Open, retrievable intrauterine device with adhesive means

Abstract

The present invention relates to an open, retrievable intrauterine device comprising an adhesive means, and in particular for culturing gametes and / or embryos in the uterus.

Description

Technical Field

[0001] The present invention relates to an open, retrievable intrauterine device having an adhesion means for securing one or more elements selected from the group consisting of embryos, male and / or female gametes, fertilized oocytes, unfertilized eggs, or combinations thereof, particularly for culturing gametes and / or embryos in the uterus. Background Technology

[0002] In natural conception, the floating embryo travels from the fallopian tube where fertilization occurs to the uterine cavity approximately 24 hours before implantation begins, around day four of its development (morula). This brief period before implantation can play a role in reducing the risk of expulsion from the uterine cavity.

[0003] However, in in-vitro fertilization (IVF), the embryo is typically transferred into the uterine cavity on day 2 or 3, meaning it exists in the uterine cavity 48 to 72 hours before its presence during natural conception. Therefore, it remains in a floating state for a longer period, which may lead to a higher risk of expulsion from the uterine cavity. Various factors are generally believed to be associated with this risk of expulsion, including uterine peristalsis and contractions, low deposition sites, and negative pressure generated during removal of the transfer catheter. Several strategies have been proposed, such as bed rest, fibrin sealant (US 6 196 965), and mechanical closure of the cervix, to avoid this problem of embryo expulsion. Unfortunately, none of these strategies have been able to address the issue.

[0004] The primary reason for embryo transfer on day 2 or 3 is the ongoing technical difficulty in optimizing in vitro culture media. In fact, in vitro culture of mammalian embryos is a fundamental process in assisted reproductive technology (ART). Typically, the in vitro cultures used in ART are envisioned to merely mimic the complexities of the in vivo and intrauterine microenvironments. However, the natural environment of gametes and embryos also contains redundant and overlapping reactive oxygen species (ROS) protection systems that cannot even be simulated in vitro (Menezo Y et al. 2016).

[0005] Recent studies have proposed that the dialogue between the mother and embryo, facilitated by a crucial intercellular communication network via extracellular vesicles, plays a vital role in implantation (Godakurama et al. 2022, Javier Gonzalez Fernandez 2023). Extracellular vesicles (EVs), such as apoptotic bodies, microvesicles (MVs), and exosomes (EXOs), are released from all cells in the body and accumulate in all fluid spaces (Beetler et al. 2023). In the reproductive field, they are secreted from the embryo (trophoblastic ectoderm) and the maternal endometrium (epithelial cells), with measured values ​​between 100 and 1000 nm. They contain lipids, proteins, RNA (incRNA, mRNA, small non-coding RNA, rRNA, miRNA), and DNA. Recently, it has also been proposed that the endometrium itself may participate in embryonic preparation for implantation. Firstly, miR-30d, containing EXO, is secreted by the endometrium and internalized by embryonic trophoblastic cells. It has been shown that it can induce genes involved in embryo implantation (Vilella et al., 2015). It has also been reported that mtDNA present in MV secreted by endometrial cells appears to be involved in embryonic ATP production. All these potential effects of the endometrium on the embryo highlight the important role of reproductive tract EV cargo in reproductive events, which is currently lacking in in vitro culture media.

[0006] Furthermore, the influence of culture conditions on epigenetic chromatin remodeling during preimplantation development has been demonstrated. Most studies use mouse embryo assays (MEA) to assess appropriate DNA methylation. One of these studies demonstrated the absence of imprinted methylation in all culture systems using commercial media (used in IVF) compared to in vivo-derived embryos. No commercial human IVF medium can be assessed by mouse embryo assays (MEA) if appropriate methylation / epigenetics is taken into account (Market-Velker BA et al. 2010). In recent studies, in vitro culture media have been shown to be associated with this alteration in chromatin epigenetic remodeling in human ART (Yves Ménézo et al., 2020).

[0007] In summary, exposure of IVF-derived embryos to suboptimal in vitro conditions can lead to epigenetic errors and potentially short-term (mosaicism, aggressive phenotypes) and long-term (developmental origin of health and disease - DOHaD) adverse effects, even across generations (Ventura et al., 2015). Over the past 15 years, post-fertilization environmental factors have been demonstrated in bovine models to influence embryo quality in terms of gene expression, cryotolerance, and metabolism (Wrenzycki et al., 2005; Lonergan et al., 2006; Duranthon et al., 2008), and depending on the duration of suboptimal in vitro exposure, can even lead to alterations in DNA methylation profiles (Salilew-Wondim et al., 2015).

[0008] Given the difficulty in replicating in vitro culture conditions to be more closely similar to intrauterine conditions, especially after invasive laparoscopic procedures such as gamete intrafallopian transfer (GIFT) and zygote intrafallopian transfer (ZIFT), research aimed at improving in vitro fertilization (IVF) now focuses on using artificial intelligence to select the optimal in vitro-derived embryos for implantation. Additionally, preimplantation genetic testing for aneuploidy (PGT-a) is being used as a means to improve implantation.

[0009] However, none of these techniques have solved the problem of embryo implantation quality in the uterine cavity. Therefore, it is still necessary to improve preimplantation embryonic development conditions to produce embryos with stronger function, better quality, and better implantation ability.

[0010] Some studies aim to develop means that allow for in vivo / intrauterine culture. In particular, three different devices are known for preimplantation genetic development of embryos.

[0011] One of them (by Invocell) The development (of the vaginal device) is a container that exists within a box, without any contact or communication with the environment, and contains oocytes and sperm, placed inside the vagina. The only elements present are temperature, darkness, and the patient's movement, which are considered to be "inside the body."

[0012] The second type is the intrauterine device disclosed in application WO 03 / 011200. It consists of a permeable silicone capsule that allows communication between its interior and exterior. Oocytes after ICSI (intracytoplasmic sperm injection) are placed in this capsule and temporarily placed in the uterus as a miniature intrauterine device (IUD) in less than 2 hours, providing a natural environment for early preimplantation embryos. The principle of this device is to allow exchange between the uterine medium and the embryo / gamete encapsulated within the device via the device wall made of a permeable material. However, even though several molecules contained in the uterine medium can pass through the permeable wall, molecular exchange and circulation of the uterine medium are insufficient, and the embryo / gamete placed in the device is not in optimal culture conditions.

[0013] Furthermore, permeable porous membranes are fragile, and handling such capsules, especially when loading and unloading the encapsulated components, or when implanting or retrieving the capsules from the uterus, can damage the capsule walls and potentially lead to the loss of the encapsulated components.

[0014] To improve intrauterine culture conditions and optimize preimplantation genetic development (PGT) of embryos / gametes, a third device (described in International Application WO2007074409) has been provided, in which, instead of a wall made of a permeable material, the device has a wall with several openings of a specific size that allows molecules of the uterine medium to enter the device but prevents the expulsion of the embryo / gamete placed within it. However, even if a few molecules of the uterine medium can enter the device, other molecules remain outside, and furthermore, endometrial cells and other cells necessary for PGT development, which are larger than the openings, cannot penetrate into the device, thus the culture conditions are not optimal. Finally, the high viscosity of the uterine fluid may explain why this device is not optimal for the exchange between the microenvironment and uterine components.

[0015] As can be seen from the above, current methods and devices do not appear to address issues occurring during the preimplantation phase, thereby improving gamete and embryo quality and implantation rates after embryo transfer to the uterine cavity. In particular, devices known in the art designed to simulate intrauterine conditions or to bring the embryo into contact with the uterine medium do not appear to be optimal. Therefore, there remains a need to provide methods and / or devices that allow for improved preimplantation conditions to optimize gamete and embryo quality and increase the chances of embryo implantation and development in the uterine cavity, thereby improving ART. Summary of the Invention

[0016] As can be seen from the background section, developing an in vitro preimplantation embryo culture method that closely mimics in vivo / uterine conditions appears to be a daunting task. Furthermore, existing devices for contacting embryos / gametes with the uterine medium do not allow for optimal embryo quality and subsequent implantation rates. This is why current research focuses more on improving methods for selecting embryos before implantation into the uterine cavity, rather than improving culture conditions in the preimplantation phase, let alone the means to allow for in vivo / uterine culture.

[0017] Surprisingly, under the aforementioned conditions, the inventors of this invention decided to continue their efforts to improve temporary in vivo / intrauterine culture for embryo / oocyte development in order to reduce the in vitro culture time before final implantation into the uterine cavity, as they considered this the best approach for improving assisted fertilization methods, particularly improving embryo function to enhance the implantation process. Maintaining the principle of using the uterine cavity as an incubator and the uterine medium as a natural culture medium, the inventors discovered a solution that allows the embryo / gamete to have very close, unrestricted contact with all elements (molecules and cells) of the uterine medium (as during natural conception). This solution comprises an open, retrievable intrauterine device containing a support member with a surface coated with means for maintaining the adhesion of the embryo / gamete and a removable cap member. When inserted into the uterine cavity, the removable cap member is removed, and the embryo / gamete, fixed to the support member of the device, is fully exposed to the uterine medium, just as during natural fertilization, but remains firmly attached to the surface of the support member. When the device is removed from the uterine cavity, the embryos / gametes remain fixed to the surface of the device's support, and the removable cover component re-covers them.

[0018] Therefore, the present invention relates to an open, retrievable intrauterine device (1) comprising:

[0019] - A solid support (2) coated with at least one adhesive compound for securing one or more elements selected from a group consisting of embryos, male and / or female gametes, fertilized oocytes, unfertilized eggs, or combinations thereof, and

[0020] - Removable cover component (4).

[0021] Therefore, since the cover part (4) of the device (1) of the present invention can be removed when the device is introduced into the uterine cavity, this allows even the highly viscous uterine fluid and all its components (molecules and cells) to make cellular contact with the element fixed on the support (2).

[0022] The main advantage of the device of the present invention is that it allows the elements fixed to the support (2) to come into direct contact with the uterine fluid without releasing them into the uterine cavity, as they are securely fixed to the support (2). In this way, the elements can be recovered after a predetermined period of time. They are recovered safely because the removable cover (4) can re-cover them as the device is removed from the uterine cavity, passing through the cervix and vagina.

[0023] Therefore, the device (1) of the present invention is characterized in that the element fixed by an adhesive means is not released into the uterine cavity. This is in contrast to intrauterine devices known in the art, especially devices for transferring embryos / sperm during assisted fertilization.

[0024] Contact between the fixation element and uterine fluid, which can contain fluid from both the uterine cavity and the fallopian tubes, can facilitate embryonic development. Furthermore, cell exchange can promote subsequent embryo reimplantation and implantation in the uterus.

[0025] The enhanced interaction with uterine fluid and all its components compared to existing technologies can be a favorable condition for the development of elements fixed to the support (2) of the device (1), particularly for the development of an embryo or the implantation of an egg for fertilization.

[0026] In addition, the open retrievable intrauterine device (1) of the present invention is able to i) improve embryo quality and invasive phenotype and euploidy levels; ii) respect this highly vulnerable period of embryonic development with genome reprogramming; iii) increase the involvement of future parents, with the mother's uterine cavity used as a natural biological incubator; iv) ensure close contact with endometrial cells and uterine fluid, providing genuine communication between the mother and embryo; v) provide a period of recovery and health for the embryo before or after all sophisticated treatments such as ICSI, vitrification or in vitro culture; and vi) perform complete in vivo culture of several oocytes, followed by late intrauterine fertilization or extended in vivo culture until the hatching process, which can be considered an in vivo assisted hatching and adhesion process when a limited number of embryos are cultured in this in vivo and natural microenvironment. Attached Figure Description

[0027] The accompanying drawings are provided by way of non-limiting examples:

[0028] Figure 1 A schematic perspective view of one embodiment of the open retrievable intrauterine device (1) of the present invention is shown;

[0029] Figure 2 A schematic perspective view of one embodiment of the open retrievable intrauterine device (1) of the present invention is shown when the cover component (4) is partially removed;

[0030] Figure 3 A schematic perspective view of the hole (3) is shown;

[0031] Figure 4 Immunohistochemical (IMH) staining of adult mouse ovarian tissue is shown. Cell nuclei were stained with DAPI, and the zona pellucida was stained with anti-ZP2 antibody conjugated with fluorescent secondary antibody (donkey anti-rat 594).

[0032] Figure 5 Immunohistochemical images of the embryo are shown: after incubation with primary anti-ZP2 antibody and fluorescent secondary antibody (donkey anti-rat 594) to stain the zona pellucida (gray). Cell nuclei were stained with DAPI (dark gray).

[0033] Figure 6 A schematic diagram of four testing conditions on mouse embryos is shown. 181 zygotes were divided into four groups and treated with KSOM medium (#1), primary antibody (#2), primary antibody followed by Dynabeads™ (#3), or Dynabeads™ alone (#4). Embryonic development was assessed every 24 hours.

[0034] Figure 7 Immunohistochemical images are shown after the addition of fluorescent secondary antibody and DAPI. Conditions without primary antibody (#1 and #4) are unstained. Conditions #2, #3, and #5 (magnets tested daily) are stained with fluorescent secondary antibody. Detailed Implementation

[0035] Other features and advantages of the open intrauterine device of the present invention will become more apparent in the following description.

[0036] Figure 1 The open-type retrievable intrauterine device (1) shown is specifically designed for use in assisted reproductive technologies to implant and temporarily maintain male and female gametes (in vivo fertilization) and / or embryos (preimplantation development) in the uterine cavity.

[0037] In principle, in in vitro assisted fertilization methods, the intrauterine device is capable of securing one or more elements (identical or different) to a support (2) at the onset of development, such as an embryo in the early stages of embryonic development. The device is introduced into the uterine cavity for a predetermined period of time (from several hours to several days) and then retrieved to extract the embryo or fertilized oocyte for monitoring development and / or for diagnostic purposes prior to intrauterine implantation.

[0038] The open retrievable intrauterine device (1) of the present invention includes a support (2) coated with an adhesion means for securing elements (embryo, male and / or female gametes, fertilized oocytes, unfertilized eggs) and a removable cover (4).

[0039] The open-type retrievable intrauterine device (1) of the present invention can have any shape suitable for insertion into a device (e.g., a catheter) for intrauterine supply. Preferably, the device (1) of the present invention has a rectangular or ellipsoidal shape.

[0040] The support member (2) of the open retrievable intrauterine device (1) according to the invention has a length between 5 mm and 20 mm, preferably between 10 mm and 15 mm, and more preferably 15 mm. The width of the support member (2) is between 0.5 mm and 1.5 mm, preferably between 0.7 mm and 1 mm, and more preferably 1 mm. The depth of the support member is between 1 mm and 10 mm, preferably between 4 mm and 8 mm, and more preferably 5 mm.

[0041] according to Figure 1 In a preferred embodiment shown, the device (1) has a rectangular shape and includes a solid support (2) and a removable cover member (4) having the same shape. In this embodiment, the support has a length of 15 mm, a width of 1 mm, and a depth of 5 mm.

[0042] Furthermore, according to a preferred embodiment, the solid support (2) contains one or more holes (3) within its interior (i.e., in the material embedded in the support). These holes are coated with adhesive means capable of securing one or more elements selected from the group consisting of embryos, male and / or female gametes, fertilized oocytes, unfertilized eggs, or combinations thereof. When the support contains holes, the holes are considered part of the support.

[0043] According to one embodiment, the shape of the hole is preferably circular (e.g., ...). Figure 1 , 2 The holes (3) on the holes can have any shape that allows the receiving of an element to be loaded into the hole. For example, the holes can have rectangular, square, elliptical or conical shapes.

[0044] Figure 3 This is a perspective view of the circular hole (3). According to this preferred embodiment, the hole (3) of the device (1) of the present invention preferably has a diameter between 0.1 mm and 0.5 mm, more preferably between 0.1 mm and 0.3 mm, and even more preferably, the diameter of the hole is 0.15 mm. The diameter of the hole can vary depending on the shape of the hole. For example, when the hole has a conical shape, the wide portion of the hole opening on the surface of the support has the same diameter as described above for a circular hole.

[0045] The solid support (2) of the device (1) is made of a biocompatible material. Generally, the material used must be tested to ensure it is non-toxic and stable in use. The material can be selected from the group consisting of polymers, ceramics, glass, elastic materials, stainless steel, metallic materials, titanium, and titanium alloys, preferably titanium or titanium alloys. Specifically, the support (2) can be prepared in a porous polymer of the polyethersulfone (PES), polyacrylate, acrylate copolymer, or polyethylene diene type.

[0046] As described above, the device (1) of the present invention further includes a removable cover component (4). According to... Figure 2 In one embodiment shown, the cover member (4) is partially removed. This removable cover member is intended to protect the element fixed to the support (2) of the device or loaded in the aperture (3) during insertion of the device (1) into a means suitable for insertion into the uterine cavity (e.g., a catheter, particularly a catheter that allows the cover member to remain folded on the device during vaginal insertion and before entry into the uterine cavity), wherein the device (1) of the present invention is released. When the device (1) is released from said means, the removable cover member (4) is partially removed, such that the element fixed to the support (2) remains fully exposed to the uterine medium. After exposure for a predetermined period of time, the removable cover member (4) is replaced on the support (2) to protect the fixed element when the device is retrieved from the uterine cavity.

[0047] In this way, the use of a removable cover component (4), which can be folded onto the surface of the support (2) when the device (1) is inserted into the supply means and removed when the device (1) reaches the uterine cavity, allows the elements fixed to the support (2) and / or the holes (3) to be exposed to the uterine medium and all its components (molecules and cells) without any restriction. This allows these elements to be in direct contact with the uterine medium in exactly the same way as during natural fertilization. In addition, the use of the removable cover component (4) allows them to be safely re-covered before being retrieved with the device (1).

[0048] The material used to fabricate the removable cover component (4) can be any material that allows removal and repositioning without damaging the element fixed to the support. For example, the material can be a shape memory material.

[0049] In the context of this invention, shape memory material refers to a material that is typically deformable when cold but typically recovers to its original (“memorized”) shape when hot. Specifically, the shape memory material used to prepare the removable cover component (4) of the device of the present invention is selected from shape memory alloys, shape memory polymers, or shape memory composite materials. The shape memory material is a biocompatible material. Preferably, the shape memory material is a shape memory biocompatible polymer.

[0050] The removable cover member (4) of the open retractable intrauterine device (1) according to the invention preferably has the same dimensions as the support member (2). Preferably, the cover member has a length between 5 mm and 20 mm, more preferably between 10 mm and 15 mm, and even more preferably 15 mm. The width of the removable cover member (4) is between 0.5 mm and 1.5 mm, preferably between 0.7 mm and 1 mm, and even more preferably 1 mm. The depth of the removable cover member (4) is between 1 mm and 10 mm, preferably between 4 mm and 8 mm, and even more preferably 5 mm.

[0051] according to Figure 1 and Figure 2 In the preferred embodiment shown, the removable cover component (4) has a rectangular shape with a length of 15 mm, a width of 1 mm, and a depth of 5 mm.

[0052] As described above, when the device is inserted into the uterine cavity, the removable cover part (4) is partially removed so that the element fixed on the support (2) and the uterine medium come into direct contact. Then, when the device is retrieved, the removable cover part (4) folds onto the support (2) during the passage of the device through the cervix and vagina.

[0053] According to one embodiment, one end of a removable cover member (4) is attached to a hole in the supply means such that when the device (1) is discharged from the supply means in the uterine cavity, the removable cover member (4) is removed from the support member (2), thereby allowing the element attached to the support member (2) to be exposed to the uterine medium. Then, when the device (1) is removed from the uterine cavity after a predetermined period of time, the device (1) is placed back into the supply means and the removable cover member (4) is placed back on the surface of the support member (2) to cover the fixed element.

[0054] The special feature of the open intrauterine device (1) of the present invention compared to other intrauterine devices disclosed in the related art is that protection of the embryo / gamete fixed to the support (2) of the device must be ensured twice: 1) when the device is inserted into the uterine cavity, and 2) when the device is retrieved from the uterine cavity along with the fixed embryo / gamete after a predetermined period of time. This is not the case with other intrauterine devices in the art, as their purpose is simply to leave the embryo in the uterine cavity rather than to retrieve it. Therefore, the removable cover member (4) must be designed to allow the embryo / gamete to be displayed in the uterine cavity and to cover them when they are introduced into and retrieved from the uterine cavity.

[0055] Because the device (1) with the fixation element must be retrieved from the uterine cavity after a predetermined period of time, it is necessary to fix the element in a firm manner, but at the same time this fixation must be reversible, as they are subsequently placed in the catheter to allow them to be introduced into the uterine cavity for implantation.

[0056] Therefore, the solid support is coated with an adhesive means (or, as referred to herein, an "adhesive compound"). In the context of this invention, the term "adhesive means" refers to a means that allows the aforementioned elements (embryos / gametes, etc.) to adhere, attach, or fix to the support (2) of the device. Therefore, the terms "adhesion," "attachment," "attachment," and "fixation," as well as terms derived from these terms, are used interchangeably herein. The adhesive means used in the open, retrievable intrauterine device of this invention are selected from any means capable of ensuring a firm but reversible attachment of the loaded elements. In particular, the adhesive means are selected from biochemical adhesive compounds or from mechanical, especially mechano-immunoadhesive means (Novo S. et al., 2013).

[0057] According to one embodiment, the biochemical adhesion compound is selected from the group consisting of compounds capable of binding to specific receptors for zona pellucida glycoprotein (ZP), cyanoacrylates, fibrin glue, biosensors mimicking the structure of a grasshopper's foot, and polycrystalline silicon barcodes for adhesion to the zona pellucida.

[0058] The biochemical adhesion compound used to coat the solid support (2) and / or pores (3) is preferably selected based on its ability to bind to specific receptors for zona pellucida glycoproteins (ZPs), which surround the mammalian oocyte (3D) until blastocyst hatching (day 5 of human embryos). The structural basis of oocyte-sperm recognition during fertilization can help identify the optimal receptors present on the sperm head for coating the support (2) and / or pores (3) of the device (1) of the present invention to increase the adhesion of the embryo / gamete thereon. Compounds that can be used to coat the support and / or pores of the device of the present invention and bind to ZPs on the oocyte and / or embryo are selected from:

[0059] - β-1,4-galactosyltransferase (GalT1), which has the ability to bind N-acetylglucosamine residues on ZP;

[0060] - The multimeric zona pellucida recognition complex (MZRC) is an aggregation of multiple receptor molecules on the sperm surface at the focal point, which adheres to and is compatible with the zona pellucida. It can be found in fully functional sperm after the maturation process.

[0061] - ZP3 R(sp56) receptor;

[0062] - The head of the capacitated sperm is directly coated on the surface of the support / hole of the device (1);

[0063] - A single layer is formed to serve as a connector, called a self-assembled monolayer (SAM);

[0064] - Antibodies that bind to specific proteins of ZP, especially ZP-2;

[0065] - Lectins involved in processes such as cell-cell recognition or cell adhesion, such as wheat germ lectin (WGA), specifically recognize N-acetylglucosamine (GlcNAc) and sialic acid, carbohydrates abundant on the plasma membrane and zona pellucida (3C) surfaces of oocytes and embryos.

[0066] In addition, biochemical adhesion methods are selected from:

[0067] - Cyanoacrylates: such as n-butyl cyanoacrylate and 2-octyl cyanoacrylate (also known as Dermabond, disclosed in Min et al., 2011);

[0068] - Fibrin glue;

[0069] - A biosensor that mimics the structure of a grasshopper's foot, providing an adhesive-free adhesion solution;

[0070] - Polysilicon barcodes for adhesion to transparent strips (Oriol Penon et al. 2012).

[0071] It is quite difficult to securely and reversibly attach embryos or gametes to a solid support without altering their normal development.

[0072] The inventors have surprisingly discovered that when certain biochemical adhesion methods are combined with mechanical methods, strong and reversible attachment of the elements, particularly oocytes and / or embryos, can be obtained. This type of attachment is particularly advantageous because it does not alter the quality of the attached element, as demonstrated in the following examples.

[0073] Therefore, according to one implementation scheme, adhesion means refers to mechanical-immunoadhesion means.

[0074] Preferably, mechanical means refer to a support or scaffold, and biochemical means refer to a device capable of binding at least one protein of the zona pellucida of an embryo, female gamete, fertilized oocyte, or unfertilized oocyte. Preferably, the support or scaffold is a bead, and mechano-immunoadhesion means refer to beads coated with said antibody.

[0075] In the context of this invention, the terms "support" or "support" are used to describe mechanical means designed as part of an adhesion means. In this document, "support" is distinct from a support member (2) included in the structure of the device (1) of this invention and on its surface fixed to the adhesion means.

[0076] The support or scaffold, particularly the beads, can be made of any material, as long as it can be coated with antibody-resistant zona pellucida. For example, such materials are attractive materials. According to a preferred embodiment, the antibody-resistant zona pellucida-coated beads are magnetic beads held on the surface of the solid support (2) and / or the pores (3) by means of providing magnetic force.

[0077] According to this embodiment, the magnetic beads are fixed to the surface of the solid support (2) and / or the surface of the hole (3) of the device via a metal element that provides magnetic force. According to another embodiment, a means of generating a magnetic field can be used to fix the magnetic beads to the solid support of the device (1).

[0078] According to a preferred embodiment, the support (2) and / or the hole (3) are coated with magnetic beads coated with a useful anti-zona pellucida antibody, the anti-zona pellucida antibody being selected from the group consisting of anti-ZP-1, anti-ZP-2 and anti-ZP-3, especially ZP-2.

[0079] The following disclosed examples describe in vitro assays using a mouse model that demonstrates good adhesion of magnetic beads coupled to the zona pellucida (ZP-2) with antibodies, without altering embryonic development whether by using this adhesion method or by generating a magnetic field.

[0080] Specifically, the inventors have developed a method for binding antibodies (primary antibodies) to the zona pellucida of the embryo in a non-toxic manner. Magnetic beads (e.g., Dynabeads) TM The binding of the beads to the primary antibody is challenging because the beads are heavy and need constant movement to prevent them from sinking to the bottom of the culture dish. The inventors discovered that by adding the magnetic beads directly to the top of the embryos, they can be slowly retrieved using a magnet. To attract the magnetic beads to the bottom of the culture dish, movement can be generated by gently stirring the beads.

[0081] In addition, the inventors were surprised to find that directly coupling the anti-ZP2 antibody to the magnetic beads and keeping them in continuous motion ensured that the magnetic beads bound in a more uniform and efficient manner throughout the zona pellucida, resulting in a higher magnetic recovery rate.

[0082] Therefore, according to the preferred embodiment, the adhesion means is magnetic beads, and the anti-ZP antibody is an anti-ZP-2 antibody.

[0083] According to another preferred embodiment, the bonding is carried out under gentle stirring that allows the movement of the beads.

[0084] In another embodiment, adhesion means refers to mechanical means, such as 3D-printed structures capable of holding the aforementioned elements, especially during their display in the uterine cavity.

[0085] A specific mechanical means is, for example, a cage, in which the size of the opening formed by the crossing of bars is smaller than the size of the element placed in the cage. Therefore, when the element is loaded in the cage, it cannot be released into the uterine cavity, but uterine fluid containing all the substances required for intrauterine culture can permeate the cage and thus come into direct contact with the loaded element.

[0086] The cage is provided with a removable door that allows the element to be loaded before the device (1) is introduced into the uterine cavity and allows the element to be removed from the cage after the device (1) has been retrieved from the uterine cavity.

[0087] The cage can be made of a non-toxic, biocompatible material. This material can be selected from the group consisting of polymers, ceramics, glass, elastic materials, stainless steel, metallic materials, titanium, and titanium alloys. According to one embodiment, the cage can be made of a shape memory material, thereby allowing loading / removal of elements through openings formed by intersecting bars. In this case, the presence of a door is not necessary.

[0088] In addition, the cage can have any shape suitable for inserting the element. For example, the cage can be square, rectangular, circular, elliptical, or conical.

[0089] The cage is fixed to the support (2) of the device (1), or, when present, fixed in the hole (3) of the device (1) by any means that allows for secure fixation. According to one embodiment, the cage may be extruded from the material of the support (2).

[0090] As described above, the elements attached to the surface of the solid support (2) and / or the hole (3) of the device of the present invention are selected from the group consisting of an embryo, a male and / or female gamete, a fertilized oocyte, an unfertilized oocyte, or a combination thereof.

[0091] Specifically, these elements are selected from mammals in the group consisting of cattle, sheep, pigs, horses, and humans. More specifically, the mammal is human.

[0092] As used in this article, the term "embryo" refers to a mammalian fertilized oocyte (zygote) in which the first mitosis has not yet occurred.

[0093] The female and male gametes are haploid reproductive male and female cells, respectively.

[0094] As used herein, the term "zygote" refers to a mammalian female gamete fertilized by a mammalian male gamete, i.e., the zygote corresponds to the zygote (diploid cell). In the early stages after fertilization, the zygote can be transferred to the uterine cavity via the device (1) of the present invention for 24 hours or 2 to 5 days (for participation in the embryonic development stage), and then retrieved for analysis. Following such analysis, if appropriate, the resulting embryo is transferred to the uterine cavity via a suitable device (catheter) to continue its implantation in the uterine wall.

[0095] The present invention also relates to a method for preparing an open, retrievable intrauterine device for placing one or more elements, the one or more elements being selected from the group consisting of embryos, male and / or female gametes, fertilized oocytes, unfertilized oocytes, or combinations thereof, the method comprising the following steps:

[0096] - The element is provided in a suitable form for attachment to the surface of the solid support (2) and / or the hole (3) of the device.

[0097] - Provides an open-type retrievable intrauterine device (1) suitable for receiving the element according to the invention.

[0098] - Attach the element to the surface of the solid support (2) and / or hole (3) of the device (1).

[0099] Furthermore, the open-type retrievable intrauterine device of the present invention is used in conjunction with an accessory (means) for placing the device in the uterine cavity. For example, a transfer catheter with an inner diameter of 1 cm to 1.3 cm can be used. Such a catheter is adapted to pass through the cervical canal, which typically has a diameter of about 1.5 cm.

[0100] As described above, the device of the present invention can be implanted into the uterus through the cervix as a standard IUD (intrauterine device) for contraception and removed after a prescribed incubation period.

[0101] The device of this invention can also be used as an implantation site in the fallopian tube. Such implantation requires surgical procedures, such as laparoscopy under general anesthesia or posterior fornixoscopy under local anesthesia. This type of in vivo intratubal embryo culture is similar to GIFT or ZIFT, except that it uses the open, retrievable intrauterine device of this invention, the incubation time is controlled, and an unlimited number of embryos can be loaded, which are retrieved after a simple flushing procedure and selected for transfer.

[0102] The device of the present invention has many advantages: the device is unlikely to cause any trouble to the uterus (little or no tissue reaction, does not induce inflammatory or fibrotic reactions and / or inappropriate damage or scarring of uterine wall tissue) because it is not implanted in the uterine wall, it does not require absolute surgery or anesthesia for insertion, and it can be inserted in a completely mobile manner.

[0103] Furthermore, the device of the present invention is designed to have means of retention within the uterus (i.e., a small suture attached to the tip of the device for connection within or outside the uterus), and can be easily retrieved (the attached suture) at any time after implantation in the uterus.

[0104] As described above, the open, retrievable intrauterine device of the present invention presents gametes and / or embryos to the natural microenvironment of the uterine cavity without encapsulation (as with similar devices in the related art). It allows gametes and embryos to obtain an optimal microenvironment within a small volume. The device of the present invention provides a closer biophysical-chemical environment with less osmotic pressure variation for developing embryos and allows the uterus to become a true transient natural incubator, providing the possibility for complete physicochemical and cellular complex communication between mother and embryo. Furthermore, complete in vivo / intrauterine fertilization can be performed within the uterine cavity, i.e., intrauterine fertilization after the device for fixing oocytes is transferred into the uterus.

[0105] The device of the present invention solves the problem of the embryo being expelled from the uterus through the internal opening of the cervical canal and into the vagina.

[0106] Therefore, as described above, open-type retrievable intrauterine devices can be successfully used for assisted reproduction.

[0107] According to one aspect, the present invention therefore relates to a method of assisted reproduction, wherein the method comprises the following steps:

[0108] - Preparation of the open-type retrievable intrauterine device (1) of the present invention, particularly according to the method described above,

[0109] - The device is placed in the uterine cavity for a predetermined period of time.

[0110] - Remove the device at the end of the time period.

[0111] - Monitor the development of elements of interest, and

[0112] - To reintroduce the element of interest into the uterine cavity or preserve the element for further treatment in the absence of the device of the present invention.

[0113] As used herein, “predetermined time period” refers to the time or period required for post-fertilization embryonic development (which is routinely carried out in vitro) before the embryo is finally transferred to the uterine cavity. “Predetermined time period” may also refer to the time required for intrauterine fertilization (i.e., fertilization in the device of the present invention) when the oocyte and motile sperm are contained in the device.

[0114] The device can be placed in the uterine cavity using the methods described above.

[0115] More specifically, the device of the present invention can be used for in vivo fertilization by injecting prepared sperm and recovered oocytes into the device for implantation into the uterus. After a defined and controlled incubation time (e.g., 2 hours) in vivo and in uterus, the sperm and oocytes are recovered, and zygotes and / or unfertilized oocytes are collected after a simple flushing procedure. Then, on day 3, selection of zygotes for cryopreservation or in vitro culture of the remaining embryos for transfer is performed.

[0116] According to one embodiment, the device of the present invention can also be used for in vivo preimplantation embryo development by injecting several embryos at different developmental stages (i.e., 6-8 cells) into the device and then implanting the device into the uterine cavity during a controlled time (i.e., 48 hours). After the device is removed from the uterus, blastocyst-stage embryos are flushed from the device and transferred to the uterine cavity using a conventional transfer catheter or frozen and delayed for another cycle.

[0117] According to another embodiment, the device of the present invention can be used for in vivo embryo-assisted hatching.

[0118] Of course, many modifications can be made to the above embodiments without departing from the scope of the present invention.

[0119] Example

[0120] The purpose of the following measurements is to evaluate:

[0121] 1) The ability of anti-ZP antibodies, especially anti-ZP-2 antibodies, to bind to the zona pellucida;

[0122] 2) Binding and recovery of anti-ZP2 magnetic beads (Dynabeads) from mouse embryos TM ) system, and

[0123] 3) Early embryonic development after incubation with antibodies / magnetic beads.

[0124] Methods and Materials

[0125] Materials required for embryo collection:

[0126] - 1 Eppendorf tube (for 1 mL KSOM)

[0127] - Five petri dishes labeled 1 to 5 (in addition to the five petri dishes, four more petri dishes are added for the rinsing step)

[0128] - 3 Eppendorf tubes marked 1°Ab; 2°Ab; BB

[0129] - Primary antibody (1°Ab) rat anti-ZP2 (1:50)

[0130] - Dynabeads TM Protein G (ThermoFisher Scientific) (referred to as 2°Ab)

[0131] - Blocking buffer (BB), which contains 3% PBS-BSA diluted in 0.1% Tween.

[0132] - KSOM medium

[0133] Preparation of mixtures:

[0134] Keep the Ab mixture on ice.

[0135] 1) Prepare the BB mixture: Dilute 3% PBS-BSA in 0.1% Tween solution and place in a test tube labeled BB.

[0136] 2) Preparation of 1°Ab mixture (1:50): 1:12.5 (4X) - 8 µL antibody in 92 µL BB - placed in a test tube labeled 1°Ab

[0137] 3) Prepare a 2°Ab mixture of Dynabeads (1:1000): 1:2500 - 0.1 µL Dynabeads in 249 µL BB. Place in a test tube labeled 2°Ab.

[0138] Embryo collection

[0139] 1) Prepare 5 different culture dishes labeled 1-5 with KSOM droplets. Figure 6 ).

[0140] 2) Collect and count single-cell mouse embryos (number of embryos: )

[0141] 3) Divide the embryos into 4 groups. (If they are twin-cell embryos, place them in another group (#5))

[0142] a.#1: embryo

[0143] b.#2: embryo

[0144] c.#3: embryo

[0145] d.#4: embryo

[0146] (-#5): (Embryo)

[0147] Incubate with primary antibody (1°Ab):

[0148] 4) Place 50 μL of the 1°Ab mixture onto the embryos in culture dishes #2 / #3 (and #5).

[0149] 5) Place 50 μL of the BB mixture onto the embryos in culture dishes #1 and #4.

[0150] 6) Incubate the embryos at 37°C for 1 hour.

[0151] 7) Take culture dish #2 and rinse twice with KSOM - Add 2 drops (50 µL) of KSOM to culture dish #1 and transfer the embryo over the two drops to allow rinsing. Transfer the embryo to a new culture dish with KSOM, labeled #2B.

[0152] 8) Repeat 1°Ab for conditions #3 and #5.

[0153] 9) For conditions #1 and #4, replace 1°Ab with BB and repeat.

[0154] Incubate with secondary antibody (2°Ab):

[0155] 10) Place 50 μL of the mixture 2°Ab onto the embryos in culture dishes #3 / #5 and #4.

[0156] 11) Place 50 μL of mixture BB onto the embryos in culture dishes #1 and #2.

[0157] 12) Incubate at 37°C for 30 minutes.

[0158] 13) Take culture dish #3B and rinse with PBS (pH 7.4) - Add 200 μL of PBS to the culture dish, gently shake and transfer the embryo to a new culture dish with KSOM, labeled #3C.

[0159] 14) For #5B and #4B, repeat.

[0160] 15) Take photos under all conditions.

[0161] 16) Place in an incubator at 37°C

[0162] For #5: Place a magnet and observe the embryo's attraction to the magnet - record a video.

[0163] The embryonic development was photographed every 24 hours for 96 hours.

[0164] If cell development stops, keep the embryos in the same culture dish. At the end of the experiment: record the number of fully developed embryos relative to the number of dead embryos.

[0165] Magnetic effect:

[0166] 17) On day 5: Magnets (one large and one small) were used for conditions #1 to #4 to transfer the embryos from one side of the culture dish to the other. Conditions #1 and #2 remained unchanged.

[0167] 18) Count the attracted and unattracted embryos under conditions #3 and #4.

[0168] result

[0169] 1. Anti-ZP2 antibody binds to the zona pellucida.

[0170] a) To test the anti-ZP-2 antibody, the inventors used a modified protocol on adult ovarian tissue. The anti-ZP-2 antibody was used as the primary antibody, and donkey anti-rat 594 (fluorescent dye) was used as the secondary antibody to verify the binding of the primary antibody to the zona pellucida. Figure 4 Fluorescent staining of the zona pellucida revealed that the anti-ZP-2 antibody specifically binds to the ZP-2 receptor. This validated the primary antibody (van Oss. et al. 1986).

[0171] b) The same protocol was applied to fixed mouse embryos suspended in Eppendorf tubes. Centrifugation was performed between staining and washing steps. The protocol was technically replicated. Figure 5 As shown, at the end of the experiment, 90% of the embryos from the control group and 93.3% of the embryos from the test group were present, and both exhibited stained zona pellucida as expected. Therefore, the protocol on these embryos was validated.

[0172] 2. Embryos exposed to antibody ZP-2-Dynabeads responded to magnetic fields.

[0173] a) First, the beads were tested individually under a microscope. After incubating the beads, a magnet was placed near the slide to attract them. The beads were observed to be attracted by the magnetic field.

[0174] b) Then, the embryos were treated with anti-ZP-2 and Dynabeads TM Incubate together. After incubation, place the magnet near the petri dish: a weak attraction is observed.

[0175] c) Finally, the inventors added magnetic beads directly to the embryos and introduced movement into the mixture. After incubation, the magnets were placed near the culture dish: attraction was observed over time.

[0176] From the above, we can conclude that inducing the production of embryos, anti-ZP-2 antibodies, and Dynabeads... TM The movement of the reaction mixture allows the magnetic attraction of the beads to the magnetic field to be improved by the magnetic field.

[0177] 3. Antibody binding does not interfere with embryonic development.

[0178] To test whether binding to anti-ZP2 antibodies could alter embryonic development, a total of 181 mouse embryos at the single-cell stage were obtained via IVF and collected and divided into four experimental groups: 45 embryos in a control group without any antibodies (#1); 45 embryos incubated with only the primary antibody (1°Ab) (#2); 46 embryos incubated with both 1°Ab and Dynabeads (2°Ab) (#3); and 45 embryos for the final condition with only 2°Ab (#4). Notably, another group (#5) was prepared using 28 embryos at the two-cell stage. #5 had the same conditions as #3 but served as a test group for applying magnets to the embryos after the experiment.

[0179] To test the potential damage to the embryos caused directly by the magnetic field of the magnet after the first incubation, condition #3 was performed twice (once with a single-cell embryo (#3) and once with a two-cell embryo (not shown)).

[0180] Experimental protocol as follows Figure 6 As shown.

[0181] Day 0: The 181 embryos were divided into 4 groups. An additional 28 two-cell embryos were selected to reproduce the conditions (#3) and were tested directly on magnets after each experimental day (#5).

[0182] Groups #2, #3, and #5 received anti-ZP-2 antibody diluted in KSOM and were incubated at 37°C for 1 h. After incubation, the embryos were rinsed twice in KSOM droplets and placed on new culture dishes. Then, groups 3, 4, and 5 received beads diluted in KSOM and were incubated at 37°C for 30 minutes. After incubation, the embryos were rinsed twice and placed on new culture dishes. Photographs were taken. All groups were incubated overnight at 37°C. Condition #5 was used for daily magnet testing. The embryos were then also incubated overnight at 37°C.

[0183] On days 1, 2, 3 and 4: All embryos were observed and photographed. Divided and undivided embryos were reported (Table 1). A magnet was used for condition (#5) to assess embryo recovery.

[0184] Table 1: Embryonic development assessment over time

[0185]

[0186] At the end of day 4: Donkey anti-rat 594 fluorescent antibody was added to all conditions to assess 1) binding of anti-ZP2 to the zona pellucida and 2) Dynabeads TM Combination with primary antibody.

[0187] like Figure 7 As observed, conditions #2, #3, and #5 exhibit fluorescence. This indicates that Dynabeads TM It may detach from the primary antibody and migrate to the bottom of the culture dish, failing to bind correctly to the primary antibody, thus allowing the fluorescent secondary antibody to bind correctly. Primary antibody and Dynabeads TM The adhesion is improved by inducing continuous motion.

[0188] Based on the above, it appears that neither the binding of anti-ZP2 antibodies nor the presence of magnetic beads interfered with embryonic development. The binding of beads to antibodies preferably occurs during continuous movement. When embryos were covered with magnetic beads, weak magnetic retrieval of the embryos was observed, meaning the embryos were thus easily retrievable, and anti-zona pellucida antibodies could also be recovered, particularly by in vitro protease treatment.

[0189] References

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Claims

1. An open-type retrievable intrauterine device (1), comprising: - A solid support (2), coated with one or more adhesive means for securing one or more elements selected from a group consisting of embryos, male and / or female gametes, fertilized oocytes, unfertilized eggs, or combinations thereof, and - Removable cover component (4).

2. The open retrievable intrauterine device (1) according to claim 1, wherein the solid support (2) comprises one or more holes (3), the holes (3) being coated with one or more adhesion means for securing one or more elements selected from the group consisting of embryos, male and / or female gametes, fertilized oocytes, unfertilized eggs or combinations thereof.

3. The open retrievable intrauterine device (1) according to claim 1 or 2, having a shape suitable for insertion into a device for intrauterine supply, preferably, the device (1) having a rectangular or ellipsoidal shape.

4. The open retrievable intrauterine device (1) according to any one of claims 1 to 3, wherein the support (2) has a length between 5 mm and 20 mm, a width between 0.5 mm and 1.5 mm, and a depth between 1 mm and 10 mm.

5. The open retrievable intrauterine device (1) according to any one of claims 1 to 4, wherein the solid support (2) is made of a biocompatible material selected from the group consisting of polymers, ceramics, glass, elastic materials, stainless steel, metallic materials, titanium and titanium alloys, preferably titanium or titanium alloys.

6. The open retrievable intrauterine device (1) according to any one of claims 2 to 5, wherein the orifice has a diameter between 0.1 mm and 0.5 mm.

7. The open recyclable intrauterine device (1) according to any one of claims 1 to 6, wherein the adhesion means is a biochemical adhesion compound.

8. The open recyclable intrauterine device (1) according to claim 7, wherein the biochemical adhesion compound is selected from the group consisting of compounds having the ability to bind to zona pellucida glycoprotein (ZP) specific receptors, cyanoacrylates, fibrin glue, biosensors mimicking the structure of a grasshopper's foot, and polycrystalline silicon barcodes for adhesion to the zona pellucida.

9. The open retrievable intrauterine device (1) according to any one of claims 1 to 6, wherein the adhesion means is a mechano-immunoadhesion means.

10. The open retrievable intrauterine device (1) according to claim 9, wherein the mechano-immunoadhesion means is preferably a scaffold coated with antibodies capable of binding at least one protein of the zona pellucida of an embryo, female gamete, fertilized oocyte or unfertilized oocyte.

11. The open retrievable intrauterine device (1) according to claim 10, wherein the support is a bead.

12. The open-type retrievable intrauterine device (1) according to claim 11, wherein, The beads are magnetic beads that are held on the surface of the support (2) by means of providing magnetic force.

13. The open retrievable intrauterine device (1) according to any one of claims 1 to 12, wherein the support (2) is coated with magnetic beads coated with antibodies against zona pellucida, the antibodies against zona pellucida being selected from the group consisting of anti-ZP-1, anti-ZP-2 and anti-ZP-3, preferably anti-ZP-2.

14. The open retrievable intrauterine device (1) according to any one of claims 1 to 6, wherein the adhesion means is a mechanical adhesion means, preferably a cage.

15. The open retrievable intrauterine device (1) according to any one of claims 1 to 14, wherein one or more elements fixed by one or more adhesive means of coating the surface of the support (2) are from mammals selected from the group consisting of cattle, sheep, pigs, horses and humans, preferably from humans.

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