WO2020035749A1

WO2020035749A1 - Adjuvant intracervical hybrid biosensor device for sperm capacitation

Info

Publication number: WO2020035749A1
Application number: PCT/IB2019/055095
Authority: WO
Inventors: Jose Maria Murcia Lora
Original assignee: Jose Maria Murcia Lora
Priority date: 2018-08-11
Filing date: 2019-06-18
Publication date: 2020-02-20
Also published as: CO2018008438A1

Abstract

The present invention relates to a modular channelled device that is placed in a woman's cervix, the device interacting with the fluids inside the female reproductive system, particularly the cervical mucus plug, to help spermatozoa with low motility to move from the arrival point into the womb, as close as possible to the Fallopian tubes. According to the invention, the biosensor device is based on a series of microtubules (4) that extend along the length of a main tubule (1) of the device, the microtubules (4) containing one or more trays (41) through which the spermatozoa flow, wherein the movement is read by a series of sensors (6) disposed on the periphery of the external structure of the tubule (1), to be able to determine how far said mobile cells have travelled.

Description

ADTRUDING INTRACERVICAL HYBRID BIOSENSOR DEVICE FOR

Sperm Training

TECHNICAL FIELD

The present invention is within the field of devices for controlling and stimulating fertility, particularly with intrauterine devices that allow sperm motility monitoring and cervical fluid samples.

BACKGROUND OF THE INVENTION

Infertility of male origin due to low sperm counts (oligozoospermia) and / or low sperm motility (asthenozoospermia) accounts for 50% of cases, among about 5 million American couples of reproductive age with fertility problems (9% ). If the global figure is taken into account, the figure is relevant.

Several important functions have been attributed to the cervix, which include sperm training. Austin introduced the term "training" when he stated that "sperm must undergo some form of change or physiological training before it is able to penetrate the egg." Training is currently considered as the process by which sperm gain the ability to develop sufficient motility by means of a flagellar movement capable of reaching the pellucid zone of the ovule, having modifications in the composition of its membrane for the ability to merge with the ovule and to carry out the acrosomic reaction, to proceed with a fusion with the ovule and perform exchange of chromosomal material, through the activation of the guanylate cycle, cyclic guanosine monophosphate (cGMP), protein kinase pathway, and activation of the phospholipase C pathway, diacylglycerate, protein kinase C.

These pathways probably share a complex regulation of events collectively called the acrosomal reaction. The results available from in vivo studies are in general those observed by the Hunner test. It is known that when sperm enter the cervix, they go to the cervical crypts, the mucus secretion site that serves as a possible storage reservoir. Sperm can retain their ability to fertilize in human cervical mucus for up to five (5) days.

From their temporary storage location within the cervical crypts, sperm can be released gradually over time, thus improving the likelihood of fertilization. Another potentially important feature of human cervical mucus is that it is able to restrict the migration of human sperm with an abnormal morphology.

The sperm training encompasses the set of physiological changes that occur in a sperm naturally, to acquire the ability to fertilize an egg. In vivo occurs after ejaculation, when sperm come into contact with the different fluids of the female genital tract. Among the most notable changes are: Modification in the pattern of sperm movement. A process that is dependent on the rheological forces associated with the mucus flow from the cervical crypts, which tend to align the mucin filaments longitudinally within the cervical canal, thus creating aqueous channels between the filaments. Given this longitudinal orientation, with mucus flow that originates in the crypts of the cervical epithelium, it has been postulated that sperm are forced to swim in the direction of least resistance, that is, along the flow tracts of mucus in the direction of the cervical crypts. These physiological properties occur in a complex genetic, immunological and hormonal environment, which is taken into account when making this liquid medium as a content fluid for this invention.

The first attempts to analyze the presence of semen with cervical mucus were carried out with the Huner test that allows to see the interaction between the two elements, mucus and sperm. This has been a way of looking at the behavior of sperm in the intracervical cavity. Together with Odeblad's studies, the closest technology is estimated and the one that has given the most contribution in this field at the level of interaction of these two factors that are difficult to assess. It has been estimated that a good correlation with the Hunner test is an indication of the interaction between cervical secretion and sperm quality, and a low sperm motility may indicate a test of Hunner deficient. The estimate given to the ability to fertilize is due to multiple processes that have already been listed. Even so, the sperm's ability to fertilize remains decisive in such a way that the most mobile are those that fertilize. The sperm training allows the sperm to be arranged to be able to have a reciprocating movement sufficient to fertilize the ovum. In cases where adequate training is not achieved, in vitro procedures have been attempted with artificial insemination, which by centrifugation and elimination of abnormal forms improves semen quality.

These techniques have demonstrated verifications of cervical mucus training. Rosselli and his colleagues investigated human sperm using electron microscopy and found that sperm incubated with cervical mucus, or a training medium enriched with 3% bovine serum albumin, presented ultrastructural training of sperm. Other research has also shown changes in sperm cover by moving through the mucin canaliculi through the cervical mucus, resulting in the removal of sperm-coated molecules from the gamete surface. These alterations of the sperm lining may be a consequence of the hydrogen and electrostatic binding forces by the glycan moiety of the mucin molecules, which causes the removal of certain molecules from the surface of the sperm. These examples and many more that are not cited, are examples of the relationship between sperm membranes, (which are a very dynamic collection of proteins and lipids) capable of responding to signals that modify cellular activities. This complex dynamic process not fully cleared occurs in situations of sperm training in vivo in a natural way, without the need to place artificial means. Taken together, it is believed that these changes in the composition of the sperm membrane are interrelated with subsequent changes in membrane ion transport and possibly in membrane fusion. Through the use of cervical secretion of fertile characteristics in vitro, several researchers have demonstrated the efficacy of parallel sperm swimming patterns. These findings have led to attempt the artificial insemination of sperm with normal morphology trained in vitro. However, it has been found that the introduction of seminal fluid into the endocervix by insemination does not solve all cases of sterility. Although sperm training has been induced in vitro, it is unclear whether the changes caused by in vitro manipulation are the same as those that occur in vivo. These findings, both in vivo and in vitro training (the latter causes many costs and failures that make the cost-benefit ratio more expensive at the health level), allow sperm to experience plasma and external acrosomal membrane fusion during the acrosomic reaction and thus proceed to subsequent fertilization. These two steps, the training of Sperm and acrosomal reaction are essential precursors of normal fertilization. Evidence of these facts is verified in sperm that have not been incubated in the female reproductive tract, or have not been trained, which cannot fertilize an egg effectively. The advantages of training within the female reproductive tract; It is known that, at the molecular level, several important changes in sperm are observed as a result of training. These changes include: Alteration or elimination of sperm coating materials, these coating materials are adsorbed or integrated into the sperm plasma membrane during transport by the epidymus and also during exposure to seminal plasma, decrease in the burden of negative surface Changes in the content and location of surface antigens, changes in conformation to intrinsic membrane proteins, and changes in membrane permeability to various ions, especially calcium, occur.

Other in vitro techniques have been developed with the intention of improving sperm mobilization capacity. These techniques perform sperm fertilization in vitro at a very high cost and many additional costs are obtained. The in vitro training does not take into account the natural biogel of the cervical mucus, it uses other procedures, in which it is performed using an artificial form. In vitro fertilization (IVF), with or without intracytoplasmic sperm injection (ICSI) has become the most widely used assisted reproduction technology in modern clinical practice to overcome the challenges of male infertility. One of the obstacles of IVF and ICSI lies in identifying and isolating the most mobile and presumably healthiest sperm. However, these techniques do not succeed at all despite the scientific advances in this field.

An object of this invention is to provide an in vivo intracervical device that improves conditions for sperm with low sperm quality, alternative to artificial reproduction techniques (ART). The most notable use has come with the widespread use of in vitro fertilization techniques since the early 1980s for couples with untreatable infertility. In particular, in vitro sperm training techniques are now performed at high costs in the laboratory as a routine part of in vitro fertilization (IVF) treatment for both male and female infertility in a generalized manner. A large amount of sperm required for standard IVF is required, pregnancy rates associated with IVF are low, and even more so with low quality sperm, which is not resolved with TRA. Despite the development of several gamete micromanipulation techniques, the results in this subpopulation of patients could not be improved. The first advance involved the creation of a cut in the zona pellucida, followed by standard IVF. This was called partial zone dissection (PZD). Another advance, called subzonal sperm insertion (SUZI), involved placing sperm directly in the perivithelial space, the region between the zonal pellucid and the ovule. Both techniques have been used successfully in humans, but did not give Acceptable success rates. Since the first success report with intracytoplasmic sperm injection (ICSI) by Palermo et al in 1992, this form of treatment has drastically changed the options available to the infertile couple.

This approach still does not solve all cases of male infertility, and skips many processes of interaction between hormonal development and sperm intercommunication, ovule during intra-cervical training, such as acrosomic reaction, which are essential components of sperm interaction. ovule, during normal fertilization. Although ICSI is certainly a treatment option, less invasive approaches to both male infertility can be developed as a result of additional research in techniques for improving sperm function in vivo, as is the case with this invention. Despite gamete micromanipulation techniques, it is clear that more research work on sperm transport, sperm-ovule training and interaction will help further progress in efforts to efficiently treat infertile couples. The use of experimental models in vivo will probably be of great benefit in attempts to better understand the processes of transport, training and, ultimately, sperm fertilization, which is the center of this invention to claim an in situ device that collaborates with the sperm training process and information can be obtained from it that has not been possible to date. Consequently, disclosures related to devices for collecting and separating sperm can be found in the state of the art in order to obtain highly mobile sperm, ideal for improving the success rate in artificial insemination processes.

This is how document US 2014315281, entitled "Microfluidic chips for acquiring sperm with high motility, production and applications thereof", which is included here in its entirety as a reference, teaches a chip that comprises an input region in one of its ends, a first flow channel in communication with the input region, a divergent channel in communication with the flow channel, one or more output regions located on both sides of the divergent channel, a second flow channel disposed downstream of the divergent channel, and an output region located on the opposite side of the input region and in fluid communication with the second flow channel. The sperm are separated according to their motility, which is determined according to the exit through which they leave the divergent channel.

On the other hand, JP2017195779, entitled "Method for the separation of mobile sperm and separation device, and liquid sperm for insemination", which is incorporated here in its entirety by way of reference, teaches a device and a method for separating sperm with high motility of others, using a crescent-shaped apparatus that comprises a series of channels with a buffer solution that generate resistance to sperm passage, so that only those with Greater motility can reach the receptacle where they are collected and prepared in a liquid solution for later use in insemination.

In accordance with the foregoing, and taking into account the devices, equipment or devices related to the technical field of the present invention, existing in the state of the art, a problem related to the solution of fertility problems caused by motility is presented General sperm is not good. The systems disclosed in the state of the art essentially only select sperm with greater motility for an artificial insemination process, but if the semen has a high sperm content with less than desirable motility, then these systems cannot fulfill their function.

Because mobile sperm can move only if they are trained, sperm semen of poor fertility, which migrate post-training, are able to optimize their swim with the help of swim channels that are formed to these low quality sperm. In addition to helping by means of swimming propulsion, it aims to improve and complete diagnostic infertility tests, postcoital tests, which are currently the most useful in this field in vivo, but of low specificity for little mobile sperm in the endocervix , which is the object and novelty of this invention and aims to be a solution-problem that is assumed before a favorable cervical factor in a fertile window, but with low sperm quality, as a cause of infertility. In turn the possibility of a biopsy liquid of the different heights of the channel for postprocessing and analysis. The present invention uses as a biological material the ultra structure of the cervical mucus, which can be seen as a complex fluid with components of high viscosity and low viscosity. The high viscosity gel phase is composed of a network of filamentous glycoproteins called mucin, as previously stated, which adapts by means of mucin macromolecules and forms a complex of interconnected micelles, which comprise a network whose interstices are capable of supporting the low viscosity phase, which is predominantly water. The movement of sperm through this cervical mucus is the object of this invention, which occurs mainly through the observation of spaces or channels filled with mucin micelles, and the progression of sperm in these spaces. The size of the channels is large enough to pass the size of the sperm heads; therefore, sperm should make their way through the mucus as they move through the genital tract of the biocompatible canal of the lower female tract.

In this way, a person skilled in the art can clearly see that there is a need to design and implement a device that allows sperm with reduced motility to pass through the cervical canal, to the womb and the ovule, where said system It should also allow a specialist to determine if the sperm are passing through the cervical canal and establish the local conditions that determine the ascent through the formation formed in the cervical secretion. All of the above must be done in situ, since it is important that the sperm are properly trained and the best conditions for this occur within the female reproductive system.

BRIEF DESCRIPTION OF THE INVENTION

It is, therefore, an object of the present invention, to provide a modular channel device that can be placed in the woman's cervix, where said device interacts with the fluids found within the female reproductive system, particularly the secretion cervical, to help sperm with low motility to move from the point of arrival to the inside of the womb, ascending through it. It is also an object of the present application, to provide a modular device of channels that can be placed in the cervix of the woman and that allows the passage of sperm through said channels, through the use of sensors (6) that detect the interruption or dispersion of light waves caused by sperm movements, where the device is useful as a diagnostic test of sperm ascent through the uterine canal. It contemplates and is designed to assess the presence of sperm in the ascension of the cervical and uterine canal by indirect assessment of the effect of interruption of light waves emitted by a biosensor that is submitted to impulses in the microfluid, to the passage of the blast wave of head and scourge that swims through a microchannel with natural fluid.

It has an articulated mechanism in the sensor mechanism that contemplates the possibility of emitting a shock wave on the biogel in interaction with the sperm ascent. This wave is contemplated that in interaction with the dispersion of the sperm ascent signal, it can be modulated and directed according to the characteristics of the sperm ascent Finally, it is another object of the present application, to provide a modular device of channels that can be placed in the cervix of the woman, and allowing samples of mucus tissue from the cervical tampon, in the form of a liquid biopsy, which can then be processed and recorded. The present invention is directed to a modular device of channels and a physical support, where said system of channels and physical support are permeable to the endocervical fluid to facilitate, by capillarity, the interaction of the biogel of the cervical mucus with the sperm in the ascent to the uterine cavity The present invention aims to confirm the presence of sperm in the ascent channel, but the device does not measure semen concentration, or average ascent rate, as the devices existing in the state of the art, on the contrary it contemplates and is designed to assess the presence of sperm in the ascension of the cervical and uterine canal by indirect assessment of the effect of interruption of light waves emitted by a biosensor that is subjected to impulses in the microfluid, to the passage of the head and scourging wave that swims through a microchannel with natural fluid. And contemplates the propiulsion of a wave of helper to the sperm swim.

The device according to the present invention consists of a module with an integrated microtubule system (4) as a flexible tubular device consisting of inert material, biocompatible material, which does not generate allergic reactions or lesions of the dermis, where the type module hybrid device, mixes technology of a natural biogel with sensors (6) in micro-nano scale to be applied in fertile window. Thus, the device is non-transferable, for use in single / multiple ovulatory cycles with fertile window for subfertile populations or not, with gestational desire, with normal or decreased sperm motility. The inside of the module has removable transparent microchannels integrated with sensors (6) in contact with the cervical fluid, to provide a method and an instrument to measure sperm training in conjunction with the ideal characteristic of the natural microfluid of the fertile window. Thus, the invasive device type module of the present invention is easy to install and is removable for analysis and post-processing of data recording, which aims to record the sperm swim range and fluid wave register adjuvant to sperm swim in the microfluidic channel transparent in sperm populations with low fertile quality in fertile window.

In one embodiment, the device of the present invention can be manufactured, without limitation, in any latex or silicone type material, although the option of other materials is contemplated, as may be apparent to one skilled in the art and how they may be commercially available, such as the materials currently used in the art for the manufacture of intrauterine devices or devices, wherein said material may preferably be transparent or translucent.

The biosensor device of the invention can be used to detect sperm in the intracervical cavity and measure sperm training.

BRIEF DESCRIPTION OF THE FIGURES

The present invention is understood more clearly from the following figures showing the components associated with the present device, as well as the novel elements with respect to the state of the art, where the figures are not intended to limit the scope of the invention. , which is only given by the appended claims, wherein:

Figure 1 corresponds to an isometric view of the biosensor device of the present invention. Figure 2 corresponds to a flat front view of the device illustrated in Figure 1.

Figure 3 corresponds to an enlarged view of the detail of the union of the internal structure of the device with the microtubules (4) and the tray (41) within said microtubules of Figure 2.

Figure 4 corresponds to an isometric view of the detail of the main tubule (1) of the device, together with the supports (2) and the sensors (6) in their bifurcated mode.

Figure 5 corresponds to the detail of the support (2) and the longitudinal structure (3) of a device with six sections. Figure 6 corresponds to a perspective view of an alternate embodiment of the device of the present invention, where the bifurcation that can occur at the end end thereof is illustrated.

DETAILED DESCRIPTION OF THE INVENTION

The device according to the present invention consists of a flexible tubular element (1) with a length of 1 to 15 cm, which is constituted by an inert, biocompatible material, between 0.1 mm to 5.0 mm in average diameter and a thickness in the range of 1 to 2 mm, where the material can be, without limitation, Any transparent or translucent type material, that is, any type of organic material that does not hinder sperm ascent can be used.

As used herein, the term "inert material" corresponds to any type of material that does not change the properties of sperm, that is, they do not affect their behavior or have a substantially substantial effect on such cells.

Thus, Figure 1 illustrates a general view of the device of the present invention, in which the elements that are part of it can be clearly illustrated, within which are:

• A flexible main tubule (1), which corresponds to a tubular cylinder that extends from an initial point to an end point and inside which the other elements of the device of the present invention are disposed, wherein said main tubule (1) it has a structure that resembles a mesh, as illustrated in Figure 4, that is, where it has solid parts and hollow parts, thus defining a plurality of compartments (1 1) or sections;

A support structure (2), which preferably has an inverted "Y" shape and where the ends of said support structure join the inner surface of the main tubule (1) in order to support a series of elements that are coupled to said structure, as detailed in Figure 5; • A longitudinal structure (3) composed of a plurality of arms extending from a central point, where the ends of each of the arms of said longitudinal structure (3) do not come into contact with the inner walls of the main tubule ( 1), thus defining a space (a) between the element located at the end of the arm and the inner wall of the tubule (1), wherein the longitudinal structure (3) extends longitudinally along the interior of the main tubule (1). In a preferred embodiment these arms form at their ends a hexagon, with their equidistant ends so that they cover most of the diameter of the main tube (1), as detailed in Figure 5;

• A plurality of microtubules (4), wherein each microtubule (4) is located at the end of each of the arms of the longitudinal structure (3), which is why the amount of said microtubules (4) depends directly on the amount of arms with which the longitudinal structure (3) is counted and, therefore, the device of the invention, wherein each microtubule (4) has a concave loop shape, that is, in cross section corresponds to a circle that has its upper part open or that its contour does not join, thus forming an arc;

• A tray (41) located inside each of the microtubules (4), wherein said tray (41) extends for the length of each microtubule (4), as seen in Figure 3, this serves to deposit of the biogel or cervical mucus, which corresponds to a liquid of changing viscosity from lower to higher as the fertile window of the patient increases, through which sperm can flow freely to be able to be detected by sensors (6), as will be defined below; Thus, due to the viscosity of the cervical mucus, the device of the invention must be used at the time of ovulation or fertility of the patient, which is related to the amount of estrogen, since the more fluid, the more transparent it is, the more Filant, more transparent and more permeable.

• A series of separators (5) corresponding to elements that separate the main structure or main tubule (1), wherein said separators (5) are located at predetermined distances from each other and also separate from the initial end and the end end of said tubule (1), wherein each separator (5) contains in its interior a support structure (2); Y

• A plurality of sensors (6) arranged on the mesh structure of the main tubule (1), specifically on the solid part of said mesh structure, that is, between each compartment (1 1) formed by the division of said structure .

The main tubule (1) has a series of compartments (1 1) along its length, such as at least 2, or preferably 2 to 10 of said compartments (11), or more preferably 5, without being limited to The amount of them. These compartments (11) allow to determine the distance traveled by the sperm, so that a larger number of compartments (11) can be had depending on the length of the device or the scale of the displacement measurement. Figure 2 shows a preferred embodiment of the present invention, in which it can be clearly seen that the main tubule (1) corresponds to a cylinder, that is, it has a cross-sectional view corresponding to a circle, in which interior All the elements of the present invention are arranged, where the space (a) that forms or remains between the inner wall of the main tubule (1) and each microtubule (4) can also be evidenced, as specified above, this in order to prevent the trays (41) and microtubules (4) from coming into direct contact with the sensors (6) arranged in the mesh structure of the main tubule (1).

The amount of biogel and the filling of each channel or tray (41) are arranged by capillarity subject to the natural forces of filling and emptying the microtubules (4) without any force involved. This type of channels or trays (41) are arranged for the swim of the sperm in movement in ascent by the microtubule (4), in such a way that the microchannel system formed by the cervical secretion biogel serves as a filling fluid for the swimming channels or trays (41). The height of the microfluidic channel or trays (41) is less than about 20 times the size of the mobile cells, for example, about 3 to 10 times the size of the mobile cells.

Preferably, as seen in Figure 3, the microtubules (4) are supported by a support system that anchors the swimming tray (41) in the manner of micro channels or fluid-filled filling pails. In a modality, the possibility of several microchannels per compartment as defined above is contemplated.

In a preferred embodiment of the invention, the size of the microtubules (4) ranges from 1 to 1250 microns wide by 1 to 500 microns deep, and is open at the ends and side face in contact with the main tubule (1 ) or tubular system. Likewise, the internal face has a grid system with microcells of 500 by 500 microns in its side walls in a semi-tubular direction.

Between the middle and lower third of the microtubules (4) are configured arranged in parallel inside the microtubule (4), 1 to 10 trays (41) supported on the inner lateral base of the microtubule wall (4) in the sense where the grilles are located. Preferably, a floor system of removable transparent material can also be established to tilt the channels in the external testing device.

In an alternative embodiment of the present invention, the device comprises an articulated system that prevents microchannels or trays (41) from leaving each microtubule (4).

The hexagonal device or longitudinal structure (3) that articulates with the main tubule (1), allows the microtubules (4) to be in contact with permeable cells through which the biogel or cervical mucus passes, these cells are distributed along the main tubule (1) and aligned with the microtubules. Each hexagonal section of the structure (3), which supports the microtubules (4) is in perfect synchrony or aligned with the permeable cells at a distance of between 1 and 200 microns from the wall of the main tube (1) to have contact with the fluid that comes from the endocervical fluid and the fluid from the endouterine genital tract.

The height of these trays (41) is in perfect synchrony with the arrangement of the permeable cells and the height of the tubular system, such that the swim trays (41), within a system of microtubules (4) form semi swimming cuvettes open to the contact and coincide with the liquid inlet cells at a distance of between 1 and 200 microns from the tubular wall in contact with the wall of the filling cell where the sensors (6) of the system are located tubular at the base of the tubule cell base (1).

Additionally, the microtubules (4) and the trays (41) are anchored in a support that is shaped like a flange or hook, so that the ends of each microtubule (4) are secured by means of it, thus preventing its modification Your orientation

In accordance with what is defined above, it is also noted that the device of the present invention has in its entirety, that is, throughout all the compartments (1 1) at the level of the side walls, porous cells permeable to the endocervical fluid and of the upper endometrial tract, where said cells are arranged at various levels, at a regular distance between each of the cells between 1 and 1000 microns. The cells are permeable, with a length of 0.1 and 0.03 mm in length, and between 0.1 mm to 20 mm in height, arranged regularly on each other along both side faces of the flexible tubule (1) on its side walls.

In a preferred embodiment, the longitudinal structure (3) of the device of the present invention is in the form of a hexagon, that is, it has six arms, as can be illustrated in Figure 2. However, it is important to note that the number of arms will depend on the application and is not limited in any way to those illustrated in the figures. Likewise, because on the mesh structure of the main tubule (1) the sensors that are going to detect the movement of the sperm and the distance they reach are located, the solid walls of said mesh structure coincide with the number of arms of the longitudinal structure (3), that is, at each end of the longitudinal structure (3) (where the microtubules (4) are located) there is a solid part of the structure of the tubule (1) that extends from the initial end to the final end of said tubule (1), which allows for a permanent sensing or detection of the sperm and the distance they reach within the device of the present invention, since the sensors (6) they are arranged on said solid parts of the mesh structure of the main tubule (1). On the other hand, laterally, each channel or tray (41) has a motion and pressure sensor system (6) that captures the movement of the sperm from the fluid before the undulating movement of the sperm head and the shock wave of a scourge on the move. Thus, each microtubule (4) has in the swim tray (41) a plurality of motion detection microsensors, which consist of light emission cells arranged along the microtubule (4), whose signals are interrupted to the passage of the mobile cells and record the height of interruption or dispersion of signal within the channel or tray (41) of fluid. These microsensor units are arranged at several equidistant levels and in synchrony with the swim trays (41), at a regular distance between one and another sensor unit (6) every 1 to 1000 microns. The signal transmission cells have a wavelength signal between 0.1 and 3.0 mm along the length of the microtubule (4) and are arranged between 0.1 mm and 20 mm in height regularly from each other along both sides lateral tubule (1).

In a preferred embodiment, they are arranged synchronously internally with the swim trays (41) between 1 and 5 compartments (1 1) in length extension along the microtubule (4). Likewise, distributed linearly positioned at an equidistant distance from each other, there are units integrated to the sensors (6), sensitive to the activation of the interruption of the swimming signal, and / or undulating pressure of the scourge. In another preferred embodiment, as seen in Figure 4, a sensor mechanism system is available in the tubular system of the main tubule wall (1). The tubule wall (1) has a thickness between 0 and 2000 microns in which the sensor system (6) and a swimming propulsion mechanism are arranged. Thus, the wall of the tubule (1) is presented as a multi-layer cylinder, limited by an external and an internal layer, between which an integration circuit of the sensors (6) is arranged.

By way of levels superimposed on one another, several layers of integration of the sensor system (6) are placed, such that the wall of the tubule (1) behaves like a microchip that allows to integrate with the described mechanisms of the cells of the same tubule (1), and of the articulated system, with microtubules (4) and swim trays (41) and biogel as swimming liquid. Preferably, the tubule wall (1) has a mechanism for separating the signals obtained in each of the 4 compartments distributed between 0 and 2 cm, 2 and 3 cm, 3 and 4 cm and an external termination or end zone between 1 and 4 cm that forks in the terminal area.

This movement sensor system for sperm to pass over any area of the tubule (1), is what allows to determine its displacement. On the tubular wall of the tubule (1) in contact with the biogel or liquid or virtual space to the side wall of the swim tray (41), microsensors for detecting cell movement displacement are linearly available mobiles, which are activated when mobile cells pass in or out of the swim tray (41).

Light emission cells are placed at a distance between 1 and 5000 microns along the length of the microtubule (4) at the height of the swim trays (41) in a hexagonal system such as the longitudinal structure (3) . In alternate embodiments of the invention, three heights of motion sensing sensor lines are presented on each side of the device axis. The light emission cells disperse the signal that is interrupted to the passage of mobile cells, and record the height in the channel at which the signal dispersion is carried out.

In this way, the sensor records the signal interruption and the impact intensity and stores it at a certain time, in such a way that each register is ordered in time before a chronological stimulation stimulation of a moving cell. This data is plotted linearly in time in a signal post-processing module, which allows the detection of a mobile sperm that has been trained and is able to ascend and give a mobile object signal, and its ascent capacity at the height of the microtubule (4) that is recorded. The sensor (6), preferably, has a data collection and visualization system when placing the device in a signal adapter that integrates and registers them when removed. These microsensor units are arranged in synchrony with the swim trays (41), at a regular distance between the side edge of the tubule wall sensor tray (1) at a distance of 1 to 1000 microns. The sensors (6) are supported on a series of cells, articulated with a circuit in their base that allows an interconnection of signals from each and every one of the sensors, arranged on a flexible surface along the framework of the tubular wall , which allows the transmission of a signal that is recorded in a different way for each sensor (6) in each ascent section, along the length of the micro tubule as discussed, integrated with a system for recording the signal through an internal microprocessor.

In this way, by means of a circuit integration system that records the movements at the passage of the sperm and the height at which the movement in the device channel has been detected, it is recorded as far as a mobile cell has reached or been detected. in the modular system.

In another embodiment of the invention, the device also has an electronic circuit system (not shown) which is integrated in the edge or the general wall of the tubule (1), where said electronic system allows to receive the signals from the sensors (6) and send it abroad so that it can be read by an external device, compatible with the emitted signal. Also, the electronic system or circuit can have a wireless signal transmission element or module, such as Bluetooth, Wi-Fi or any wireless communication, without limitation, so that it can be read remotely by some type of compatible device, such as a mobile phone, tablet, laptop, etc. The tubular module contemplates an adapter of the sample tubule that gives the external reception when it is removed from the endocervical canal. This adapter records the changes in the swim step sensors and the activation of the swim pressure wave emission sensors. The possibility of programming the activation of the emission signals of the devices is contemplated either for detection only of spermatic ascent and / or for the emission of pressure wave only at the passage of the sperm head before the ON-OFF signal of scanning of the head to the reciprocating movement, and / or to the scourge stimulation.

In one embodiment of the invention, the device can have, at the distal part, a flexible terminal section as a fixing that allows an angle of between 0 and 90 degrees of lateral opening to the right and left of the device, in such a way that the same tubular section of the microtubule (4) with or without trays (41) is open and permeable to the continuation of free swimming of the sperm in the uterine cavity and its ascent to the oviduct, as seen in Figure 4 and 6.

This modality of the device consists of a section that forks in Y, this section is located between 3-5 cm from the proximal terminal part of the main tubule (1). This fork system is located closed by a catheter, in which the device is inserted as a shirt. The possibility of an application adapter of a constant pressure of gradual application is contemplated, on the cervix which, being distensible, responds to the internal pressure (within the endocervical canal) expanding within the anatomical limits to assume the diameter or shape of the tubule main (1). The cervix is temporarily fixed to that diameter. Then it will gradually return to its normal resting diameter of approximately 3-4 mm. The catheter emits measurement signals to verify its introduction and subsequent withdrawal. Thus confirming the correct posture of the device of the present invention.

This catheter functions as a removable jacket or sleeve adapter made of flexible material in the sample tubule (1) that is applied to the module as a whole for insertion into the canal through the external cervical orifice (OCE) and also for when it is retired. Said adapter is inserted with a constant and measured force, after medical evaluation according to the length of the major axis of the uterus and the cervix. The device is arranged to be placed by direct intracervical vision by trained personnel, with a force between 0.5 - 7 Newton, equal range for its extraction, and its confirmation of placement and withdrawal can be done under ultrasound control. The removable jacket or sleeve adapter is removed by leaving the device inserted in the canal and checking its proper uterine placement. The coupling system between the tubular system and said articulated device is carried out at the level of the tubular system by means of a linear axis groove of 1 to 5 microns thick on the tubular system, which allows the support of the articulated system to be anchored. In this slot the support (2) is inserted at an angle of 30 ° in the lower and upper part of the articulated support device.

This system or support structure (2) for inverted Y-shaped anchoring is distributed along all sections of the tubule (1) defined by the spacers (5), to the terminal area of the tubule (1), of such that on a wedge-like system, or parallel slit-like line along the device's distribution compartments (1 1), it is fixed as an anchoring system to the tubular device by closing the two sheets of the main tubule (1) in the anterior part of the tubule (1).

The inverted Y-shaped support system or structure (2) consists of a collection system of 1 to 500 microns thick in thickness from 0.1 to 2000 in microns in the axial zone of the support system, and two rods in An angle of 30 ° that goes to the lower end of 0.1 to 2000 microns, thus forming a perimeter rectangle over the entire extent of the shared structures, as seen in Figure 5.

The device can also have in its proximal terminal some filament systems (8) that open transversely and are fixed to the cervix to avoid involuntary exit, these filaments (8) are equally flexible, and serve as a control for the removal of the device. In addition, several types of filament lengths (8) adapted to the best AP diameter from the ECE of the endocervical canal to the uterine fundus can be available, as shown in Figure 4.

In one embodiment of the present invention, the device comprises a tubule adapter that opens in the form of an unfolded open sheet and is inserted as a sample onto an external receiving device when it is removed and removed from the endocervical canal. This adapter records the changes in the swim path sensors (6) and the activation of the swim pressure wave emission sensors.

In yet another embodiment of the present invention, the activation of the emission signals of the devices for detection can only be programmed for sperm ascent and / or for pressure wave emission only at the passage of the sperm head before the ON-OFF signal, and / or a type of signal that can be recorded according to the modality of study of the personalized behavior of the head sweep to the reciprocating movement, and / or to the scourge stimulation.

This information can be fed to a computer to obtain a reconstructed virtual reproduction of the signal register of mobile structures during the signal pick-up period. However, the device must be removed once the fertile period has ended with the intention of fertility. Before the implantation window is given, the device must integrate accepted fertile window recognition systems to estimate the recognition of fertility, or new integration models that allow the assessment of biophysical properties of cervical secretion in fertile window or through changes of vulvar cervical secretion.

These systems allow the detection of the peak day by methods of monitoring the fertile window of gradual changes in cervical secretion and a check or review of the device's output is performed within a range of 1 - 3 days after ovulation. This is determined by computer help, support via infertility pattern recognition, through applications of fertility recognition methods, and / or support via mail, cloud, etc.

The fertile window is considered prudent to incorporate the device and based on fertility recognition methods it is considered prudent to remove it once the most fertile day has ended before the phase change, the closest to the methods currently recognized for Phase change diagnosis in cases of intention to evaluate liquid biopsy for endocervical study, in cases where the interest is liquid biopsy.

It is removed early in the postovulatory phase before the zygote migration occurs. Because the capacity of ascent and vitality The sperm can be 5 days and the fertile window time is usually around 7 to 10 days, the recognition of the fertile phase is estimated by a check term developed by the fertility recognition methods of one-two-three . As soon as phase change is detected, its withdrawal is contemplated, in order to interfere with the state of implantation that begins towards the fifth day of intrauterine life. In order to avoid any kind of interaction with a viable product in progress, there is sufficient margin in the luteal phase to migrate the blast from the tube to the uterus without any risk of involvement by the endometrial endocervical device.

In another alternate embodiment, the device of the present invention can be equipped with micro cameras in annotated compartmentalized areas, adapted to the wall of the tubule (1) in its internal section in contact with the light of the tubular system at an angle between 0 and 90 degrees, in such a way that the reading areas are articulated by way of verification with the ascent compartments when the sensors (6) are contacted with the reading device.

The device according to the present invention allows the reading of the liquid biopsy of the trays (41) that are removed when the articulated area is dismantled. Being arranged parallel to the tubule (1), they are placed with the reading unit when the tubular system is automatically removed or disassembled. The reader system has a tray for receiving the microchannels (41) that allow, by means of an optical adapter, the capture of the signal that leaves the fluid material drying, because it evaporates with air.

In addition to what is defined above, the device of the present invention, in another alternate mode, can have a branch system at the end of the tubule (1), as illustrated in Figure 6, wherein said branch system allows the tubule bifurcates or divides into two equal tubules that extend into the terminal area of the uterine fundus, which allows mobile or sperm cells to reach the ostium area of the tubes of the female reproductive system, in order to read also the distance that these sperm travel.

Claims

1. A biosensor device to detect the presence of sperm within the uterine canal, characterized in that it comprises:

• a main tubule (1);

• a support structure (2) whose ends meet the inner walls of the main tubule (1);

• a longitudinal structure (3) composed of a plurality of arms extending from a central point, where the longitudinal structure (3) extends along the interior of the main tubule (1);

• a plurality of microtubules (4), wherein each microtubule (4) is located at the end of each of the arms of the longitudinal structure (3);

• one or more trays (41) located inside each of the microtubules (4), wherein said tray (41) extends over the length of each microtubule (4);

• sensors (6) arranged on the main tubule (1) in its inner wall.

2. The device according to claim 1, characterized in that the main tubule (1) is cylindrical, is made of a flexible material and has a mesh-like structure.

3. The device according to claim 1, characterized in that the support structure (2) has an inverted Ύ ”shape.

The device according to claim 1, characterized in that it further comprises separators (5) that separate the main structure or main tubule (1), wherein said separators (5) are located at predetermined distances from each other and also separate of the initial end and the final end of said tubule (1), wherein each separator (5) contains in its interior a support structure (2).

5. The device according to claim 1, characterized in that the longitudinal structure (3) is hexagonal and has six arms.

6. The device according to claim 1, characterized in that it further comprises on the side walls, porous cells permeable to the endocervical fluid and the upper endometrial tract, arranged at various heights.

The device according to claim 1, characterized in that it further comprises an electronic circuit system integrated in the edge or wall of the tubule (1), which in turn comprises a wireless transmission module.

The device according to claim 1, characterized in that it further comprises at the proximal end filaments (8) that open transversely and are fixed to the cervix.

The device according to claim 1, characterized in that it further comprises micro cameras in compartmentalized areas adapted to the wall of the tubule (1) in its internal section in contact with the light of the tubular system at an angle between 0 and 90 degrees .

The device according to claim 1, characterized in that it further comprises a bifurcation system at the end of the tubule (1) that divides it into two equal tubules that extend into the fallopian tubes.

1 1. Use of the biosensor device of the invention to measure sperm training.