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

Abstract

The invention belongs to the field of material science, and relates to a method and a device for realizing controlled movement, which can be applied to in-vivo reproduction, medical care and the like. The invention aims to provide a method and a device capable of obviously reducing invasive use and obviously improving the implantation rate. According to the method for achieving the purpose, gametes and / or zygotes and / or embryos are / is connected to one or more carriers in a releasable mode, and the carriers carrying or not carrying the gametes and / or zygotes and / or embryos move independently or under the external action in a directional mode. Furthermore, the device for achieving the above-mentioned purpose comprises at least a carrier having a maximum dimension of 500 [mu] m in all spatial directions, said carrier consisting at least predominantly of a biocompatible material.

Description

Technical Field

[0001] The present invention belongs to the fields of materials science, biology and medicine, and relates to a method for at least controlling the movement of gametes and / or zygotes and / or embryos in a fluid, and a device for achieving said controlled movement, which can be applied, for example, to in vivo reproduction and medical care, wherein in addition to achieving controlled movement of gametes and / or zygotes and / or embryos, for example, safe development of gametes and / or zygotes and / or embryos can also be achieved. Background Art

[0002] Infertility is a problem that affects 48.5 million couples of childbearing age worldwide, accounting for about 11% of the total population. Possible causes of female infertility include ovulatory disorders, blocked fallopian tubes, endometriosis, and uterine and / or cervical factors.

[0003] Male infertility is often caused by poor sperm quality, which can manifest as low sperm motility, abnormal sperm morphology or low sperm count. This reduces the chances of fertilizing an egg in vivo.

[0004] Known infertility treatments include low-cost and minimally invasive hormone stimulation or intrauterine insemination (injecting sperm into the uterus during ovulation).

[0005] In addition, other known methods such as In-Vitro Fertilisation (IVF) or Intracytoplasmic Sperm Injection (ICSI) can also achieve pregnancy, which is particularly suitable for cases where tubal infertility or severe male infertility is confirmed.

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

[0007] However, the subsequent embryo transfer remains a critical stage, resulting in clinical pregnancy in only 32% of cases. In addition, the implantation rate of each embryo remains low (about 17%), and the method often has to be repeated several times without success, resulting in high economic and social costs.

[0008] Even when the first three embryo transfers were performed with genetically tested euploid embryos at the blastocyst stage and were performed in women with anatomically normal uterine structures, implantation rates were only between 60.3% and 69.9%.

[0009] Poor implantation rates and, therefore, pregnancy rates of transferred embryos obtained through IVF and ICSI may be due to stress during in vitro preparation and culture, lifestyle factors of the treated couple, disease, uterine or endometrial abnormalities, embryo factors, or different techniques in the IVF laboratory or during embryo transfer.

[0010] However, in most cases, no obvious reason can be found. For the above medical problems, other diagnostics such as hysteroscopy and endometrial biopsy or treatment of endometrial lesions, changes in ovulation induction regimen, blastocyst transfer, assisted hatching, and pre-implantation screening may be helpful.

[0011] A feasible method to improve the implantation rate of repeated implantation failure (RIF) is to transfer gametes or zygotes or in vitro fertilized eggs (embryos) back to the fallopian tube through laparoscopy, also known as gamete intrafallopian tube transfer / zygote intrafallopian tube transfer (GIFT / ZIFT). It is speculated that the advantage of this method is that it provides a suitable physiological environment for embryo development and optimal synchronization between embryo and endometrial preparation. However, the reproducibility of this method is very low and depends on the operator's skills and the culture conditions before the gametes or embryos are transferred back to the fallopian tube or uterus.

[0012] Furthermore, this approach is highly invasive, requiring surgery and anesthesia to insert laparoscopic macroscopic imaging and manipulation tools into the female body, which may result in side effects such as tubal trauma, inflammation, tubal pregnancy, infection, or intracavitary lesions.

[0013] Nevertheless, this treatment appears to have achieved a relatively high pregnancy rate of 39.8% in patients with high-order RIF (long duration of infertility and a high number of failed standard IVF-ET cycles), so this approach still has untapped potential.

[0014] Other methods are known to improve the above problems, in particular to increase the motility of motile cells (such as sperm). In the method proposed in DE10 2012 212 427A1, one or more motile cells are introduced or attached to one or more magnetic particles, and then the magnetic particles with the introduced or attached motile cells are moved in a directed manner by applying an external magnetic field.

[0015] This method increases the activity and controlled motility of active cells, and can control the movement of active cells in a desired direction.

[0016] Such methods are not applicable to non-motile cells.

[0017] For example, non-motile cells refer to sperm or general egg cells that have lost their motility.

[0018] Movement of the egg occurs when the funnel-shaped fallopian tube extends to the ovary and receives the egg during ovulation. This causes the fallopian tube to contract rhythmically, and tiny cilia (ciliated cells) transport the egg within the fallopian tube, pushing it toward the uterus (Wikipedia, Keywords: Movement of the egg).

[0019] A known method is that an egg or embryo is provided with a layer of magnetic particles, and a magnetic field is applied by a permanent magnet or an electromagnet to fix the egg or embryo in the uterus (US 6,695,766 B4). The egg or embryo with the magnetic particle layer is transported to the uterus through a catheter. The diameter of the magnetic particles can be 0.1 μm to 200 μm. These magnetic particles aggregate with the egg or embryo, so that the reactive groups on the surface of the magnetic particles react with the reactive groups on the surface of the egg or embryo, thereby achieving adhesion of the magnetic particles to the surface of the egg or embryo.

[0020] There is also known a method for making non-motile cells motile, in which the non-motile cells and non-motile sperm are connected to a microstructure, wherein the microstructure is at least partially composed of a magnetic material, and a non-reciprocating motion of the microstructure and the non-motile cells is achieved through a time-varying three-dimensional external magnetic field (see patent document DE 10 2014201 760A1).

[0021] In addition, US 6050935 A discloses a container device for intravaginal fertilization and embryo transfer, which can be applied to intravaginal fertilization. For this purpose, the container is inserted into the vaginal vault.

[0022] The container comprises a container body with an opening, for introducing culture medium, one or more ovums (oncytes) and sperm, using a collecting catheter to carry one or more embryos subsequently. The container body has a main chamber for accommodating culture medium, ovums and sperm and a microchamber for collecting one or more embryos. The container is enclosed in a capsule made of a soft elastic material. The ring on a part of the cyst body can be adjusted in length according to anatomical conditions. The microchamber has a passage that can accommodate the tip of the catheter, so that the risk of embryo damage is eliminated simultaneously when collecting the embryo. The microchamber allows the embryo to be microscopically detected in situ before the embryo is transplanted into the uterine cavity.

[0023] The disadvantage of the known solutions of the prior art is that, on the one hand, invasive methods are known and used for embryo transfer, and on the other hand, the implantation rate and pregnancy rate of the transferred embryos are still relatively low. Similarly, the existing methods use relatively large devices, which may cause damage to the embryos and / or tissues, or cause the embryos to be transferred to the wrong position to cause ectopic pregnancy. The low accuracy of the known methods and devices can also lead to multiple embryo fertilization and birth, which is also undesirable because multiple pregnancy has high risks to both the mother and the fetus. Summary of the invention

[0024] The object of the present invention is to provide a method and a device for the controlled movement of at least gametes and / or zygotes and / or embryos in a fluid, which device can be used in a significantly less invasive manner and which method has the effect of significantly improving implantation rates and thereby improving pregnancy rates.

[0025] The invention as set out in the attached claims solves the above-mentioned problems. Advantageous embodiments of the invention are the subject matter of the dependent claims, so that the invention also includes the combination of the dependent claims in the sense of "and", as long as they are not mutually exclusive.

[0026] In the method according to the present invention, at least for the controlled movement of gametes and / or zygotes and / or embryos in a fluid, the gametes and / or zygotes and / or embryos are releasably connected to one or more carriers, and the carriers carrying or not carrying gametes and / or zygotes and / or embryos move in a directed manner independently or under external influence.

[0027] Advantageously, the gametes and / or zygotes and / or embryos are linked to the carrier, and the link can be established and / or released by physical or chemical means.

[0028] It is also advantageous to use a carrier or carrier assembly carrying or not carrying gametes and / or zygotes and / or embryos, and to mechanically or digitally connect them to one or more in vitro devices in a releasable or non-releasable contact manner by friction bonding and / or shape bonding, wherein, more advantageously, the in vitro device is used to control and / or move and / or load the carrier prior to in vivo transplantation.

[0029] More advantageously, independently moving carriers are employed, wherein a plurality of carriers move independently of one another in the same direction or in different directions, or move in groups in the same direction.

[0030] Advantageously, the carrier is also moved by an external physical field, such as a magnetic field or an ultrasound field, or by a chemical, thermal or physical stimulus.

[0031] It is also advantageous if the position and movement of the carrier is monitored by imaging methods.

[0032] It is also advantageous if environmental parameters of the carrier are determined, transmitted and monitored in situ by means of sensors or actuators on or in the carrier and / or parameter changes are effected based on determined environmental parameters of the carrier.

[0033] According to the invention, the device for the controlled movement of at least gametes and / or zygotes and / or embryos in a fluid comprises at least one carrier having a maximum dimension of 500 μm in all spatial directions and consisting at least predominantly of a biocompatible material.

[0034] Advantageously, the at least one carrier has dimensions in all spatial directions of 10 nm to 100 μm, advantageously 1000 nm to 80 μm, more advantageously 10 nm to 1000 nm.

[0035] Also advantageously, the biocompatible material of the carrier is fully degradable in vivo.

[0036] More advantageously, the outer shell of the carrier is entirely composed of biocompatible material.

[0037] Also advantageously, the biocompatible material is selected from: hydrogels such as gelatin, methacrylate, collagen, silk, alginate; or biodegradable metal oxides; or metal alloys such as FeMgSi or FePt, which may or may not contain hard magnetic materials such as NdFeB, CrO2 or BaFe 12 O1, or it contains or does not contain superparamagnetic iron oxide nanoparticles, such as SPION or iron platinum nanoparticles; or other materials coated with biocompatible materials, such as surface coatings made of proteins, gold or polymers (such as polyparaxylene or polyethylene glycol diacrylate (PEGDA)).

[0038] It is also advantageous if the carrier comprises components: holders, clamps, lassos, catheters, cavities for releasably connecting gametes and / or zygotes and / or embryos; sensors and / or actuators.

[0039] It is also advantageous if the carrier comprises drive means for independent movement.

[0040] It is also advantageous if the carrier is a microrobot or a nanorobot.

[0041] It is also advantageous if the carrier has a material which enables the carrier to be moved by external or local action.

[0042] Likewise advantageously, the support comprises organic, inorganic and / or magnetic materials.

[0043] It is also advantageous if sensors or actuators are present on or in the carrier for determining, transmitting and in situ monitoring of environmental parameters of the carrier and / or for implementing parameter changes based on determined environmental parameters of the carrier.

[0044] Also advantageously, the one or more carriers are connected to an in vitro device for controlling and / or moving and / or loading the carriers prior to in vivo implantation, the connection being achieved by mechanical means or digitally.

[0045] It is also advantageous if the carrier comprises functional materials and / or biomolecules for the protection and / or growth of gametes and / or zygotes and / or embryos, wherein, more advantageously, the carrier comprises antioxidants, maturation factors, nutrients, protective molecules for reducing thermal and mechanical stress.

[0046] By means of the present invention, disclosed herein for the first time is a method and device for the controlled movement of gametes and / or zygotes and / or embryos in a fluid, wherein the device is used in a significantly reduced invasive manner and a significantly improved implantation rate and thereby a significantly improved pregnancy rate is achieved by the method.

[0047] This is achieved by a method for controlled movement of gametes and / or zygotes and / or embryos in a fluid, wherein the gametes and / or zygotes and / or embryos are releasably attached to one or more carriers.

[0048] Gametes, also known as sex cells or reproductive cells, are a special type of cell. During sexual reproduction, two gametes combine to form a zygote.

[0049] A zygote is a diploid eukaryotic cell formed during sexual reproduction by the fusion of two haploid sex cells (usually an egg and a sperm).

[0050] An embryo is a living organism in the early stages of its development.

[0051] According to the present invention, the gametes and / or zygotes and / or embryos to be mobilized can be from humans and animals.

[0052] The connection and release of the gametes and / or zygotes and / or embryos to the one or more carriers can be achieved by physical and / or chemical means.

[0053] The physical means may be mechanical means such as a holder, a clamp, a lasso, a catheter, a cavity on or within the carrier.

[0054] Likewise, micro- to nano-actuators may be present on or in the carrier material, for example with gripping arms or fingers, which can be opened and closed by electrical, mechanical, thermal and / or chemical stimulation. Advantageously, such micro- to nano-actuators have dimensions of the order of magnitude of gametes and / or zygotes and / or embryos.

[0055] Advantageously, the carrier also has a cavity or capsule, preferably with permeable or semi-permeable walls, in which the gametes and / or zygotes and / or embryos or other materials can be accommodated.

[0056] As a mechanical mechanism, the carrier is particularly advantageously frictionally and / or shape-bonded to the microcatheter. In this case, the microcatheter is connected to a device for controlling and / or moving and / or loading the carrier before implantation in the body. Thus, the carrier according to the invention can be inserted into the body via a conventional cannula or egg cell transplantation catheter. Since the dimensions of the catheter and the carrier are at least micrometer-sized, even more complex and sensitive areas of the body, such as the fallopian tube, can be reached.

[0057] The connection of the microcatheter to the outside of the body can advantageously be achieved by mechanical means or digital means.

[0058] In this case, the carrier according to the invention may be releasably or non-releasably connected to the mechanical means, such as the microcatheter.

[0059] According to the present invention, a free movable carrier capable of independent movement can exist as a non-bound carrier.

[0060] Such a carrier may be a movable fixture and / or a capsule, or may be in the shape of a rod and / or a cylinder.

[0061] The carrier can also be subdivided, for example, divided into different modules within the same carrier, so that different components (gametes / zygotes / embryos, magnetic particles, contrast agents, antioxidants, etc.) can be accommodated separately and individually.

[0062] These vectors can be implanted into the uterus via a conventional cannula or an embryo transfer catheter.

[0063] These mobile, non-bound carriers can, for example, move in a directed manner under the action of an external field. For example, the carriers, with or without gametes and / or zygotes and / or embryos or other materials, can swim, crawl, move, roll, and reach desired areas, particularly difficult-to-reach complex and / or sensitive areas, such as fallopian tubes, without mechanical connection to the outside of the body.

[0064] Advantageously, the movement of the carrier is monitored in real time by means of bioimaging techniques with the highest possible spatial and temporal resolution and controlled accordingly.

[0065] The attachment can be achieved chemically through functional groups and / or gels, for example by incorporating the carrier into a hydrogel, coupling to a stimuli-sensitive linker, coupling via hydrophilic / hydrophobic interactions, coupling via hydrodynamic or electrostatic or magnetic or acoustic forces.

[0066] The disengagement between the carrier and at least the gamete and / or zygote and / or embryo can be achieved by disengaging physical connection or disengaging chemical connection, and can also be achieved by adopting in vivo degradable, particularly biodegradable carrier materials. The degradation rate should adapt to the situation of the destination of each implantation of the gamete and / or zygote and / or embryo and the required residence time for this purpose, for example, is limited by comprehensive factors such as local environment or locally present protease or external effects (such as utilizing local temperature to rise). Once the gamete and / or zygote and / or embryo and arrive at their destination, the biodegradable carrier material will be dissociated.

[0067] According to the invention, the carrier, whether carrying gametes and / or zygotes and / or embryos or not, is then moved in a directed manner independently or under external influence.

[0068] The carrier is first moved outside the body without the carrier carrying the gametes and / or zygotes and / or embryos, or is moved or introduced into the body using other devices (such as cannulas or catheters) so as to subsequently pick up and hold the gametes and / or zygotes and / or embryos and transport them to the desired location.

[0069] The carrier can also be moved and / or controlled to move in a directed manner by local influences such as chemotaxis, thermotaxis, thiotaxis or rheology. The carrier can also be controlled by external physical fields such as magnetic fields, ultrasound and / or infrared light.

[0070] However, the carrier can also be connected to the gametes and / or zygotes and / or embryos in vitro and then transported together into the body. This can also be accomplished by other means such as cannulae or catheters, or the carrier carrying the gametes and / or zygotes and / or embryos moves independently or under external action.

[0071] For example, a carrier can be provided for the gametes and / or zygotes and / or embryos in vitro, and then the gametes and / or zygotes and / or embryos are transported through the cervix to the entrance of the uterus, for example using a non-surgical embryo transfer tool (NSET) or a flexible cannula.

[0072] At the desired location, for example in the uterus, the carrier can then be separated from the gametes and / or zygotes and / or embryos by an external or local chemical or physical action. Advantageously, this external action can be an external fluid dynamic field, a magnetic field, an electrostatic field and / or an acoustic field.

[0073] Also advantageously, imaging methods or external sensors can be used to monitor the position and movement of the carrier. The carrier can trigger a local reaction or biomarker that can then be detected in a biological fluid. For example, such detection can be performed by external rapid detection sensors or PCR. Similarly, the "reporter" portion of the carrier can also undergo local morphological changes or be activated, which can be detected, for example, by magnetic resonance or PET or other imaging methods.

[0074] Furthermore, according to the invention, the device for the controlled movement of gametes and / or zygotes and / or embryos in a fluid comprises at least one carrier having a maximum dimension of 500 μm in each spatial direction, the carrier being at least predominantly composed of a biocompatible material.

[0075] Advantageously, the maximum dimension of the carrier in all spatial directions is from 10 nm to 100 μm, advantageously from 1000 nm to 80 μm, more advantageously from 10 nm to 1000 nm.

[0076] Furthermore, on the one hand, the size and material of the carrier depends on the gametes and / or zygotes and / or embryos to be transported, but the carrier is also at least mainly composed of a biocompatible material that can sense the microenvironment of the gametes and / or zygotes and / or embryos and react to it, such as changing shape or surface properties, such as releasing the required substances to ensure safe transportation and safe development of the gametes and / or zygotes and / or embryos during their implantation in the fallopian tube or uterus. Also advantageously, the carrier material is permeable to nutrients, antioxidants and growth factors that can and should pass through the carrier material into the body or enter the carrier from the fallopian tube fluid.

[0077] The maximum dimension of the carrier in all spatial directions does not exceed the minimum dimension of the fallopian tube, which is about 500 μm in diameter.

[0078] In any case, the dimensions of the carrier should be as small as possible, but the dimensions of the carrier can also be up to approximately 500 μm, since the carrier must move within the folded and thus also stretchable adaptive tissue.

[0079] Advantageously, the vector is of a size similar to that of the gametes and / or zygotes and / or embryos so as to be able to enter the narrowest area of ​​the fallopian tube without damaging surrounding tissue.

[0080] The carrier has a size and shape such that it protects the gametes and / or zygote and / or embryo during transport, for example into an ampoule, so that they can develop under as natural conditions as possible until they reach the endometrium, i.e. the uterine mucosa in the uterine cavity. This can be achieved, for example, by means of a capsule in which the gametes and / or zygote and / or embryo and other materials are encapsulated during transport.

[0081] It is also particularly advantageous if the outer shell of the carrier consists entirely of biocompatible materials. This is particularly important if the carrier used needs to remain in the body and / or degrade in the body. Other medically harmless materials may also be used if the carrier can and should be removed from the body.

[0082] Also advantageously, the biocompatible material of the carrier is completely degradable in vivo.

[0083] According to the present invention, the carrier material may be degraded after the carrier has performed its function in the body but has not been removed from the body by other measures, methods or devices.

[0084] Such biocompatible materials are in particular hydrogels such as gelatin, methacrylates, collagen, silk, alginates or biodegradable metal oxides, all of which are preferably biodegradable, permeable and / or soft and can interact gently with the surrounding tissues in the body.

[0085] Other biocompatible materials include metal alloys such as FeMgSi or FePt, with or without hard magnetic materials such as NdFeB, CrO2 or BaFe 12 O 19 ), or contain or not contain superparamagnetic iron oxide nanoparticles (such as SPION 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 polyparaxylene or polyethylene glycol diacrylate (PEGDA)).

[0086] In addition, the carrier may include antioxidants, hormones, medicines and / or permeable materials as required, so as to exchange nutrients from the secretory cells in vivo, particularly in the fallopian tube. Such materials may also be epigenetic regulators, immune system protection factors, oxidative stress and heat stress protection factors or auxiliary substances (embryo trophic factors, growth factors) of embryonic division and development. The material used for the carrier may significantly reduce the friction between the carrier and the gamete and / or zygote and / or the embryo, thereby avoiding damage and cytotoxicity and stress that may be caused to the gamete and / or zygote and / or the embryo. Equally advantageously, simultaneously can carry out or assist embryonic development and transport the required nutrients and the passage / exchange of the fallopian tube fluid of secretion.

[0087] Advantageously, the carrier comprises functional materials and / or biomolecules for the protection and / or growth of the gametes and / or zygotes and / or embryos. Such functional materials may also be nanosensors for monitoring environmental parameters of the microenvironment, such as oxygen levels, glucose levels, growth factors, etc., which parameters may also be regulated in situ by the nanoactuators of the carrier or the materials contained therein.

[0088] The production of carriers made of biocompatible and advantageously biodegradable materials can be carried out using two-photon lithography processes or by processes for producing strained materials (strain engineering) or 3D / 4D printing techniques.

[0089] The vectors can also be produced by droplet microfluidics. The advantage of this production process is that the gametes and / or zygotes and / or embryos can be introduced directly into individual droplets of biodegradable or irritation-sensitive polymers.

[0090] Other possibilities for producing the vector include chemical synthesis or by template-based processes.

[0091] These droplets can then be implanted in the body and moved in a directed manner by ultrasound or magnetic propulsion or local stimulation such as temperature gradients, chemical gradients, or flow.

[0092] The magnetic propeller can be placed in a microfluidic channel to promote the capture of the gametes and / or zygotes and / or embryos in the droplets by generating a differential flow. However, capture can also be achieved and / or promoted by self-assembly techniques or by utilizing capillary forces, hydrodynamic forces or hydrophilic / hydrophobic interactions. Similarly, the capture of the gametes and / or zygotes and / or embryos can be achieved in vitro by coupling or loading into the carrier by optical tweezers, magnetic tweezers or acoustic tweezers techniques.

[0093] Advantageously, the carrier may comprise drive means for independent movement. Advantageously, these drive means may be microrobots or nanorobots.

[0094] However, using a magnetic propeller as part of the carrier also results in the carrier moving independently with or without carrying gametes and / or zygotes and / or embryos.

[0095] Structural materials (such as PEGDA) or hollow hydrogel tubes or 3D printed elastomers (such as silicone, polyurethane, polyolefin, styrene block copolymer, etc.) can be used as carriers in the form of microrobots.

[0096] Materials such as Fe, FePt for magnetic motion or electroactive polymers such as polypyrrole or other stimuli-responsive hydrogels can be used to actuate the microrobots.

[0097] Some inorganic layers made of or containing gold (Au) or platinum (Pt), alloys or core-shell nanoparticles can also be used for sensing technology, or gold-based nanomaterials or quantum dots (QDs) can be used for imaging, and silver (Ag) can be used to avoid the formation of biofilms.

[0098] Due to the independent movement, the carrier itself can generate a slight flow, so that the carrier can move in the fluid (usually a viscoelastic medium) in the body. In particular, for example, due to its peristalsis and ciliary beating in the fallopian tube, these carriers can also move in reverse flow or reverse backflow.

[0099] If the carrier contains magnetic material, the carrier can also be transported by an external magnetic field. This can also be done when the carrier is in the form of a droplet. Likewise, the carrier can contain a fluid, whereby directional movement of the carrier is achieved by ultrasound from outside the body or by artificial and / or biohybrid flagella-like actuation.

[0100] Furthermore, the carrier in the form of a droplet can also be multifunctional by incorporating additional agents during its formation, such agents can be active ingredients present in the microcapsules, magnetic materials in the beads and / or infrared reporter molecules, reflectors or absorbers, so as to be able to track the carrier during its movement, in particular in vivo.

[0101] The carrier may also contain antioxidants and estrogens to protect the gametes and / or zygotes and / or embryos during transport.

[0102] In addition, organometallic materials or oxygen-sensitive particles can also be used as components of the carrier to monitor the metabolic conditions of the gametes and / or zygotes and / or embryos on the way in the body. The materials and components of this type of carrier can also be called nanosensors or nanoactuators.

[0103] Such nanosensors or nanoactuators can measure, inter alia, the concentration 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 the harmful metabolites.

[0104] Similarly, the nanosensor or nanoactuator is also used to monitor in situ the parameters of the microenvironment, such as pH, secreted proteins, growth factors, reactive oxygen species (ROS), hormones, fallopian tube secretions, and activate a corresponding reaction of the carrier, such as local release of drugs / molecules / antioxidants / growth factors or change its shape, so as to release the gametes and / or zygotes and / or embryos, for example. In addition, these detection parameters can be determined by bioimaging or in vitro biofluid analysis, such as by lateral flow sensors or PCR. Also advantageously, the carrier comprises components, which include retainers, clamps, lassos, catheters, cavities to which the gametes and / or zygotes and / or embryos are releasably connected, sensors and / or actuators.

[0105] These components can be controlled directly by the carrier through an onboard power supply or by an external field.

[0106] This may also allow the vector to sense the environment, analyze the environment and the situation of the gametes and / or zygotes and / or embryos in vivo, and gain insight into the function and structure of the female reproductive tract during various stages of the estrous cycle.

[0107] Likewise, the carrier according to the invention can be used to carry sensors into the region of gametes and / or zygotes and / or embryos to monitor embryonic development in situ, or to stimulate cells or release molecules in situ using mechanical, optical and / or electronic actuators. Such sensors can not only monitor embryonic development, but also measure environmental parameters in vivo (particularly in the fallopian tube), such as local pH, temperature, glucose levels, etc., and transmit the measured values ​​to the body.

[0108] Advantageously, one or more of the carriers may be mechanically or digitally coupled to an in vitro device for controlling movement and / or components of the carrier.

[0109] According to the present invention, the carrier can be attached to the body, for example, to a catheter or a tether, and can move or move in the body in this way or in an unattached manner. This movement or motion can be floating, rolling, sliding and / or moving, and can also be movement caused by peristalsis or surrounding fluid traveling waves.

[0110] Advantageously, the external effect is an external magnetic field, external ultrasound or a combination thereof, which can be used simultaneously for the application of the imaging method. The technical solution according to the present invention can deliver and release gametes and / or zygotes and / or embryos of the highest quality in vivo non-invasively. Advantageously, the carrier used for this purpose is a multifunctional micro robot with a maximum size of 500 μm in all spatial directions, which is at least mainly composed of intelligent biocompatible materials and manufactured by advanced microtechnology.

[0111] The technical solution according to the present invention can support and improve in vivo fertilization and embryo transplantation.

[0112] The technical solution according to the invention can also be successfully used in particularly hard-to-reach areas of the reproductive system, such as the fallopian tube. 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 during embryo development and transport to the uterus, especially when the endometrium is prepared for embryo implantation.

[0113] To date, existing methods and devices have not targeted the fallopian tubes, which are tiny internal organs that are difficult to reach.

[0114] Compared with existing in vitro techniques, the assisted reproductive method proposed by the present invention can achieve in vivo transplantation. The method and device can also be extended to other medical fields, such as for administering drugs to treat diseases (such as cancer, endometriosis and / or other female and male reproductive health problems) and / or for transplantation to other organs, such as for sampling for diagnosis or local diagnosis.

[0115] The carrier according to the present invention is advantageously a micro- to nano-robot.

[0116] (i) capable of reliably capturing and protecting the gametes and / or zygotes and / or embryos during transport between different environments;

[0117] (ii) allowing secreted molecules to enter through ciliated cells of the oviduct or the embryo itself;

[0118] (iii) is biocompatible and / or advantageously biodegradable

[0119] (iv) capable of moving in fluids (mainly viscoelastic media) and preventing backflow within the fallopian tube; (v) not damaging the fallopian tube, which is an extremely sensitive organ;

[0120] (vi) allow in situ examination of reproductive organs and the local microenvironment of gametes and / or zygotes and / or embryos;

[0121] (vii) being able to adjust the functions of the gametes and / or zygotes and / or embryos (e.g., molecule release, shape change, permeability, etc.) according to the microenvironment and health status of the obtained gametes and / or zygotes and / or embryos;

[0122] (viii) can potentially carry drugs, for example to correct genetic defects in the gametes and / or zygotes and / or embryos during delivery, or to arrest their development at an early stage if obvious, incurable dysfunction occurs in the embryos.

[0123] For example, a microcatheter tool may be used as a component on the carrier to release the gametes and / or zygotes and / or embryos at a desired location through an external or internal trigger mechanism, which may also be used to pass through complex bends of the fallopian tube in a minimally invasive manner.

[0124] The carrier according to the present invention can be inserted into the uterus or fallopian tube through the vagina by a cannula or catheter. At this point, the carrier can capture and transport the gametes and / or zygotes and / or embryos, for example, by a micro-spherical clamp or a cystic embryo carrier.

[0125] A significant advantage of the technical solution according to the present invention is that in particular gametes and / or zygotes (i.e. sex cells and early embryos) and late embryos can be moved in a directional manner, and can also be used for gamete intrafallopian transfer (GIFT) or zygote intrafallopian transfer (ZIFT). In addition to the known methods for stabilizing embryos in the uterus, it is now also possible to adopt minimally invasive or even non-invasive methods to move the gametes and / or zygotes and / or embryos in a directional manner. According to the present invention, this directional movement can be carried out until the fallopian tube.

[0126] According to the invention, the carrier, advantageously the microrobot, used for this purpose does not have to remain in the body, nor does it have 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 located in a capsule, which is then in direct contact with the carrier.

[0127] Compared with laparoscopic and intrauterine embryo transfer, the technical solution according to the present invention has the following advantages:

[0128] -Minimally invasive or even non-invasive

[0129] The carrier according to the present invention is smaller than the size of existing surgical instruments. The carrier can be a combined, such as a robotic catheter, or a non-combined, floating, rolling, sliding and / or moving micro- to nano-robot.

[0130] - Material selection

[0131] According to the invention the carrier is biocompatible and advantageously biodegradable, for example to meet the residence time required for the gametes and / or zygotes and / or embryos to be implanted at the desired location.

[0132] -Other options

[0133] According to the present invention, the carrier can also be loaded with other functional materials and / or biomolecules, such as antioxidants, maturation factors, nutrients, protective molecules for reducing thermal stress and mechanical stress, to support embryonic development.

[0134] -Other parts

[0135] According to the invention, the carrier can also be equipped with mechanical, optical and / or electronic micro- to nano-sensors or actuators.

[0136] The advantages of the present invention are particularly suitable for situations with a high correlation of multiple embryo transfer failures, i.e. situations where conventional in vitro fertilization methods are used to transfer embryos in the uterine area but fail to achieve a successful pregnancy. Due to the gentle interaction of the carrier according to the present invention with the surrounding tissues in the body, a significantly improved implantation rate can be achieved compared to the appropriate but cumbersome handling and imaging tools currently used in various steps of the assisted reproductive process (starting from egg retrieval to further uterine transfer of embryos or laparoscopically assisted intrafallopian tube transfer), thereby achieving a pregnancy outcome.

[0137] Furthermore, according to the present invention, it can be ensured that only high-quality embryos are connected to the carrier and introduced into the fallopian tube.

[0138] To ensure high quality of the embryo / gamete and maintain this high quality during transportation, the carrier may include nanosensors that can measure various variables during embryo development and, in some cases, regulate these variables.

[0139] The present invention also has the advantage that substantially no non-biocompatible materials are used, or non-biocompatible materials do not directly contact the gametes and / or zygotes and / or embryos. Since the carrier according to the present invention can be separated from the gametes and / or zygotes and / or embryos under any circumstances, even a carrier made of non-biocompatible materials will not have a harmful effect on the gametes and / or zygotes and / or embryos and can be easily removed from the body.

[0140] The technical solution according to the present invention can improve the implantation rate, thereby significantly improving the pregnancy outcome. DETAILED DESCRIPTION

[0141] Hereinafter, the present invention will be explained in detail with reference to several embodiments.

[0142] Embodiment 1:

[0143] One carrier is a microcatheter with a diameter of 100 μm, made of the biocompatible material PEGDA, and the shell of the microcatheter is produced by 3D printing technology. The microcatheter integrates an embryo cavity, a micropump, and sensors for optical / electronic monitoring of the embryo.

[0144] The embryo and the surrounding fluid and nutrients are gently sucked into the microcatheter cavity outside the body by a micropump, and then inserted into the cervix through the vagina by cannula. The microcatheter is then moved to the uterine mucosa in a directed manner by ultrasound. The position and condition of the embryo are monitored by sensors and external imaging devices to determine whether the embryo has reached the desired position.

[0145] Embryo positioning does not require anesthesia or local anesthesia and lasts about 1 hour. The catheter can be removed after positioning.

[0146] Embodiment 2:

[0147] Using droplet fluidics technology and biocompatible gelatin as a carrier, microcapsules with a diameter of 500 μm were made.

[0148] Sperm and egg cells are introduced into the microcapsules using droplet fluidics technology and nanopropellers and nanosensors made of magnetic materials and nutrients.

[0149] The microcapsules are then moved by an external magnetic field through the vagina into the uterus and finally into the fallopian tubes, where the biocompatible material begins to degrade, releasing sperm and eggs for fertilization during the luteal phase of the estrous cycle.

[0150] Because the zygote migrates further to the uterus through the peristalsis of the fallopian tube and can implant on the mucosa, the resulting zygote can develop into an embryo under more natural conditions and arrive at the uterus in complete synchronization with the endometrial preparation.

[0151] The zygote can thereby be located naturally without anesthesia, but can also be located under local anesthesia.

[0152] The biocompatible material of the microcapsules, along with the magnetic material and the fluid surrounding the fallopian tubes, is removed from the body in approximately one hour.

Claims

1. A method for the controlled movement of at least gametes and / or zygotes and / or embryos in a fluid, wherein the gametes and / or zygotes and / or embryos are releasably connected to one or more carriers, and the carriers carrying or not carrying gametes and / or zygotes and / or embryos move in a directed manner independently or under external influence.

2. The method according to claim 1, wherein: The gametes and / or zygotes and / or embryos are connected to the carrier, and the connection can be achieved and / or released by physical or chemical means.

3. The method according to claim 1, wherein: A carrier or carrier component carrying or not carrying gametes and / or zygotes and / or embryos is used to achieve mechanical or digital connection with one or more in vitro devices through friction bonding and / or shape bonding, in a releasable or non-releasable contact manner.

4. The method according to claim 3, wherein: Prior to in vivo implantation, an in vitro device is used to control and / or move and / or load the vector.

5. The method according to claim 1, wherein: Independently moving carriers are used, wherein a plurality of carriers move independently of each other in the same direction or in different directions, or move in groups in the same direction.

6. The method according to claim 1, wherein: The carrier is moved by an external physical field, such as a magnetic field or an ultrasound field, or by a chemical, thermal or physical stimulus.

7. The method according to claim 1, wherein: The position and movement of the carrier is monitored by imaging methods.

8. The method according to claim 1, wherein: By means of sensors or actuators on or in the carrier, environmental parameters of the carrier are determined, transmitted and monitored in situ, and / or parameter changes are implemented based on the determined environmental parameters of the carrier.

9. A device for the controlled movement of gametes and / or zygotes and / or embryos in a fluid, the device comprising at least a carrier having a maximum dimension of 500 μm in all spatial directions, the carrier at least mainly consisting of a biocompatible material.

10. The device according to claim 9, wherein: The dimensions of at least one of the carriers in all spatial directions are 10 nm to 100 μm, advantageously 1000 nm to 80 μm, more advantageously 10 nm to 1000 nm.

11. The device according to claim 9, wherein: The biocompatible material of the carrier is completely degradable in the body.

12. The device according to claim 9, wherein: The outer shell of the carrier is completely composed of biocompatible material.

13. The device according to claim 9, wherein: The biocompatible material is selected from: hydrogels such as gelatin, methacrylate, collagen, silk, alginate; or biodegradable metal oxides; or metal alloys such as FeMgSi or FePt, which contain or do not contain hard magnetic materials such as NdFeB, CrO2 or BaFe 12 O 19 , or it may or may not contain superparamagnetic iron oxide nanoparticles, such as SPION or iron platinum nanoparticles; or other materials coated with biocompatible materials, such as surface coatings made of proteins, gold or polymers such as polyparaxylene or polyethylene glycol diacrylate (PEGDA).

14. The device according to claim 9, wherein: The carrier comprises components, which are: a holder, a clamp, a lasso, a catheter, a cavity that can be releasably connected to gametes and / or zygotes and / or embryos; a sensor and / or an actuator.

15. The device according to claim 9, wherein: The carrier comprises drive means for independent movement.

16. The device according to claim 9, wherein: The carrier is a micro robot or a nano robot.

17. The device according to claim 9, wherein: The carrier includes a material that enables the carrier to be moved by external or local action.

18. The device according to claim 17, wherein: The carrier includes organic, inorganic and / or magnetic materials.

19. The device according to claim 9, wherein: Sensors or actuators are present on or in the carrier for determining, transmitting and in-situ monitoring of carrier environment parameters and / or implementing parameter changes based on determined carrier environment parameters.

20. The device according to claim 9, wherein: One or more carriers are connected to an in vitro device to control and / or move and / or load the carriers prior to in vivo implantation, wherein the connection is achieved by mechanical means or digitally.

21. The device according to claim 9, wherein: The carrier includes functional materials and / or biomolecules for the protection and / or growth of the gametes and / or zygotes and / or embryos.

22. The device according to claim 21, wherein The carrier includes antioxidants, maturation factors, nutrients, protective molecules for reducing thermal and mechanical stress.