Patent Application
20220331455
The present invention is related to a cartridge. More in particular, the present invention relates to a cartridge by which a liquid held in the cartridge can be mixed, within the cartridge, with a further liquid held in the cartridge or with a pressurized gas. The present invention further relates to a cartridge system comprising such a cartridge and a device in which the cartridge can be releasably inserted, wherein the device is configured for providing pressurized gas(ses) to be used as propellant(s) for moving the liquid(s) inside the cartridge for the purpose of mixing the liquid(s), and/or to be used as gas to be mixed. The present invention also relates to a device for releasably receiving the abovementioned cartridge.
When a therapeutic or diagnostic liquid is to be used intracorporeally, it is essential that the sterility of the liquid can be ensured. When such liquid can be used without additional processing steps such as mixing the liquid with another liquid, it is possible to supply the liquid in a sterile container intended for one person. Alternatively, a larger source of sterile liquid can be used from which the required quantity can be drawn. However, in this latter case, strict requirements apply to the environment in which the reservoir is placed and the manner in which the desired quantities are obtained therefrom. This latter aspect makes the use of larger reservoirs impractical for environments such as hospitals or clinics.
A different situation however occurs when the liquid needs to be processed before use. For example, the therapeutic or diagnostic substance to be administrated to the patient requires a personalized composition or dosage. Alternatively, it may happen that the therapeutic or diagnostic substance is inherently instable and must be administrated quickly after preparation. In such situations, ensuring sterility of the end product is more difficult.
An object of the present invention is to provide a solution to the abovementioned problem.
According to the invention, this object is achieved with a cartridge as defined in claim 1. This cartridge comprises a cartridge body, one or more gas inlets formed in the cartridge body, and a fluid storage system formed in the cartridge body and comprising one or more fluid storage units, each fluid storage unit being configured for holding a respective fluid and for outputting said fluid in response to a pressurized gas being supplied to the fluid storage unit through a gas inlet among the one or more gas inlets by using the supplied gas as a propellant.
The cartridge further comprises a mixing unit arranged in or mounted to the cartridge body and being in fluid communication with the fluid storage unit(s) using a fluid channel or fluid channels formed in the cartridge body. The mixing unit is configured for mixing respective fluids outputted from respective fluid storage units or for mixing a fluid outputted from a fluid storage unit with a pressurized first gas received through a gas inlet among the one or more gas inlets. At least one fluid held in the fluid storage system is a liquid. In a preferred embodiment, each fluid storage unit holds a liquid. When multiple fluid storage units are used, the liquids held by these units may or may not be identical.
With the cartridge of the invention it becomes possible to hold the liquid(s) to be mixed in a sterile manner inside the cartridge. Moreover, pressurized gas(ses) is/are used to control the mixing process by using this/these gas(ses) as propellants. Hence, the liquid(s) can be mixed within the cartridge thereby avoiding the possible non-sterile transport of liquid between the mixing unit and a reservoir of liquid. The only fluids that are exchanged with the cartridge are gaseous, and gases can be kept sterile in a much more convenient manner than liquids.
As the liquid(s) can be kept in fluid storage unit(s) in a sterile manner, it becomes possible to produce and store the cartridges for a considerable period of time prior to administration.
The invention is particularly related to cartridges in which at least one liquid is held in the fluid storage system that is intended for intracorporeal use in a human or animal, for example for intravenous use or intra-cavity use. For example, the at least one liquid may comprise or may be used to form a diagnostic agent, such as a contrast agent for medical imaging, or a therapeutic agent, such as a medicament. Nevertheless, the present invention can also relate to other applications wherein the sterility of the liquid to be mixed and the sterility of the mixed product are of importance.
Each fluid storage unit may comprise a fluid storage unit inlet and a fluid storage unit outlet, wherein the fluid storage unit is configured such that the pressurized gas supplied to the fluid storage unit through the fluid storage unit inlet pushes the fluid in the fluid storage unit through the fluid storage unit outlet. By using a gas, which can be kept sterile relatively easily, as a propellant, the sterility of the liquid(s) can be ensured during transport from the fluid storage unit to the mixing unit. In addition, at least one fluid storage unit may comprise a storage chamber configured for receiving a sealed off container in which a liquid is held in a sterile and sealed off manner, and a liquid reservoir in fluid communication with the storage chamber, wherein the fluid storage unit inlet is connected to one of the storage chamber and the liquid reservoir and wherein the fluid storage unit outlet is connected to the liquid reservoir. The liquid reservoir can be configured for collecting liquid that is released from the container after the container has been broken, ruptured, cut, or pierced. The sealed off container may for example comprise a blister package. This sealed off container may be fixedly held in the storage chamber, for example by means of an adhesive. Alternatively, the blister package is inserted into the storage chamber just before use. For example, the blister package may comprise an adhesive strip by which the blister package can be fixed to the cartridge. Such adhesive strip could be covered by a covering strip that is to be removed when the blister package is to be fixed to the cartridge. Hence, the present invention may relate to embodiments wherein the cartridge and sealed off container are two separate items that are sold to the end-user by a single entity or separately by different entities, or the invention may relate to embodiments wherein the sealed off container is fixed to the cartridge before the combination is sold to the end-user.
For at least one fluid storage unit, the liquid reservoir may be formed as a part of the storage chamber. In this case, the liquid that is released from the sealed off container is collected at least partially in the storage chamber itself. Alternatively, the at least one fluid storage unit may comprise a fluid channel formed in the cartridge body connecting the storage chamber and the liquid reservoir. Hence, after the liquid is released it will be transported through this fluid channel to the liquid reservoir.
For a fluid storage unit among the at least one fluid storage unit, the storage chamber may comprise a supporting surface for supporting the sealed off container and at least one protruding pin or needle extending towards the sealed off container for the purpose of puncturing through the sealed off container if sufficient force is exerted onto the sealed off container. The sealed off container may be deformable such that when force is exerted, a wall or segment of the container engages the pin or needle. When sufficient force is applied, the pin or needle will puncture the sealed off container thereby releasing the liquid that is held by that container. It should be noted that the present invention does not exclude other means by which the container may be broken, cut, ruptured, or otherwise opened for the purpose of releasing the liquid. The pin or needle may protrude from the supporting surface. In other embodiments, the pin(s) or needle(s) may be provided at a different surface such that when the container is supported by the support surface and no external force is exerted onto the container, the pin(s) or needle(s) do not engage the container.
In addition, at least one fluid storage unit may be provided with a protective ring that protrudes away from the cartridge body further than the sealed off container when it is placed in the storage chamber. In this manner, when the cartridge is placed onto a table with the container facing downward towards the table, there will be no significant force that is exerted onto the container.
The cartridge may comprise a plurality of the fluid storage units, wherein the fluid storage unit inlets of at least two fluid storage units are in fluid communication with each other. In this case, an identical gas can be used for the at least two fluid storage units. In a further embodiment, the gasses used as propellants by the plurality of fluid storage units may be identical. Additionally or alternatively, the gas inlet through which the pressurized first gas is received can be the same as the gas inlet through which the pressurized gas is received that is used as propellant by at least one fluid storage unit. The pressurized first gas can be different from the pressurized gas(ses) that is/are used as propellant(s) by the at least one fluid storage unit.
The present invention particularly relates to the combinations of gasses and liquids as described in table 1. In this table, (m) indicates that a gas is to be used as a gas to be mixed, and (p) indicates that it is to be used as a propellant. For example, the second combination mentioned in the table indicates that a first gas is used as the pressurized first gas to be mixed, and a second gas is used as a propellant for propelling the different liquids, i.e. liquid 1 and liquid 2 held in respective fluid storage units, towards the mixing unit. In the fifth combination, a first gas is fed through gas inlet 1 and is used both as a propellant and as gas to be mixed. Other combinations are not excluded.
Among these combinations, the invention particularly relates to embodiments wherein the cartridge has a single fluid storage unit, and two gas inlets, wherein a first gas inlet among the two gas inlets is in fluid communication with the mixing unit and wherein a second gas inlet among the two gas inlets is in fluid communication with the fluid storage unit. This corresponds to the third combination in the table above.
The mixing unit can be configured to mix at least one liquid received from the fluid storage system with the pressurized first gas, wherein the mixing unit comprises a microfluidics device configured for generating microbubbles within the at least one liquid that are filled with the pressurized first gas. The microfluidics device may comprise two or more substrates, for example glass substrates, in which at least one substrate comprises a structure of grooves made, for example, using wet etching, and which substrates are bonded together, for example using fusing bonding, to form a structure of channels having cross-sectional dimensions in a range of 1-1000 micrometer. The microfluidics device can be configured for generating microbubbles having a diameter below 10 micrometer, and preferably in a range of 2-5 micrometer. Such microbubbles can be used as a contrast agent for ultrasound imaging or for therapeutic application in combination with ultrasound, such as ultrasound directed drug delivery or focused ultrasound therapy. For such application, the pressurized first gas may comprise one or more gases from the group consisting of SF6, N2, CO2, O2, H2, He, Ar, ambient air, and perfluorocarbon gases, such as CF4, C2F6, C2F8, C3F6, C3F8, C4F6, C4F8, C4F10, C5F10, C5F12 and mixtures thereof. Additionally or alternatively, at least one liquid received from the fluid storage system may comprise at least one liquid from the group consisting of water, dispersion of lipids, such as phospholipids, or proteins in an aqueous solution, active pharmaceutical ingredients, and/or alcohols. Either the pressurized first gas or the liquid(s) received from the fluid storage system may comprise a surfactant suitable for populating a fluid interface between the pressurized first gas and liquid(s) from the fluid storage system, and to thus encapsulate and stabilize the microbubbles and to thereby prevent the dissolution of the bubbles. The surfactant may, for example, include a film-forming (mixture of) phospholipid(s), e.g. a mixture of DPPC, DSPC, DPPA, and DPPE-MPEG5000.
When used in the abovementioned application for generating a contrast agent for ultrasound imaging, the cartridge preferably comprises a gas inlet for receiving the pressurized first gas, and a gas inlet for receiving the propellant gas to be used for the single fluid storage unit.
The microfluidics device may comprise a first inlet for receiving the pressurized first gas, a second inlet for receiving said at least one liquid, and a bubble formation channel for generating the microbubbles based on a flow of the first pressurized gas received through the first inlet and a flow of the at least one liquid received through the second inlet. Additionally, the cartridge body may comprises a first opening, a second opening, and a third opening, wherein the first opening is in fluid communication with the gas inlet that receives the pressurized first gas, and wherein the second opening is in fluid communication with the fluid storage system for the purpose of receiving the at least one liquid. In this case, the microfluidics device is positioned relative to the cartridge such that the first opening is aligned with the first inlet of the microfluidics device, the second opening with the second inlet of the microfluidics device, and the third opening with an outlet of the microfluidics device. The microfluidics device may be fixedly connected to the cartridge body using an adhesive or a monolithic bond. Alternatively, the microfluidics device can be integrally formed with the cartridge body.
The microfluidics device may comprise a flow focusing junction, a first channel connected on one end to the second inlet and on another end to the flow focusing junction, a second channel connected on one end to the second inlet and on another end to the flow focusing junction, and a third channel connected on one end to the first inlet and on another end to the flow focusing junction. The bubble formation channel may be connected to the flow focusing junction. Moreover, the flow focusing junction may be configured to receive a flow of said at least one liquid from two opposing directions via the first and second channels that impinges in a perpendicular manner onto a flow of the first pressurized gas received via the third channel. The flow of the pressurized gas may be directed from the third channel into the bubble formation channel.
A microfluidics device as described above is known from WO 2013/141695 and WO 2016/118010. The contents of these publications are incorporated herein for all purposes.
The cartridge may comprise an outlet formed in the cartridge body for outputting the fluids mixed by the mixing unit. This outlet can be formed to allow a Luer taper connection with a syringe.
The cartridge may comprise a buffer reservoir formed in the cartridge body and arranged in between the mixing unit and the outlet, wherein the buffer reservoir has a capacity that exceeds the volume of liquid held in the fluid storage system. Typically, the buffer reservoir is at least 30 percent larger than the volume of liquid held in the fluid storage system.
The cartridge may further comprise a venting hole formed in the cartridge body that is in fluid communication with the buffer reservoir. The venting hole is provided to prevent over-pressure in the buffer reservoir. Furthermore, the venting hole allows the buffer reservoir to be purged with a predefined gas prior to mixing. For example, in the embodiment with the microfluidics device described above, it is possible to purge the buffer reservoir with the same gas as the gas that fills the microbubbles. By having the buffer reservoir filled with this gas, the stability of the microbubbles can be improved, e.g. the dissolution rate of the microbubbles can be reduced compared to embodiments wherein other gaseous media are present in the buffer reservoir. The venting hole further allows pressure equalization in the buffer reservoir when the liquid is extracted from the buffer reservoir, e.g. using a syringe. Without the venting hole, an under-pressure would be generated inside the buffer reservoir that would destroy the microbubbles and complicate the extraction of the liquid inside the buffer reservoir.
The cartridge may further comprise a fluid channel formed in the cartridge body in between the one or more gas inlets and the mixing unit, a fluid channel formed in the cartridge body in between the one or more gas inlets and the fluid storage system, a fluid channel formed in the cartridge body in between the fluid storage system and the mixing unit, a fluid channel formed in the cartridge body in between the mixing unit and the buffer reservoir, and a fluid channel formed in the cartridge body in between the buffer reservoir and the venting hole. These fluid channels may extend essentially in a same fluid channel plane. In some embodiments, the cartridge may comprise a top surface and a bottom surface that are relatively close together and wherein the top surface and bottom surface essentially extend in a plane that is parallel to the fluid channel plane. Such cartridge may be bar shaped.
The cartridge may be configured to be in a first orientation during said mixing, wherein, in the first orientation, a normal to the fluid channel plane is substantially horizontal, the mixing unit is positioned at a lower position relative to the fluid storage system and relative to the gas inlet through which the pressurized first gas is received, and the fluid channel between the mixing unit and the buffer reservoir outputs in the buffer reservoir at a lower end of the buffer reservoir, preferably at or close to a lowest point of the buffer reservoir in this orientation. Hereinafter, the wording horizontal and vertical will be used as relating to a direction of Earth's gravitational force unless otherwise stated. For example, vertical shall be used to refer to a direction perpendicular to Earth's surface and horizontal to a direction parallel to Earth's surface.
Typically, the gas that fills the microbubbles is heavier than ambient air. When the cartridge is held in the first orientation, and the buffer reservoir has been flushed with this gas prior to mixing, liquid exiting the microfluidics device will, when entering the buffer reservoir, engage this gas and/or the already outputted liquid. In this manner, the stability of the microbubbles can be improved as contact between the outputted liquid and ambient air that may be present in the buffer reservoir can be minimized.
The cartridge can be configured to be in a second orientation e.g. during storage, wherein, in the second orientation a normal to the fluid channel plane is substantially vertical, and the fluid channel between the mixing unit and the buffer reservoir outputs in the buffer reservoir at a position above a liquid-air interface in the buffer reservoir to prevent liquid outputted by the mixing unit into the buffer reservoir to flow back into the fluid channel between the mixing unit and the buffer reservoir when the cartridge is in the second orientation. Hence, after mixing with the cartridge being held in the first orientation, the cartridge may be arranged flat on a table. This configuration generally corresponds to the second orientation. By arranging the fluid channel between the mixing unit and the buffer reservoir in the manner described, it can be achieved that the liquid in the buffer reservoir will not flow back through this fluid channel towards the mixing unit.
The fluid channel between the venting hole and the buffer reservoir may output in the buffer reservoir at a position above the liquid-air interface when the cartridge is in the second orientation. Hence, when the cartridge is arranged flat on a table, i.e. corresponding to the second orientation, liquid in the buffer reservoir can be prevented from flowing into the fluid channel towards the venting hole.
The buffer reservoir can be vertically elongated when the cartridge is held in an orientation in which a normal to the fluid channel plane is horizontal, e.g. the first orientation. In this manner, liquid that is outputted by the mixing unit into the buffer reservoir only sees a relatively small area in which it may be exposed to the gas(ses) in the buffer reservoir. By having the elongated shape, the stability of microbubbles can therefore be improved.
The buffer reservoir can be transparent to allow a user to visually inspect its contents or the level thereof.
It should be noted that the abovementioned features related to the buffer reservoir would equally be advantageous for applications other than the formation of microbubbles.
The cartridge may further comprise filters arranged in each of said one or more gas inlets formed in the cartridge body, and, when applicable, in the venting hole. These filters are configured to prevent bacteria and/or other pathogens from entering the cartridge. These filters are preferably hydrophobic. At least one filter may comprise a filter membrane, a first filter support, and a second filter support, wherein the first and second filter supports are fixedly attached to or integrally formed with the cartridge body and wherein the filter membrane is arranged in between the first and second filter supports. The first and second filter supports prevent that the filter membranes are removed from the cartridge, or are ruptured of torn in case of sudden changes in under-pressure or over-pressure. The first and second filter supports may comprise ribs extending over the openings for the gas inlet(s) and venting hole either from an outside of the cartridge body or from an inside of the cartridge body.
The cartridge may have been formed by fixedly attaching a first cartridge part and a second cartridge part using ultrasonic welding, each cartridge part comprising a base layer. Prior to fixedly attaching these parts, one of the first and second cartridge part may have comprised ridges and/or protruding portions extending from the base layer that were configured to cooperate with protruding portions and/or ridges extending from the base layer of the other of the first and second cartridge part during ultrasonic welding. As a result of the ultrasonic welding, the protruding portions have become integrally connected to the corresponding ridges. The integrally connected ridges and protruding portions, and the base layer of the first and second cartridge parts may together define at least one of the mixing unit, the fluid storage system, the one or more gas inlets, the outlet, the buffer reservoir, and the fluid channels for connecting them. Preferably, all of these structures are formed in this manner. The first and second cartridge parts can be made, using injection molding, from one or more materials from the group of thermoplastic materials such as polycarbonate.
According to a second aspect, the present invention provides a cartridge system that comprises a cartridge as described above and a device comprising a housing with an opening in which the cartridge can be releasably inserted. The device comprises one or more nozzles for inserting a respective pressurized gas into the one or more gas inlets, respectively, for the purpose of said mixing by the mixing unit of the cartridge.
The cartridge can be configured as comprising the abovementioned sealed off container. In this case, the device may further comprise an engaging unit for engaging the sealed off container arranged in a storage chamber of at least one fluid storage unit for the purpose of causing the sealed off container to break, rupture, or to become cut or pierced.
The device may comprise a drive system for bringing the nozzles and/or engaging unit into and out of engagement with the one or more gas inlets and the sealed off container, respectively. The device may comprise a controller for controlling the drive system. Moreover, at least one of said one or more nozzles may be connected to a controllable valve, wherein the controller is configured for controlling a flow of pressurized gas through said at least one of said one or more nozzles via the controllable valve. The device may comprise one or more reservoirs for holding pressurized gas, said one or more reservoirs being connected to the one or more nozzles. Alternatively, the device may comprise one or more further gas inlets that are connected to the one or more nozzles, respectively, wherein the one or more further gas inlets are configured to be connected to one or more gas reservoirs external to the device. Accordingly, the device can rely on internal storage of the required gases or may be connected to an outside infrastructure by which the required gases are provided. In both cases, the controllable valves are preferably arranged in the device.
The controller may be configured to control the device to be operable in a first state in which the nozzles and engagement unit are positioned at a distance from the cartridge. The system may further be operable in a second state in which the controller controls the drive system to bring the nozzles into contact with the one or more gas inlets and wherein the controller controls the controllable valve(s) such that pressurized gas(ses) is/are fed to the cartridge via the respective nozzle(s) and gas inlet(s) of the cartridge. In this manner, the various fluid channels inside the cartridge and optionally the buffer reservoir can be flushed with one or more prescribed gases.
The device may further be operable in a third state in which the controller controls the drive system to cause the engaging unit to engage the sealed off container for the purpose of causing the sealed off container to break, rupture or to become cut or pierced, and to subsequently control the controllable valve(s) to provide pressurized gas(ses) to the cartridge via the respective nozzle(s) and gas inlet(s) of the cartridge for the purpose of said mixing by the mixing unit of the cartridge. Typically, some time is reserved between the moment of applying the propellant gases and the moment at which the sealed off container releases its liquid to allow all or most of the liquid to be collected in the liquid reservoir of the relevant fluid storage unit prior to the mixing process.
The controller may be configured to control the controllable valve(s) to stop the supply of pressurized gas(ses) to the cartridge when changing from the second state to the third state. In this manner, the flow of the liquid from the sealed off container to the liquid reservoir is not affected.
The drive system may comprise a first unit in which the one or more nozzles are moveably mounted and in which the engagement unit is mounted. The drive system may further comprise an actuator for moving the first unit relative to the cartridge when the cartridge is inserted into the device.
The nozzles can be mounted in a spring-biased manner in the first unit to allow the nozzles to move relative to the first unit in a first direction towards the cartridge and perpendicular thereto. As described above, the first unit may move towards the cartridge to allow the nozzles to engage the cartridge. At that time, the engagement unit is not engaging the sealed off container. Such engagement is obtained when the first unit moves even further towards the cartridge. By having the nozzle(s) mounted in the first unit in a spring biased manner, the nozzle(s) may move back towards the first unit during this last movement of the first unit while maintaining engagement with the gas inlet(s). In this manner, damage of the nozzle(s) and/or gas inlet(s) of the cartridge can be prevented.
The engagement unit may be movably mounted to the first unit. Movement of the engagement unit relative to the first unit can be used to accommodate for non-zero tolerances in the relative position and/or shape of the sealed off container and the gas inlet(s). For example, the engagement unit may be able to translate in one or more directions other than the direction towards the cartridge, and/or to rotate about these directions. Similar degrees of freedom may apply to one or more nozzles. In both cases, the degrees of freedom are used to accommodate for tolerances in the manufacturing process of the cartridge. Put differently, the degrees of freedom allow alignment of the nozzles and engagement unit relative to the cartridge.
The drive system may further comprise a second unit that is coupled to the first unit, wherein the first unit is able to move in at least one degree of freedom relative to the second unit, and wherein the actuator is configured to move the second unit in the first direction, i.e. towards the cartridge. In this manner, the movement of the second unit is completely dictated by the actuator. However, movement of the first unit may generally also depend on the alignment of the nozzles and engagement unit with the cartridge. This is made possible by the fact that the first unit may move relative to the second unit. The mutual movement between the first and second units can be made possible by having the second unit coupled to the first unit using one or more bended leaf springs. Hence, the actuator will drive the first unit indirectly, i.e. via the second unit.
The first unit may be able to move relative to the second unit in a second direction orthogonal to the first direction and in a third direction orthogonal to both the first and second direction. Referring to the first direction towards the cartridge as the z-direction, the first and second direction may correspond to an x-direction and a y-direction, respectively. The first unit can further be able to rotate about the first direction relative to the second unit. Preferably, the first unit is only able to move relative to the second unit by translating in the x-direction and/or y-direction and by rotating about the z-direction.
A nozzle among the one or more nozzles can be able move along the first direction and to rotate about the first direction relative to the first unit, and wherein another nozzle among the one or more nozzles is able to move along the first direction, the second direction, and the third direction, and to rotate about one of the second and third direction. For example, in case two nozzles are used, a first nozzle is only able to move along the z-direction and to rotate about this direction. The other nozzle may in this case be able to move only along the x-direction, the y-direction, and the z-direction, and to rotate about the y-direction. The other degrees of freedom for these nozzles may be fixed.
The drive system may comprise a threaded spindle that is driven by the actuator and which extends in the first direction and wherein the second unit is coupled to the threaded spindle to cause a translation of the second unit in the first direction when the threaded spindle rotates. Preferably, rotation of the spindle will only cause a movement of the second unit in the first direction.
The device may further comprise a second frame that is fixedly connected to the housing, wherein the threaded spindle is rotatably received in the second frame, the second frame preferably comprising a wall segment that extends substantially perpendicular to the first direction and in which the threaded spindle is rotatably received.
The device may comprise a force sensor for sensing a force with which the engagement unit is pressing against the sealed off container, wherein the controller is configured to control the drive system in dependence of the sensed force.
The abovementioned second frame may comprise a first part and a second part coupled to the first part, wherein the first and second parts are able to move relative to each other when a force is exerted onto the cartridge by the engagement unit. In this case, the force sensor can be configured for determining said force in dependence of a mutual displacement between the first and second parts. For example, the first and second parts may be connected using a structure that is compressible in the first direction, such as a meandering bar or a lattice of bars. The compression can be determined using a position sensor in a known manner. The output of the position sensor in combination with known mechanical properties of the compressible structure can then be used to calculate the force exerted onto the cartridge or a parameter that represents and/or corresponds to such force.
According to a third aspect, the present invention provides a cartridge configured for mixing a liquid held in the cartridge, within the cartridge, with a further liquid held in the cartridge or with a pressurized gas supplied to the cartridge, wherein the liquid is intended for intracorporeal use in a human or animal, for example for intravenous use or intra-cavity use, wherein the liquid held in the cartridge comprises or is used to form a diagnostic agent, such as a contrast agent for medical imaging, or a therapeutic agent, such as a medicament. This cartridge may be configured as the cartridge defined before.
According to a fourth aspect, the present invention provides a cartridge system, comprising the cartridge in accordance with the third aspect of the invention and a device in which the cartridge can be releasably inserted, wherein the device is configured for providing pressurized gas(ses) to be used as propellant(s) for moving the liquid(s) inside the cartridge for the purpose of mixing the liquid(s), and/or to be used as gas to be mixed. This device can be configured as described before.
Next, the invention will be described in more detail referring to the appended drawings, wherein:
Cartridge 100 comprises a cartridge body 101 and is configured for mixing a liquid held in a sealed off container 120, within the cartridge, with a gas supplied through gas inlet 111. To that end, cartridge 100 comprises a mixing unit in the form of a microfluidics device that generates microbubbles filled with the gas that is supplied via gas inlet 111. This mixing unit will be discussed in more detail later in connection with
As the microfluidics device is a passive device, i.e. it requires energy to work, a pressurized gas has to be fed to gas inlet 111 and towards the microfluidics device. Moreover, once the liquid is released from container 120, a pressurized gas will be fed to gas inlet 110 to push the released liquid towards the microfluidics device. Put differently, the gas supplied to gas inlet 110 will be used as a propellant for propelling the liquid released from container 120 towards the microfluidics device.
The liquid in container 120 can be released by breaking container 120. To that end, sufficient force should be exerted onto container 120 as will be explained later.
Device 200 is configured to perform the actions described above. In other words, when a cartridge 100 is inserted in opening 202, device 200 will ensure that appropriate gases are supplied to cartridge 100 and that container 120 will be broken. This functionality will be explained later when referring to
An output of the microfluidics device is connected to a buffer reservoir 140 in which the mixed liquid can be temporarily stored. This reservoir, which will be discussed in more detail in connection with
As shown in
The gas supplied to gas inlet 110, which will be used as propellant, may be SF6. This same gas may be fed to gas inlet 111. As will be explained later, based on these fluids, the microfluidics device will generate a suspension of microbubbles filed with SF6 in an aqueous solution. Such suspension may be used as a contrast agent for ultrasound imaging.
The size of the SF6 core of the microbubble in combination with the shell formed by the phospholipids determines the resonance frequency of the microbubble. When the microbubble is subjected to an ultrasound wave of a suitable frequency, equaling or at least approaching the resonance frequency of the microbubble, the bubble will resonate at the resonance frequency of the microbubble. This resonance can be picked up by the ultrasound imaging apparatus. In this manner, a high contrast can be achieved between microbubble-rich and microbubble-poor regions.
Both first part 101A and second part 101B comprise ridges and/or protrusions that extend from a base layer. This base layer may comprise structures, such as recesses, for the formation of structures in the final cartridge such as buffer reservoir 140. Examples of protrusions 102 and ridges 103 are shown in
Now returning to
Again returning to
As can be seen in
Openings 125B, 111B are used for transporting liquid and gas, respectively, to microfluidics device 130, which is illustrated in
First and second channels 132A, 132B and channel 133 exit in a flow focusing junction 134. At this junction, a flow of the SF6 gas inside channel 133 is restricted by flows of the liquid in channels 132A, 132B such that SF6 filled microbubbles are generated in bubble formation channel 135. The liquid having the microbubbles is outputted from microfluidics device 130 through opening 130B in cartridge body 101. It is noted that the operation of microfluidics device 130 is known from WO 2013/141695 and WO 2016/118010. Microfluidics device 130 is typically fabricated from a glass substrate, such as borosilicate glass, or a polymeric material.
Now referring again to
Via fluid channel 112A, which extends between buffer reservoir 140 and venting hole 112, excess pressure can be relieved.
Buffer reservoir 140 is connected to outlet 113. Buffer reservoir 140 can be extracted through outlet 113 using a syringe. A Luer taper connection is used for outlet 113 to provide a sealed connection between the syringe and outlet 113. It is noted that when liquid is extracted from buffer reservoir 140, ambient air may be attracted through venting hole 112 for pressure equalization thereby preventing severe under-pressure in buffer reservoir 140 that would destroy the microbubbles and complicate the extraction of the liquid.
After the liquid is collected in buffer reservoir 140, cartridge 100 can be taken out of device 200. Typically, the user will then place cartridge 100 on a supporting surface, such as a table. To prevent the inadvertent flow of liquid from reservoir 140 into fluid channel 130A, it is ensured that in this orientation of cartridge 100, fluid channel 130A and fluid channel 112A exit into buffer reservoir 140 at a position above the gas-liquid interface. Accordingly, to achieve this advantage, the capacity of reservoir 140 should be chosen in dependence of the volume of liquid in container 120.
Now referring to
From center portion 122B, three needles 124 extend toward container 120. When sufficient force is exerted on the topside of container 120, the backside thereof will bend downward thereby engaging needles 124. Consequently, the backside of container 120 will be punctured and the liquid inside container 120 will be released. This liquid will flow through an opening 123, which is located at an upper portion of center portion 122B. Once flown through opening 123, the liquid will be collected in liquid reservoir 125. Consequently, when cartridge 100 is inside device 100, a small amount of liquid will remain in storage chamber 122 below opening 123. The positioning of opening 123 should be such that when cartridge 100 is inside device 200, opening 123 remains above gas-liquid interface 126. In this manner, the gas fed through gas inlet 110 cannot push liquid inside liquid reservoir back into storage chamber 122.
Next, the functionality of device 200 will be described referring to
Spindle 214 is rotatably mounted in wall segment 221. This wall segment is part of a frame 220 that is fixedly connected to housing 201. Here, it is noted that
As shown in
Now referring to
In
Now referring to
Now referring to both
Next, a possible operational cycle of the cartridge system of
As a first step, cartridge 100 is mounted in device 200 through opening 202 in
When cartridge 100 is just placed in opening 202, the system and therefore device 200 is in a first state in which unit 240 and U-frame 230 are positioned relatively far away from cartridge 100. Thereafter, controller 250 will operate actuator 210 to move U-frame 230 towards cartridge 100. As a result, nozzles 242A, 242B will engage inlets 110, 111. Due to the degrees of freedom of these nozzles and the degrees of freedom of unit 240 relative to U-frame 230, an alignment of unit 240 relative to cartridge 100 will be obtained. In addition, when properly engaged, controller 250 will control controllable valves 251, 252 that are arranged in between a container 1000 with pressurized SF6 and nozzles 242A, 242B. More in particular, valves 251, 252 are controlled to allow gas inlets 110, 111 and the components of cartridge 100 connected thereto to be flushed with SF6. This is referred to as the second state of the system and device 200. When the flushing action is finished, controller controls actuator 210 to move U-frame 230 and therefore unit 240 closer to cartridge 100 such that engagement unit 241 can engage container 120. During this movement, nozzles 242A, 242B will move backwards relative to unit 240 against the spring-biasing force. In fact, the spring constant of springs 243A, 243B determines to a large extent the force with which nozzles 242A, 242B are pressing on inlets 110, 111, respectively. It should further be noted that a single container 1000 may also be used as the gas supplied to inlets 110, 111 is identical.
During the movement of unit 240, controller 250 checks the force exerted by engagement unit 241 onto reservoir 120 using force sensor 253. This latter sensor may already have sensed a force caused by the nozzles 242A, 242B engaging inlets 110, 111, respectively. In particular, the reaction force exerted onto nozzles 242A, 242B by inlets 110, 111, respectively, is transferred via unit 240, U-frame 230, and spindle 214 onto wall segment 221. Consequently, as can be derived from
When engagement unit 241 presses sufficiently hard on reservoir 120 the latter will break and will release its liquid to liquid reservoir 125. Thereafter, valves 251, 252, which were typically closed during the time the liquid was released from container 120, are controlled to start the mixing process. Valves 251, 252 are preferably controlled after the liquid has reached the liquid reservoir 125.
During the mixing process, SF6 is fed to inlet 110 to act as propellant to move the liquid out of liquid reservoir 125 to microfluidics device 130. At the same time, SF6 is fed to inlet 111 as the gas to be used by microfluidics device 130 for generating microbubbles.
After a predetermined amount of time, valves 251, 252 are closed by controller 250 and unit 240 is moved away from cartridge 100. Thereafter, cartridge 100 can be removed from device 200 with the microbubble suspension being held in buffer reservoir 140.
The last part of the process, i.e. moving unit 240 towards cartridge 100 thereby allowing engagement unit 241 to engage reservoir 120 and the subsequent mixing process is performed when the system and therefore device 200 is in a third state.
In the above, the present invention has been explained using an embodiment that was targeted at the creation of a microbubble suspension intended to be used intracorporeally as a contrast agent. The skilled person will however appreciate that the present invention is not limited to such application. Other applications wherein a sterile liquid held in the cartridge is to be mixed, within the cartridge, with another sterile liquid held in the cartridge or a gas supplied to the cartridge, are equally possible.
Using the system of the application, a user may repeatedly generate case or person specific mixing products that can be generated just before use. Sterility of the end product is guaranteed because the crucial components, i.e. the liquid(s), are held in the container and because the mixing process also occurs in the cartridge. Contact with external devices, i.e. device 200, only involves the exchange of gaseous media. This exchange can be performed in a sterile manner using off-the-shelf filters.
Accordingly, an advantage of the present invention is that device 200 can be arranged in a non-sterile environment, for example an examining room in a hospital, while still allowing a sterile mixing product to be obtained.
In view of the above, it must be concluded that the present invention is not limited to the embodiments shown. Instead, various modifications are possible and other applications can be realized without departing from the scope of the invention, which is defined by the appended claims.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/NL2019/050547 | 8/26/2019 | WO |
