preferred. In some embodiments, the delivery system includes a soft installation tip material to reduce trauma to the uterine surface during insertion and injection of the mixed fluid, and the materials of the installation tip are further described below.

[0066] Figure 3 is a partial view of a basic tip 126 for placement tip 102. Tip 126 has an open end relative to a cylindrical catheter. The results shown in the embodiments below demonstrate that, with appropriate hydrogel fluidity, placement tip 126 can provide the desired filling of the uterus, and that its morphology and relatively large opening reduce resistance to hydrogel delivery. In alternative embodiments, the opening from the catheter may direct the hydrogel radially away from the catheter to fill the uterine volume, and in these embodiments, the distal end may be closed.

[0067] Figures 4A–G show various embodiments of the installation tip 102, which are provided with radially positioned openings along the circumference of the catheter. As shown, the positioning of the side ports may be symmetrical and opposite, extending around the radius, and / or helical, but a wide range of suitable forms may be appropriate. Those skilled in the art will understand that the port positioning shown in Figure 4 is a two-dimensional depiction of a three-dimensional installation tip. The side ports as shown represent a pattern and may be present essentially around the circumference in some embodiments, and in additional sections of the circumference in other embodiments. Figure 4A shows an installation tip provided with side ports designed as circular holes in a cross pattern. Figure 4B shows an installation tip provided with side ports designed as circular holes in an alternating cross pattern. Figure 4C shows an installation tip provided with side ports designed as circular holes in a helical pattern. Figure 4D shows an installation tip with a terminal outlet 132 and a cap 134. It is shown that the fluid 136, e.g., a precursor fluid, exits below the rim of the cap 134. The cap 134 may include a valve or an operating outlet through which the fluid 136 passes. Figure 4E shows an installation tip provided with side ports configured as a series of longitudinal slits. The ports and / or terminal outlets may have holes configured in a square, rectangular, circular, oval, diamond, triangular, or polygonal shape, or a mixture of shapes and sizes. Figure 4F shows an installation tip provided with side ports configured as a checkerboard pattern of square holes. The number, shape, size, and arrangement configuration of the side ports and terminal outlets may be selected to maintain columnar strength with respect to the catheter during insertion into the uterine cavity, while simultaneously providing a desired coating pattern on the uterine surface for the selected hydrogel precursor. Embodiments of a catheter tip provided only with an open distal end as a port are presented in the following examples, while achieving excellent filling of the uterine cavity while substantially maintaining the hydrogel within the cavity.

[0068] Figure 4G shows a mounting tip with multiple side ports arranged in a spiral configuration. From the side port 140, the diameter of the side ports and the spacing between them decrease in the proximal direction, starting from the most distal side port. In one embodiment relating to Figure 4G, the outer diameter of the mounting tip 138 is approximately 0.07 inches, and the side ports 140 are located along the distal portion. In some embodiments, the side ports 140 may be located at the most distal point, approximately 1 cm, 3 cm, or 5 cm from the mounting tip 138. In some embodiments, the length of the most distal side port 140 is approximately 0.125 inches and the width is approximately 0.625 inches.

[0069] Figure 5 shows the uterine cavity 150, the placement tip 166, the internal os 154, the cervical canal 158 with a length of approximately 4 cm, the external os 162, the cap element 170, and the catheter 174. Generally, in a particular patient, the healthcare provider knows the patient's uterine anatomical structure with reasonable accuracy regarding the length of the uterus and the length of the cervical canal, and the catheter closure can be adjusted to result in a specified distance from the posterior uterine lining to the catheter tip. The distance from the catheter tip to the posterior uterine lining after catheter placement can be about 0.25 cm to about 2.0 cm, and in further embodiments, about 0.35 cm to about 1.25 cm. A uterine sounding instrument may be used to estimate the distance using conventional procedures, and the sounding instrument may be held next to the outflow limiter to adjust the position of the cap. Those skilled in the art will recognize that additional distances beyond those specified above are conceivable and within the scope of this disclosure.

[0070] As described above, the installation tip 102 preferably provides a non-traumatic structure to the patient, which may be characterized by softness and flexibility. In some embodiments, the non-traumatic tip may be formed from an elastomer, such as silicone rubber, rubber, polyisoprene, butyl rubber, or a mixture thereof. In further embodiments, the non-traumatic tip may be a second material to the main catheter shaft material, cojoined at the distal end by high-frequency welding, melting, gluing, or other known attachment methods. In other embodiments, the non-traumatic tip includes a coating added to the end by attachment of a different material or by an overlay of a co-extruded soft, flexible material. Materials for non-traumatic tips may be characterized with respect to their softness using Shore durometer values, and may have a Shore hardness of 20 to 80, and in further embodiments, a range of 50 to 70 on the 00 scale. In embodiments where a transcervical access system may be used to extract fluid, a catheter with a harder tip may be used. Those skilled in the art will recognize that additional durometer values ​​beyond those specified above are conceivable and fall within the scope of this disclosure.

[0071] Figure 6 shows various embodiments of a cap element 109 that is shaped to serve as a backflow prevention device or cervical cap to prevent excess material from flowing out during precursor fluid delivery, and as a reference guide for the placement of the installation tip 102. In this regard, the cap element 109 of the outflow limiter 106 may be highly curved overall, without sharp edges, and have a radially widened diameter compared to the catheter 108. Figure 6 shows (A) conical, (B) teardrop, (C) oval, (D) spherical, (E) flattened hemispherical, and (F) dome-shaped cap elements. Embodiments with a dome-shaped cap element may be used to provide a concave seal against the exocervix. The outflow limiter design may be selected to perform the desired function of sealing the cervical canal 158. Generally, such an object may be circular, conical, or have one or more angled faces, ensuring a secure and tight fit within the outer opening into the cervix, and allowing for complete coating of the uterine lumen and at least the inner portion of the cervix when the hydrogel has solidified sufficiently to avoid loss in the cervix, by stabilizing the hydrogel within the enclosed volume, and allowing for filling with hydrogel, if necessary, like a gently pressurized tamponade. Thus, the cap element 109 may have a radial diameter of about 5 mm to about 1.5 cm with respect to the catheter axis, and a length of about 2 mm to about 4 cm, and in some embodiments about 4 mm to about 3 cm along the catheter axis. Those skilled in the art will recognize that additional ranges within the specified dimensional ranges are conceivable and within the scope of this disclosure. The cap element 109 may be formed from any suitable material, such as polymers, for example, polymers suitable for catheters and implantation tips.

[0072] Figure 7A shows an embodiment in which the catheter assembly 105 has a catheter 192 and an outflow limiter 106. The outflow limiter 106 includes a cap element 186 and a tubular member 188 proximal to the cap element 186. The tubular member 188 is supported by the catheter during infusion and is less flexible overall than the distal portion of the catheter 192 of the cap element 186. Figure 7A shows the assembled device, while Figure 7B shows the separated catheter 192 and outflow limiter 106. The catheter 192 includes a connector or hub 194 and the tubular element 196. The length of the catheter 192 is designed to be inserted into the uterine cavity with the cap element 186 in contact with the external opening into the cervix, called the external or external os. The tubular member 188 may have an adjustable position when assembled to match the overlap of all or part of the length of the tubular element 196 from the cap element 186 to the connector 194. Furthermore, the tubular element 196 may be uniform or non-uniform along its length with respect to its structure and / or composition. As described above, the catheter tip may be very soft to avoid tissue damage during hydrogel infusion, however, a very soft polymer may make applicator handling more difficult if incorporated along the entire length of the tubular element 196. In some embodiments, the tubular element 196 includes a distal port 184, including the tip in some embodiments, and a proximal portion 183 that is harder than the distal portion 185, indicated by a dashed line for dividing these regions. Optional positions for separating the harder proximal region are further described below. The proximal portion 183 may be formed from a section of tubing that covers and secures the upper side of the catheter, a change in the catheter material, and / or thickening of the catheter wall. Embodiments with a more rigid proximal section 183, as shown in Figures 7A and 7B, provide the user with greater stability when instrumenting the device in the cervix.

[0073] Referring to Figure 7A, the proximal end of the cap element 186 is attached to a tubular member 188 to provide an outflow limiter 106, as shown in the separated configuration in Figure 7B. In the assembled configuration of Figure 7A, the tubular member 188 externally reinforces at least a portion of the length of the catheter 192 proximal to the cap element. The tubular member 188 also allows the outflow limiter 106 to be grasped to facilitate the procedure. The length of the tubular member 188 can be about 5 cm to about 20 cm, about 6 cm to about 19 cm in further embodiments, and about 7 cm to about 18 cm in some embodiments. Those skilled in the art will recognize that additional ranges of lengths beyond those specified above are conceivable and within the scope of this disclosure. The outflow limiter 106 is typically engaged to cover a portion of the catheter 192, as shown in Figure 7A, for insertion of the catheter into the patient's body. The outflow limiter 106 allows the user to adjust the position of the cap element 186 to give a distal catheter length value within the ranges specified above. In some embodiments, the tubular member 188 can introduce frictional interaction with the catheter surface internally to prevent unintended movement of the outflow limiter 106. The user can set the position of the outflow limiter 106 and maintain its position along the catheter 192 by avoiding unintended sliding of the tubular member 188. In other embodiments, the position of the cap element 186 can be adjusted and / or maintained between the catheter 192 and the outflow limiter 106 by a clip, ridge, etc., that engages with a flange on a pair of elements. Since the cap element 186 is fixedly attached to the tubular member 188, the design of the tubular member 188 prevents accidental loss of the cap element 186.

[0074] Figure 8A shows a specific embodiment of the catheter assembly 193, including the catheter 197, the outflow limiter 195, and the connector 194. Figure 8B shows a magnified cross-section of the portion of Figure 8A indicated by the dashed rectangle. Figure 8C shows an exploded view of the catheter assembly 193. The catheter 197 includes a core tube 191 and an overtube 192, both of which engage with and are secured to a connector 194, which may be a female Luer connector or the like. When assembled, the catheter 197 has a distal section with a smaller diameter than the proximal section due to the presence of the overtube. The connector 194 can be secured by adhesive, thermal bonding, crimping, or a combination thereof, as long as the central lumen remains open. The overtube 192 can be held in place by simply securing it to the connector 194, or similarly by thermal bonding, adhesive bonding, or other preferred techniques to the core tube 191. The overtube 192 may provide rigidity to the proximal end of the catheter 197 and provide frictional engagement to the outflow limiter 195. The overtube 192 may be made of a thicker and / or harder material than the core tube 191. In some embodiments, the length of the overtube 192 may be about 5 cm to about 20 cm, in further embodiments about 6 cm to about 19 cm, and in some embodiments about 7 cm to about 18 cm. Those skilled in the art will recognize that additional ranges of lengths beyond those specified above are conceivable and within the scope of this disclosure.

[0075] Referring to Figure 8C, the outflow limiter 195 includes a conical cap element 198 and a tubular member 199. The conical cap element 198 is attached to the tubular member 199 by adhesive or other suitable fastening modality. Referring to Figure 8B, the conical cap element 198 has a cavity with a distal diameter 200, a proximal diameter 201, and a stepped reduction section 202. The stepped reduction section 202 reduces the diameter of the cavity within the conical cap element. The stepped reduction section 202 provides a mechanical stop to prevent the outflow limiter 195 from sliding in the direction more proximal to the overtube 192. The conical cap element 198 has a narrow stenosis at its distal end, which frictionally connects to and grips the catheter 197, thereby restricting the movement of the outflow limiter 195 along the catheter. Therefore, although its position can be selected by a medical professional, friction with the overtube 192 can itself provide the desired limitation on the relative movement of the outflow limiter 195.

[0076] Figure 9 shows an embodiment in which the catheter assembly 193 has an outflow limiter including a cap element 204, which is inflatable like a balloon and filled with gas or fluid through a port 205 to be customized to a size that fits desirablely within the neck. In some embodiments, the fluid may be air, saline solution, or other fluid. The port 205 may have a termination, such as a Luer connector, for attachment to a device, to deliver and / or remove the fluid. In some embodiments, a syringe or the like may be used to inflate the cap element 204 through the port 205, for example, through a Luer connector, to achieve a desired volume. Generally, the port 205 is connected to the cap element 204 by a balloon lumen. For example, as shown in cross-section in the inset of Figure 9, a tubular member 207 may have a balloon lumen 209 while providing a slidable engagement over the upper side of the catheter 208. Generally, the balloon lumen may have any form known in the art, concentric or non-concentric, as shown, for example, in the inset of Figure 9. In some embodiments, after the hydrogel is placed, the cap element 204 may be deflated through the port 205 to facilitate the removal of the tubular member 207. The tubular member 207, together with the port 205, may allow the catheter 208 to slide down, enabling the removal of the catheter 208 while the cap element holds the tubular member 207 engaged with the external os. In some embodiments, deflation may be performed using a syringe or other negative pressure device.

[0077] In some embodiments, it may be desirable to deliver a plug into the cervix to assist in controlling the stabilization of the hydrogel delivered into the uterus and the internal cervical os of the cervix. Referring to Figure 10, the plug 210 may have an internal lumen that allows it to slide over the upper side of the catheter 212. The cervical plug 210 may be positioned in the cervix before the delivery of the hydrogel precursor into the uterus, and the cervical plug 210 may be left in place after the catheter is removed. The cervical plug 210 may swell upon contact with moist tissue, and the expansion of the cervical plug may help maintain the plug's position when the catheter is removed. Alternatively, or in addition to this, the cervical plug may be held in place by a healthcare professional when the catheter is removed.

[0078] It may be desirable to control fluid delivery using both a cervical plug and an outflow limiter. In particular, an outflow limiter can facilitate proper placement of the plug and maintenance of the plug during fluid delivery. Referring to Figure 11, the catheter assembly 193 includes a catheter 212, an outflow limiter 214, and a plug 210. The plug 210 is positioned to abut against a cap element 216, allowing for proper placement of the cervical plug 210 when the cap element is positioned at the external os of the cervix. If necessary, the cervical plug 210 may be connected to a tether 211 to facilitate removal of the plug 210.

[0079] The cervical plug 210 may have a shape selected based on its purpose. Figure 12 shows, but is not limited to, some representative examples of plug shapes. Any reasonable shape may be selected as it serves the purpose of preventing discharge. Figure 12A shows a cylindrical shape, which matches the natural shape when swollen. Figure 12B shows an oblong shape of the plug 210, which may present some limitation of insertion beyond the external os of the cervix, but then the shape helps to keep it in place. Figure 12C shows a capped end shape, which, like a capping element, is shaped to engage with the internal os of the cervix, allowing the capped end to guide the insertion of the catheter to the desired depth without the use of a separate discharge limiter. The capped end may facilitate the later removal of the cervical plug if necessary. Figure 12D shows a cervical plug composed of a pair of separate materials M1 at the ends and a central material M2, where M2 may swell but M1 may not swell as much, or vice versa. Generally, the cervical plug is known to have any reasonable shape that resists expulsion.

[0080] The cervical plug 210 may or may not be biodegradable. If the cervical plug is not biodegradable, it may be removed by the patient or healthcare worker at some appropriate point in the future, for example, by using a tether 211 (see Figure 11). Similarly, the cervical plug 210 may or may not swell significantly. Embodiments of swelling may be achieved using a hydrogel. The cervical plugs may be pre-fabricated and dried into a xerogel for delivery, or they may be delivered in a slightly hydrated form to provide the desired elasticity. Biodegradable and non-biodegradable hydrogels and other polymers are described above and can be applied for use in plugs. In some embodiments, the hydrated cervical plug may have a length of about 1.05 cm to about 4.0 cm, and in further embodiments, 1.25 cm to about 3.5 cm, and an average diameter of about 4.5 mm to about 9 mm, and in further embodiments, about 5 mm to about 8 mm, and a maximum diameter of about 5 mm to about 12 mm, and in further embodiments, about 5.5 mm to about 10 mm, relative to the axis of the central lumen, at the time of delivery. The cervical plug is generally prefabricated as a whole, while the hydrogel may provide desired features that other soft materials may prefer. Swelling from the initial state, which may be positive or negative, may range from -50 wt% to about 1000 wt%, in further embodiments about -25 to about 300 wt%, and in other embodiments about -10 wt% to about 200 wt%. Swelling is evaluated at 24 hours in buffered saline solution relative to the cervical plug as delivered. Those skilled in the art will recognize that additional ranges of the dimensions and swelling of the cervical plug described above are conceivable and within the scope of this disclosure.

[0081] treatment As described above, transcervical access systems comprising the catheter systems described herein can be effectively used for the delivery and / or removal of fluids from the uterine cavity. The transcervical access systems in the various embodiments described above are particularly effective for the delivery of hydrogels. Therefore, there is extensive discussion regarding the delivery of hydrogels. Various applications for the delivery of other fluids are also described. Fluid removal can be helpful for specific goals or other procedures, such as the removal of fluids before hydrogel delivery, or the removal of fluids delivered into the uterine cavity following the use of fluids.

[0082] Figure 13 illustrates the procedure for transcervical placement of a hydrogel into the uterus. A vaginal speculum 220 is inserted into the vagina 222 to dilate it. The placement tip 228 of the catheter 230 is guided into the uterus 226 through the vagina 222 and cervix 224. The placement tip 228 is flexible at its distal end, thereby allowing it to adapt to the shape of the uterus 226 and reducing the risk of trauma. A cap element 232 is positioned at a distance from the distal end of the placement tip 228 to limit the insertion depth of the placement tip 228 into the uterus. In one embodiment, the cap element 232 is adjusted to an appropriate distance from the distal end of the placement tip 228 so that the physician can comfortably manipulate the syringe when the placement tip 228 is positioned with the cap element 232 adjacent to the opening into the cervix, with the tip appropriately spaced away from the posterior wall of the uterus. In some embodiments, the cap element 232 is part of an adjustable outflow limiter (see Figure 7B, element 190). In some embodiments, the catheter 230 with the cap element 232 is placed in the uterus 226 by a physician with the syringe assembly 233 not attached, and then in the next step, the syringe assembly 233 is attached to the catheter 230, for example, via a Luer connector 226. In some embodiments, a standard empty syringe may first be placed on the Luer connector 226 to draw fluid from the uterine cavity, and following the completion of the removal of this fluid, the syringe may be removed and replaced with the syringe assembly 233. Such stepwise procedures may facilitate insertion and use by a single user. As described above, in suitable embodiments, the cap element may be adjusted and / or fixed in a position along the length of the catheter by manually adjusting the proximal end of the outflow limiter. When positioned adjacent to the opening to the cervix, the cap element 232 may function to seal the uterine cavity by being completely filled and coated with hydrogel. This provides physicians with a means to prevent leakage of the hydrogel injected at the external cervical os.Furthermore, in some embodiments, if the cap element 232 is inflatable, it may be further adjusted to fit into the neck by filling it with a fluid, such as a gas or liquid.

[0083] In any embodiment of the cap element, distance markers along the catheter may help position the cap element 232 at a suitable location for inflation. After the insertion tip 228 and the cap element 232 are positioned as desired, the syringe assembly 233 is used to introduce one or more precursors and, where appropriate, an accelerator solution into the Y-connector (optionally including a static mixing element) to provide a mixed hydrogel-forming composition before entering the catheter 230. The mixed fluid remains sufficiently fluid until they exit the insertion tip 228 and subsequently further polymerize and / or crosslink to form a hydrogel 238 that occupies the uterine cavity. In some embodiments, the injection is continued without stopping until completion to prevent occlusion of the catheter 230 and / or insertion tip 228 due to hydrogel formation. In some embodiments, the syringe assembly 233 includes a plunger cap to facilitate the appropriate volume ratio dispensed from two syringes.

[0084] An outline of procedures particularly suitable for applications using hydrogel compositions and transcervical delivery into the uterus is presented below. As described above, the hydrogel precursor and any auxiliary compositions may be delivered together with one, two, or three or more reservoirs, e.g., syringes. The compositions may or may not be premixed before use and immediately before being placed in the syringe. In some embodiments, the syringe may be filled remotely for use, or the syringe may be filled for use from one or more storage solutions without using a combination of compositions, although volume adjustment is made possible. Generally, the liquid injected, e.g., the hydrogel precursor, may be 2cc to 30cc, in further embodiments 3cc to 20cc, and in some embodiments 5cc to 12cc. Those skilled in the art will recognize that additional ranges of volumes beyond those specified above are conceivable and within the scope of this disclosure. When a single syringe is used for the delivery of the hydrogel precursor, crosslinking may be controlled by mixing time, by the use of external radiation, e.g., UV light, by contact with water, by body temperature from the patient, by pH changes, or combinations thereof. If multiple syringes are used, various reagents can be appropriately divided for mixing during delivery. As described above, the hydrogel can be formed from various combinations of one or more precursors, either the polymer itself or otherwise, and accelerators, catalysts, initiators, activators, etc., can be optionally used. Generally, any reasonable combination of hydrogel components / reagents can be adapted to the applicator.

[0085] In some embodiments, it is assumed that two hydrogel precursor components are mixed in an applicator structure before delivery to a catheter and delivered from a dual syringe applicator. One of the solutions or multiple solutions to be mixed may contain a visualization agent. If the syringe is not connected to a fitting, in a suitable embodiment, the syringe may be connected once filled as desired, where appropriate.

[0086] The following delivery methods can conveniently be used in two syringe formats to form an intrauterine hydrogel barrier: 1) Prepare each syringe with the desired liquid composition. 2) Attach a Y-type connector to each syringe. 3) Load the syringe into the syringe holder. 4) Place the plunger cap on the end of the syringe. 5) Based on the patient's determined anatomical structure, position the outflow limiter at the correct depth on the catheter shaft, and once the outflow limiter is in contact with the cervical external os, position the distal catheter tip approximately below the floor of the uterine cavity. 6) Attach a syringe equipped with a Y-type connector to the catheter. 7) Insert the catheter into the uterus via the cervix until the flow limiter touches the external os. (Note that steps 6) and 7) can be reversed if necessary.) 8) While gently pressing the flow limiter against the cervix, continuously deliver the hydrogel by pressing the applicator cap with relatively constant force until the syringe is empty. 9) Wait up to 10 seconds, then gently remove the catheter, leaving the outflow limiter and / or cervical plug in place. 10) After the catheter has been safely removed, the outflow limiter may be carefully removed if used, and if a cervical plug is present, it may be left in place. A short waiting period after catheter removal to remove the outflow limiter may or may not be desired.

[0087] Once the syringes are prepared, they can be attached to a Y-type connector, generally using a standard connector, such as a Luer connector, as described in step 2 above. To enable convenient delivery, in some embodiments, the syringes are generally placed in a syringe holder (as described in step 3 above)) to allow for one-handed handling, and the plunger caps may be positioned to allow for simultaneous, uniform delivery of liquid from both syringes, possibly using one hand. The applicator tip can be inserted into the patient's body to a desired depth, which may be marked by a cap element, etc. If necessary, the applicator tip may be positioned before the syringe is fully connected.

[0088] With the applicator tip in place, the uterine cavity may optionally be flushed to remove blood, fluid, and possibly other material remaining from the procedure. For example, a syringe containing a flushing solution such as buffered saline or other desired fluid may be attached to the connector of the applicator tip for flushing. While the use of the applicator tip may be preferable, flushing may be performed using a different channel, possibly before the applicator tip is positioned. Flushing may be performed with a selected amount of fluid or may be continued until the space appears to have been cleaned by the release. Optionally, a syringe may be used to withdraw the flushing solution along with any other material from the patient.

[0089] When the hydrogel precursor is ready for delivery into the uterine cavity, the Y-connector can be attached to the connector on the applicator tip (step 6). In alternative embodiments, if the applicator tip is not used for flushing, the Y-connector can be attached to the applicator tip before placing the applicator tip into the patient's body. Thus, the hydrogel precursor is delivered into the patient's body (step 7). Since the syringe cap is generally pressed relatively continuously, excessive crosslinking does not occur within the applicator tip, but strict continuous delivery is not required. The delivery rate can be nearly constant, but again, this is not essential, or even desirable if the force for delivery changes as the cavity fills. In some embodiments, it is desirable to start the delivery of the hydrogel before a pot life of more than 60 minutes. In alternative hydrogel formulations, this time can be modified, and in some embodiments, the hydrogel can be stable for a reasonable shelf life significantly longer than the treatment time.

[0090] Fluid delivery may continue until pressure from the uterus pushes back against the cap element. This pushback indicates that the uterine cavity is full of fluid. Once the cavity is full, the infusion may be stopped, or a selected amount of overfilling may be introduced to generate mild pressure, resulting in a tamponade-like filling within the uterine cavity. This may be desired in procedures including intrahysterectomy, which may leave an open venous channel that continues to bleed postoperatively. After stopping delivery, it is desirable to wait a short period to allow crosslinking and gelation to occur. After waiting for an appropriate period, such as at least 10 seconds and less than 5 minutes, the applicator tip is removed (step 9). Generally, the outflow limiter is kept in place with the cap element in place, so that catheter removal does not significantly pull the hydrogel with it. If a cervical plug is used, this is also left in place. Once the catheter has been removed, the cap element may also be carefully removed, leaving the cervical plug, if used. In a well-crosslinked state, the amount of hydrogel lost from the uterine cavity should be minimal, if any. The integrity of hydrogel delivery can be verified using ultrasound.

[0091] For intrauterine applications, hydrogel systems may be suitable for transcervical delivery, and hydrogels may function as materials that reduce or eliminate tamponade and adhesion formation. The design of hydrogel properties to facilitate these functions is described herein, and delivery procedures using applicators are described below.

[0092] With appropriately selected hydrogel properties, the hydrogel was observed to conformally fill the uterine space. It was also observed that the horns were filled up to the fallopian tube openings, but the fallopian tubes remained without hydrogel. The use of an overflow limiter and / or cervical plug helps reduce the desirability of withdrawing the catheter during an infusion event to prevent the barrier from passing through or being removed at the exit of the device.

[0093] The length, inner diameter, outer diameter, and material of the catheter vary depending on the access conditions, and the following discussion is generally applicable to any of the procedures described herein unless otherwise specifically indicated. The catheter, including the implantation tip, needs to be of an appropriate size to facilitate delivery, have a low profile, and cause an acceptable level of low trauma when inserted and advanced to the treatment site. In embodiments preferred for the formation of hydrogel implants in the uterus, the implantation tip has a distal outer diameter of about 1 mm to about 3 mm to allow delivery through the cervix. The proximal outer diameter of the catheter may be about 2 mm to about 6 mm, about 2.5 mm to about 5 mm in further embodiments, and about 2.5 mm to about 4.5 mm in further embodiments. The catheter length from the distal tip to the connector may be about 14 cm to about 30 cm, about 15 cm to about 28 cm in further embodiments, and about 16 cm to about 26 cm in other embodiments. In some embodiments, the catheter OD needs to be practically small to reduce the size of the removal trajectory after the formation of the cross-linked gel in the uterus. In other embodiments, the distal profile of the catheter to be positioned in the neck should be 9 Fr or less, 8 Fr or less in some embodiments, and 3 Fr to 7 Fr in further embodiments. Those skilled in the art will recognize that additional length and diameter ranges within the specified diameter ranges described above, such as 6 Fr, 5 Fr, and 4 Fr, are conceivable and within the scope of this disclosure.

[0094] Hydrogel deployment is often performed by tactile means without visualization, but visualization can be made possible under ultrasound by adding a visualization agent, such as microbubbles, or under X-ray guidance by adding a radiopaque-proofing agent. In embodiments of particular interest, the hydrogel composition has a coloring agent to facilitate visual observation, as further described in the description of the hydrogel. If necessary, the treatment space may be filled with or flushed with a solution, such as inert saline, to remove blood and other biofluids from the treatment space before delivery of the hydrogel. The applicator described in the drawings may optionally include an additional lumen to allow the flushing solution to exit the treatment space. Alternatively, a non-inert solution, such as a drug solution, may be delivered into the treatment space.

[0095] Figures 14–17 illustrate transcervical procedures using various embodiments of the improved procedure based on the transcervical access system design described herein, with Figure 14 relating to a removable outflow limiter, Figure 15 relating to the use of a cervical plug, Figure 16 relating to the use of both a removable outflow limiter and a cervical plug, and Figure 17 relating to a cervical plug with a tether or grip that allows removal of the cervical plug at a selected future point in time. These drawings are presented as procedure flowcharts, with the procedure flow proceeding from top to bottom.

[0096] Referring to Figure 14, in this embodiment, the transcervical applicator takes the form of an applicator 250, which is shown with an outflow limiter 252 attached to a catheter 254 positioned to be inserted 260 into the uterus 258 in the uterine cavity 259, passing through the cervical outer os 256 and the cervical inner os 258. Following insertion 260, as shown in the second drawing of Figure 14, a cap element 255 is positioned at the cervical outer os 256 and the catheter 254 is in the uterine cavity 259. A hydrogel precursor is injected into the uterine cavity 264, filling the cavity with hydrogel 266. The catheter 254 is then removed 268, as shown in the fourth drawing of Figure 4, leaving the outflow limiter 252 with the cap element 255 at the cervical outer os 256. With the outflow limiter 252 removed, the last figure in Figure 14 shows the uterus 258 filled with hydrogel 266 extending beyond the internal cervical os.

[0097] Referring to Figure 15, the top first figure shows an applicator 280 with a cervical plug 282 attached to a catheter 284 positioned for insertion through the external os 286 of the cervix into the uterus 288 within the uterine cavity 290. Following insertion 294, the second figure in Figure 15 shows the catheter 284 with its tip in the uterine cavity 290 with the cervical plug 282 in the cervix beyond the external os 286. Following the injection 298 of a hydrogel precursor into the uterine cavity, the hydrogel 300 fills the uterine cavity 290 up to the cervical plug 282. The catheter 284 is then removed from the uterus 288 304, leaving the cervical plug 282 in place.

[0098] Referring to Figure 16, the upper figure shows an applicator 310 comprising an outflow limiter 312 and a cervical plug 314 distal to the cap element 315 of the outflow limiter 312, which is fitted over the upper side of a catheter 316 positioned to be inserted into the external os of the cervix into the uterus 320 in order to position the catheter tip in the uterine cavity 322. Following insertion 326, the second figure in Figure 16 shows the tip of the catheter 316 in the uterine cavity 322 with the cervical plug 314 in the cervix and the cap element 315 positioned at the external os of the cervix. Following the injection of the hydrogel precursor 330, the third figure in Figure 6 shows the hydrogel 332 in the uterine cavity 322 up to the cervical plug 314. Following the removal of the catheter 316 from the uterus 320 334, the hydrogel 332 fills the uterus, the cervical plug 314 is in place within the cervix, and the outflow limiter 312 is positioned with its cap element at the external os of the cervix. Following the removal of the outflow limiter 312 336, the final figure in Figure 16 shows the uterus 320 filled with hydrogel 332 with the cervical plug 314 still in place.

[0099] Referring to Figure 17, the upper diagram shows an applicator 340 containing a capped cervical plug 342 in a catheter 344 positioned to be inserted through the external os 346 of the cervix to the uterus 348 in the uterine cavity 350. Upon insertion 352, the second diagram shows the tip of the catheter 344 in the uterine cavity 350 with the cervical plug having passed through the cervix and its capped end at the external os of the cervix. Upon delivery of the hydrogel precursor 353, as shown in the third diagram of Figure 17, the hydrogel 351 fills the uterine cavity 350. Upon removal of the catheter 344 354, the fourth diagram of Figure 17 shows the hydrogel 351 filling the uterine cavity 350 with the capped cervical plug 342 remaining in place.

[0100] As described above, the transcervical access systems described herein can more commonly be used for fluid delivery. For example, a transcervical access system may be used for saline delivery as part of a sonohysterography procedure. If necessary, different tip structures, such as the arrangement of one or more infusion ports, may be selected in the appropriate location. With the transcervical access systems described herein, physicians may have various options for infusing fluids, such as saline. For example, after fluid delivery, the catheter may be removed, leaving the limiter in place, which may be easier to maintain in place than the entire catheter assembly. In further or alternative embodiments, therapeutic fluids may be delivered.

[0101] In an equivalent configuration, a catheter assembly with suction force may be used to remove endometrial tissue of a lesion by fluid and / or cell examination.

[0102] Drug delivery In many applications, the hydrogel applied in contact with the patient's tissue may contain a bioactive agent. Intrauterine drug delivery routes offer several potential advantages. Firstly, the uterine and vaginal linings are less prone to local irritation than the mucous membranes of the cheeks or eyes, due to their proximity to the depot. Secondly, intrauterine enzyme activity is significantly lower than that of the gastrointestinal route. Thirdly, intrauterine routes can avoid the metabolic losses due to first-pass administration seen in oral administration routes, improving the bioavailability of the drug and potentially reducing the required dose. Furthermore, the uterine cavity provides a cecum, which, unlike the gastrointestinal tract with its continuous flow, can be filled. Like any topical delivery device, intrauterine therapeutic targets generally benefit greatly from improved treatment with reduced systemic effects resulting from higher doses of traditional administration routes. The use of hydrogels formed in situ for drug delivery is described in U.S. Patent No. 9,125,807 to Sawhney, et al., "Adhesive Hydrogels for Ophthalmic Drug Delivery" (incorporated herein). Hydrogels can also be improved with respect to imaging, as described in U.S. Patent No. 8,383,161 to Campbell, et al., "Radiopaque Covalently Crosslinked Hydrogel Particle Implants" (incorporated herein).

[0103] Cross-linked hydrogel materials can conveniently be used for topical or systemic drug therapy by intrauterine administration. Bioactive agents or drug compounds that can be added and delivered from the cross-linked polymer or gel include, for example: proteins, glycosaminoglycans, carbohydrates, nucleic acids, and other inorganic or organic bioactive compounds, where specific bioactive agents are not limited to: enzymes, anti-infective agents, antifungal agents, anti-inflammatory agents, antitumor agents, local anesthetics, analgesics, hormones, angiogenic agents, angiogenic inhibitors, growth factors, antibodies, neurotransmitters, psychotropic agents, anticancer agents, chemotherapeutic agents, drugs affecting fertility, genes, oligonucleotides, or combinations thereof. In some embodiments, the type of treatment targets medical conditions relating solely to women's health; these may be local conditions within the uterus itself, and / or health conditions that can be treated by transmucosal transport into the systemic circulation within the uterus, such as hormone therapy for postmenopausal women.

[0104] To prepare a crosslinked hydrogel composition, the above-mentioned bioactive compounds can be mixed with a crosslinkable polymer precursor before preparing an aqueous solution or during the sterile production of the functional polymer. This mixture can then be mixed with a crosslinking agent or a second precursor solution, for example, during delivery, to produce a crosslinked material containing the bioactive substance. Functional polymers made from inert polymers, such as Pluronic, Tetronics, or Tween surfactants, may be used for the release of small molecule hydrophobic drugs.

[0105] In some embodiments, one or more activators are segregated in a separation phase, which is mixed with the precursor or other reagents when the crosslinking agent and the crosslinkable polymer react to form a crosslinked hydrogel. This segregation limits or prevents the involvement of bioactive substances in chemical crosslinking reactions, such as the reaction between ester groups and amine groups. The separation phase may also help to control the release kinetics of the activators from the crosslinked product or gel, where the “separation phase” may be an oil (oil-in-water emulsion), a biodegradable excipient, and the like. Biodegradable excipients that may contain an activator include encapsulating excipients such as fine particles, microspheres, microbeads, and micropellets, where the activator is encapsulated in bioerodable or biodegradable polymers, such as poly(anhydride), poly(hydroxy acid), poly(lactone), poly(trimethylene carbonate), poly(glycolic acid), poly(lactic acid), poly(glycolic acid)-co-poly(glycolic acid), poly(orthocarbonate), poly(caprolactone), crosslinked biodegradable hydrogel network structures such as fibrin glue and fibrin sealant, caged and entrapping molecules such as cyclodextrin, and polymers and copolymers such as molecular sieves. Microspheres made from polymers and copolymers of poly(lactone) and poly(hydroxy acid) are particularly suitable as biodegradable encapsulating excipients. The use of therapeutic microspheres for in-situ-forming hydrogels is described in U.S. Patent Application Publication No. 2016 / 0166504 to Jarrett et al., "Hydrogel Drug Delivery Implants" (incorporated herein).

[0106] When using a crosslinked composition for drug delivery as described above, the amounts of the crosslinkable polymer, crosslinking agent, and dosage agent introduced into the host are selected depending on the specific drug and the conditions being treated. In one embodiment, a crosslinked topical barrier is formed in situ, for example, by an electrophilic-nucleophilic reaction, where two mixed precursors are simultaneously injected into the uterine cavity and widely dispersed before the gelation and crosslinking of the topical barrier. The therapeutic agent can then be dispersed within the crosslinked topical barrier.

[0107] Controlled drug delivery rates can be achieved using this hydrogel system by attaching bioactive molecules to a cross-linked hydrogel network structure through degradability and covalent bonding. By using composites fabricated from a range of hydrolysis times, the controlled release profile can be extended to a longer duration.

[0108] In particular, in intrauterine delivery, the bioactive agent may include an anti-infective or antifungal agent for the treatment of uterine infection, where the efficacy of the bioactive agent is enhanced due to its proximity to the local target. In some cases, prophylactic deployment of anti-infective agents may be necessary during high-risk procedures or in high-risk immunocompromised populations. Anti-inflammatory agents, such as NSAIDs (e.g., ibuprofen) or corticosteroids (e.g., prednisone), are another type of agent that may be used to treat conditions such as endometriosis, without the systemic side effects associated with the long-term consumption of these agents. In other embodiments, as an adjunct barrier, a hydrogel containing an antibacterial or antiviral agent is applied to the susceptible cervix to prevent infection-induced preterm birth. A range of antibiotics are known in the art and can be delivered by being included in the hydrogel.

[0109] The delivery of hormones and other active ingredients can benefit from local intrauterine delivery, ranging from the treatment of endometriosis and contraception to hormone replacement therapy (HRT) in postmenopausal women. Oral contraceptive use is associated with an increased risk of thromboembolism and breast cancer. Less harmful side effects of oral contraceptive use, such as mood swings, weight gain, intermenstrual bleeding and petechiae, and decreased libido, can lead to inconsistent oral administration or discontinuation, resulting in a failure rate as high as 5% during the first year of oral contraceptive use. At another stage of the life cycle, oral HRT in postmenopausal women is associated with an increased risk of coronary heart disease, stroke, and venous thromboembolism, as well as an increased risk of breast cancer with longer treatment duration.

[0110] An intrauterine device (IUD) is a mechanical device that can deliver hormones slowly and directly to the uterus. Mirena (a commercially approved levonorgestrel-releasing IUD) is approved for delivery and effectiveness lasting up to 5 years. IUDs offer the advantage of long-term local delivery of progesterone or levonorgestrel through a reservoir integrated into the arm of the T-shaped device. While IUDs have been clinically demonstrated to have fewer side effects associated with lower systemic uptake of hormone therapy, they still carry risks of irregular bleeding, perforation, and bacterial / fungal colonization as a result of the mechanical nature and design of the device.

[0111] In one embodiment, application involves the delivery of an in-situ forming hydrogel having an excess of hormones ranging from 10, 20, 30 to over 50% suspended in a premixed hydrogel precursor component of an applicator system. Sustained hormone delivery is achieved by the low solubility of these drugs, enabling long-term direct delivery to the uterus for the treatment of conditions such as endometriosis. In HRT, higher hormone doses suitable for contraception or the treatment of endometriosis may have adverse side effects even when delivered directly to the uterine space. In other embodiments, where precise delivery control is required, low-sustaining levels of hormone therapy can be achieved by secondary encapsulation of the hormones and suspension of the encapsulated active ingredient in a premixed precursor component of an applicator system for delivery. In some embodiments, secondary encapsulation may use non-erosive materials to achieve delivery times for even longer treatments; these non-erosive particles are released when the hydrogel matrix is ​​broken down and reabsorbed, and then released by normal excretion.

[0112] Endometrial cancer begins in the layer of cells that make up the uterine lining (endometrium). Endometrial cancer is sometimes called uterine cancer. Other types of cancer can form in the uterus, including uterine sarcomas, but they are much less common than endometrial cancer. Treatment plans for endometrial cancer include surgical removal of the uterus, fallopian ducts, and ovaries. In more advanced stages, radiotherapy may be used in combination with chemotherapy and / or hormone therapy. Local administration of chemotherapy is used in combination with radiotherapy or systemic chemotherapy to improve patient outcomes.

[0113] In other embodiments, the application of hydrogel to the uterine cavity utilizes the high-density angiogenesis of the uterus, primarily the uterine veins, to deliver the active ingredient systemically. Active ingredients delivered via the uterus avoid the first-pass effect, where the total oral bioavailability of the drug may be reduced due to absorption into the hepatic portal system and metabolism by the liver, leading to an overdose before achieving the therapeutic effect. For some active ingredients, oral delivery is not an option at all due to the complete loss of the drug in the first-pass effect. In other cases, oral administration results in side effects associated with repeated dosing.

[0114] Bisphosphonates, a type of drug used to treat osteoporosis, are associated with gastrointestinal disorders, inflammation, and esophageal erosion. In one embodiment, intrauterine application of a hydrogel containing bisphosphonate particles or suspensions of encapsulated bisphosphonates was associated with oral administration to provide a systemic therapeutic level using small amounts of the drug without side effects. In postmenopausal women, intrauterine drug reservoirs may be used to deliver the drug over extended periods of several months.

[0115] In addition to, or as an alternative to, drug delivery by in situ-forming hydrogels, drug delivery may be carried out using cervical plugs. Drug delivery using cervical plugs is somewhat similar to drug delivery by hydrogel puncture plugs used in the eye, except for the difference in size. Therefore, the formation of drug-filled plugs may be adapted from U.S. Patent No. 8,409,606 to Sawhney et al. ("Drug Delivery Through Hydrogel Plugs") and U.S. Patent No. 10,617,563 to Jarrett et al. ("Coated Implants") (incorporated herein).

[0116] Selected Embodiment - Adhesion Prevention Improved applicators and associated delivery methods may be applicable to a range of purposes, for example, drug delivery as described in previous sections. In some embodiments of particular interest, the method includes preventing intrauterine adhesions, and the method includes introducing a fluid material into the uterus to form a tamponade along the inner surface of the uterus. The tamponade may be effective in reducing bleeding and derives potential patient benefits by reducing postoperative adhesion formation by preventing the outflow of serous-blood-like exudate. As described herein, the material may be a hydrogel, and the improved process described herein provides a convenient, effective, and reproducible formation of the tamponade or implant. The material may separate at least two opposing portions of its surface to prevent contact between two opposing portions of the uterus. The material may substantially fill the uterus to result in effective suppression of adhesion formation, and the material may further fill the cervix to further suppress adhesion formation. The material may be introduced using light pressure filling to produce a tamponade against bleeding from surgically excised venous channels. The material can be administered by a flexible catheter with a non-traumatic tip. The material can be administered by a catheter as detailed in the various embodiments described above. The resulting application can be visualized under ultrasound during and after administration, the degree of tissue separation can be quantified, and this can lead to improvements in preventing adhesions.

[0117] Embodiments of the application utilize a visualization agent. The visualization agent lies within the visible spectrum and, ideally, has a blue or green color for visualization against tissue. The visualization agent in the hydrogel system may be used to confirm that the uterine space is sufficiently filled and to confirm the initiation of crosslinking of the material. In some embodiments, the application uses FD&C Blue #1 to provide a radiostable precursor.

[0118] The material may include a hydrophilic polymer. In some embodiments, the material may include a polymer containing the group -(CH2CH2O)-. The material may further include a therapeutic agent. The material may be biodegradable in vivo. The material may be biodegradable by hydrolysis. The material may be biodegradable in vivo in less than about 14 days. The material may be in contact with a surface for at least about 1 day. The material may be biodegradable in vivo for more than about 1.5 days but less than about 7 days. In some embodiments, the material remains for 3 to 10 days. For usefulness in premenopausal women, a hydrogel that degrades within 21 days is desirable.

[0119] The material may be substantially formed in the uterus. The material may be partially formed outside the uterus, and the formation of the hydrogel may be completed in the uterus. The material may be formed from at least two chemically distinct precursors that react with each other to form a hydrogel. The at least two precursors may include a first precursor having a first functional group and a second precursor having a second functional group, where the first functional group reacts with the second functional group to form a covalent bond. The material may be formed from two precursors that contain the functional groups necessary to form a covalent bond but are mixed in a single solution, where the premixed solution is activated by the introduction of a second solution to accelerate the reaction conditions. The first functional group may include an electrophile, and the second functional group may include a nucleophile. The electrophile may include a succinimide ester. The nucleophile may include an amine. In some embodiments, the electrophile is a high molecular weight succinimide ester, and the nucleophile is a low molecular weight amine, such as trilysine. The first precursor may contain at least three first functional groups, or at least two, four, six, or eight. The second precursor may contain at least four second functional groups, or at least two, six, or eight. In some embodiments, the material and its applications allow for premixing using a high molecular weight first precursor and a low molecular weight second precursor.

[0120] The material may be formed from at least one precursor that forms a hydrogel when exposed to an activator such as an accelerator. The at least one precursor may contain a polymerizable functional group having at least one vinyl moiety before exposure to the activator. The polymerizable functional group having at least one vinyl moiety may be, for example, an acrylate, a methacrylate, or a methyl methacrylate. The polymerizable functional group may be polymerizable using free radical polymerization, anionic polymerization, cationic vinyl polymerization, addition polymerization, stepwise polymerization, or condensation polymerization. The activator may be a high-pH polymerization initiator or buffer.

[0121] The material may be formed from a composition of at least two polymers having opposite ionic charges that react with each other, a polymer containing a poly(alkylene) oxide and another polymer that associates with the polymer containing the poly(alkylene) oxide, a thixotropic polymer that forms a hydrogel after introduction into the uterus, a polymer that forms a hydrogel when cooled, a polymer that forms physical crosslinks in response to divalent cations, and a thermoreversible polymer. The material may include natural polymers. The material may further include a visualization agent. An embodiment is a method for preventing adhesions in the uterus, the method comprising crosslinking at least one precursor to form a hydrogel in the uterus so as to tamponade the surface of the uterus. The hydrogel may be effective in reducing bleeding. At least one precursor may be dry.

[0122] The desired intrauterine anti-adhesion device delivers a hydrogel composition that is easy to use, locally persists throughout the primary phase of adhesion, and is reabsorbable and biocompatible without interfering with normal tissue repair processes. See Torres-De La Roche LA, Campo R, Devassy R, et al. Adhesions and Anti-Adhesion Systems Highlights. Facts Views Vis Obgyn. 2019;11:137-149 (incorporated herein). The desired system may persist long enough to meet the healing time window (3-10 days), but not long enough for the adhesion barrier itself to be encapsulated as part of the healing response. When preventing intrauterine adhesions, accidental contact during the procedure or tissue damage resulting from the procedure itself can lead to loss of basement membrane structure, blood-material interactions, provisional matrix formation, cell necrosis, and inflammatory responses. These events can similarly affect the degree or extent of granulation tissue formation, foreign body reaction, and the development of fibrosis or fibrous capsule. In implants, the organizing process due to fibrous tissue development leads to the well-known fibrous capsule formation at the tissue / material interface. The ideal persistence of a reabsorbable adhesion barrier material is 2:1: The material needs to persist for a considerable time to provide a suitable barrier for adhesion formation, but not long enough for adhesion to form due to the fibrous covering of the barrier material itself.

[0123] Unlike previously commercially available hydrogel adhesion barriers for uterine applications that have persistence exceeding four weeks, the exemplary hydrogels described herein utilize only a short persistence window with a tabletop disappearance time of less than approximately 14 days. These hydrogels can be formed using succinimidyl succinate (SS) or succinimidyl glutarate (SG) ester materials at various concentrations ranging from 7 to 15%, and in some embodiments, from 9 to 11%. [Examples]

[0124] The following examples used a transcervical access system supplied with two solutions, one in each of two syringes. The first solution was the first precursor, or a mixture of the first and second precursors. The second solution was the second precursor, or an accelerator / catalyst. The solutions were mixed in the system while in use with a static mixer, and the mixed solution contained an electrophilic precursor and a nucleophilic precursor. The transcervical access system was effective, as described with respect to Figure 1B. The electrophilic precursor was selected from a 4-armed PEG-based precursor (4A20kSG or 4A40kSG) with a molecular weight of either 20,000 Da or 40,000 Da and succinimidyl glutarate (SG) functional end groups, or an 8-armed PEG-based precursor (8A15kSS) with a molecular weight of 15,000 Da and succinimidyl succinate (SS) ester functional end groups. The nucleophilic precursor was either trilysine acetate or an 8-armed PEG-based precursor (8A20kNH2) with a molecular weight of 20,000 Da and a primary amine-terminated functional group. The concentrations of the precursor in one or more solutions were adjusted to result in equimolar delivery of nucleophilic-terminated groups versus reactive amine-terminated groups to a given delivery system.

[0125] Example 1: Tabletop study This example demonstrates the effectiveness of a transcervical access system in a tabletop study using a uterine model.

[0126] In this embodiment, a bivalve-shaped tabletop uterine model was used. The uterine model consisted of a mold of the uterine cavity shape within each side of a plastic bivalve-shaped container. When closed, the model had a circular opening and tubular space at one end that mimicked the cervix, as well as an internal triangular space that mimicked the uterine cavity.

[0127] In this embodiment, a closed uterine model was pre-filled with saline using a syringe or catheter to mimic residual fluid in the uterine cavity that may be present after transcervical hysteroscopy. The experimental design allowed for testing the effectiveness of the transcervical access system with respect to dilution resistance. The transcervical access system was assembled as shown in Figure 1B. A set of first solutions was prepared as a mixture of electrophilic and nucleophilic precursors, with a 1:1 ratio of reactive ester-terminal groups to reactive amine-terminal groups for each formulation. A 1.5 ml aliquot of the first solution in 20 mM mononucleotide buffer solution, pH 4, was drawn into the first syringe. A 1.5 ml sodium borate / dibasic sodium phosphate accelerator solution at pH 9.9 was drawn into the second syringe. In both cases, the first solution was colored with FD&C blue #1 at a diluted concentration. The second solution was not colored.

[0128] A syringe containing an accelerator solution and a syringe containing a polymer precursor solution were attached to a Y-connector via Luer lock connectors. Plunger caps were attached to the ends of the syringes to ensure equal deployment of the two syringes. The Y-connector containing the static mixing element was connected to a 0.25-inch tube adapter via a third Luer lock connector. The tube adapter was attached to a 0.25-inch ID catheter made of clear silicone tubing (Silastic®). The catheter had an open-end lumen tip. The location of the cap element was adjusted along the catheter length using an outflow limiter to ensure that the tip of the catheter was positioned near the bottom of the simulated body cavity during the insertion step. The catheter of the catheter system was inserted into the cervical opening of the uterine model until the cap element was firmly positioned in contact with the simulated cervical opening.

[0129] Once positioned, the plunger cap was pressed to simultaneously inject the entire volume of solution from each syringe into the catheter, and then into the uterine cavity filled with saline. The injection itself took 2–10 seconds and was completed in less than 10 seconds. The insertion, positioning, and injection steps were performed by one-handed operation of the transcervical access system. The hydrogel initially formed within a timeframe of a few seconds, and the saline exited through the mold opening beyond the cap element. Initial gelation was generally observed for 3–5 seconds, as evident from auxiliary mold opening experiments. After injection, the cap element was kept in contact with the outer opening, but the catheter was removed from the uterine model. After a few seconds, the outflow limiter containing the cap element was removed. Comparative studies were also conducted in which the catheter and cap element were removed from the mold simultaneously. The sample was allowed to continue gelling for up to 5 minutes to ensure complete hardening.

[0130] During delivery, the catheter tip remained clear, and no hydrogel was observed when the catheter was removed from the mold. The bivalve mold was opened, and the hydrogel was examined. It was observed that the hydrogel filled the mold, including the cervical cavity.

[0131] Visual inspection of fluid migration from the mold and the formed hydrogel demonstrated that the transcervical access system was able to form a solid, flexible, dilution-resistant hydrogel that filled the uterine cavity, including the cervix. The transcervical access system also successfully formed a relatively rigid hydrogel with a relatively fast gelling time, which contributed to the successful intrauterine retention of the model. The results of this study are significant because they indicate that the transcervical access system was effectively used in the presence of residual intrauterine fluid to form a hydrogel that was rigid enough to separate the uterine wall and was not discharged at the end of the placement procedure. The results suggest that the transcervical catheter system can be effectively used to separate the uterine wall after procedures that cause tissue damage, allowing for independent healing of these tissue surfaces and preventing adhesion formation. The results also suggest that the placed hydrogel resisted dilution from any remaining intrauterine fluid after hysteroscopic transcervical procedures, such as excision to remove unwanted tissue from the uterine cavity.

[0132] Example 2: Comparative study of perihysterectomy in humans This comparative example illustrates the use of existing transcervical catheters for delivering hydrogel into the human uterus.

[0133] Six human patients were part of this study. A modified Cook® Goldstein Sonohysterography Catheter was used for each patient. The Cook Goldstein Sonohysterography Catheter has a movable acorn-shaped positioner that can be positioned along the catheter, with an ink band placed on the catheter as a reference mark. The catheter was connected via a Luer lock to a dual syringe assembly as described below. In this study, the Cook Goldstein Sonohysterography Catheter was modified by cutting the catheter at the proximal locations of both the rounded closed tip and the oval side port. As modified, the catheter had an open port at the distal tip.

[0134] Six female patients were selected for the study. Patient selection was based, firstly, on the determination that a hysterectomy was medically necessary for the patient, and secondly, on the patient's willingness to participate in the experimental study. Prior to enrollment in the study, participants underwent diagnostic hysteroscopy and ultrasound examinations to ensure that there were no lesions that would make them ineligible for the study, and these were videotaped to assess endometrial thickness, cervical length, uterine cavity length and width, and both orifices.

[0135] For each patient, a first syringe was filled with a first solution containing a mixture of 18% (w / v) electrophilic precursor with reactive ester-terminated groups and a certain amount of nucleophilic precursor to provide ester-terminated and amine-terminated groups in a 1:1 ratio. A second syringe was filled with a second solution containing an accelerator buffer salt at pH 9.8. The first precursor solution contained a diluted concentration of methylene blue. The second precursor solution was uncolored. The syringe containing the accelerator solution and the syringe containing the polymer precursor solution were attached to a Y-connector for mixing by Luer lock connectors. Plunger caps were attached to the ends of the syringes to ensure equal deployment of the two syringes. The Y-connector was connected to a 21-gauge tube adapter by a third Luer lock connector. The tube adapter was attached to a 21-gauge catheter made of clear polyethylene tubing. The acorn-shaped body was adjusted along the catheter length based on each patient's anatomical structure to ensure that the tip of the catheter was positioned at a selected location within the uterine cavity during the insertion step.

[0136] Following hysteroscopy and ultrasound, each woman underwent radiofrequency non-hysteroscopic endometrial ablation. Following the ablation procedure, a modified Cook-Goldstein sonohysterography catheter was used to implant the hydrogel in the uterus. The delivery system catheter was inserted through the vagina into the cervix until resistance and visible catheter length indicated that the acorn-shaped implant was positioned in contact with the cervical opening. Once positioned, the plunger cap was pressed to inject 10 ml of fluid from a syringe into the catheter and then into the uterine cavity. One finger of the surgeon was used to control the acorn-shaped implant. The amount of force applied to the acorn-shaped implant by the surgeon was used to regulate the amount of fluid released from the cervix during implantation. After injection, the catheter with the acorn-shaped implant attached was removed from the patient. As shown in Figure 18, the catheter was coated with hydrogel, which was later observed to have caused defects in the hydrogel implant within the cervical canal. The procedure was modified so that the acorn-shaped object was held in place by continuous manual pressure applied with the surgeon's fingers while the catheter was being pulled through it and removed from the patient. This modification ensured that there was little to no hydrogel pulled out when the catheter was removed from the patient. After pressing the acorn-shaped object by hand for a few seconds, it was removed from the patient using ring forceps. Throughout the entire procedure, it was observed that the catheter tip did not become clogged during delivery.

[0137] Next, a hysterectomy was performed using surgical techniques to remove the entire intact uterus, as per standard treatment. No hydrogel discharge occurred during the hysterectomy. The removed uterus was incised and evaluated for the presence and distribution of hydrogel implants. All perihysterectomies demonstrated well-formed implants. In each patient, intrauterine implant coverage was observed to be complete within the uterine body, and no gel was found in the fallopian tubes. Implants in the cervical canal were observed to be less damaged in implants placed with the modified procedure compared to unmodified procedures. Figure 19 shows a series of lesion photographs from one patient in which the modified procedure was used: upper left, removed uterus; upper right and lower left, removed uterus cut and opened to show the placed hydrogel; lower right, cut and opened uterus with the removed implant. It can be seen that the gel coated the uterine cavity, and the removed implant is a continuous solid hydrogel with the shape of the uterine cavity. The thickness of the removed hydrogel implant was approximately 1 cm.

[0138] While the results of this comparative study were promising, it encountered various difficulties. The first difficulty was that the standard Cook Goldstein Sonohysterography Catheter could not deliver the precursor solution without clogging. This difficulty was partially addressed by cutting the tip of the catheter, but in that process, the original rounded, closure tip was removed, making it more difficult to introduce the catheter into the uterus. The second difficulty involved logistical and procedural challenges related to using the acorn-shaped body as a seal. It was observed that the standard Cook Goldstein Sonohysterography Catheter could not be used to control the pressure of the acorn-shaped body on the cervix without additional human intervention, thereby controlling the outflow of the hydrogel during the procedure. In particular, the catheter was found to be too flexible to transmit sufficient force to the acorn-shaped body along its length. As a result, controlling the acorn-shaped body generally required the insertion of a physician's or assistant's finger into the vagina to make direct contact with the acorn-shaped body. Furthermore, an assistant was required to provide traction for the support hook and the endoscope. The process required a physician and an assistant. Another difficulty was the release of hydrogel when removing the catheter, as mentioned above. In the reconstructive procedure, pulling the catheter through the acorn was difficult because the acorn was relatively firmly attached to the catheter, and this firm attachment was part of the Catheter's design intended to prevent the acorn from slipping or being lost during the procedure. In the event of such loss, a ring forceps is recommended for retrieving the acorn. In the case of a Catheter used with a reconstructive procedure that involves pulling the catheter through the acorn and leaving the acorn to function as a seal, the procedure also required the removal of the acorn using forceps. This comparative example highlights the importance of catheter systems that can be operated more conveniently and effectively by the surgeon with one hand, without the need for forceps and without the need for an assistant.The transcervical access system described above corrects the challenges in these problematic procedures and results in more complete hydrogel filling of the uterine cavity, particularly the cervix.

[0139] Example 3: Exvivo uterine tabletop study This example demonstrates the effectiveness of a transcervical access system for delivering hydrogels to the human uterus, as demonstrated by an ex vivo uterine tabletop study.

[0140] In this example, a human uterus was obtained according to a standard medical research protocol. The weight of the ex vivo uterus was 101 grams.

[0141] A transcervical access system similar to that shown in Figure 1B was used. The volume of each syringe was 10 ml. A set of first solutions was prepared as a mixture of electrophilic and nucleophilic precursors, with a 1:1 ratio of reactive ester-terminal groups to reactive amine-terminal groups for each formulation. A 5 ml aliquot of the first solution in 20 mM mononucleotide buffer solution, pH 4, was drawn into the first syringe. A 5 ml sodium borate / dibasic sodium phosphate accelerator solution at pH 9.9 was drawn into the second syringe. In both cases, the first solution was colored with FD&C blue #1 at a diluted concentration. The second solution was not colored. A uterine fundus probe (Integra LifeScience, product number 30-6000) was used to determine the depth of the uterine fundus for exvivo. The uterine fundus probe was then positioned along the assembly of catheter 108 and outflow limiter 106. The position of the outflow limiter's cap element was adjusted along the catheter using the uterine sphincter as a guide to ensure a gap of approximately 1 cm between the distal end and base of the installation tip 102 during the use of the transcervical access system. The catheter and outflow limiter were connected to the Y-connector and syringe assembly via a Luer fitting. The catheter was inserted into the uterus until the distal portion of the cap element entered the cervix and the proximal portion of the cap element was pressed against the cervical opening. Forceps were used to grasp the cervical lips to provide resistance during the insertion process. The system was held by the syringe holder 118 and strong pressure was applied between the cervix and the cap element while the plunger was pushed to fully deploy the hydrogel precursor from the two syringes. The catheter was then withdrawn from the uterus, leaving the outflow limiter in contact with the cervical opening. After approximately 2 seconds, the outflow limiter was grasped by the support sheath 103 and the cap element 109 was pulled away from the cervix. There was no evidence that the hydrogel precursor or hydrogel had been removed from the uterus. The uterus was weighed again and determined to be 108 grams. The weight increase after the placement of the placed hydrogel was 7 grams.

[0142] Immediately afterward, the uterus was dissected along the sagittal plane. A continuous hydrogel was observed that completely filled the uterine cavity, including the cervix. The solid hydrogel was removed, and it was found that it retained its shape after removal. The uterus was further evaluated by dissecting the fallopian tube to confirm the presence of the hydrogel. No hydrogel was found in the fallopian tube. The results of this study indicate that the transcervical access system is effective in delivering hydrogel to the human uterus to form a hydrogel that fully fills the uterine cavity, and is firm enough to separate the uterine wall and prevent discharge at the end of the placement procedure. Furthermore, the hydrogel did not enter the fallopian tube.

[0143] The cited technical papers (which are incorporated herein by reference to the extent indicated below) 1.Di Spiezio Sardo,A.,Calagna,G.,Scognamiglio,M.,O'Donovan,P.,Campo,R.,& De Wilde,RL(2016).Prevention of intrauterine post-surgical adhesions in hysteroscopy.A systematic review.European Journal of Obstetrics and Gynecology and Reproductive Biology, 203, 182-192. https: / / doi.org / 10.1016 / j.ejogrb.2016.05.050. 2.Hesham Al-Inany.Intrauterine adhesions. An update.Acta Obstet Gynecol Scand 2001;80:986-993. 3.Schenker,J.G.(1996).Etiology of and therapeutic approach to synechia uteri.European Journal of Obstetrics and Gynecology and Reproductive Biology,65(1),109-113.https: / / doi.org / 10.1016 / 0028-2243(95)02315-J. 4.Gomel,V. et al.: Pathophysiology of Adhesion Formation and Strategies for Prevention. J.Repro. Med. 41:1,1996 5.Acunzo,G.,et al.(2003).Effectiveness of auto-cross-linked hyaluronic acid gel in the prevention of intrauterine adhesions after hysteroscopic adhesiolysis:A prospective,randomized,controlled study.Human Reproduction,18(9),1918-1921.https: / / doi.org / 10.1093 / humrep / deg368 6.Guida,M.,et al.(2004).Effectiveness of auto-crosslinked hyaluronic acid gel in the prevention of intrauterine adhesions after hysteroscopic surgery:A prospective,randomized,controlled study.Human Reproduction,19(6),1461-1464.https: / / doi.org / 10.1093 / humrep / deh238. 7.Johns DA,et al.,Initial feasibility study of a sprayable hydrogel adhesion barrier system in patients undergoing laparoscopic ovarian surgery.J Am Assoc Gynecol Laparosc10(3):334-338,2003. 8.Taskin,O.,et al.,(2000).Role of endometrial suppression on the frequency of intrauterine adhesions after resectoscopic surgery.Journal of the American Association of Gynecologic Laparoscopists,7(3),351-354.https: / / doi.org / 10.1016 / S1074-3804(05)60478-1. 9.diZerega,G.S.: Use of Adhesion Prevention Barriers in Ovarian Surgery,Tubalplasty,Ectopic Pregnancy,Endometriosis,Adhesiolysis,and Myomectomy. Curr.Opin.Obstet. Gynechol.8:3,1996. 10.Drug Facts and Comparisons.Facts and Comparisons,Publishers,St.Louis MO 1996. 11.Taskin,O.,Sadik,S.,Onoglu,A.,Gokdeniz,R.,Erturan,E.,Burak,F.,& Wheeler,J.M.(2000).Role of endometrial suppression on the frequency of intrauterine adhesions after resectoscopic surgery.Journal of the American Association of Gynecologic Laparoscopists,7(3),351-354.https: / / doi.org / 10.1016 / S1074-3804(05)60478-1. 12.Al-Inany,H.(2001).Intrauterine adhesions:An update.Acta Obstetricia et Gynecologica Scandinavica,80(11),986-993.https: / / doi.org / 10.1034 / j.1600-0412.2001.801103.x. 13.Diamond,M.P.,Daniell,J.F.,Feste,J.,Surrey,M.W.,McLaughlin,D.S.,Friedman,S.,…Martin,D.C.(1987).Adhesion reformation and de novo adhesion formation after reproductive pelvic surgery.Fertility and Sterility,47(5),864-866.https: / / doi.org / 10.1016 / S0015-0282(16)59181-X. 14.Raziel A.,Arieli Sholmo:Investigation of the uterine cavity in recurrent aborters.Fertil Steril 1994;62:5,1080-1082. 15.Schenker,J.G.,& Margalioth,E.J.(1982).Intrauterine adhesions:an updated appraisal.Fertility and Sterility,37(5),593-610.https: / / doi.org / 10.1016 / s0015-0282(16)46268-0 15.March CM.Update:Intrauterine adhesions.Fertil News 1996;Vol.XVIV,No.1.Forum 16.Taylor,P.J.,Cumming,D.C.,& Hill,P.J.(1981).Significance of intrauterine adhesions detected hysteroscopically in eumenorrheic infertile women and role of antecedent curettage in their formation.American Journal of Obstetrics and Gynecology,139(3),239-242.https: / / doi.org / 10.1016 / 0002-9378(81)90001-6. 17.Nappi,C.,Di Spiezio Sardo,A.,Greco,E.,Guida,M.,Bettocchi,S.,& Bifulco,G.(2007).Prevention of adhesions in gynaecological endoscopy.Human Reproduction Update,13(4),379-394.https: / / doi.org / 10.1093 / humupd / dml061. 18.Nappi,C.,Di Spiezio Sardo,A.,Greco,E.,Guida,M.,Bettocchi,S.,& Bifulco,G.(2007).Prevention of adhesions in gynaecological endoscopy.Human Reproduction Update,13(4),379-394.https: / / doi.org / 10.1093 / humupd / dml061. 19.Piredda,A.,Marconi,D.,Exacoustos,C.,Sorrenti,G.,Zumpano,A.,Szabolcs,B.,…Zupi,E.(2003).Initial Feasibility Study of an Hydrogel Adhesion Barrier System in Patients Treated by Operative Hysteroscopy for Intrauterine Benign Pathologies.32° Annual Meeting of the AAGL,Las Vegas,Novembre 19-22,2003,10(3),25-26. 20.Victory,R.,Berman,J.,Diamond,M.,Kruger,M.,& Mcneeley,S.(2004).Evaluate the Safety and Efficacy of FlowFil Preventing Postoperative Uterine Bleeding and ThermaChoice Endometrial Ablation:33° Annual Meeting of the AAGL,San Francisco,Novembre 10-13,2004,11(3),29-30.

[0144] The embodiments described herein are for illustrative purposes only and are not intended to limit the scope. Additional embodiments are within the scope of the claims. Furthermore, although the present invention has been described with reference to specific embodiments, those skilled in the art will recognize that modifications may be made in form and detail without departing from the spirit and scope of the invention. Any use by reference to the above documents is limited so as not to refer to subject matter contrary to the express disclosure herein. As suggested by the description, unless otherwise specifically indicated, to the extent that a particular structure, composition and / or process comprising components, elements, raw materials or other classifications is described herein, it is understood that the disclosure herein covers particular embodiments, embodiments comprising particular components, elements, raw materials, other classifications or combinations thereof, and embodiments that are essentially derived from such particular components, raw materials or other classifications or combinations thereof, which may include additional features that do not alter the fundamental nature of the subject matter.

Claims

1. A transcervical access system for moving fluids with simple operation: A graspable structure comprising one or more fluid reservoirs and one or more actuators for directing flow from or into the one or more fluid reservoirs; A catheter comprising a tubular element having a lumen, an outer diameter, an average wall thickness, and one or more distal ports, wherein the catheter engages the grippable structure in such a manner that when the actuator is activated, it brings fluid flow through the tubular element of the catheter; and An outflow limiter comprising a tubular member and a cap element fixedly attached to or near the end of the tubular member, wherein the tubular member has an inner lumen with an inner diameter larger than the outer diameter of the tubular element of the catheter, the outflow limiter is slidable over the catheter and removable from the catheter, the length of the tubular member is shorter than the length of the tubular element of the catheter, the position of the tubular member allows for adjustment of the distal catheter length, and the distal catheter length includes the length from the distal end of the catheter to the distal end of the cap element, the outflow limiter A transcervical access system, including one.

2. The transcervical access system according to claim 1, wherein the length of the catheter is approximately 16 cm to approximately 26 cm, the outer diameter of the catheter is approximately 1 mm to approximately 3 mm at the distal end, and the tubular element has a flexible distal end.

3. The transcervical access system according to claim 1 or 2, wherein one or more distal ports of the catheter are open-end ports that coincide with the distal end of the tubular element, and the catheter has a non-traumatic distal tip.

4. The transcervical access system according to claim 1 or 2, wherein one or more distal ports of the catheter are open-end ports that coincide with the distal end of the tubular element.

5. The transcervical access system according to any one of claims 1 to 4, wherein the tubular element includes a reinforcing segment having a wall thickness greater than the average wall thickness of the tubular element and an outer diameter less than the inner diameter of the inner lumen of the tubular member, the length of the reinforcing segment being about 30% to about 70% of the length of the catheter, the tubular member frictionally engaging with the reinforcing segment so that the length of the distal catheter can be set such that it resists to some extent the change in length depending on the position of the outflow limiter, and the system is suitable for one-handed operation.

6. The transcervical access system according to any one of claims 1 to 5, wherein the tubular member can be grasped during one-handed operation of the system.

7. The transcervical access system according to any one of claims 1 to 6, wherein the outflow limiter includes a concave surface, and the outflow limiter is attached to the tubular element along the concave surface.

8. The transcervical access system according to any one of claims 1 to 7, further comprising a cervical plug having a lumen with an inner diameter larger than the outer diameter of the tubular element of the catheter, so that the cervical plug can slide over the upper side of the catheter, and the cervical plug is removable from the tubular element and is attached distal to the distal end of the outflow limiter.

9. The transcervical access system according to claim 8, wherein the hydrated cervical plug has a length of about 1.0 cm to about 4.0 cm and an average outer diameter of about 4.5 mm to about 9 mm, the cervical plug comprises a pre-made hydrogel or a pre-made xerogel, the cervical plug swells by -25 wt% to +300 wt% when measured after 24 hours in a neutral buffered saline solution, and the cervical plug is hydrolytically degradable within a period selected from 1 day to 5 weeks.

10. The transcervical access system according to claim 8 or 9, wherein the cervical plug is biodegradable.

11. The transcervical access system according to any one of claims 1 to 10, wherein the distal tip of the catheter contains a polymer having a Shore hardness of about 20A to about 80A, and the tubular element and the tubular member together have rigidity that allows for the creation of a fluid seal between the cap element and the neck.

12. The transcervical access system according to any one of claims 1 to 11, wherein the catheter, the tubular member, and the cap element independently comprise silicone rubber, natural rubber, polyisoprene, butyl rubber, polyethylene, polypropylene, nylon, polyether block amide, polyurethane, polysiloxane, polyvinyl chloride, polycarbonate, PET, copolymer, or a mixture thereof.

13. The transcervical access system according to any one of claims 1 to 12, wherein the cap element includes a conical, teardrop, egg-shaped, flattened spherical, or dome-shaped form, and the cap element has a length of about 5 mm to about 3 cm and a width of about 5 mm to about 1.5 cm.

14. Transcervical access system according to any one of claims 1 to 13, wherein the one or more fluid reservoirs include a first syringe having a connector and a second syringe having a connector, the system further includes a Y-branch conduit having a first branch connected to the first syringe and a second branch connected to the second syringe, and a mixing chamber connected to the first branch and the second branch, the mixing chamber including a mixing structure for bringing a mixed flow from a distal outlet, the catheter being connected to the distal outlet of the mixing chamber so that the mixed fluid flows through the tubular element of the catheter, and the one or more actuators including plates operably connected to the plungers of the syringes to advance the plungers simultaneously.

15. The transcervical access system according to claim 14, wherein the mixing structure includes a static mixer.

16. The transcervical access system according to claim 14 or 15, wherein the mixing chamber is further connected to a plurality of ports.

17. A transcervical access system for moving fluid within the uterus with simple operation: A graspable structure comprising one or more reservoirs and one or more actuators for directing flow from or into the one or more fluid reservoirs; A catheter comprising a tubular element having a lumen, an outer diameter, and one or more distal ports, wherein the catheter engages the graspable structure in a manner that brings fluid flow through the tubular element of the catheter; and A cervical plug having an inner lumen with an inner diameter larger than the outer diameter of the tubular element of the catheter, wherein the cervical plug is slidable over the catheter and removable from the catheter, and the cervical plug has an outer diameter suitable for placement in the cervix. A transcervical access system, including one.

18. The transcervical access system according to claim 17, wherein the tubular element includes a reinforcing segment having a wall thickness greater than the average wall thickness of the tubular element and an outer diameter smaller than the inner diameter of the inner lumen of the cervical plug, the length of the reinforcing segment is about 30% to about 70% of the length of the catheter, the cervical plug is removable from the reinforcing segment, the reinforcing segment and the tubular element are occupied by solid material and / or the cervical plug includes an oval shape, and the system is suitable for one-handed operation.

19. The transcervical access system according to claim 17 or 18, further comprising a flow limiter including a tubular member and a cap element fixedly attached to the tubular member at or near its end, wherein the tubular member has an inner lumen with an inner diameter larger than the outer diameter of the tubular element of the catheter, so that the flow limiter can slide over the catheter and be removed from the catheter, the cervical plug may be attached distal to the distal end of the flow limiter, the length of the tubular member is shorter than the length of the tubular element of the catheter, the length of the tubular member allows for adjustment of the distal catheter length, and the distal catheter length includes the length from the distal end of the catheter to the distal end of the cervical plug.

20. The transcervical access system according to any one of claims 17 to 19, wherein the length of the catheter is approximately 16 cm to approximately 26 cm, the outer diameter of the catheter is approximately 1 mm to approximately 3 mm at the distal end, and the tubular element has a flexible distal end.

21. The transcervical access system according to any one of claims 17 to 20, wherein one or more distal ports of the catheter are open-end ports that coincide with the distal end of the tubular element, and the catheter has a non-traumatic distal tip.

22. The transcervical access system according to any one of claims 17 to 21, wherein the cervical plug has a length of about 2 cm to about 6 cm and an initial average outer diameter of about 3 mm to about 10 mm, and the cervical plug swells by -25% to +300% when measured after 24 hours in a physiological solution.

23. The transcervical access system according to any one of claims 17 to 22, wherein the cervical plug is biodegradable.

24. The transcervical access system according to any one of claims 17 to 23, wherein the cervical plug comprises a pre-made hydrogel or a pre-made xerogel, and the cervical plug is hydrolyzable within a period selected from 1 day to 5 weeks.

25. The transcervical access system according to any one of claims 17 to 24, wherein the cervical plug comprises cross-linked polyethylene glycol.

26. The transcervical access system according to any one of claims 17 to 25, wherein the position of the cervical plug can be selected to a specific location along the catheter.

27. The transcervical access system according to any one of claims 17 to 26, further comprising a therapeutic agent for the cervical plug.

28. A method for moving fluid transcervically into or from the uterine cavity of a patient, the method being: The transfer of fluid into or from the patient's uterine cavity using a catheter system, the catheter system being: A graspable structure comprising a hydrogel precursor reservoir and an actuator. A catheter comprising a tubular element having a lumen, an outer diameter, and one or more distal outlets, wherein the catheter is connected to a reservoir in such a manner that it provides fluid flow through the tubular element of the catheter, and the tubular element has a length suitable for transcervical intrauterine delivery, and A blocking structure comprising a lumen having an inner diameter larger than the outer diameter of the tubular element of the catheter, wherein the blocking structure is slidable over the catheter, and the blocking structure is positioned to adjust the distal catheter length, the distal catheter length comprising the length from the distal end of the catheter to the distal end of the blocking structure. Including; and The catheter is removed from the patient, while the blocking structure is left in place to prevent the fluid from leaking out of the neck. Methods that include...

29. The blocking structure includes an outflow limiter comprising a tubular member and a cap element fixedly attached to the tubular member at or near the distal end of the tubular member, wherein the inner diameter of the tubular member is larger than the outer diameter of the tubular element of the catheter, allowing the tubular member to slide over the catheter, the length of the tubular member is shorter than the length of the tubular element of the catheter, and the cap element has a geometric shape suitable for sealing the cervix without fully entering the cervical canal, thereby suppressing the outflow of the hydrogel precursor from the uterine cavity during transfer. The method according to claim 28, further comprising removing the outflow limiter after a selected period of time, while leaving the in situ-forming hydrogel in the uterine cavity.

30. The method according to claim 28, wherein the blocking structure includes a cervical plug having an inner diameter larger than the outer diameter of the tubular element of the catheter, the cervical plug being able to slide over the catheter, the cervical plug being positioned in the cervix when the hydrogel precursor is transferred into the patient's uterine cavity, and the cervical plug being retained in the cervix when the catheter is removed.

31. The method according to claim 30, wherein the cervical plug is hydrolyzed within a period selected from 1 day to 5 weeks.

32. The blocking structure further includes an outflow limiter comprising a tubular member and a cap element fixedly attached to the tubular member at or near the distal end of the tubular member, wherein the outflow limiter has an inner diameter larger than the outer diameter of the tubular element of the catheter, allowing the outflow limiter to slide over the catheter, and the length of the tubular member is shorter than the length of the tubular element of the catheter. The method according to claim 30 or 31, further comprising removing the outflow limiter after a selected period of time while leaving the cervical plug in the cervix.

33. The method according to claim 32, wherein the cervical plug comprises a pre-made hydrogel or a pre-made xerogel, the cervical plug swells to -25 wt% to +300 wt% after being placed at least partially within the cervix, and the swollen cervical plug expands the internal os.

34. The method according to claim 32 or 33, wherein the cervical plug is adjacent to the distal end of the outflow limiter, and removing the outflow limiter includes rotating the outflow limiter along its longitudinal axis to disconnect it from the cervical plug and leave the cervical plug at least partially inside the cervix.

35. The method according to any one of claims 28 to 34, wherein the transfer and removal can be performed with one hand.

36. The method according to claim 29, wherein the outflow limiter has a length suitable for gripping, and the method can be performed with one hand.

37. The method according to any one of claims 28 to 36, wherein the hydrogel is formed in situ and effectively fills the uterine cavity.

38. The method according to any one of claims 28 to 37, wherein the hydrogel essentially inhibits contact between cervical tissues, and the hydrogel persists in the uterine cavity for a period selected from about one day to about six weeks.

39. The method according to claim 30, wherein the cervical plug and / or the hydrogel essentially inhibits contact between cervical tissues.

40. The method according to any one of claims 28 to 39, wherein the hydrogel precursor forms a hydrogel within about 1 second to about 6 seconds after being transferred, and the hydrogel is selectively formed in the uterine cavity.

41. The method according to any one of claims 28 to 40, wherein the blocking structure is positioned at a location along the catheter, and the distal end of the catheter is at a selected location away from the uterine cavity floor during the transfer.

42. The method according to any one of claims 28 to 41, further comprising draining the fluid from the uterine cavity using the system without the reservoir of the hydrogel precursor before transfer.

43. The method according to any one of claims 28 to 42, wherein the blocking structure is positioned to suppress the outflow of the hydrogel precursor from the uterine cavity during transfer.

44. The method according to any one of claims 28 to 43, wherein the transfer is completed in approximately 30 seconds or less.

45. The method according to any one of claims 28 to 43, wherein the selected period is approximately 1 second to approximately 15 seconds.

46. The method according to any one of claims 28 to 45, wherein the volume of the delivered hydrogel precursor is about 10 ml to about 30 ml, and the delivered hydrogel produces a tamponade effect.

47. The method according to any one of claims 28 to 46, wherein the hydrogel precursor comprises a coloring agent, and the delivery is continued until the colored fluid is visible.

48. The method according to any one of claims 28 to 47, wherein the inhibitory structure further comprises a therapeutic agent.

49. The method according to any one of claims 28 to 48, wherein the catheter has an open-end port that coincides with the distal end of the tubular element, and the catheter has a non-traumatic distal tip.

50. The method according to any one of claims 28 to 49, wherein the tubular element includes a distal end with a narrow diameter having an outer diameter smaller than the average outer diameter of the tubular element.

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