Reservoir, carbon monoxide release device, treatment system, living cell treatment device, method of treating mammals, and carbon monoxide

Abstract

The present invention relates to a reservoir (10) configured to be inserted into a human and / or animal body, comprising a housing (12) and a chamber (14) defined within the housing (12). The chamber (14) is configured to receive a primary substance (42), the primary substance (42) being configured to selectively release carbon monoxide upon activation of the activated substance (44). The chamber (14) is closed by a wall (16) of the housing (12) that is permeable to the carbon monoxide emitted by the primary substance (42) such that the reservoir (10) can release the carbon monoxide emitted by the primary substance (42) into the environment. The reservoir (10) is configured such that the activating substance (44) can be introduced into the chamber (14) from outside the housing (12) in a state in which the main substance (42) has been arranged within the chamber (14). The invention also relates to a device (40) for selectively releasing carbon monoxide, a treatment system (60; 80) and kits, methods for treating mammals, the use of carbon monoxide and methods for treating biological cells.

Description

[0001] Various substances, such as gases and / or liquids, are used for therapeutic purposes, such as treating one or more diseases. The corresponding substances can be applied externally, such as applied to the skin of a subject (e.g., a human and / or an animal). However, in some cases, it may be necessary and / or more effective to introduce the corresponding substances into the body of the subject.

[0002] In some cases, it may be advantageous to store the corresponding substance in a housing (e.g., a capsule) to facilitate administration of the corresponding substance to the corresponding treatment site (e.g., into the body of the corresponding subject). This may allow the corresponding substance to be released at the treatment site, e.g., within the body of the subject, particularly once the housing (e.g., a capsule) has reached a specific region in the body of the subject, such as a target region. This may enhance the therapeutic effect of the substance and / or prevent or at least limit adverse reactions that the substance may have on one or more regions of the subject's body.

[0003] For example, carbon monoxide (CO) is known to have beneficial therapeutic effects on humans and / or animals. For example, in the presence of one or more stress factors in a subject, the body can naturally initiate an increase in carbon monoxide production to trigger or increase one or more countermeasures and / or defense mechanisms to respond to the stress factors. Therefore, exogenous supplementation of carbon monoxide has a high therapeutic potential as a medical substance.

[0004] However, there are several challenges in administering carbon monoxide to a subject. For example, carbon monoxide is generally considered a toxic gas. In particular, if a subject is exposed to carbon monoxide to a certain degree, for example, if the carbon monoxide is inhaled, the carbon monoxide can mix and bind with hemoglobin in the subject's blood. As a result, less oxygen can be delivered to body tissues and vital organs, such as the brain and heart, which can have adverse effects, such as reversible and / or irreversible damage to the human and / or animal body, or even death.

[0005] Therefore, there is a need for a safe and / or controlled means of administering carbon monoxide. Carbon monoxide release systems have been proposed in the prior art.

[0006] For example, EP 3 242 552 B1 (the entire contents of which are incorporated herein by reference) discloses a gas release device comprising two compartments. One compartment contains carbon monoxide release molecules (CORMs), while the other compartment contains an activated substance that triggers the release of carbon monoxide from the carbon monoxide release molecules. Once the two substances from the two compartments combine, a chemical reaction leading to the release of carbon monoxide is triggered. Both compartments are surrounded by a gas permeable membrane that is permeable to carbon monoxide. The membrane is impermeable to the carbon monoxide release molecules, the activated substance, and the reaction byproducts.

[0007] In addition, WO 2021 / 074159 A1 (the entire contents of which are incorporated herein by reference) describes a film-based gas release device for oral applications. The device includes two compartments, which are separated by an internal diaphragm and surrounded by a gas permeable membrane. One compartment is loaded with carbon monoxide release molecules, and the other compartment contains an activated substance, which triggers the release of carbon monoxide from carbon monoxide release molecules. One of the compartments includes a hollow tip open end with an inclined cone, which can be moved toward the internal diaphragm by an extrusion device to destroy the internal diaphragm, so that the carbon monoxide release molecules and the active substance are mixed, which causes carbon monoxide to be released via a gas permeable membrane.

[0008] In addition, WO 2021 / 180908 A1 (the entire contents of which are incorporated herein by reference) discloses a treatment system configured for external treatment of wounds, inflammatory diseases of the skin, and inflammatory diseases of subcutaneous skin tissue, joints, and tendons. The treatment system includes a reaction chamber comprising carbon monoxide-releasing molecules and a gas-permeable but liquid-impermeable and solid-impermeable membrane. The carbon monoxide-releasing molecules can be mixed with a carbon monoxide-releasing triggering compound in the reaction chamber.

[0009] However, there are some disadvantages to the carbon monoxide release devices known in the prior art. For example, the configuration of the carbon monoxide release devices known in the prior art, such as the two-compartment construction of the device disclosed in WO 2021 / 074159 A1, is relatively complex, which makes them relatively large and / or potentially prone to failure. In addition, due to the relatively complex configuration, the manufacture of the corresponding carbon monoxide release devices known in the prior art may also be relatively costly and / or relatively time-consuming and / or relatively prone to failure. In addition, the system described in WO 2021 / 180908 A1 is specifically configured to treat the outer surface of a subject, in particular the skin of the subject. To this end, the system described in WO 2021 / 180908 A1 includes a relatively complex material mixture and an airtight portion to direct the released carbon monoxide to the skin. Therefore, the system lacks flexibility for a wider range of applications.

[0010] The various applications of carbon monoxide for different diseases and the respective signaling mechanisms are discussed in, for example, Gibbons et al., Carbon monoxide in gastrointestinal physiology and its potential in therapeutics, Aliment Pharmacol Ther. 2013 Oct; 38(7): 689–702.

[0011] It is therefore an object of the present invention to provide an improved means for administering carbon monoxide to a subject.

[0012] A first aspect of the present disclosure relates to a reservoir. The reservoir may be configured to be inserted into a human and / or animal body, preferably inserted through one or more natural orifices of the corresponding body. The reservoir may include at least one housing and at least one chamber defined within the housing. The chamber may be configured to receive and store at least one main substance, which is configured to selectively emit carbon monoxide. The main substance may be configured to emit carbon monoxide after being activated by at least one activating substance. The main substance may be configured to emit carbon monoxide substantially immediately after the main substance and the activating substance are mixed. Alternatively, the main substance may be configured to emit carbon monoxide in a delayed manner, i.e., after the main substance and the activating substance are mixed for a certain period of time. The reaction between the main substance and the activating substance that causes the main substance to emit carbon monoxide may also be a heat-dependent substance, for example, so that when the mixture of the main substance and the activating substance is heated to a certain threshold temperature (e.g., by body heat in the human and / or animal body), the main substance begins to release carbon monoxide.

[0013] The chamber may be enclosed by at least one wall of the housing, wherein at least a portion of the wall is at least partially permeable to carbon monoxide evolved by the primary substance, such that the reservoir may at least partially release the carbon monoxide evolved by the primary substance to the environment.

[0014] The "environment" can be a treatment site, such as in the human and / or animal body, or in a container for receiving biological cells, preferably living cells, such as immune cells, such as CAR T cells and / or stem cells, and / or gametes, such as sperm and / or oocytes, wherein the cells are treated with carbon monoxide released by the reservoir.

[0015] The reservoir may be configured so that the activation substance can be introduced into the chamber from outside the housing while the main substance is already arranged in the chamber. Once the activation substance is introduced into the chamber, the activation substance and the main substance may react to release carbon monoxide through the wall of the housing.

[0016] Therefore, compared with the corresponding carbon monoxide release device known in the prior art, the activation material may not be contained in the reservoir. On the contrary, in the state where the main substance has been arranged in the chamber, that is, in the state where the main substance is sealed in the chamber relative to the environment, preferably in a substantially fluid-tight and / or gas-tight manner, the activation material can be introduced into the chamber from the outside of the shell. In other words, the main substance can be stored in the chamber until the reservoir is used. Before the reservoir is applied, the activation material can be introduced into the chamber from the outside of the shell to activate the main substance. This can allow the construction of the reservoir to be simplified. In particular, since the activation material can be introduced into the chamber from the outside of the shell, the reservoir may not need to include a separate chamber to accommodate the activation material before mixing the main substance and the activation material when the main substance has been arranged in the chamber. Therefore, the reservoir can be configured in a relatively simple manner, for example, by only including a single chamber for accommodating the main substance, wherein the activation material can be directly introduced into the chamber accommodating the main substance, so that the main substance and the activation material can be mixed in the chamber. Furthermore, compared to carbon monoxide release devices known from the prior art (e.g. EP 3 242 552 B1 and WO 2021 / 074159 A1), one or more means for separating the activation substance and the main substance are not required and can therefore be omitted. This can also provide a more compact reservoir compared to carbon monoxide release devices known from the prior art, which can facilitate the application of the reservoir (e.g. ingestion).

[0017] In addition, due to the simplified construction of the reservoir as described above, the manufacture of the reservoir can also be simplified, which can reduce the manufacturing work of the reservoir, such as manufacturing costs and / or manufacturing time. In addition, the manufacturing process for manufacturing the reservoir can generally be less prone to errors.

[0018] In addition, the reservoir is configured so that the activation substance can be introduced into the chamber from outside the housing in a state where the main substance is already arranged in the chamber, which can provide a relatively simple and / or reliable activation process for activating the main substance that releases carbon monoxide. Therefore, a relatively safe and / or relatively reliable mechanism can be provided to release carbon monoxide, which can prevent or at least reduce the risk that the main substance and the activation substance that release carbon monoxide may have an adverse reaction to the subject treated by the reservoir. For example, if the subject is exposed to the carbon monoxide releasing substance and / or the corresponding activation substance, for example due to a fault in the reservoir construction and / or due to erroneous activation of the reservoir, the carbon monoxide releasing substance and / or the corresponding activation substance may be toxic to the subject.

[0019] In addition, configuring the reservoir to be inserted into the human and / or animal body can increase the potential application range of the reservoir, which can increase the flexibility of use of the reservoir. For example, the reservoir can be configured for in vivo use, such as by rectally and / or orally introducing the reservoir into the body of a subject. For example, the entire reservoir can be configured as a capsule, such as a capsule configured to be inserted (preferably manually) into one or more body cavities of an animal and / or a human, such as by oral and / or rectal administration to an animal and / or a human (e.g., a child and / or an adult); and / or to the ear of an animal and / or a human to treat (e.g., but not limited to) otitis media and / or other inflammatory diseases, where the targeted release of CO can have therapeutic uses; and / or to the vagina of an animal and / or a human.

[0020] Preferably, the reservoir is configured to be ingested, e.g., swallowed, by a human and / or animal. Furthermore, configuring the reservoir to be inserted into the human and / or animal body still allows the reservoir to be used in a variety of other ways, e.g., by providing ex vivo therapeutic treatment, e.g., by arranging the reservoir in a container that contains one or more biological cells, preferably one or more living cells, e.g., immune cells, such as CAR T cells and / or stem cells, and / or gametes, such as sperm or oocytes, for therapeutic treatment and / or to avoid degradation of the ex vivo biological cells. Preferably, the reservoir is configured to be inserted into the human and / or animal body via one or more natural orifices of the respective body.

[0021] In contrast, the system described in WO 2021 / 180908 A1 is specifically configured for treating the external surface of a subject, in particular the subject's skin. To this end, the system described in WO 2021 / 180908 A1 includes a relatively complex mixture of different materials and an airtight portion to direct the released carbon monoxide to the skin. The construction and use of a mixture of different materials leads to a relatively complex and relatively expensive production process. In addition, the construction and use of a mixture of different materials makes it challenging, or even impossible, to miniaturize the device to a smaller size to allow the device to be inserted into the human body and / or animal body, for example, through the mouth and / or rectum.

[0022] Preferably, the entire wall of the housing, for example the entire circumference around the housing / reservoir, is permeable to carbon monoxide emitted by the primary substance, which may allow carbon monoxide emitted by the primary substance to be released from a relatively large surface of the reservoir. This may increase the therapeutic effect of the reservoir.

[0023] Preferably, the reservoir is configured so that the activating substance can be introduced into the chamber from outside the housing in a state where the main substance has been arranged in the chamber, so that after the introduction of the activating substance has been completed, for example after the introduction device, such as the hollow needle, has been withdrawn from the housing, the portion of the housing into which the activating substance is introduced, for example via the introduction device, such as the hollow needle, provides a substantially liquid-tight and gas-tight seal. In other words, the portion of the housing through which the activating substance is introduced can be configured to reseal after the introduction of the activating substance has been completed, for example, when the introduction device (such as the hollow needle) has been withdrawn from the housing.

[0024] The reservoir may include one or more designated portions configured to allow and / or facilitate the introduction of the activated substance into the chamber and / or provide a substantially liquid-tight and airtight seal after the introduction of the activated substance has been completed, for example when an introduction device, such as a hollow needle, has been withdrawn from the housing. For example, the housing may include one or more designated portions configured to be pierced by an introduction device, preferably a hollow needle, to introduce the activated substance into the chamber and to reseal after the introduction device has been removed from the chamber. The one or more designated portions may include a material that increases the volume, such as a thicker material, compared to adjacent portions of the housing, for example, to facilitate piercing the housing by the one or more designated portions and / or facilitate resealing of the one or more designated portions once the corresponding introduction device has been removed from the chamber.

[0025] The reservoir may have a substantially smooth outer contour and / or a rounded outer contour. In other words, the reservoir may have no sharp edges on the outer contour of the reservoir, preferably on the entire outer contour. This may facilitate and reduce discomfort to the subject when the reservoir is introduced into the subject, such as by ingestion, such as swallowing the reservoir and / or when the reservoir is introduced rectally.

[0026] The housing can be configured as a single integral component. In this case, for example, the primary substance and the activated substance can be introduced into a completely enclosed chamber via a portion of the wall of the housing, for example, by piercing the wall with a hollow needle and injecting the primary substance and the activated substance into the chamber. Alternatively, the housing can include multiple components, such as an assembled body and cover.

[0027] Preferably, the entire reservoir may be made of a single material, such as silicone. Being made of a single material does not mean that the entire reservoir is integrally constructed as a single piece. On the contrary, being made of a single material means that only a single material, such as silicone, is used during the manufacturing process of the reservoir. This may further reduce the manufacturing effort for manufacturing the reservoir and / or may further simplify the construction of the container. This may also facilitate adjusting the size of the reservoir, for example by reducing the size of the reservoir, to suit the respective application.

[0028] The activating substance can be selected from a variety of suitable substances. At least when the activating substance is applied to activate the main substance that releases carbon monoxide, the activating substance can be a liquid and / or a gas. For example, the activating substance can be FeCl3, Ce(SO4)2 or H2O2, preferably FeCl3.

[0029] The main substance may be configured to release carbon monoxide after being activated, for example, by reacting with the activating substance. The main substance that releases carbon monoxide may be selected from a variety of suitable substances. At least when the activating substance is applied to activate the main substance that releases carbon monoxide, the main substance may be a liquid and / or a gas and / or a solid. The main substance that releases carbon monoxide is preferably a metal carbonyl compound, more preferably a carbonyl molybdenum compound, most preferably a salt former of MO(CO)3(CNCH2CO2H)3, preferably Na3Mo(CO)3(CNCH2CO2)3.

[0030] Although the present disclosure focuses on the emission of carbon monoxide from the reservoir, the reservoir may be configured to emit any gas, in particular any type of gas that can be used for therapeutic purposes. The primary substance and the activating substance may then be selected accordingly to provide the respective desired gas, and the material of the wall of the housing may be selected accordingly to be at least partially permeable to the respective gas.

[0031] As described above, the reservoir preferably includes only a single chamber. In a state where the main substance has been arranged in the chamber, the activation substance can be introduced into the chamber from the outside of the shell, into the single chamber, so that the main substance and the activation substance can react when the activation substance is inserted into the single chamber from the outside of the shell.

[0032] The walls of the housing may be impermeable to one or more of: solids, liquids, toxic substances, preferably at least substances containing heavy metal atoms, and by-products, preferably at least toxic by-products from the reaction between the main substance and the activated substance.

[0033] Preferably, the reservoir is configured to release carbon monoxide in vivo and / or in vitro. Preferably, the reservoir is configured to be inserted (preferably manually) into one or more body cavities of an animal and / or human (e.g., a child and / or an adult), for example by oral and / or rectal administration, and / or inserted into the ear of an animal and / or human for the treatment of (e.g., but not limited to) otitis media and / or other inflammatory diseases, where targeted release of CO may have therapeutic uses; and / or into the vagina of an animal and / or human. Preferably, the reservoir is configured to be ingested, for example swallowed, by a human and / or animal.

[0034] Preferably, at least one portion of the housing is configured to be pierced by an introduction device configured to introduce the activation substance into the chamber to activate the primary substance. Preferably, at least one portion of the housing is configured to reseal, preferably in a substantially liquid-tight and / or air-tight manner, after the introduction device has been withdrawn from the housing. The introduction device may comprise a hollow needle, such as a syringe having a hollow needle.

[0035] Preferably, the housing comprises at least one body and at least one cover. Preferably, the body and the cover are configured to be connectable to each other, preferably in a substantially liquid-tight and / or gas-tight manner. The body and the cover may be connected to each other by a friction-type connection, a form-locking connection and / or a material-bonded connection, for example by at least one adhesive, for example at least one silicone adhesive.

[0036] Preferably, the cover and / or the body comprises protrusion(s) configured to extend into the chamber when the cover and the body are connected to each other.

[0037] Preferably, the projection is configured as a diaphragm, which can be pierced by an introduction device, which is configured to introduce an activated substance into a chamber to activate a main substance, wherein the projection is configured to be preferably resealed in a substantially liquid-tight and / or airtight manner after the introduction device has been extracted from the projection. The diaphragm of the reservoir is configured to introduce an activated substance into the chamber as a projection, which extends into the chamber, rather than extending outward from the chamber, which can prevent the projection from causing discomfort to the subject when the reservoir is inserted into the subject's body, such as the rectum and / or oral cavity, and / or generally hinders the application or application of the reservoir. For example, when the reservoir is applied in vitro, such as for processing biological cells in a container, preferably living cells, the projection extending outward from the chamber may also be disadvantageous. For example, the projection extending outward from the chamber may increase the external dimensions of the reservoir, which may make it more difficult to arrange the reservoir in a relatively compact space, such as, arranged in a container accommodating living cells, and the living cells will be processed by the carbon monoxide emitted by the reservoir. In addition, configuring the diaphragm of the reservoir to introduce the activating substance into the chamber as a protrusion extending into the chamber can prevent or at least reduce the risk of damage to the diaphragm once the activating substance has been inserted into the chamber of the reservoir, which damage could result in the release of the primary substance of carbon monoxide and / or the unintended release of the activating substance, and / or could result in one or more substances (e.g., body fluids) entering the reservoir, for example, through a damaged portion of the diaphragm.

[0038] The protrusion may have any shape. Preferably, the cross-section of the protrusion has a substantially circular cross-sectional shape transverse to the longitudinal axis extending into the chamber when the lid and body are connected to each other.

[0039] Preferably, the protrusion has a rounded or chamfered edge, for example at the intersection between one or more side walls and one or more end faces of the protrusion, where the protrusion terminates in the chamber along the longitudinal axis of the housing. This may facilitate assembly of the reservoir. In particular, this may facilitate assembly of the lid and the body, for example by preventing, or at least reducing the risk of, relatively sharp edges of the protrusion getting caught on surfaces of the lid or the body during assembly of the lid and the body, which may make assembly more difficult or may even prevent assembly, and / or by preventing, or at least reducing the risk of, a portion of the reservoir being damaged during assembly of the lid and the body.

[0040] Preferably, when the body and the cover are connected to each other, the protrusion has a length extending into the chamber and / or along the longitudinal axis of the cover and / or the body, which is at least 1 mm, more preferably at least 1.2 mm, more preferably at least 1.4 mm, more preferably at least 1.6 mm, more preferably at least 1.8 mm, more preferably at least 2 mm, more preferably at least 2.2 mm, more preferably at least 2.4 mm, more preferably at least 2.6 mm, more preferably at least 2.8 mm, more preferably at least 3 mm, more preferably at least 3.2 mm, more preferably at least 3.4 mm, more preferably at least 3.6 mm, more preferably at least 3.8 mm, more preferably at least 4 mm, more preferably at least 4.2 mm, more preferably at least 4.4 mm, more preferably at least 4.6 mm, more preferably at least 4.8 mm, more preferably at least 5 mm, more preferably at least 5.2 mm, more preferably at least 5.4 mm, more preferably at least 5.6 mm, more preferably at least 5.8 mm, most preferably at least 6 mm. The above-mentioned protrusion length values ​​can provide a balance between sufficient length and the protrusion being configured as a diaphragm to allow the activating substance to be introduced into the chamber through the protrusion, so that the introduction point in the protrusion can be resealed after the introduction of the activating substance is completed, while limiting the amount of space occupied by the protrusion in the chamber.

[0041] Preferably, the body and / or the lid have a groove, which preferably extends annularly or semi-annularly around the longitudinal axis of the body and / or the lid. Preferably, a part of the other of the body and the lid is configured to be at least partially inserted into the groove for connecting the body and the lid to each other. This can provide a more reliable and strong connection between the lid and the body. In addition, when assembling the lid and the body, the groove can provide a guiding device, which can facilitate the assembly of the lid and the body. In addition, configuring a part of the other of the body and the lid to be at least partially inserted into the groove for connecting the body and the lid to each other can at least partially provide a seal between the body and the lid.

[0042] Preferably, when the cover and the body are connected to each other, the projection at least partially defines a slot, preferably along an outer circumference of the projection.Preferably, the slot extends at least partially coaxially around the projection.

[0043] Preferably, the body and / or the cover are made of silicone, preferably biocompatible silicone, preferably medical grade silicone.

[0044] Preferably, the entire lid is integrally formed. Alternatively or additionally, the entire body may be integrally formed. This may facilitate the manufacturing process for making the lid and / or the body. Alternatively, or additionally, this may facilitate assembly of the lid and the body. The lid and / or the body may each be molded and / or cast from a single material, such as silicone.

[0045] Preferably, the cover and / or the body has a Shore A hardness of from 20 Shore A to 80 Shore A, preferably from 30 Shore A to 50 Shore A.

[0046] Preferably, the body and / or the lid comprises at least one sealing and / or friction enhancing element, which is preferably arranged along at least one connection interface between the body and the lid to increase the sealing effect and / or friction between the body and the lid when the body and the lid are connected to each other. This can provide and / or increase the force acting between the body and the lid, such as adhesion and / or friction, to increase the sealing effect and / or friction between the body and the lid when the body and the lid are connected to each other. Alternatively, or in addition, the sealing and / or friction enhancing element can increase the engagement area and / or adhesion area between the body and the lid. This can reduce the risk of leakage and / or leakage from the reservoir via the interface between the body and the lid, and / or can prevent or at least reduce the risk of undesired disconnection or at least partial disconnection of the lid and the body.

[0047] Preferably, the sealing and / or friction enhancing element comprises at least one protrusion extending from an interface surface of the cover and / or the body. The interface surface may extend along a connection interface between the cover and the body. When the body and the cover are connected to each other, the protrusion may extend toward the other of the cover and the body and may engage with the other of the cover and the body. The protrusion may increase the force acting between the cover and the body to increase the sealing effect between the cover and the body and / or increase the connection force between the cover and the body, for example, to prevent or at least reduce the risk of an undesirable disconnection or at least partial disconnection of the cover and the body. The protrusion may provide or increase a press-fit between the cover and the body.

[0048] Preferably, the lid or the body includes a protrusion. The interface surface of the other of the lid and the body (which extends along the connection interface between the lid and the body) can be substantially smooth and / or continuous and / or without a protrusion and / or without a recess. This can increase the force acting between the lid and the body. Alternatively, the other of the lid and the body can include at least one recess, for example, at least one recess configured to at least partially receive a protrusion, and / or at least one protrusion.

[0049] Preferably, the projection extends at least partially along the circumference of the interface surface of the cover and / or the body, preferably along the entire circumference, preferably repeatedly, preferably in a spiral manner and / or a thread-like manner and / or a meandering manner and / or a zig-zag manner. This can provide a relatively large surface along which the projection can provide an increased sealing effect and / or increased friction. The circumference can be an inner circumference and / or an outer circumference.

[0050] Preferably, the projection may be made of the same material as the rest of the cover and / or the projection and / or the body. Preferably, the projection and the projection are formed integrally and / or monolithically by manufacturing the cover and / or the body with the corresponding projection(s) in a single molding process.

[0051] Preferably, the lid comprises a projection. The distal end of the projection (when the lid and the body are connected to each other, it extends to the farthest in the body) can have one or more rounded and / or chamfered edges. Alternatively, or in addition, when the lid and the body are connected to each other, the projection can be tapered toward the distal end of the projection at least along a portion of the projection, and the distal end extends to the farthest in the body. This can facilitate the manufacture of the lid, for example, if the lid is manufactured by a molding process, then compared to a cylindrical projection, by making the molded lid easier to remove from the mold and / or reduce the risk of damage during removal. In addition, compared to configuring the projection to have one or more sharp edges at the distal end, this can, for example, avoid or at least reduce the overflow of the substance (e.g., activated substance) after removing the introduction device (e.g., hollow needle) used to introduce the substance into the reservoir by leaving space or additional space at the edge of the distal end of the projection.

[0052] Preferably, the entire container has a maximum dimension, preferably a length extending along the longitudinal axis of the container, of no more than 25 mm, preferably no more than 24 mm, more preferably no more than 23 mm, more preferably no more than 22 mm, more preferably no more than 21 mm, more preferably no more than 20 mm, more preferably no more than 19 mm, more preferably no more than 18 mm, more preferably no more than 17 mm, more preferably no more than 16 mm, more preferably no more than 15 mm, more preferably no more than 14 mm, more preferably no more than 13 mm, more preferably no more than 12 mm. Configuring the reservoir to be relatively compact according to the above maximum dimension may facilitate introduction of the reservoir into the human and / or animal body, in particular via one or more natural orifices in the human and / or animal body, such as through the mouth and / or rectum. Furthermore, providing a relatively compact reservoir may allow the reservoir to be at least more easily and / or more flexibly arranged in a relatively compact space, for example, arranged in a container containing biological cells (preferably living cells) that are to be treated with carbon monoxide emitted by the reservoir.

[0053] Preferably, the maximum dimension of the entire reservoir in a direction extending substantially transverse to the longitudinal axis of the body and / or the longitudinal axis of the cover is no more than 12 mm, more preferably no more than 11 mm, more preferably no more than 10 mm, more preferably no more than 9 mm, more preferably no more than 8 mm, more preferably no more than 7 mm, more preferably no more than 6 mm, more preferably no more than 5 mm, more preferably no more than 4 mm. As described above, configuring the reservoir to be relatively compact, according to the maximum dimension of the reservoir, in a direction extending substantially transverse to the longitudinal axis of the body and / or the longitudinal axis of the cover, may facilitate the introduction of the reservoir into the human and / or animal body, in particular through one or more natural orifices in the human and / or animal body, such as the mouth and / or rectum, and / or may facilitate at least easier and / or more flexible arrangement of the reservoir in a relatively compact space, for example in a container containing living cells to be treated with carbon monoxide.

[0054] Preferably, the body has at least one body wall which at least partially defines the chamber. Preferably, the main body wall is at least partially permeable to carbon monoxide emitted by the main substance after the main substance has been activated by the activating substance, and wherein the thickness of the main body wall ranges from 0.4 mm to 2.5 mm, preferably 0.5 mm to 2.4 mm, more preferably 0.5 mm to 2.3 mm, more preferably 0.5 mm to 2.2 mm, more preferably 0.5 mm to 2.1 mm, more preferably 0.5 mm to 2 mm, more preferably 0.5 mm to 1.9 mm, more preferably 0.5 mm to 1.8 mm, more preferably 0.5 mm to 1.7 mm, more preferably 0.5 mm to 1.6 mm, more preferably 0.5 mm to 1.5 mm, more preferably 0.5 mm to 1.4 mm, more preferably 0.5 mm to 1.3 mm, more preferably 0.5 mm to 1.2 mm, more preferably 0.5 mm to 1.1 mm, more preferably 0.5 mm to 1 mm, more preferably 0.5 mm to 0.9 mm. In any event, the above body wall thickness values ​​provide a balance between the build size of the reservoir (or the size of the cavity within the body wall, which may be reduced to achieve greater body wall thickness) and the effectiveness of the therapeutic effect provided by the reservoir.

[0055] The thickness of the body wall can have an impact on the release characteristics of carbon monoxide from the chamber via the body wall. In particular, at least when the body wall uses the same material, a thinner body wall can allow carbon monoxide to be released at a higher rate than a thicker body wall. In this regard, the desired release rate of carbon monoxide can depend on the corresponding application of the reservoir, such as the corresponding desired therapeutic effect, the total amount of carbon monoxide to be released and / or the type of therapeutic treatment to be performed. Therefore, the thickness value of the above-mentioned body wall can be selected according to the desired application.

[0056] Although it is described above that the membrane / protrusion can be provided by the protrusion of the cover, such a membrane or protrusion can be provided at the bottom of the body (for example, when the body is integrally formed but the cover is used) and / or the side (wall) of the body instead. In other words, the wall of the body at the bottom and / or side can have a thickness corresponding to the preferred protrusion length described above.

[0057] Preferably, the body has a bottom end that is disposed opposite the cover relative to a direction extending from the cover toward the bottom end when the cover and the body are connected to each other. Preferably, the bottom end has a convex outer shape. Configuring the bottom end to have a convex outer shape may facilitate and / or reduce discomfort to the subject when the reservoir is introduced into the subject's body, e.g., by ingesting, e.g., swallowing the reservoir, and / or by rectally introducing the reservoir.

[0058] Preferably, the lid has at least one flange and the body has a body wall that at least partially defines the chamber. Preferably, when the lid and the body are connected to each other, the flange is configured to extend along at least part of the body wall. This configuration can provide a more reliable and strong connection between the lid and the body. In addition, when assembling the lid and the body, the flange can provide a guide for the body wall, which can facilitate the assembly of the lid and the body. The flange can be configured as a collar that extends radially and / or axially relative to the longitudinal axis of the reservoir.

[0059] Preferably, the groove and the protrusion are preferably integrally provided on the lid. Preferably, the groove is at least partially defined by at least a portion of the flange and at least a portion of the protrusion, preferably such that a portion of the body, preferably a portion of the annular wall of the body, can be at least partially inserted between the protrusion and the flange to connect the body and the lid to each other. This may provide a more reliable and robust connection between the lid and the body. Furthermore, when assembling the lid and the body, the flange and the protrusion may provide a guide for at least a portion of the wall of the body, which may facilitate assembly of the lid and the body.

[0060] Preferably, the body and the cover are connectable to each other by material bonding, preferably by an adhesive, preferably an adhesive made of silicone, preferably a biocompatible silicone, preferably a medical grade silicone.

[0061] Preferably, the size of the entire reservoir corresponds to or is at least no larger than a standard pharmaceutical capsule size, preferably a standard pharmaceutical capsule size of 5 to 000.

[0062] Preferably, the size of the entire reservoir corresponds to or is at least no greater than 2, 1 or 0 standard pharmaceutical capsule sizes.

[0063] Preferably, the body and / or the cover are manufactured by a molding process, preferably a compression molding process and / or an injection molding process.

[0064] A second aspect of the present disclosure relates to a device for selectively releasing carbon monoxide, the device comprising a reservoir according to any configuration disclosed herein. The device may also include at least one main substance configured to selectively emit carbon monoxide. The main substance can be stored in a chamber of the reservoir and can be configured to emit carbon monoxide, so that the emitted carbon monoxide is released through at least a portion of the wall of the reservoir after being activated by at least one activation substance.

[0065] The configuration and advantages as detailed above with respect to the reservoir apply correspondingly to the device.

[0066] Preferably, according to the second aspect of the present disclosure, the entire device may be configured as a capsule.

[0067] A third aspect of the present disclosure relates to a treatment system for treating biological cells with carbon monoxide, wherein the biological cells are preferably living cells, preferably immune cells, such as CAR T cells and / or stem cells, and / or gametes, and the treatment system may include at least one container configured to receive the biological cells and at least one carbon monoxide source, preferably at least one device for selectively releasing carbon monoxide according to the second aspect of the present disclosure. The container and the carbon monoxide source may be arranged relative to each other so that the biological cells can contact the carbon monoxide provided by the carbon monoxide source to treat the biological cells.

[0068] The configuration and advantages as detailed above with respect to the reservoir apply accordingly to the sexual therapy system.

[0069] The therapeutic system may be configured to provide one or more effects to the biological cells that at least partially preserve the biological cells.

[0070] Preferably, the biological cell is an immune cell, such as a CAR T cell and / or a stem cell, and / or a gamete. The gamete preferably comprises a sperm or an egg cell, preferably wherein the sperm is contained in semen, ejaculated semen and / or a buffer system.

[0071] The biological cells may be human gametes and / or human immune cells. Alternatively or additionally, the gametes and / or immune cells may be from animals, preferably from cows, horses, pigs, sheep, goats, camels, alpacas, dogs and / or cats.

[0072] The container may be configured to receive, preferably completely receive, the biological cells and the carbon monoxide source.

[0073] The container may comprise at least one compartment configured to receive and preferably accommodate and / or secure the carbon monoxide release device, preferably in a captured manner. This may allow the treatment system to be preassembled, in particular by arranging the carbon monoxide release device in the compartment prior to use, preferably prior to distribution to an application location (e.g. one or more laboratories). This may facilitate operation and / or use of the treatment system, and / or may prevent the carbon monoxide release device from being lost and / or separated from the container (e.g. during transport and / or handling).

[0074] The biological cell and the means for releasing carbon monoxide may be placed in a single compartment within the container.

[0075] Alternatively, the biological cell and the device for releasing carbon monoxide can be placed in separate compartments of the container, the compartments preferably being separated from each other by at least one wall and / or barrier permeable to carbon monoxide. The wall and / or barrier may have one or more openings configured to allow carbon monoxide to pass through it to reach the biological cell. Preferably, the compartment for receiving the carbon monoxide release device is arranged at the bottom of the container and / or along the bottom of the container, in particular so that the biological cell is at least partially arranged above the compartment, in particular on the upper wall of the compartment. This can increase the degree and / or efficiency of the biological cell being exposed to the carbon monoxide released by the device. Alternatively, the compartment may be arranged at the top and / or side of the container and / or along the top and / or side of the container.

[0076] The container may comprise a lid, which is preferably configured to provide a seal with the container to seal the contents of the container from the environment, preferably in an airtight manner.

[0077] A fourth aspect of the invention relates to a kit, preferably for treating biological cells, preferably living cells, with carbon monoxide in vitro or in vivo. The kit comprises at least one device for selectively releasing carbon monoxide according to the second aspect of the invention. The kit may also comprise at least one activating substance, preferably wherein the activating substance is contained in an introduction device having a hollow needle, or at least configured to be provided in an introduction device having a hollow needle, the hollow needle being configured to pierce the device to selectively release carbon monoxide. More preferably, the hollow needle is configured to pierce the cover of the device to selectively release carbon monoxide. The introduction device may be part of the kit.

[0078] The configuration and advantages as detailed above with respect to the reservoir apply accordingly to the kit.

[0079] A fifth aspect of the present disclosure relates to a method for treating a mammal (e.g., a human) in vivo with carbon monoxide. The method may include providing at least one device for selectively releasing carbon monoxide according to the second aspect of the present invention. The method may also include activating the main substance with at least one activating substance, for example by introducing the activating substance into a chamber of the device through a cover or body of the device. The method may further include introducing the at least one device into a mammal, preferably into one or more body cavities of a mammal, for example by oral ingestion and / or through the rectum, and / or into the ear of an animal and / or a human for the treatment of, for example (but not limited to), otitis media or other inflammatory diseases in which the targeted release of CO may have therapeutic uses, and / or into the vagina of an animal and / or a human.

[0080] The configuration and advantages as detailed above with respect to the reservoir apply correspondingly to the method.

[0081] A sixth aspect of the invention relates to carbon monoxide for treating biological cells, preferably living cells, in and / or outside a mammal, preferably for treating gastrointestinal diseases. Preferably, the carbon monoxide is released from a device for selectively releasing carbon monoxide, preferably from a device according to any embodiment described herein (see the second aspect above), in and / or outside a mammal.

[0082] The configuration and advantages as detailed above with respect to the reservoir apply accordingly to the sixth aspect.

[0083] A seventh aspect of the invention relates to a method of treating biological cells (preferably living cells, more preferably ex vivo) with carbon monoxide. The method may include providing a treatment system according to the third aspect above. The method may include arranging the biological cells in a container. The method may include triggering the release of carbon monoxide from a carbon monoxide source. The carbon monoxide provided by the carbon monoxide source may contact the biological cells.

[0084] The configurations and advantages described above apply accordingly to the seventh aspect.

[0085] Preferably, the treatment system is provided by arranging in the vessel at least one device configured to selectively release carbon monoxide, preferably at least one device according to any embodiment described herein with respect to the second aspect as described above.

[0086] Preferably, triggering the release of carbon monoxide comprises activating a primary species of the carbon monoxide source with at least one activating species.

[0087] Preferably, the activating substance is introduced into a chamber in which the primary substance is arranged. Preferably, the activating substance is introduced by an introduction device. The introduction device may comprise a hollow needle configured to pierce a wall of the chamber.

[0088] Preferably, the treatment system comprises at least one first chamber and at least one second chamber. The biological cells may be arranged in the first chamber. The at least one main substance may be arranged in the second chamber. The second chamber may be separated from the first chamber by at least one wall. At least a portion of the wall is permeable to the carbon monoxide released by the main substance, so that the carbon monoxide released by the main substance is released from the second chamber into the first chamber.

[0089] Preferably, carbon monoxide is released from the device in at least a portion of the gastrointestinal tract of a mammal, for example, for treating a gastrointestinal disorder, for example, an inflammatory bowel disease such as ulcerative colitis and / or Crohn's disease.

[0090] Preferably, the device is introduced into the mammal enterally, preferably by ingestion and / or rectally.

[0091] The following list of aspects provides preferred embodiments of the present disclosure:

[0092] 1. A reservoir, preferably configured to be inserted into a human and / or animal body, the reservoir comprising:

[0093] at least one housing;

[0094] at least one chamber defined within said housing;

[0095] wherein the chamber is configured to receive and store at least one primary substance, the primary substance being configured to selectively emit at least one gas, preferably at least carbon monoxide, wherein the primary substance is configured to emit the gas after being activated by at least one activation substance;

[0096] wherein the chamber is enclosed by at least one wall of the housing, wherein at least a portion of the wall is at least partially permeable to gas evolved by the primary substance, such that the reservoir is able to at least partially release the gas evolved by the primary substance into the environment; and

[0097] Wherein: the reservoir is preferably configured so that the activation substance can be introduced into the chamber from outside the housing in a state where the main substance has been arranged in the chamber.

[0098] 2. A reservoir according to aspect 1, wherein the reservoir comprises only a single chamber.

[0099] 3. A reservoir according to aspect 1 or 2, wherein the wall of the housing is impermeable to one or more of the following: solids, liquids, toxic substances, preferably at least substances containing heavy metal atoms, and by-products, preferably at least toxic by-products from the reaction between the main substance and the activated substance.

[0100] 4. A reservoir according to any one of the preceding aspects, wherein the reservoir is configured to release the gas, preferably carbon monoxide, in vivo and / or ex vivo.

[0101] 5. The reservoir according to any one of the preceding aspects, wherein the reservoir is configured to be inserted into a human and / or animal body.

[0102] 6. The reservoir according to any one of the preceding aspects, wherein the reservoir is configured for oral and / or rectal administration into the human and / or animal body.

[0103] 7. The reservoir according to any of the preceding aspects, wherein the reservoir is configured to be ingested, preferably swallowed, by humans and / or animals.

[0104] 8. A reservoir according to any of the preceding aspects, wherein at least a portion of the shell is configured to be pierced by an introduction device, the introduction device being configured to introduce an activating substance into the chamber to activate the main substance, and wherein at least a portion of the shell is configured to be resealed after the introduction device has been withdrawn from the shell, preferably in a substantially liquid-tight and / or air-tight manner.

[0105] 9. A reservoir according to any one of the preceding aspects, wherein the housing comprises at least one body and at least one cover, wherein the body and the cover are configured to be connectable to each other, preferably in a substantially liquid-tight and / or air-tight manner.

[0106] 10. The reservoir according to aspect 9, wherein the cover and / or the body comprises a protrusion configured to extend into the chamber when the cover and the body are connected to each other.

[0107] 11. A reservoir according to aspect 10, wherein the protrusion is configured as a diaphragm, which is pierceable by an introduction device, the introduction device is configured to introduce an activating substance into the chamber to activate the main substance, and the protrusion is configured to reseal preferably in a substantially liquid-tight and / or air-tight manner after the introduction device has been withdrawn from the protrusion.

[0108] 12. A reservoir according to aspect 10 or 11, wherein when the body and the lid are connected to each other, the protrusion has a length extending into the chamber and / or along the longitudinal axis of the lid and / or the body, the length being at least 1 mm, more preferably at least 1.2 mm, more preferably at least 1.4 mm, more preferably at least 1.6 mm, more preferably at least 1.8 mm, more preferably at least 2 mm, more preferably at least 2.2 mm, more preferably at least 2.4 mm, more preferably at least 2.6 mm, more preferably at least 2.8 mm, more preferably at least 3 mm, more preferably at least 3.2 mm, more preferably at least 3.4 mm, more preferably at least 3.6 mm, more preferably at least 3.8 mm, more preferably at least 4 mm, more preferably at least 4.2 mm, more preferably at least 4.4 mm, more preferably at least 4.6 mm, more preferably at least 4.8 mm, more preferably at least 5 mm, more preferably at least 5.2 mm, more preferably at least 5.4 mm, more preferably at least 5.6 mm, more preferably at least 5.8 mm, most preferably at least 6 mm.

[0109] 13. A container according to any one of Aspects 9 to 12, wherein the body and / or the lid has a groove, which preferably extends annularly or semi-annularly around the longitudinal axis of the body and / or the lid, wherein a portion of the other of the body and the lid is configured to be at least partially inserted into the groove for connecting the body and the lid to each other.

[0110] 14. A container according to aspect 13, wherein, when the cover and the body are connected to each other, the protrusion at least partially defines the groove, preferably defines the groove along the outer circumference of the protrusion, wherein preferably the groove extends at least partially coaxially around the protrusion.

[0111] 15. The reservoir according to any one of aspects 9 to 14, wherein the body and / or the cover are made of silicone, preferably biocompatible silicone, preferably medical grade silicone.

[0112] 16. A container according to any one of aspects 9 to 15, wherein the entire lid is integrally formed.

[0113] 17. A reservoir according to any one of aspects 9 to 16, wherein the entire body is integrally formed.

[0114] 18. A container according to any one of aspects 9 to 17, wherein the cover and / or the body has a Shore A hardness of from 20 Shore A to 80 Shore A, preferably from 30 Shore A to 50 Shore A.

[0115] 19. A container according to any one of Aspects 9 to 18, wherein the body and / or the lid include at least one sealing and / or friction enhancing element arranged along at least one connection interface between the body and the lid to increase the sealing effect and / or friction between the body and the lid when the body and the lid are connected to each other.

[0116] 20. A reservoir according to aspect 19, wherein the sealing and / or friction enhancing element includes at least one protrusion (e.g., a rib) extending from an interface surface of the lid and / or body, the interface surface extending along a connection interface, wherein when the body and the lid are connected to each other, the protrusion extends toward and engages the other of the lid and the body.

[0117] 21. A container according to aspect 20, wherein the cover or the body includes a protrusion, and the interface surface of the other of the cover and the body (which extends along the connection interface between the cover and the body) is substantially smooth and / or continuous and / or has no protrusions and / or no recesses.

[0118] 22. A container according to aspect 20 or 21, wherein the protrusion extends at least partially along the circumference of the interface surface of the cover and / or the body, preferably along the entire circumference, preferably multiple times, preferably in a spiraling manner and / or a thread-like manner and / or a meandering manner and / or a zig-zag manner.

[0119] 23. The reservoir according to any one of aspects 9 to 22, wherein the cover comprises a protrusion, and wherein:

[0120] The distal end of the protrusion (which extends furthest into the body when the cover and body are connected to each other) has one or more rounded and / or chamfered edges;

[0121] and / or

[0122] When the cover and the body are connected to each other, the protrusion tapers at least along a portion of the protrusion toward a distal end of the protrusion, the distal end extending furthest into the body.

[0123] 24. A reservoir according to any one of aspects 20 to 23, wherein the projection and the protrusion are integrally and / or monolithically formed.

[0124] 25. A reservoir according to any of the preceding aspects, wherein the entire reservoir has a maximum dimension, preferably a length extending along the longitudinal axis of the reservoir, not exceeding 25 mm, preferably not exceeding 24 m, more preferably not exceeding 23 m, more preferably not exceeding 22 mm, more preferably not exceeding 21 mm, more preferably not exceeding 20 mm, more preferably not exceeding 19 mm, more preferably not exceeding 18 mm, more preferably not exceeding 17 mm, more preferably not exceeding 16 mm, more preferably not exceeding 15 mm, more preferably not exceeding 14 mm, more preferably not exceeding 13 mm, more preferably not exceeding 12 mm.

[0125] 26. A reservoir according to any of the preceding aspects, wherein the maximum dimension of the entire reservoir in a direction extending substantially transversely to the longitudinal axis of the body and / or the longitudinal axis of the lid is no more than 12 mm, more preferably no more than 11 mm, more preferably no more than 10 mm, more preferably no more than 9 mm, more preferably no more than 8 mm, more preferably no more than 7 mm, more preferably no more than 6 mm, more preferably no more than 5 mm, more preferably no more than 4 mm.

[0126] 27. A reservoir according to any one of aspects 9 to 26, wherein the body has at least one body wall, which at least partially defines a chamber, wherein the body wall is at least partially permeable to gas released by the main substance after the main substance has been activated by the activating substance, and wherein the thickness of the body wall ranges from 0.4mm to 2.5mm, preferably 0.5mm to 2.4mm, more preferably 0.5mm to 2.3mm, more preferably 0.5mm to 2.2mm, more preferably 0.5mm to 2.1mm, more preferably 0.5mm to 2mm, more preferably 0.5mm to 1.9mm, more preferably 0.5mm to 1.8mm, more preferably 0.5mm to 1.7mm, more preferably 0.5mm to 1.6mm, more preferably 0.5mm to 1.5mm, more preferably 0.5mm to 1.4mm, more preferably 0.5mm to 1.3mm, more preferably 0.5mm to 1.2mm, more preferably 0.5mm to 1.1mm, more preferably 0.5mm to 1mm, more preferably 0.5mm to 0.9mm.

[0127] 28. A container according to any one of aspects 9 to 27, wherein the main body has a bottom end, which is arranged opposite to the cover relative to a direction extending from the cover toward the bottom end when the cover and the main body are connected to each other, wherein the bottom end has a convex outer shape.

[0128] 29. A container according to any one of aspects 9 to 28, wherein the lid has at least one flange and the body has a body wall that at least partially defines the chamber, wherein the flange is configured to extend along at least a portion of the body wall when the lid and the body are connected to each other.

[0129] 30. A container according to any one of Aspects 9 to 29, wherein the groove and the protrusion are preferably integrally arranged on the lid, wherein the groove is at least partially defined by at least a portion of the flange and at least a portion of the protrusion, preferably so that a portion of the body, preferably a portion of the annular wall of the body, can be at least partially inserted between the protrusion and the flange for connecting the body and the lid to each other.

[0130] 31. A reservoir according to any one of aspects 9 to 30, wherein the body and the cover can be connected to each other by material bonding, preferably by an adhesive, the adhesive is preferably an adhesive made of silicone, the silicone is preferably a biocompatible silicone, preferably a medical grade silicone.

[0131] 32. The reservoir according to any of the preceding aspects, wherein the size of the entire reservoir corresponds to or is at least not larger than a standard pharmaceutical capsule size, preferably a standard pharmaceutical capsule size of 5 to 000.

[0132] 33. The reservoir according to any of the preceding aspects, wherein the size of the entire reservoir corresponds to or is at least no greater than 2, 1 or 0 standard drug capsule sizes.

[0133] 34. The reservoir according to any of the preceding aspects, wherein the body and / or the lid are manufactured by a molding process, preferably a compression molding process and / or an injection molding process.

[0134] 35. An apparatus for selectively releasing at least one gas, preferably at least carbon monoxide, comprising:

[0135] A reservoir according to any one of the preceding aspects; and

[0136] At least one primary substance configured to selectively emit gas, wherein the primary substance is stored within a chamber of the reservoir and configured to emit gas such that the emitted gas is released through at least a portion of a wall of the reservoir after being activated by at least one activating substance.

[0137] 36. A therapeutic system for treating biological cells (preferably living cells, preferably immune cells and / or gametes) with at least one gas (preferably at least carbon monoxide), comprising:

[0138] at least one container configured to receive the biological cell;

[0139] at least one source of gas (preferably carbon monoxide) according to aspect 35, preferably at least one device for selectively releasing at least one gas (preferably at least carbon monoxide);

[0140] The container and the gas source are arranged relative to each other such that the biological cells can be contacted with a gas provided by the gas source to treat the biological cells.

[0141] 37. A therapeutic system according to aspect 36, wherein the container is configured to receive the biological cells and the gas source, preferably all of them.

[0142] 38. A kit for treating biological cells, preferably living cells, with at least one gas, preferably at least carbon monoxide, ex vivo or in vivo, the kit comprising:

[0143] at least one device for selectively releasing at least one gas, preferably at least carbon monoxide, according to aspect 35; and

[0144] At least one activating substance, preferably wherein the activating substance is contained within an introduction device having a hollow needle configured to pierce the device to selectively release a gas, more preferably wherein the hollow needle is configured to pierce a cover of the device to selectively release a gas.

[0145] 39. A method of treating a mammal (e.g., a human) in vivo with at least one gas (preferably at least carbon monoxide), the method comprising:

[0146] According to aspect 35, at least one device for selectively releasing at least one gas, preferably at least carbon monoxide, is provided;

[0147] activating the primary substance with at least one activating substance, such as by introducing the activating substance into a chamber of the device through a lid or a body of the device;

[0148] At least one device is introduced into the mammal, for example by oral ingestion and / or rectal ingestion and / or into the ear of the mammal and / or into the vagina of the mammal.

[0149] 40. Carbon monoxide for use in treating biological cells (preferably living cells) in vivo and / or in vitro in a mammal, preferably for use in treating gastrointestinal diseases (preferably inflammatory diseases of the gastrointestinal tract), or gastrointestinal transplantation, wherein the carbon monoxide is released from a device according to aspect 35 in vivo and / or in vitro in a mammal.

[0150] 41. Carbon monoxide according to aspect 40, wherein the carbon monoxide is released from the device in at least a portion of the gastrointestinal tract of the mammal.

[0151] 42. Carbon monoxide according to aspect 40 or 41, wherein the device is introduced into the body of a mammal enterally, preferably by ingestion and / or via the rectum and / or into the ear of a mammal and / or into the vagina of a mammal.

[0152] 43. Carbon monoxide according to aspect 40, 41 or 42, wherein the disease is one or more of: diabetic gastroparesis, postoperative ileus, inflammatory bowel disease (e.g. ulcerative colitis and / or Crohn's disease), sepsis, gastritis, gastric ulcer, gastrointestinal ischemia-reperfusion injury, non-alcoholic steatohepatitis.

[0153] 44. A method for treating biological cells (preferably living cells, more preferably ex vivo) with carbon monoxide, the method comprising:

[0154] Providing a processing system according to aspect 36;

[0155] Arranging biological cells in a container;

[0156] The release of carbon monoxide from a carbon monoxide source is triggered, wherein the carbon monoxide provided by the carbon monoxide source contacts a biological cell.

[0157] 45. The method of aspect 44, wherein the treatment system is provided by arranging at least one device configured to selectively release carbon monoxide in the container, preferably at least one device according to aspect 35.

[0158] 46. ​​The method of aspect 44 or 45, wherein triggering the release of carbon monoxide comprises activating a primary species of the carbon monoxide source with at least one activating species.

[0159] 47. The method of aspect 46, wherein the activation substance is introduced into the chamber in which the primary substance is arranged, preferably, wherein the activation substance is introduced by an introduction device, wherein the introduction device comprises a hollow needle configured to pierce the wall of the chamber.

[0160] 48. A method according to any one of aspects 44 to 47, wherein the treatment system comprises at least one first chamber and at least one second chamber, wherein the biological cells are arranged in the first chamber, and wherein at least the main substance is arranged in the second chamber, preferably wherein the second chamber is separated from the first chamber by at least one wall, preferably wherein at least a portion of the wall is permeable to carbon monoxide released by the main substance, so that the carbon monoxide released by the main substance is released from the second chamber into the first chamber.

[0161] Preferred embodiments of the present invention will be further described below with reference to the accompanying drawings. The described embodiments do not limit the present invention.

[0162] Figure 1 schematically illustrates an exploded view of a reservoir according to an embodiment of the present disclosure;

[0163] Figure 2 The schematic diagram shows Figure 1 Another exploded view of the reservoir shown;

[0164] Figure 3 The schematic diagram shows Figure 1 and 2 Another exploded view of the reservoir shown;

[0165] Figure 4 The schematic diagram shows Figures 1 to 3 The assembly state of the reservoir in;

[0166] Figure 5 A schematic diagram of a side view of a device for selectively releasing carbon monoxide is shown, the device comprising Figures 1 to 4 The reservoir shown in ;

[0167] Figure 6 schematically illustrates a side view of a treatment system according to an embodiment of the present disclosure;

[0168] Figure 7schematically illustrates a side view of a processing system according to another embodiment of the present disclosure;

[0169] Figure 8 The schematic diagram shows Figures 1 to 6 An improvement in the lid of the reservoir shown in;

[0170] Fig. 9A Shows Figures 1 to 8 Correlation between the amount of carbon monoxide released from the medium storage and the mass of the main substances;

[0171] Fig. 9B Shows Figures 1 to 8 Correlation between the amount of carbon monoxide released from the reservoir and the volume of activated material;

[0172] Fig.10 The results of an exemplary treatment of sperm with carbon monoxide gas are shown schematically;

[0173] Fig.11 Another schematic diagram shows the results of an exemplary treatment of sperm with carbon monoxide gas;

[0174] Fig.12 The results of a further exemplary treatment of sperm with carbon monoxide gas are shown in another schematic diagram.

[0175] Figures 1 to 3 An exploded view of a reservoir 10 according to an embodiment of the present disclosure is shown. Figure 4 Shown in assembled state Figures 1 to 3 The reservoir 10 in the embodiment of the present invention. The reservoir 10 can be configured to be inserted into a human and / or animal body. Preferably, the reservoir 10 is configured to be inserted, preferably manually, into one or more body cavities of the human and / or animal body, such as by oral administration, such as by ingestion, such as by swallowing the reservoir 10, and / or through the rectum and / or into the ear and / or vagina of an animal and / or human.

[0176] The reservoir 10 may include at least one housing 12 and at least one chamber 14 defined within the housing 12. The chamber 14 may be configured to receive and store at least one primary substance configured to selectively emit carbon monoxide. In particular, the primary substance may be configured to emit carbon monoxide after being activated by at least one activation substance.

[0177] The chamber 14 may be enclosed by at least one wall 16 of the housing 12. At least a portion of the wall 16 may be at least partially permeable to carbon monoxide released by the primary substance, such that the reservoir 10 may at least partially release the carbon monoxide released by the primary substance into an environment, such as a treatment site, within the subject's body. The reservoir 10 may be configured such that the activating substance may be introduced into the chamber 14 from outside the housing 12, for example, by an introduction device, such as a syringe, having a hollow needle configured to pierce a portion of the housing 12 in a state where the primary substance has been disposed within the chamber 14.

[0178] The wall 12 of the housing 16 may be impermeable to one or more of: solids, liquids, toxic substances, preferably at least substances containing heavy metal atoms, and byproducts, preferably at least toxic byproducts from the reaction between the main substance and the activated substance.

[0179] like Figures 1 to 3 As shown in , the reservoir 10 may include only a single chamber 14. This may allow the reservoir 10 to be relatively compact. However, as an alternative, the reservoir 10 may include multiple chambers 14.

[0180] The housing 12 may include at least one body 18 and at least one cover 20. The body 18 and the cover 20 may be configured to be connected to each other, preferably in a substantially liquid-tight and / or air-tight manner, so that the chamber 14 is substantially completely enclosed and isolated from the environment, preferably in a substantially liquid-tight and / or air-tight manner. The body 18 and the cover 20 may be connected to each other, for example, by a friction-type connection, a shape-locking connection and / or a material-bonded connection, for example, by at least one adhesive, such as at least one silicone adhesive. The body 18 and / or the cover 20 may be made of silicone. Preferably, the entire reservoir 10 is made of a single material, such as silicone.

[0181] like Figures 1 to 3 As shown, the cover 20 may include a protrusion 22 configured to extend into the chamber 14 when the cover 20 and the body 18 are connected to each other.

[0182] The protrusion 22 may be configured as a septum that is pierceable by an introduction device configured to introduce an activating substance into the chamber 14 to activate the main substance. A suitable introduction device may be a syringe having a hollow needle configured to pierce the protrusion 22 and extend into the chamber 14 to deposit the activating substance in the chamber 14. Preferably, the protrusion 22 or septum is configured to reseal after the introduction device has been withdrawn from the protrusion 22, preferably in a substantially liquid-tight and / or air-tight manner.

[0183] Alternatively, or in addition, the body 18 may include protrusions and / or diaphragms that may be attached to the Figures 1 to 320 and 18. The protrusions and / or diaphragms provided on the main body may also be configured to extend into the chamber 14, or at least be arranged in the chamber 14, when the lid 20 and the main body 18 are connected to each other. For example, the bottom of the main body 18 (e.g., the end of the main body 18 opposite to the lid 20) and / or the side wall of the main body 18 may provide a diaphragm. To this end, the wall at the bottom and / or the side may have a greater thickness than the peripheral (e.g., cylindrical) portion of the wall 16. The wall at the bottom and / or the side may have a thickness of at least 1.2 mm, preferably at least 2 mm, more preferably at least 3 mm, more preferably at least 4 mm, and even more preferably at least 5 mm.

[0184] like Figures 1 to 3 As shown in FIG. 1 , the cover 20 may have a groove 24 (see FIG. Figure 2 and 3 ), which may extend annularly or semi-annularly around the longitudinal axis 26 of the body 18 and / or the cover 20. Figures 1 to 3 As shown in , the slot 24 may extend coaxially at least partially around the protrusion 22 .

[0185] The cover 20 may include at least one flange 25, which may be configured to extend along at least a portion of the wall 16 when the cover 20 and the body 18 are connected to each other (see FIG. Figure 4 ).

[0186] The groove 24 and the protrusion 22 may be provided on the cover 22, such as Figures 1 to 3 , preferably integrally arranged. The groove 24 may be at least partially defined by at least a portion of the flange 25 and at least a portion of the protrusion 22, preferably along the outer circumference 28 of the protrusion 22, as shown in Figures 1 to 3. A portion of the wall 16 may be at least partially inserted between the protrusion 22 and the flange 25, i.e., inserted into the groove 24, to help the body 18 and the cover 20 connect to each other.

[0187] Alternatively, or in addition, the body 18 may include a groove that may be similar or identical to the groove 24 provided in the closure cover 20, such as Figures 1 to 3 A portion of the cover 20 may be configured to be at least partially inserted into a groove provided on the main body 18 to facilitate connecting the main body 18 and the cover 20 to each other.

[0188] Figure 5 An apparatus 40 for selectively releasing carbon monoxide is shown, comprising Figures 1 to 4 The storage device 10 shown in FIG. 1 and the main substance 42 for releasing carbon monoxide. Figure 5 As shown, the primary substance 42 may be stored within the chamber 14 of the reservoir 10 and may be configured to emit carbon monoxide such that the emitted carbon monoxide is at least partially released through the wall 16 of the reservoir 10 after being activated by at least one activation substance 44 .

[0189] Figure 5 The description of the main substance 42 and the activated substance 44 in the embodiment is only exemplary and schematic. The main substance 42 is preferably a powder and / or a granule. Alternatively, the main substance 42 may be a liquid and / or a gas. Similarly, the activated substance 44 may be a powder, a granule, a liquid and / or a gas.

[0190] The activation substance 44 can be introduced into the chamber 14 of the reservoir 10 via the introduction device 46. Figure 5 As shown, the introduction device 46 can be configured as a syringe having a hollow needle 48, which is configured to pierce the cap 20, more specifically the protrusion 22, to introduce the activation substance 44 into the chamber 14 to activate the main substance 42. The cap 20 can be configured to reseal after the introduction device 46 has been withdrawn from the cap 20, preferably in a substantially liquid-tight and / or air-tight manner.

[0191] As mentioned above, the reservoir 10, more specifically Figures 1 to 5 The device 40 shown in the figure can be configured to treat an animal and / or human body by releasing carbon monoxide in the body. Preferably, the reservoir 10, more specifically the device 40, is configured to be inserted, preferably manually, such as by oral administration, such as by swallowing the reservoir 10, more specifically the device 40, and / or by rectal administration and / or into the ear and / or vagina of an animal and / or human, into one or more body cavities of the human and / or animal body. By doing so, living cells in the human and / or animal body can be treated with carbon monoxide released by the reservoir 10, more specifically the device 40.

[0192] Alternatively, however, reservoir 10, and more particularly device 40, may be configured to treat biological cells, preferably living cells, ex vivo by releasing carbon monoxide ex vivo. Figure 6 Such a treatment system 60 is shown in FIG. The treatment system 60 is configured to treat biological cells 62, preferably living cells, preferably immune cells and / or gametes, with carbon monoxide. The treatment system 60 can be configured to provide one or more effects to the biological cells 62 that at least partially preserve the biological cells 62. The treatment system 60 can include at least one container 64 configured to receive the biological cells 62 and at least one carbon monoxide source, wherein the treatment system 60 is configured to treat the biological cells 62 with carbon monoxide. Figure 6 The configuration shown is composed of Figure 5The device 40 shown is embodied. The container 64 and the carbon monoxide source device 40 can be arranged relative to each other so that the biological cells 62 can be contacted with the carbon monoxide provided by the device 40 to treat the biological cells 62. The container 64 can include a lid 66, which is preferably configured to provide a seal with the container 64 to seal the contents of the container 64 from the environment, preferably in an airtight manner. Alternatively or additionally, the treatment system 60 can be configured for ex vivo treatment of an animal and / or human body, for example by applying carbon monoxide to an external surface of the animal and / or human body, such as the skin, which can also be considered to treat biological cells within the meaning of the present disclosure.

[0193] Figure 7 A schematic diagram of an alternative treatment system 80 is shown for ex vivo treatment of biological cells, preferably living cells, by ex vivo release of carbon monoxide. The treatment system 80 may include at least one container 82 configured to receive biological cells 62 and at least one carbon monoxide source, Figure 7 In the configuration shown, for example but not limited to, Figure 5 40 is shown. The container 82 and the carbon monoxide source device 40 can be arranged relative to each other so that the biological cells 62 can be contacted with the carbon monoxide provided by the device 40 to treat the biological cells 62. The container 82 may include at least one compartment 84, which is configured to receive and preferably accommodate and / or fix the device 40, preferably in a captured manner. Alternatively, or in addition to the compartment 84, the container 82 may include one or more fixing means, such as one or more clips, which are configured to fix the carbon monoxide release device 40 in the container 82 (preferably, restrained and / or substantially immovable). As another option, the device 40 may be omitted, and the main substance 42 may be placed directly in at least one chamber defined in the container 82, such as directly placed in the compartment 84. For example, the compartment 84 itself may form the reservoir 10, for example, the wall of the compartment 84 may form the housing 12 of the reservoir 10 or at least a part thereof. This can allow the therapeutic system 80 to be preassembled, in particular by arranging the device 40 in the compartment 84 prior to use, preferably prior to distribution to an application location (eg, one or more laboratories). This can facilitate the handling and / or use of the therapeutic system 80.

[0194] Preferably, the compartment 84 is arranged at the bottom of the container 82 and / or along the bottom, in particular so that when the treatment system 80 is in operation, the biological cell 62 is at least partially arranged above the compartment 84, in particular on the upper wall 86 of the compartment 84. The upper wall 86 of the compartment 84 may be permeable to the carbon monoxide released by the device 40. This arrangement can increase the contact of the biological cell 62 with the carbon monoxide released by the device 40. The upper wall 86 may include one or more openings 88, which are configured to allow carbon monoxide to pass through the upper wall to reach the biological cell 62. Alternatively, the compartment 84 may be arranged at the top and / or at least one side of the container 82.

[0195] The container 82 can be configured to receive multiple carbon monoxide sources, such as multiple devices 40, for example by including multiple compartments 84, preferably each compartment 84 is configured to receive at least one carbon monoxide source, such as a carbon monoxide source of a device 40, in addition to (and independently of) the compartment configured to receive the biological cells 62.

[0196] The container 82 may include a lid 90 that is preferably configured to provide a seal with the container 82 to seal the contents of the container 82 from the environment, preferably in an airtight manner. Alternatively or additionally, the treatment system 80 may be configured for ex vivo treatment of an animal and / or human body, such as by applying carbon monoxide to an external surface of the animal and / or human body, such as the skin, which may also be considered to be treating biological cells within the meaning of the present disclosure.

[0197] Any type of triggering mechanism may be provided to trigger the carbon monoxide source (eg, device 40 ) to release carbon monoxide, particularly when the carbon monoxide source is disposed in container 82 , more particularly in compartment 84 , and / or cells 62 are disposed in container 82 .

[0198] Figure 8 The schematic diagram shows Figures 1 to 6 A further embodiment of the lid 20 of the reservoir 10 is shown in; Figure 8 The illustrated cover 20 includes at least one protrusion 70 (e.g., rib) extending from an interface surface 72 of the cover 20. The interface surface 72 can extend along the connection interface between the cover 20 and the body 18. When the body 18 and the cover 20 are connected to each other, for example, Figures 4 to 6 As shown in , the protrusion 70 may extend toward the body 18 (eg, along an inner surface of the body 18) and engage therewith.

[0199] The projection 70 may extend at least partially along the circumference of the interface surface 72 of the cover 20, preferably along the entire circumference, preferably multiple times, preferably in a spiral and / or thread-like manner, such as Figure 8In the exemplary embodiment, the projection 70 may extend in a meandering manner and / or in a zigzag manner. This may provide a relatively large surface along which the projection 70 may provide an enhanced sealing effect and / or enhanced friction and / or enhanced connection force.

[0200] The interface surface of the body 18 extends along the connection interface between the cover 20 and the body 18, and is preferably substantially smooth and / or continuous and / or has no protrusions and / or has no recesses. Alternatively, the body 18 may have one or more protrusions and / or one or more recesses, for example, one or more recesses configured to receive the protrusion 70.

[0201] Alternatively, or in addition, the body 18 may include at least one protrusion that is configured similarly or identically to the protrusion 70 .

[0202] The distal end 76 of the protrusion 22 (which extends furthest into the body 18 when the cap 20 and body 18 are connected to each other) can have one or more rounded and / or curved edges 94. Alternatively, or in addition, the protrusion 22 can taper toward the distal end 76 of the protrusion 22 along at least a portion of the protrusion 22. This can facilitate manufacturing of the cap 20, for example, if the cap 20 is manufactured by a molding process, by enabling the molded cap to be more easily removed from the mold and / or reducing the risk of damage during removal compared to a cylindrical cap 20 / protrusion 22. In addition, compared to configuring the protrusion 22 to have one or more sharp edges at the distal end 76, this can prevent or at least reduce the risk of damage during removal of an introduction device (e.g., a hollow needle, e.g., a needle) used to introduce a substance into the reservoir 10. Figure 5 The overflow of a substance (eg, an activated substance) after the introduction device 46 is shown, for example by leaving a space or additional space at the edge of the distal end 76 of the protrusion 22.

[0203] Figure 8 The cover 20 shown may have Figure 2 and 3 The slot 24 is shown in FIG.

[0204] Fig. 9A The correlation between the amount / volume (in mL) of carbon monoxide (CO) released from the reservoir 10 and the mass (in mg) of the main substance 42 ("Mo-CORM") once the activation substance 44 and the main substance 42 have been combined in the chamber 14 of the reservoir 10 is shown. The amounts of carbon monoxide (CO) released are 1.30 mL, 0.95 mL, 0.44 mL, and 0.23 mL, respectively, corresponding to 15 mg, 10 mg, 5 mg, and 2.5 mg of the main substance 42 ("Mo-CORM"), respectively.

[0205] Fig. 9BThe correlation between the amount / volume of carbon monoxide (CO) released from the reservoir 10 (in mL) and the volume of the activated substance 44 ("FeCl") (in μL) is shown once the activated substance 44 and the main substance 42 have been combined in the chamber 14 of the reservoir 10. The carbon monoxide (CO) release ranges from 0.95 mL to 0.34 mL, corresponding to 50 μL to 10 μL of the activated substance 44 ("FeCl"), respectively.

[0206] Illustrative Example of Treatment of Sperm Using Carbon Monoxide:

[0207] The following examples illustrate the improvement of sperm properties (such as redox potential, DNA fragmentation and / or sperm motility, particularly progressive motility) when exposed to carbon monoxide gas.

[0208] Specifically, Example 1 relates to treating sperm using carbon monoxide emitted by a treatment system comprising a capsule having two compartments, as described in more detail below. The results of Example 1 are shown in FIG. Fig.10 and 11 shown.

[0209] Example 2 is directed to treating sperm using carbon monoxide emitted by a treatment system comprising a reservoir (e.g., a capsule) having a single chamber or compartment defined in a housing, e.g., a configuration similar or identical to that of the reservoir according to any of the embodiments described herein with respect to the first aspect of the present disclosure. The results of Example 2 are shown in Fig.12 middle.

[0210] The following results of the two examples show that for different treatment systems (for the different treatment systems used in Examples 1 and 2), sperm properties (such as redox potential, DNA fragmentation and / or sperm motility, especially forward motility) can be improved when exposed to carbon monoxide gas.

[0211] Embodiment 1:

[0212] method

[0213] In this example, capsules (18-22 mm in length, 6-8 mm in diameter) filled with 15 mg of CO releasing molecules (Mo-CORM) and 150 μl of aqueous FeCl3 solution (583.3 mg / mL) were used to store 0.7 mL to about 2.9 mL of sample in a standard 15 mL Falcon tube.

[0214] Capsules, CORM and FeCl3 were prepared as follows:

[0215] Preparation of capsules

[0216] The capsules were produced by additive manufacturing. Two compartments separated by a diaphragm contained in one of the compartments were 3D printed. The compartments containing the aqueous FeCl3 solution were printed in a drop-on-demand manner (multi-jet modeling process) using an Objet Eden 350 printer (with 96 nozzles, droplet size 40 μM, resolution X = 600 dpi, Y = 600 dpi; Stratasys, Deden Prairie, Minnesota, USA). As resin, the photopolymer VeroBlackPlus (Stratasys, Deden Prairie, Minnesota) was used, and the structure was cured by UV polymerization at 365 nm using a UV lamp. In addition, a water-soluble support structure (SUP705, Stratasys, Deden Prairie, Minnesota) was used, which was removed by a washing step (drinking water; isopropyl alcohol) after the printing process.

[0217] The CORM-containing compartments were produced by laser sintering (LS), using polyamide PA2200 (EOS GmbH, Krailing, Germany) as material, processed by a Formiga P110 3D printer (EOS GmbH, Krailing, Germany) including a CO2 laser (wavelength 10.6 μm, layer thickness 0.1 mm). The silicone membrane (SIK8649) surrounding the two compartments was obtained from RAUMEDIC AG (Helmbrechst, Germany). CAD software (VISI 2019 & 2020, Vero UK, Cheltenham, UK) was used for production-ready design.

[0218] Preparation of CORM

[0219] The synthesis of trisodium tricarbonyl-[tri(isocyanoethyl acetate)] molybdenum (Na3Mo(CO)3(CNCH2CO2)3, Mo-CORM) was modified from a previous method (Achatz, D et al. Zeitschrift für anorganische undallgemeine Chemie 2005, 631(12), 2339-2346). Briefly, 2.64 g (10.0 mmol) of molybdenum hexacarbonyl was dissolved in 35 mL of anhydrous acetonitrile (99.8%; 90°C; 22 h) under dry and inert conditions to obtain an intermediate acetonitrile complex. Then, 4.7 mL of ethyl isocyanoacetate (3.5 eq.; 35 mmol; 4.86 g) was added at 55°C to displace the acetonitrile to obtain the complex. The ester was then hydrolyzed with NaOH (16 eq.) in 20 mL of tetrahydrofuran at room temperature. The free acid was formed by the addition of aqueous HCl. Finally, NaOH ethanol solution (5 mmol NaOH / 1 mmol Mo-CORM) was added to obtain the trisodium salt. All reagents were purchased from Sigma Aldrich (Schnelldorf, Germany) and used without further purification.

[0220] Preparation of FeCl3 aqueous solution

[0221] FeCl3*6H2O was purchased from Sigma Aldrich (Schnelldort, Germany) and prepared into an aqueous solution with a concentration of 583.3 mg / mL using deionized water.

[0222] Sperm analysis

[0223] 1.46mL to 5.7mL of human semen / sperm were collected from healthy men aged 25 to 50 years and placed in 100mL sample bottles on site. The samples were then divided into two equal parts, each for subsequent incubation with CO (wCO) and without CO (woCO). In order to estimate the sperm concentration in the samples and establish an initial baseline for each sample, a routine spermatogenesis chart analysis was performed before the samples were transferred to 15mL gas-tight Falcon tubes. The samples were incubated at 25-35°C for 90 minutes in a closed container with and without an activated capsule system. During this incubation period, liquefaction occurred naturally. The samples were then analyzed for total motility, forward motility, static redox potential, and DNA fragmentation.

[0224] The samples were evaluated for total motility, progressive motility, and concentration using the CEROS II (Hamilton Thorne, Beverly, MA) computer-assisted sperm analysis (CASA) system. A 6-μL sperm sample was diluted 1:1 with gamete and embryo processing medium (with albumin) (MHM-C, FujiFilm / IrvineScientific, Santa Ana, CA) and assessed for concentration and motility levels (total and progressive motility).

[0225] Static redox potential (sORP) levels were determined using a male infertility oxidation system (MiOXSYS, Englewood, CO). 30 μL of sperm sample was transferred to the sample application port on the MiOXSYS sensor and analyzed for 2 minutes.

[0226] To determine DNA fragmentation, count-based microscopic analysis was performed. For this purpose, sperm samples were diluted to a maximum of 20xE6 sperm per mL with MHM-C (Gamete and Embryo Processing Solution (with Albumin), FujiFilm, IrvineScientific) and analyzed with Halo Sperm G2 Kit (Halotech, Madrid, Spain). The samples were mixed with the prepared agarose according to the manufacturer's instructions. Then 8 μL of the resulting mixture was placed on a microscope slide and cooled for 5 minutes by removing the heat source. The prepared samples were further processed according to the manufacturer's instructions: denaturant treatment for 7 minutes, lysis solution treatment for 20 minutes, distilled water treatment for 5 minutes, 70% ethanol treatment for 2 minutes, 100% ethanol treatment for 2 minutes, eosin staining solution treatment for 7-10 minutes, and thiazide staining solution treatment for 7-10 minutes. At least 300 sperm were then analyzed using bright field microscopy.

[0227] result

[0228] 1. (Static) Oxidation Reduction Potential (sORP) Level

[0229] Fig.10 The "Relative Redox Potential" data points in the Figures are obtained from the following fractions for each test subject: sORP wCOsubjectn / sORP woCOsubjectn, where sORP woCOsubjectn is set to 1. As a measure of oxidative stress (caused by ROS etc.) in sperm (sperms / spermatozoa), the sORP data show a trend towards being lower in CO exposed samples (wCO) compared to samples not exposed to CO (woCO). This is evident from the location of the data points, where four of the data points are located below the dashed woCO=1 reference line. Thus, without being bound by theory, these results suggest that CO exposure results in a reduction in the levels of reactive oxygen species (ROS) in sperm compared to sperm not exposed to CO ( Fig.10 ).

[0230] 2. DNA fragmentation

[0231] Fig.11 The "Relative DNA Fragmentation" data points shown in derive from the following fraction for each subject: DNA fragmentation wCO subject n / DNA fragmentation woCO subject n, with DNA fragmentation woCO subject n set to 1. Fig.11 It is evident from the graph that DNA fragmentation is reduced in samples exposed to CO compared to samples not exposed to CO. This is evident from the position of the data points, which all lie below the dashed woCO=1 reference line.

[0232] In summary, the results suggest that exposure of sperm to CO leads to desirable / improved characteristics of gametes (e.g., reduction in oxidative stress / redox potential / ROS levels ( Fig.10 ) and reduction of DNA fragmentation ( Fig.11 ) and improvement of their forward motion).

[0233] Thus, the present inventors have surprisingly found that carbon monoxide (CO) when in contact with gametes such as spermatozoa results in the preservation of spermatozoa. As a result of the gametes being incubated with CO, these spermatozoa have been shown to have desirable characteristics (compared to spermatozoa not exposed to CO) and are therefore particularly useful for ART.

[0234] Embodiment 2:

[0235] Example 2 illustrates the improvement of sperm motility parameters (i.e., redox potential) in response to different carbon monoxide (CO) incubation durations. Sperm from the same subject was treated with carbon monoxide or remained untreated as an "untreated" control. The duration of treatment with CO was different (60, 90, 180, or 270 min).

[0236] method

[0237] In this example, sperm samples were treated with one, three, or six reservoirs / capsules, each containing 5 mg Mo-CORM (equivalent to 0.44 mL CO), for 60-270 minutes, or left untreated for the same period of time.

[0238] Using these materials, the reservoir and Mo-CORM were prepared as follows: FeCl3 was used for Mo-CORM activation.

[0239] Material

[0240] All chemicals required for the synthesis of Mo-CORM and its activation, including molybdenum hexacarbonyl, ethyl isocyanoacetate, acetonitrile, anhydrous tetrahydrofuran, sodium hydroxide (pa), hydrochloric acid (pa), anhydrous ethanol, FeCl3*6H2O, and nitric acid (65%, pa), were purchased from Sigma-Aldrich Chemie GmbH (Schnelldorf, Germany). Gamete and embryo handling medium (with albumin) (MHM) for sperm dilution was purchased from Irvine Scientific (Santa Ana, CA). 270 ppm CO calibration gas was purchased from Linde AG (Munich, Germany). Polyamide (PA2200) and duroplast photopolymer MED610+VeroBlackPlus (RGD875) were provided by EOS GmbH (Krailling, Germany) and Stratasys Ltd. (Recovot, Israel), respectively. Silicone R 6.65×0.4 mm was purchased from RAUMEDIC AG (Helmbrechts, Germany). SF332K-Silicone (mixing ratio 1:1, viscosity before mixing: 7000-8000cP, stiffness after mixing: 33ShA, density 1.11g / cc, breaking point: 4.7N / mm 2 ) and SF45 2K-Silicone (mixing ratio 1:1, viscosity before mixing: 8500cP (at 23°C), stiffness after mixing: 45ShA, density: 1.12g / cc, breaking point: 3.5±0.5N / mm 2 ), purchased from Silikonfabrik (Ahrensburg, Germany). All casting molds were constructed from polytetrafluoroethylene (Vink, Germany) on a neo CNC machine (Datron AG, Germany). Loctite SI 5248, Loctite 4902, Loctite HY 4011, and Loctite SF7701 were purchased from Henkel (Düsseldorf, Germany). Needle 0.9*40mm and U100 insulin needles 0.3*8 mm were purchased from B. Braun (Melsungen, Germany). Unless otherwise stated, all other reagents were purchased from Sigma Aldrich Chemie GmbH and were of at least pharmaceutical grade.

[0241] Reservoir Manufacturing

[0242] All parts were molded using custom-designed Teflon casting molds. After filling the mold, a vacuum was applied for 5 minutes to extract any air bubbles. The casting was then filled again to the brim and vacuum was applied for another 5 minutes. After that, the respective casting was pressed into silicone and fixed with a clamp. After drying at 40°C for 24 hours, the cast mold was separated from the casting with compressed air. The shell and cover were cast separately. The cavity was filled with Mo-CORM. The cover and upper edge of the shell were then prepared in some forms by applying an adhesive primer. The adhesive was then applied and the two parts were pressed together. Moving the two parts relative to each other in a circular motion resulted in an even distribution of the adhesive.

[0243] Synthesis of Mo-CORM

[0244] CORM trisodium tricarbonyl-[tris(isocyanoethyl acetate)]molybdenum (Na3Mo(CO)3(CNCH2CO2)3, Mo-CORM) was synthesized as previously disclosed. Briefly, molybdenum hexacarbonyl was stirred in anhydrous acetonitrile to exchange three of its ligands for acetonitrile. These ligands were exchanged for EICA ligands. Purification and cation exchange gave Mo-CORM as a white solid.

[0245] Sperm preparation

[0246] Human spermatozoa were collected from healthy volunteers in 100 mL sample containers. Then, the ejaculated semen was divided into equal parts and packed into 15 mL airtight Falcon tubes, and one sample was exposed to one or more activation reservoirs / capsules. Then, after a predetermined time, the static oxidation-reduction potential (sORP) of both samples was analyzed by MiOXSYS.

[0247] Static Oxidation Reduction Potential (sORP) Analysis

[0248] Static redox potential (sORP) levels were determined using an oxidative male infertility measurement system (MiOXSYS, Englewood, CO) according to the manufacturer's instructions. 30 μL of sample was transferred to the sample application port on the MiOXSYS sensor and analyzed for 2 minutes. Results were expressed in millivolts (mV) and normalized to semen sperm concentration (mV / 10 6 sperm / mL).

[0249] result

[0250] Fig.12The beneficial effects of contacting gametes with carbon monoxide on gamete vitality parameters (i.e., the redox potential of treated gametes) are clearly shown. This is particularly evident from the gamete samples of subjects 38_7 and 42_1, which were contacted with carbon monoxide for 60 minutes and 90 minutes, respectively. When untreated, the samples of both subjects showed high redox potentials (black bars), but when treated with carbon monoxide, a sharp decrease in the redox potential of each sample can be observed (white bars). Redox potential measurements provide an indication of oxidative stress in gametes, and high redox potentials (such as in the untreated gamete samples of subjects 38_7 and 42_1) may have a negative impact on the vitality and quality of gametes. Therefore, the inventors were surprised to find that carbon monoxide (CO) leads to improvements in gamete vitality parameters and quality when contacted with gametes such as sperm.

Claims

1. A reservoir (10) configured to be inserted into a human and / or animal body, comprising: at least one housing (12); at least one chamber (14) defined within the housing (12); wherein the chamber (14) is configured to receive and store at least one primary substance (42) configured to selectively emit carbon monoxide, wherein the primary substance (42) is configured to emit carbon monoxide after being activated by at least one activation substance (44); wherein the chamber (14) is enclosed by at least one wall (16) of the housing (12), wherein at least a portion of the wall (16) is at least partially permeable to carbon monoxide evolved by the primary substance (42), such that the reservoir (10) is capable of at least partially releasing carbon monoxide evolved by the primary substance (42) into the environment; and The reservoir (10) is configured such that the activation substance (44) can be introduced into the chamber (14) from outside the housing (12) in a state where the main substance (42) has been arranged in the chamber (14).

2. The reservoir (10) according to claim 1, wherein the reservoir (10) comprises only a single chamber (14).

3. The reservoir (10) according to any of the preceding claims, wherein the reservoir (10) is configured to release carbon monoxide in vivo and / or ex vivo.

4. The reservoir (10) according to any one of the preceding claims, wherein the reservoir (10) is configured to be administered orally and / or rectally and / or vaginally and / or via the ear into the human and / or animal body.

5. The reservoir (10) according to any one of the preceding claims, wherein the reservoir (10) is configured to be swallowed by a human and / or an animal.

6. A reservoir (10) according to any of the preceding claims, wherein the housing (12) comprises at least one body (18) and at least one cover (20), wherein the body (18) and the cover (20) are configured to be connectable to each other, preferably in a substantially liquid-tight manner.

7. The reservoir (10) according to claim 6, wherein the cover (20) and / or the body (18) comprises a protrusion (22) configured to extend into the chamber (14) when the cover (20) and the body (18) are connected to each other.

8. A reservoir (10) according to claim 7, wherein the protrusion (22) is configured as a diaphragm, which can be pierced by an introduction device (46), the introduction device (46) being configured to introduce an activation substance (44) into the chamber (14) to activate the main substance (42), wherein the protrusion (22) is configured to reseal after the introduction device (46) has been withdrawn from the protrusion (22), preferably in a substantially liquid-tight manner.

9. A container (10) according to any one of claims 6 to 8, wherein the body (18) and / or the lid (20) include at least one protrusion (70), the protrusion (70) extending from an interface surface (72) of the lid (20) and / or the body (18), the interface surface (72) extending along a connection interface between the lid (20) and the body (18), wherein when the body (18) and the lid (20) are connected to each other, the protrusion (70) extends toward the other of the lid (20) and the body (18) and engages the other of the lid (20) and the body (18), preferably wherein the lid (20) or the body (18) includes the protrusion (70), and the interface surface of the other of the lid (20) and the body (18) (which extends along the connection interface between the lid (20) and the body (18)) is substantially smooth and / or continuous and / or has no protrusions and / or no recesses.

10. The reservoir (10) according to any one of the preceding claims, wherein: The size of the entire reservoir (10) corresponds to or is at least not larger than the standard pharmaceutical capsule size, preferably the standard pharmaceutical capsule size is 5 to 000; and / or The dimensions of the entire reservoir (10) correspond to or are at least no greater than 2, 1 or 0 standard pharmaceutical capsule dimensions.

11. A device (40) for selectively releasing carbon monoxide, comprising: A reservoir (10) according to any one of the preceding claims; as well as At least one primary substance (42) configured to selectively emit carbon monoxide, wherein the primary substance (42) is stored in a chamber (14) of a reservoir (10) and is configured to emit carbon monoxide such that the emitted carbon monoxide is at least partially released through a wall (16) of the reservoir (10) after being activated by at least one activating substance (44).

12. A therapeutic system (60; 80) for treating biological cells (62), preferably living cells, preferably gametes and / or immune cells, with carbon monoxide, the therapeutic system comprising: at least one container (64; 82) configured to receive said biological cell (62); at least one source of carbon monoxide (40), preferably at least one device (40) for selectively releasing carbon monoxide according to claim 11; The container (64; 82) and the carbon monoxide source (40) are arranged relative to each other so that the biological cells (62) can be contacted with carbon monoxide provided by the carbon monoxide source (40) to treat the biological cells (62).

13. A kit for treating biological cells (62), preferably living cells, with carbon monoxide ex vivo or in vivo, the kit comprising: at least one device (40) for selectively releasing carbon monoxide according to claim 11; as well as At least one activating substance (44), preferably wherein the activating substance (44) is contained within an introduction device (46) having a hollow needle (48), the hollow needle being configured to pierce the device (40) to selectively release carbon monoxide, more preferably wherein the hollow needle (48) is configured to pierce a cover (20) of the device (40) to selectively release carbon monoxide.

14. A method of preparing a carbon monoxide delivery device for use, the method comprising: providing at least one device (40) for selectively releasing carbon monoxide according to claim 11, the device being configured to be inserted into one or more body cavities of the human and / or animal body, preferably by oral ingestion and / or rectal insertion; The primary substance (42) is activated with at least one activating substance (44) by introducing the activating substance (44) into the chamber (14) of the device (40) through the cover (20) or the body (18) of the device (40).

15. A method of treating a mammal, such as a human, in vivo with carbon monoxide, the method comprising: Providing at least one device (40) for selectively releasing carbon monoxide according to claim 11; The primary substance (42) is activated with at least one activating substance (44), such as by introducing the activating substance (44) into the chamber (14) of the device (40) through the cover (20) or the body (18) of the device (40). The at least one device (40) is introduced into one or more body cavities of a mammal, for example by oral ingestion and / or rectally.

16. Carbon monoxide for use in treating biological cells, preferably living cells, in vivo and / or in vitro in a mammal, preferably for treating gastrointestinal diseases, wherein the carbon monoxide is released from a device according to claim 11 in vivo and / or in vitro in a mammal.

17. A method for treating biological cells (62), preferably living cells, more preferably ex vivo, with carbon monoxide, the method comprising: Providing a treatment system according to claim 12; Arranging biological cells (62) in a container (64; 82); The release of carbon monoxide from a carbon monoxide source is triggered, wherein the carbon monoxide provided by the carbon monoxide source contacts a biological cell (62).

18. The method of claim 17, wherein the treatment system is provided by arranging at least one device (40) configured to selectively release carbon monoxide in the container (64; 82), preferably at least one device (40) according to claim 11.

19. The method according to claim 17 or 18, wherein triggering the release of carbon monoxide comprises activating the main substance (42) of the carbon monoxide source with at least one activation substance (44).

20. A method according to claim 19, wherein the activated substance (44) is introduced into a chamber (14) in which the main substance (42) is arranged, preferably, wherein the activated substance (44) is introduced via an introduction device (46), wherein the introduction device (46) comprises a hollow needle (48) configured to pierce the wall of the chamber.

21. A method according to any one of claims 17 to 20, wherein the treatment system comprises at least one first chamber and at least one second chamber, wherein the biological cells (62) are arranged in the first chamber, and wherein at least one main substance (42) of the carbon monoxide source is arranged in the second chamber, wherein the second chamber is separated from the first chamber by at least one wall (16; 86), wherein at least a portion of the wall (16; 86) is permeable to the carbon monoxide released by the main substance (42), so that the carbon monoxide released by the main substance (42) is released from the second chamber into the first chamber.

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