Method and device at least for the controlled movement of gametes and / or zygotes and / or embryos in fluids

Abstract

The invention lies in the field of material sciences and relates to a method of the kind that can be used, for example, in in-vivo reproduction and in healthcare, and to a device for realizing the controlled movement. The object of the present invention is to make available a method and a device, where the device can be used much less invasively and where much higher implantation rates can be achieved by the method. The object is achieved by a method in which gametes and / or zygotes and / or embryos are releasably connected to one or more substrates, and the substrates, with or without gametes and / or zygotes and / or embryos, are moved in a targeted manner autonomously or by means of external influences. The object is further achieved by a device at least containing a substrate which has maximum dimensions in all spatial directions of 500 µm and which consists at least for the most part of biocompatible materials.

Description

[0001] Method and device for at least the controlled movement of gametes and / or zygotes and / or embryos in fluids

[0002] The invention relates to the fields of materials science, biology and medicine and concerns a method at least for the controlled movement of gametes and / or zygotes and / or embryos in fluids, as can be used, for example, in in vivo reproduction and in healthcare, wherein, in addition to the controlled movement of gametes and / or zygotes and / or embryos, for example, a safe development of the gametes and / or zygotes and / or embryos can also be realized, and a device for realizing the controlled movement.

[0003] Infertility is a problem that affects 48.5 million couples of reproductive age worldwide, or approximately 11% of the population. Possible causes in women include ovulatory disorders, tubal obstruction, endometriosis, and uterine and / or cervical factors. In men, infertility is typically caused by poor sperm quality, manifested by low motility or abnormal morphology, or a low sperm count. This reduces the chances of fertilizing the egg in vivo.

[0004] Common infertility treatments include low-cost and minimally invasive hormonal stimulation or intrauterine insemination, in which sperm is injected into the uterus during ovulation.

[0005] In vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) are also known methods for achieving pregnancies. These procedures are particularly indicated when tubal infertility or severe male infertility is diagnosed.

[0006] The use of these procedures has increased rapidly due to improved protocols and better gamete selection techniques, now reaching fertilization rates of approximately 95%.

[0007] However, the subsequent embryo transfer remains the critical stage, with only 32% of cases resulting in clinical pregnancies. Furthermore, implantation rates per embryo remain very low (~17%), and the procedure often has to be repeated several times without success, resulting in high economic and social costs.

[0008] Even in the first three embryo transfers of a genetically tested euploid embryo at the blastocyst stage and the treatment of women with an anatomically normal uterus, implantation rates are only between 60.3-69.9%.

[0009] Possible causes for these low implantation rates and thus pregnancy rates of transferred embryos obtained through IVF and ICSI may include the stress to which the gametes are exposed during the in vitro preparation and culture steps, lifestyle factors of the treated couple, diseases, uterine or endometrial abnormalities, embryonic factors, or even different techniques in the IVF laboratory or during embryo transfer. However, in most cases, no obvious explanation is found. For these medical problems, further diagnostics, such as hysteroscopy and endometrial biopsy or treatment of endometrial injuries, modifications of the stimulation protocol, blastocyst transfer, assisted hatching, and preimplantation screening, could help.

[0010] A promising procedure for improving implantation rates in cases of RIF (repeated implantation failure) appears to be the intrafallopian transfer of gametes or zygotes, or the in vitro fertilized egg (embryo) back into the fallopian tube by laparoscopy, also called gamete / zygote intrafallopian transfer (GIFT / ZIFT). The advantage of this procedure is believed to be the provision of a suitable physiological environment for embryonic development and optimal synchronization between embryonic and endometrial preparation. However, the reproducibility of these procedures is very low and depends on the skill of the surgeon and the culture conditions before the gametes or embryo are transferred back into the fallopian tube or uterus.

[0011] In addition, this procedure is highly invasive, requiring surgery and anesthesia to insert the macroscopic imaging and manipulation tools for laparoscopy into the female body. This can lead to side effects such as tubal trauma, inflammation, ectopic pregnancy, infection, or intraluminal pathologies.

[0012] Nevertheless, this treatment appears to have resulted in comparatively high pregnancy rates of 39.8% in patients with high-order RIF (prolonged infertility duration and a high number of failed standard IVF-ET cycles), so this procedure may still have untapped potential.

[0013] Other methods are known to improve the problems described, particularly for improving the mobility of motile cells, such as sperm. According to DE 102012212427 A1, a method is known in which one or more motile cells are introduced or attached into or to one or more magnetic particles, and subsequently, by applying an external magnetic field, the magnetic particles with the motile cells introduced into or attached to them are moved in a directed manner.

[0014] This procedure improves the activity and controlled mobility of motile cells and controls the movement of motile cells in a desired direction.

[0015] Such methods are not suitable for immobile cells.

[0016] Immobile cells include, for example, sperm that have lost their mobility or egg cells in general.

[0017] The movement of an egg cell occurs during ovulation (ovulation), when the funnel-shaped fimbria folds over the ovary and absorbs the egg. The fallopian tube contracts in a rhythmic movement. Tiny cilia (ciliary cells) transport the egg cell through the fallopian tube. They push the egg cell toward the uterus (Wikipedia, keyword "movement of an egg cell").

[0018] A known method involves coating an egg or embryo with a layer of magnetic particles, and then stabilizing the egg or embryo in the uterus by applying a magnetic field via a permanent magnet or an electromagnet (US 6,695,766 B4). The egg or embryo, coated with the layer of magnetic particles, is transported into the uterus using a catheter. The magnetic particles can have a diameter of 0.1 to 200 pm. These magnetic particles are brought into contact with the egg or embryo so that the reactive groups on the surface of the magnetic particles can react with reactive groups on the surface of the egg or embryo, thus causing the magnetic particles to adhere to the surface of the egg or embryo.

[0019] Also known is a method for producing the mobility of immobile cells, in which the immobile cell, immobile sperm, is connected to a microstructure, wherein the microstructure consists at least partially of magnetic materials and a non-reciprocal movement of the microstructure with the immobile cell is carried out by means of a time-varying three-dimensional external magnetic field (DE 10 2014 201 760 A1).

[0020] Furthermore, US6050935 A discloses a container assembly for intravaginal insemination and embryo transfer, which is used for intravaginal insemination. For this purpose, the container is inserted into the vaginal vault.

[0021] The container has a container body with an opening for introducing a culture medium, one or more eggs, and sperm, and for the subsequent removal of one or more embryos using a collection catheter. The container body has a main chamber for containing the culture medium, eggs, and sperm, and a microchamber for collecting one or more embryos. The container is encased in a capsule made of soft, elastic material. A loop on one part of the capsule adjusts the length to the anatomical conditions. The microchamber has a channel that accommodates the catheter tip to facilitate the removal of the embryos while eliminating the risk of injury to the embryos. The microchamber allows microscopic inspection of the embryos in situ before transfer into the uterine cavity.

[0022] A disadvantage of the known solutions of the state of the art is that, on the one hand, invasive procedures for implanting embryos are known and used, and, on the other hand, relatively low implantation rates and thus pregnancy rates of transferred embryos are still achieved. Furthermore, the known procedures use comparatively large devices, which can lead to injury to the embryos and / or tissue, or even to the implantation of the embryo in the wrong location, resulting in an ectopic pregnancy. Likewise, the low accuracy of the known procedures and devices leads to the fertilization and birth of multiple embryos, which is also undesirable, as multiple pregnancies pose a high risk to both mother and baby.

[0023] The object of the present invention is to provide a method and a device at least for the controlled movement of gametes and / or zygotes and / or embryos in fluids, in which the device can be used in a significantly less invasive manner and in which the method enables significantly higher implantation rates and thus pregnancy rates to be achieved.

[0024] The problem is solved by the invention defined in the patent claims. Advantageous embodiments are the subject of the dependent claims, whereby the invention also includes combinations of the individual dependent claims in the sense of an AND connection, as long as they are not mutually exclusive.

[0025] In the method according to the invention at least for the controlled movement of gametes and / or zygotes and / or embryos in fluids, gametes and / or zygotes and / or embryos are detachably connected to one or more carriers, and the carriers with or without gametes and / or zygotes and / or embryos are moved independently or by means of external influences.

[0026] Advantageously, a connection is made between gametes and / or zygotes and / or embryos and the carrier(s), which can be made and / or dissolved by physical or chemical means.

[0027] Also advantageously, carriers or components of the carriers with or without gametes and / or zygotes and / or embryos are used, which are mechanically or digitally connected with a force- and / or form-fitting, detachable or non-detachable contact with one or more ex vivo arranged devices, wherein even more advantageously ex vivo arranged devices are used for controlling and / or moving and / or loading the carriers before the in vivo transfer.

[0028] Furthermore, it is advantageous to use carriers that move independently, with several carriers moving independently of one another in the same or different directions or moving as a swarm in the same direction.

[0029] It is also advantageous to move the carriers using an external physical field, such as a magnetic or ultrasonic field, or using chemical, thermal, or physical stimuli. It is also advantageous to monitor the position and movement of the carriers using imaging techniques.

[0030] It is also advantageous if, by means of sensors or actuators located on or in the carriers, parameters from the environment of the carrier are determined, transmitted and monitored in situ and / or changes in the parameters are realized based on determined parameters from the environment of the carrier.

[0031] The device according to the invention for at least the controlled movement of gametes and / or zygotes and / or embryos in fluids contains at least one carrier with maximum dimensions in all spatial directions of 500 pm, which consists at least predominantly of biocompatible materials.

[0032] Advantageously, the at least one carrier has dimensions in all spatial directions from 10 nm to 100 pm, advantageously from 1000 nm to 80 pm, even more advantageously from 10 to 1000 nm.

[0033] Another advantage is that the biocompatible materials of the carriers are completely degradable in the body.

[0034] Another advantage is that the outer shell of the carrier is made entirely of biocompatible materials.

[0035] Also advantageous as biocompatible materials are hydrogels, such as gelatin, methacrylates, collagen, silk, alginates, or biodegradable metal oxides, or metallic alloys, such as FeMgSi or FePt, with or without hard magnetic materials, such as NdFeB, CrO2, or BaFeO, or superparamagnetic iron oxide nanoparticles, such as SPIONs or iron-platinum nanoparticles, or other materials coated with biocompatible materials, such as surface coatings made of proteins, gold, or polymers, such as parylene or polyethylene glycol diacrylate (PEGDA). It is also advantageous if the carriers have components that are holders, grippers, loops, catheters, cavities for detachable connection to gametes and / or zygotes and / or embryos, sensors, and / or actuators.

[0036] It is also advantageous if the carriers have drive devices for independent movement.

[0037] It is also advantageous if the carriers are micro- or nanorobots.

[0038] It is also advantageous if the supports are made of materials that allow the supports to be moved by external or local influences.

[0039] It is also advantageous if the carriers contain organic, inorganic and / or magnetic materials.

[0040] It is also advantageous if sensors or actuators are present on or in the carriers that determine, transmit and monitor parameters from the carrier's environment in situ and / or implement changes to the parameters based on parameters determined from the carrier's environment.

[0041] It is further advantageous if the carrier(s) are connected to ex vivo arranged devices for controlling and / or moving and / or loading the carriers before the in vivo transfer, wherein the connection is realized via mechanical devices or digitally.

[0042] It is also advantageous if the carriers comprise functional materials and / or biomolecules for the protection and / or growth of the gametes and / or zygotes and / or embryos, wherein even more advantageously the carriers comprise antioxidants, maturation factors, nutrients, protective molecules for reducing thermal and mechanical stress.

[0043] The present invention makes it possible for the first time to provide a method and a device for the controlled movement of gametes and / or zygotes and / or embryos in fluids, in which the device can be used in a significantly less invasive manner and in which the method enables significantly higher implantation rates and thus pregnancy rates to be achieved.

[0044] This is achieved by a method for the controlled movement of gametes and / or zygotes and / or embryos in fluids, in which gametes and / or zygotes and / or embryos are releasably connected to one or more carriers.

[0045] Gametes, also known as sex cells or germ cells, are specialized cells, two of which unite to form a zygote during sexual reproduction.

[0046] A zygote is a eukaryotic diploid cell that results from the fusion of two haploid sex cells, usually an egg and a sperm, during sexual reproduction.

[0047] An embryo is a living being in the early stages of its development.

[0048] The gametes and / or zygotes and / or embryos to be moved according to the invention can be of humans and animals.

[0049] The union and also the dissolution of the union between the gametes and / or zygotes and / or embryos and the one or more carriers can be effected by physical and / or chemical means.

[0050] Physical means can be mechanical means such as holders, grippers, slings, catheters, cavities on or in the carrier.

[0051] Likewise, nano- to microactuators can be present on or in the carrier material, for example, with gripping arms or fingers that can be opened or closed by electrical, mechanical, thermal, and / or chemical stimuli. Such nano- to microactuators advantageously have dimensions on the order of the size of gametes and / or zygotes and / or embryos.

[0052] It may be advantageous for the carrier to also have cavities or capsules, preferably with permeable or semi-permeable walls, into which the gametes and / or zygotes and / or embryos or other materials can be accommodated.

[0053] Particularly advantageous mechanical means include carriers that are force- and / or form-fittingly attached to microcatheters. The microcatheter is connected to devices for controlling and / or moving and / or loading the carriers prior to in vivo transfer. A carrier according to the invention can therefore be inserted into the body via a conventional cannula or an egg cell transfer catheter. Due to the at least micro-dimensions of the catheter and carrier, even complex and sensitive areas of the body, such as the fallopian tube, can be reached.

[0054] This connection of the microcatheter to the outside of the body can advantageously be realized via mechanical devices or digitally.

[0055] In such a case, the carrier according to the invention can be detachably or non-detachably bound to the mechanical means, such as the microcatheter.

[0056] Furthermore, freely movable supports that can move independently can be provided as unbound supports according to the invention.

[0057] Such carriers can be mobile grippers and / or capsules or can be in the form of rods and / or cylinders.

[0058] The carriers can also be divided, for example into different modules within the same carrier, allowing different components (gametes / zygote / embryo, magnetic particles, contrast agents, antioxidants, etc.) to be held and also kept separately.

[0059] The transfer of these carriers into the body can be done via a conventional cannula or an embryo transfer catheter into the uterus.

[0060] These mobile, unbound carriers can be moved in a directed manner, for example, by the action of an external field. Thus, the carriers, with or without gametes and / or zygotes and / or embryos or other materials, can swim, crawl, walk, or roll, but without any mechanical connection to the outside of the body, to the desired areas, especially those difficult to reach and / or sensitive areas, such as the fallopian tube.

[0061] Advantageously, the movement of the wearers is monitored and controlled in real time using bioimaging with the highest possible spatial and temporal resolution.

[0062] Chemically, the connection can be realized via functional groups and / or gels, for example by incorporating the carrier into hydrogels, coupling to stimulus-sensitive linkers, coupling via hydrophilic / hydrophobic interactions, via hydrodynamic or electrostatic or magnetic or acoustic forces.

[0063] The dissolution of the bond between the carrier and at least gametes and / or zygotes and / or embryos can be achieved by breaking the physical bonds or dissolving the chemical bonds, but also by using carrier materials whose degradation, and in particular biological degradation, occurs in the body. The degradation rate should be adapted to the respective transfer of the gametes and / or zygotes and / or embryos to the destination and the required residence time, and should be controlled, for example, by the composition of the local environment or locally present proteases or by external influences such as the use of local temperature increases. Once the gametes and / or zygotes and / or embryos have reached their destination, the biodegradable carrier material can then dissolve.

[0064] According to the invention, the carriers with or without gametes and / or zygotes and / or embryos are then moved independently or by means of external influences.

[0065] The carriers can also be moved outside the body without gametes and / or zygotes and / or embryos, or they can be moved and introduced into the body using other devices, such as cannulas or catheters, to then pick up and hold the gametes and / or zygotes and / or embryos and transport them to the desired location. Likewise, the carriers can be moved and / or their movement can be controlled by local influences, such as chemotaxis, thermotaxis, thigmotaxis, or rheotaxis. The carriers can also be controlled by external physical fields such as magnetic fields, ultrasound, and / or infrared light.

[0066] The carriers can also be connected to the gametes and / or zygotes and / or embryos outside the body and then transported together into the body. This can also be done via other means, such as cannulas or catheters, or the carriers with the gametes and / or zygotes and / or embryos can move independently or be moved by external influences.

[0067] For example, the gametes and / or zygotes and / or embryos can be provided with a carrier in vitro and then transported through the cervix to the entrance of the uterus, for example using a non-surgical embryo transfer set (NSET) or a flexible cannula.

[0068] At the desired location, for example, in the uterus, the carriers can then be separated from the gametes and / or zygotes and / or embryos by external or local chemical or physical triggers. Such external influences can advantageously be external hydrodynamic, magnetic, electrostatic, and / or acoustic fields.

[0069] Also advantageously, the position and movement of the carriers can be monitored using imaging techniques or external sensors. The carrier can trigger local reactions or biomarkers that can later be detected in biological fluids. This detection can be performed, for example, using external rapid test sensors or PCR. Likewise, a local change in shape or activation of a "report" part of the carrier can occur, which can be detected, for example, using magnetic resonance imaging, PET, or other imaging techniques.

[0070] Furthermore, the device according to the invention for the controlled movement of gametes and / or zygotes and / or embryos in fluids contains at least one carrier with maximum dimensions in all spatial directions of 500 pm, which consists at least predominantly of biocompatible materials. Advantageously, the maximum dimensions of the carriers in all spatial directions are from 10 nm to 100 pm, advantageously from 1000 nm to 80 pm, and even more advantageously from 10 to 1000 nm.

[0071] Furthermore, the size and materials of the carrier are determined, on the one hand, by the gametes and / or zygotes and / or embryos to be transported, but the carriers are also at least predominantly made of biocompatible materials that can themselves perceive and respond to the microenvironment of the gamete and / or zygote and / or embryo, for example, by changing their shape or surface properties in order to release necessary substances that ensure safe transport and development of the gametes and / or zygotes and / or embryos during transfer into the fallopian tube or uterus. Likewise, the carrier materials are advantageously permeable to nutrients, antioxidants, and growth factors, which can and should pass through the carrier materials into the body in vivo or from the oviduct fluid into the carrier.

[0072] The maximum dimensions of the supports do not exceed the minimum dimensions of the fallopian tubes in all spatial directions, with a diameter of approximately 500 pm.

[0073] In any case, the carrier has dimensions as small as possible, but carriers with dimensions of up to approximately 500 pm are also possible, since the areas in which the wearer has to move are adaptable fabrics that are folded and therefore stretchable.

[0074] Advantageously, the carriers are of a similar size to the gametes and / or zygotes and / or embryos in order to allow access to the narrowest regions of the fallopian tube without damaging the surrounding tissue.

[0075] The carriers are designed and shaped to protect the gametes and / or zygotes and / or embryos during transport, for example, to the ampulla, so that they can develop under as natural conditions as possible until they reach the uterine endometrium, the lining of the uterus. This can be achieved, for example, by using capsules in which the gametes and / or zygotes and / or embryos, or other materials, are enclosed during transport.

[0076] It is also particularly advantageous if the outer shell of the carrier is made entirely of biocompatible materials. This is especially important when using a carrier that is intended to remain in the body and / or be degraded there. If the carrier can and should be removed from the body, other medically safe materials can also be used.

[0077] Another advantage is that the biocompatible materials of the carrier are completely degradable in the body.

[0078] According to the invention, the degradation of the carrier materials occurs when the carrier has fulfilled its function in the body and is not removed from the body by other measures, methods or devices.

[0079] Such biocompatible materials include, in particular, hydrogels such as gelatin, methacrylates, collagen, silk, alginates or biodegradable metal oxides, all of which are as biodegradable, permeable and / or soft as possible and exert a gentle interaction with the surrounding tissue in the body.

[0080] Other biocompatible materials include metallic alloys, such as FeMgSi or FePt, with or without hard magnetic materials, such as NdFeB, CrO2, or BaFe^2O, or superparamagnetic iron oxide nanoparticles, such as SPIONs or iron-platinum nanoparticles. Other materials coated with biocompatible materials can also be used, such as surface coatings made of proteins, gold, or polymers, such as parylene or polyethylene glycol diacrylate (PEGDA).

[0081] Furthermore, the carriers can contain materials, as needed, that are or contain antioxidants, hormones, medications, and / or are permeable to the exchange of nutrients from the secretory cells in the body, particularly in the oviduct. Such materials can also contain factors for epigenetic regulation, protection of the immune system, protection against oxidative stress and heat stress, or supportive substances for the cleavage and development of the embryo (embryotrophic factors, growth factors). The materials used for the carriers significantly reduce friction between the carrier and the gametes and / or zygotes and / or embryos, thereby avoiding potential damage, cytotoxicity, and stress to the gametes and / or zygotes and / or embryos.Likewise, the passage / exchange of nutrients and secreted oviductal fluid for embryonic development and transport is advantageously enabled or supported at the same time.

[0082] Advantageously, the carrier(s) comprise functional materials and / or biomolecules for the protection and / or growth of the gametes and / or zygotes and / or embryos. Such functional materials can also be nanosensors for monitoring environmental parameters of the microenvironment, such as oxygen levels, glucose levels, growth factors, etc., which can also be regulated in situ by the nanoactuators of the carrier or materials contained therein.

[0083] The supports made of biocompatible and advantageously biodegradable materials can be manufactured using two-photon lithography or strain engineering techniques or 3D or 4D printing technologies.

[0084] The carriers can also be manufactured using droplet microfluidics. This manufacturing process offers the advantage that gametes, zygotes, and / or embryos can be incorporated into individual droplets made of biodegradable or stimuli-sensitive polymers.

[0085] Further possibilities for producing the carriers are through chemical synthesis or through template-based processes.

[0086] Later, these droplets can be transferred into the body and moved in a directed manner using ultrasonic waves or magnetic propellers or local stimuli such as temperature gradients, chemical gradients, or flows.

[0087] The magnetic propellers can be placed in microfluidic channels, thus facilitating the capture of gametes, zygotes, and / or embryos into the droplets by generating differential flows. Capture can also be achieved and / or facilitated by self-assembly techniques or by exploiting capillary forces, hydrodynamic forces, or hydrophilic-hydrophobic interactions. Likewise, capture of gametes, zygotes, and / or embryos can be achieved by coupling or loading the carriers in vitro using optical, magnetic, or acoustic tweezers.

[0088] Advantageously, the carriers can have drive devices for independent movement. These can then advantageously be micro- or nanorobots.

[0089] But also the use of magnetic propellers as part of the carriers can lead to independent movement of the carriers with or without gametes and / or zygotes and / or embryos.

[0090] Structural materials such as PEGDA, hollowed hydrogel tubes, or 3D-printed elastomers such as silicone, polyurethane, polyolefin, and styrene block copolymers can be used as supports for microrobots.

[0091] Materials that can be used to drive the microrobots include Fe, FePt for magnetic movement, or electroactive polymers such as polypyrrole or other stimulating hydrogels.

[0092] Some inorganic layers made of or containing, for example, Au or Pt, alloys or core-shell nanoparticles can also be used for sensing, or Au-based nanomaterials or quantum dots (QDs) can be used for imaging, or Ag can be used to prevent biofilm formation.

[0093] Through their independent movement, the carriers themselves can create a slight flow, which allows them to move through the body's fluids, which are usually viscoelastic media. They can also move against the flow or against backflow, as occurs, for example, in the fallopian tube through its peristaltic movement and the beating of the cinnae.

[0094] If the carriers contain magnetic materials, they can also be transported via external magnetic fields. This can also be achieved if the carriers are in droplet form. Likewise, the carriers can contain fluids through which directional movement of the carriers is achieved by means of ultrasound from outside the body or by an artificial and / or biohybrid flagellar-like propulsion.

[0095] Furthermore, droplet-shaped carriers can also be multifunctional by incorporating additional agents during their formation. These agents can be active ingredients contained in microcapsules, magnetic materials in beads, and / or infrared reporters, reflectors, or absorbers to enable tracking of the carriers during their movement, especially in vivo.

[0096] The carriers may also contain antioxidants and estrogen to protect the gametes and / or zygotes and / or embryos during their transport.

[0097] Furthermore, the use of organometallic materials or oxygen-sensitive particles as components of the carriers is also possible to monitor the metabolism of gametes and / or zygotes and / or embryos during their journey in vivo. Such materials and components of the carrier can also be referred to as nanosensors or nanoactuators.

[0098] Such nanosensors or nanoactuators can measure the concentrations of harmful metabolites, glucose levels, and the oxidation state of the embryo and release drugs or substances, such as antioxidants, nutrients, and growth factors, in situ to combat harmful metabolites.

[0099] Likewise, nanosensors or nanoactuators can be used to monitor microenvironmental parameters such as pH, secreted proteins, growth factors, reactive oxidative species (ROS), hormones, and substances secreted by the oviduct in situ, and to activate a corresponding response from the carrier, such as the local release of drugs / molecules / antioxidants / growth factors or their shape change, for example, for the release of gametes and / or zygotes and / or embryos. Furthermore, such detected parameters can be determined by bioimaging or by external biofluid analysis, such as via lateral flow sensors or PCR. Likewise advantageously, the carriers can comprise components that are holders, grippers, loops, catheters, cavities for detachable connection to gametes and / or zygotes and / or embryos, and / or sensors or actuators.

[0100] These components can be controlled directly by the carrier via on-board power supplies, but also externally via fields,

[0101] This could also lead to carriers in the future being able to sense their surroundings, analyze the environment and the gametes and / or zygotes and / or embryos during their journey within the body, and gain deeper insights into the function and structure of the female reproductive tract during the different stages of the estrous cycle.

[0102] Likewise, the carriers according to the invention can be used to place sensors in the area of ​​the gametes and / or zygotes and / or embryos, which can be used for in-situ monitoring of embryonic development, or to provide mechanical, optical, and / or electrical actuators for cellular stimuli or for in-situ molecule release. Such sensors can not only monitor embryonic development but also measure environmental parameters such as local pH, temperature, glucose levels, etc., both in vivo and particularly in the fallopian tube, and transmit the measured values ​​outside the body.

[0103] Furthermore, the carrier(s) can be advantageously connected mechanically or digitally to ex vivo arranged devices for controlling the movement and / or the components on the carrier.

[0104] The carriers according to the invention can be attached outside the body, for example, to catheters or tethers, and can move or be moved within the body either independently or in a floating manner. The movement can be swimming, rolling, sliding, and / or walking, or can be a peristaltic movement or movement triggered by a traveling wave of the surrounding fluid.

[0105] The external influences are advantageously external magnetic fields or external ultrasound, or a combination thereof, whereby these external influences can simultaneously be used for the application of imaging techniques. With the solution according to the invention, gametes and / or zygotes and / or embryos of the highest quality can be non-invasively transported and released in vivo. The carriers used for this purpose are advantageously multifunctional microrobots with maximum dimensions of 500 μm in all spatial directions, which consist at least predominantly of intelligent, biocompatible materials and are manufactured using advanced microtechnologies.

[0106] The solution according to the invention can support and improve fertilization and embryo implantation in vivo.

[0107] Likewise, the solution according to the invention can be successfully applied, particularly in hard-to-reach areas of the reproductive system, such as the fallopian tubes. The fallopian tube is an organ that plays an important role in the migration / support of gametes and zygotes during fertilization. The fallopian tube is also important in the development and transport of an embryo to the uterus, and especially precisely when the endometrium is ready for embryo implantation.

[0108] Previously known procedures and devices did not target the fallopian tube, which is a tiny and intrinsic organ that is difficult to access.

[0109] In contrast to established in vitro techniques, the proposed invention allows assisted reproduction techniques to be transferred in vivo. The method and device can also be extended to other medical scenarios, for example, for administering drugs to treat diseases such as cancer, endometriosis, and / or other problems of female and male reproductive medicine and / or for transfer to other organs, e.g., for taking samples for diagnosis or for local diagnosis.

[0110] The carriers according to the invention, which are advantageously nano- to microrobots, i) have the ability to reliably capture and secure the gamete and / or zygote and / or embryo during transport between different environments, ii) allow access of the secreted molecules either through the ciliary cells of the oviduct or through the embryo itself, iii) are biocompatible and / or advantageously biodegradable, iv) are able to move in the fluids, which are mostly viscoelastic media, and against backflows in the oviduct, and v) do not damage the oviduct, which is a very delicate organ, vi) allow in situ detection of the reproductive organ and the local microenvironment of the gametes and / or zygotes and / or embryos, vii) can control their function (e.g., the release of molecules, shape change, permeability rate, etc.).) adapt according to the perceived microenvironment and the health status of the gametes and / or zygotes and / or embryos, viii) can potentially carry drugs, for example, to correct genetic defects of the gametes and / or zygotes and / or embryos during transport or to arrest their development at an early stage if there is a striking, incurable malfunction of the embryo.

[0111] Components on the carrier may include, for example, microcatheter tools that release the gametes and / or zygotes and / or embryos at the desired positions through externally or internally triggered mechanisms, but can also be used to pass through the complex bends of the fallopian tube in a minimally invasive manner.

[0112] The carriers according to the invention can be introduced through the vagina into the uterus or fallopian tube using a cannula or catheter. There, they can then capture and transport gametes and / or zygotes and / or embryos, for example, using spherical microgrippers or capsule-like embryo carriers.

[0113] A key advantage of the inventive solution is that gametes and / or zygotes, i.e., sex cells and early embryos, can be moved in a directed manner, alongside later embryos, and can also be used for gamete intrafallopian tube transfer (GIFT) or zygote intrafallopian tube transfer (ZIFT). In addition to the well-known stabilization of embryos in the uterus, gametes and / or zygotes and / or embryos can now also be moved in a minimally to non-invasive manner. According to the invention, this directed movement can extend into the fallopian tube.

[0114] The carriers used according to the invention, advantageously microrobots, do not need to remain in the body and do not need to be in direct contact with the gametes and / or zygotes and / or embryos during contact. The gametes and / or zygotes and / or embryos can, for example, be contained in a capsule, which is then in direct contact with the carrier.

[0115] Further advantages of the solution according to the invention compared to laparoscopy and intrauterine embryo transfer are:

[0116] - less invasive to non-invasive

[0117] The carriers according to the invention are smaller than current surgical tools. They can be tethered, for example, as robotic catheters, or as untethered, swimming, rolling, gliding, and / or walking nano- or microrobots.

[0118] - Selection of materials

[0119] The carriers according to the invention are biocompatible and advantageously biodegradable, which can be adapted, for example, to the residence time required for the transfer of gametes and / or zygotes and / or embryos to the desired location.

[0120] - further functional possibilities

[0121] The carriers according to the invention can also be loaded with other functional materials and / or biomolecules to support embryonic development (e.g. antioxidants, maturation factors, nutrients, protective molecules to reduce thermal and mechanical stress).

[0122] - additional components

[0123] The carriers according to the invention can also be equipped with mechanical, optical and / or electrical micro- or nanosensors or actuators.

[0124] The advantages of the present invention are particularly relevant in cases of multiple embryo implantation failures, where conventional in vitro fertilization methods are used and embryo transfer to the uterine site fails to achieve pregnancy. Due to the gentle interaction of the carriers according to the invention with the surrounding tissue in the body, significantly improved implantation rates and thus pregnancy outcomes can be achieved compared to the conventional and bulky manipulation and imaging tools currently used in various steps of the assisted reproduction process, starting with oocyte retrieval and subsequent uterine implantation of the embryo or laparoscopically assisted intrafallopian transfer.

[0125] Furthermore, the invention ensures that only a high-quality embryo is connected to the carrier and introduced into the fallopian tube.

[0126] To ensure that the embryos / gametes are of high quality and retain this quality even during transport, the carrier can contain nanosensors that can measure and, in some cases, regulate various variables of the embryonic development process.

[0127] The present invention also has the advantage that essentially no non-biocompatible materials are used, or that these do not come into direct contact with the gametes and / or zygotes and / or embryos. Since the carriers according to the invention are always detachable from the gametes and / or zygotes and / or embryos, even non-biocompatible materials of the carriers have no adverse effect on the gametes and / or zygotes and / or embryos and can be easily removed from the body.

[0128] With the solution according to the invention, higher implantation rates can be achieved and thus pregnancy outcomes can be significantly improved.

[0129] The invention is explained in more detail below using several exemplary embodiments. Example 1:

[0130] A 100 μm diameter microcatheter made of PEGDA, a biocompatible material that forms the outer shell of the microcatheter, is 3D-printed. The microcatheter incorporates a cavity for an embryo, a micropump, and a sensor for optical / electronic monitoring of the embryo.

[0131] The micropump gently draws an embryo, along with its surrounding fluid and nutrients, into the cavity of the microcatheter outside the body. It is then inserted through a cannula through the vagina into the cervix. The microcatheter is then guided toward the uterine lining using ultrasound. The sensor and external imaging devices monitor the position and condition of the embryo, and its arrival at the desired location is determined.

[0132] After positioning the embryo, which is performed without anesthesia or with local anesthesia and takes approximately 1 hour, the catheter can be removed.

[0133] Example 2:

[0134] Using droplet fluidics, a microcapsule with a diameter of 500 pm is produced from gelatin as a biocompatible material.

[0135] Both sperm and an egg cell are introduced into the microcapsule using droplet fluidics, along with nanopropellers and nanosensors made of a magnetic material, as well as nutrients.

[0136] The microcapsule is then moved through the vagina into the uterus and finally into the fallopian tube using external magnetic fields. At this point, the biocompatible material begins to degrade, releasing the sperm and egg, and fertilization of the egg occurs during the luteal phase of the estrus cycle.

[0137] Afterwards, the resulting zygote can develop into an embryo under more natural conditions and reach the uterus in perfect synchronization with the endometrial preparation, as the zygote migrates further to the uterus through the peristalsis of the fallopian tube and can implant itself in the mucous membrane.

[0138] The zygote is thus positioned naturally without anesthesia, but it can also be performed under local anesthesia.

[0139] The biocompatible material of the microcapsule is removed from the body in approximately 1 hour, together with the magnetic material, along with the fluid surrounding the fallopian tube.

Claims

Patent claims 1. A method for at least the controlled movement of gametes and / or zygotes and / or embryos in fluids, in which gametes and / or zygotes and / or embryos are detachably connected to one or more carriers, and the carriers, with or without gametes and / or zygotes and / or embryos, are moved independently or by means of external influences.

2. Method according to claim 1, in which a connection between gametes and / or zygotes and / or embryos and the carrier(s) is realized, which connection can be realized and / or dissolved by means of physical or chemical means.

3. Method according to claim 1, in which carriers or components of the carriers with or without gametes and / or zygotes and / or embryos are used, which are mechanically or digitally connected with a force-fitting and / or form-fitting, detachable or non-detachable contact to one or more devices arranged ex vivo.

4. The method according to claim 3, wherein ex vivo arranged devices are used for controlling and / or moving and / or loading the carriers prior to in vivo transfer.

5. Method according to claim 1, in which carriers are used which move independently, wherein several carriers move independently of one another in the same or different directions or move as a swarm in the same direction.

6. Method according to claim 1, wherein the carriers are moved by means of an external physical field, such as a magnetic or ultrasonic field, or by means of chemical, thermal or physical stimuli.

7. The method according to claim 1, wherein the position and movement of the carriers are monitored by means of imaging techniques.

8. Method according to claim 1, in which parameters from the environment of the carrier are determined, transmitted and monitored in situ by means of sensors or actuators located on or in the carriers and / or changes in the parameters are realized based on determined parameters from the environment of the carrier.

9. Device for at least the controlled movement of gametes and / or zygotes and / or embryos in fluids, comprising at least one carrier with maximum dimensions in all spatial directions of 500 pm, which consists at least predominantly of biocompatible materials.

10. Device according to claim 9, wherein the at least one carrier has dimensions in all spatial directions of 10 nm to 100 pm, advantageously of 1000 nm to 80 pm, even more advantageously of 10 to 1000 nm.

11. Device according to claim 9, wherein the biocompatible materials of the carriers are completely degradable in the body.

12. Device according to claim 9, wherein the outer shell of the carrier consists entirely of biocompatible materials.

13. Device according to claim 9, wherein the biocompatible materials are hydrogels, such as gelatin, methacrylates, collagen, silk, alginates or biodegradable metal oxides, or metallic alloys, such as FeMgSi or FePt, with or without hard magnetic materials, such as NdFeB, CrO2 or BaFe^2O, or superparamagnetic iron oxide nanoparticles, such as SPIONs or iron-platinum nanoparticles, or other materials coated with biocompatible materials, such as surface coatings of proteins, gold or polymers, such as parylene or polyethylene glycol diacrylate (PEGDA).

14. Device according to claim 9, wherein the carriers comprise components which are holders, grippers, loops, catheters, cavities for detachable connection to gametes and / or zygotes and / or embryos, sensors and / or actuators.

15. Device according to claim 9, wherein the carriers have drive devices for independent movement.

16. Device according to claim 9, wherein the carriers are micro- or nanorobots.

17. Device according to claim 9, wherein the supports comprise materials with which the supports are moved by external or local influences.

18. Device according to claim 17, wherein the carriers contain organic, inorganic and / or magnetic materials.

19. Device according to claim 9, in which sensors or actuators are present on or in the carriers, which determine, transmit and monitor parameters from the environment of the carrier in situ and / or implement changes in the parameters based on determined parameters from the environment of the carrier.

20. Device according to claim 9, wherein the carrier(s) are connected to ex vivo arranged devices for controlling and / or moving and / or loading the carriers prior to in vivo transfer, wherein the connection is realized via mechanical devices or digitally.

21. Device according to claim 9, wherein the carriers comprise functional materials and / or biomolecules for the protection and / or growth of the gametes and / or zygotes and / or embryos.

22. Device according to claim 21, wherein the carriers comprise antioxidants, ripening factors, nutrients, protective molecules to reduce thermal and mechanical stress.