System for providing microvapoles with predefined size and / or size distribution

Abstract

A system for providing microvesicles, in particular microvesicles, having a predefined size and / or size distribution, the system comprising:-means (150) for receiving microvesicles in a microvesicle carrier liquid to obtain a heterogeneous mixture comprising microvesicles; -a holding unit (140) for holding a heterogeneous mixture comprising microvesicles, the heterogeneous mixture comprising microvesicles and a microvesicle carrier liquid, in particular a salt solution; -a homogenization mechanism (160) arranged for homogenizing the heterogeneous mixture comprising the microvesicles held in the holding unit; -an auxiliary reservoir (180) containing a microvesicle carrier liquid, in particular a salt solution, where the auxiliary reservoir is arranged in fluid connection with the holding unit.

Description

Technical Field

[0001] The present invention relates to a system for providing microvesicles having a predefined size and / or size distribution, preferably a system for generating microvesicles having a predefined size and / or size distribution, a disposable cartridge for use in such a system, and a base system arranged to receive the disposable cartridge. Background Art

[0002] Focused ultrasound (FUS) combined with gaseous microvesicles has emerged as a potential new method for effective drug delivery to the brain. Recent studies have shown that this approach can transiently permeate the blood-brain barrier (BBB) under pulsed energy irradiation in the presence of microvesicles (e.g., nanodroplets / microdroplets, microcapsules, microbubbles). Microvesicles are heterogeneous membrane-bound objects enclosed by an outer membrane and having a core portion, such as a fluid (i.e., a gas or a liquid). Compositions for generating such microvesicles are described, for example, in European Patent EP 1784 288 B1.

[0003] For effective drug delivery, it is important that the microvesicles, typically microbubbles, have a predefined size and / or size distribution, where the distribution is preferably as narrow as possible. Existing systems for generating microvesicles typically result in a too wide size distribution of the generated microvesicles. Additionally, in current systems, microvesicles are typically generated in a dedicated system, which produces a microvesicle suspension, i.e., a heterogeneous mixture comprising microvesicles and a microvesicle carrier liquid. Thereafter, a syringe is typically filled manually and connected to an infusion line to introduce the microvesicles into the circulatory (blood) system of a subject.

[0004] Because of this, the process is rather labor-intensive and subject to various possible human errors. Due to all the different processing steps, the microvesicle suspension will further start to degrade, making the drug delivery less effective than it could be in theory. Summary of the Invention

[0005] Accordingly, it is an object of the present invention to improve the quality of the generated microvesicles and thereby the effectiveness of drug delivery by providing a system according to the present invention, which at least partially alleviates at least some of the problems raised above.

[0006] In a first aspect, the present invention relates to a system for providing microvesicles according to claim 1, the microvesicles preferably having a predefined size and / or size distribution, the system comprising:

[0007] - means for receiving microvesicles in a microvesicle carrier liquid to obtain a heterogeneous mixture comprising microvesicles, in particular means for receiving microbubbles in a microbubble carrier liquid to obtain a heterogeneous mixture comprising microbubbles;

[0008] - A holding unit for holding a heterogeneous mixture containing microvesicles, the heterogeneous mixture comprising microvesicles and a microvesicle carrier liquid, in particular a salt solution;

[0009] - A homogenizing mechanism arranged to homogenize, preferably continuously, the heterogeneous mixture containing microvesicles held in the holding unit.

[0010] The disadvantage of the previously described prior art process is that by separately generating microvesicles and then manually filling a syringe and connecting the syringe to an infusion line, the generated microvesicles and the microvesicle carrier liquid start to separate from each other directly after the generation step, whereby the concentration of the microvesicles is no longer uniform and the mixture thus deteriorates. As in the system according to the invention, the obtained heterogeneous mixture is preferably continuously homogenized, and the microvesicles can be stored for a longer time without deterioration due to the preferably continuous homogenization, and the concentration of the microvesicles in the mixture remains substantially constant in the holding unit. It should be noted that continuous homogenization can also mean that the homogenization process can be carried out with small interruptions or intervals during the process. The homogenizing mechanism is preferably arranged to homogenize the heterogeneous mixture during and / or at least just before the preferably dispensing, i.e., administering, of the microvesicles from the holding unit to a subject. Thus, the heterogeneous mixture is more uniform compared to a non-uniform heterogeneous mixture, enabling an improved treatment. Microvesicles having a gaseous core portion are generally referred to as microbubbles and can thus be considered a special type of microvesicle.

[0011] As will be explained in more detail below, the device for receiving the generated microvesicles can receive microvesicles generated externally, i.e., microvesicles not generated in the system. Preferably, the system, and then the system for generating microvesicles, includes a microvesicle generating unit for generating microvesicles having a predefined size and / or size distribution, in particular a microbubble generating unit for generating microbubbles having a predefined size and / or size distribution, wherein the microvesicle generating unit includes an inlet side and an outlet side, the inlet side being arranged to receive a first fluid through a first inlet and a second fluid through a second inlet, the first fluid and the second fluid being mixed by the microvesicle generating unit to generate microvesicles, and the outlet side being arranged downstream and being arranged to discharge the generated microvesicles.

[0012] Preferably, the system further comprises an auxiliary reservoir containing a microvesicle carrier fluid, in particular a salt solution, wherein the auxiliary reservoir is arranged in fluid connection with the holding unit. The auxiliary reservoir allows the microvesicle carrier fluid to be delivered to the holding unit, which advantageously allows dilution of the heterogeneous mixture containing microvesicles in the holding unit in the presence of such a mixture in the holding unit, among other things. This advantageously allows the heterogeneous mixture containing microvesicles to be stored in the holding unit at a relatively high microvesicle concentration and diluted only prior to administration of the mixture to a subject. Storing the heterogeneous mixture containing microvesicles at a concentration higher than the concentration of the mixture expected when the mixture is administered to a subject advantageously increases the stability of the microvesicles in the mixture.

[0013] The system is preferably arranged to produce microvesicles, in particular microbubbles, having a predefined size and / or size distribution, more preferably having a size in the range from 0.1 μm to 20 μm, preferably from 1 μm to 10 μm, most preferably from 2 μm to 5 μm, or the microvesicles, in particular microbubbles, have a size distribution according to the following specifications: the mode, median or mean of the diameter is between 2 μm and 5 μm and the geometric standard deviation (GSD) < 1.25, most preferably GSD < 1.1.

[0014] In a preferred embodiment, the holding unit comprises means for discharging the heterogeneous mixture containing microvesicles from the holding unit for administration to a subject, preferably in a precisely controlled manner, of the heterogeneous mixture containing microvesicles, preferably the heterogeneous mixture containing microvesicles continuously homogenized by a drive homogenization mechanism, preferably, wherein the holding unit is in fluid communication with a connector, such as a Luer type connector, arranged for connection to an infusion line arranged in fluid communication with the circulatory (blood) system of the subject.

[0015] Since the holding unit can be selectively and directly in fluid contact with the subject for drug delivery, the steps of manually filling a syringe and connecting the syringe to an infusion line are prevented, which reduces the risk of human error and enables a continuously homogenized mixture to be provided to the subject, as this significantly reduces the time span between the mixture leaving the system and entering the circulatory system of the subject.

[0016] Preferably, the system further comprises a mixing unit in fluid communication with at least the holding unit and the connector via an outlet, wherein the mixing unit further comprises an inlet for receiving a microvesicle carrier fluid, in particular saline, wherein the mixing unit is arranged to combine the heterogeneous mixture containing microvesicles from the holding unit and the microvesicle carrier fluid at the mixing unit outlet for supply to the connector. Such a mechanism is also referred to as a "co-flow" mechanism.

[0017] It will be understood that many of such mechanisms, as well as the following mechanisms to be described, can also be applied in a general system for providing microvesicles, which general system has only means for receiving the generated microvesicles and / or holding units, i.e., without a homogenization unit and / or an auxiliary reservoir. Such a system will hereinafter be referred to as a general system.

[0018] This allows dilution of the heterogeneous mixture containing microvesicles with a microvesicle carrier liquid, preferably saline, while transporting the heterogeneous mixture containing microvesicles from the holding unit towards the connector and, optionally, while administering the heterogeneous mixture containing microvesicles to a patient, also referred to as a subject. The additional dilution of the heterogeneous mixture containing microvesicles allows an increase in the flow rate of the heterogeneous mixture containing microvesicles without increasing the amount of microvesicles being administered. This increased flow rate is beneficial for preventing the heterogeneous mixture containing microvesicles from sedimenting during administration. In other words, the increased flow rate prevents the microvesicles from floating upwards in the mixture and thus potentially being trapped inside various fluid connectors in the system, such as in infusion lines and connectors.

[0019] Preferably, the system is arranged to adjust the ratio of the heterogeneous mixture containing microvesicles flowing into the mixing unit to the microvesicle carrier liquid. This adjustability allows the concentration of microvesicles administered to the subject to be adjusted based on need. The use of the mixing unit, also referred to as a co-flow mechanism, allows the concentration of microvesicles in the heterogeneous mixture containing microvesicles stored in the holding unit to be set at a relatively high level. The possibility of diluting the heterogeneous mixture containing microvesicles from the holding unit during administration, also referred to as infusion, allows a wide range of adjustment of the actual concentration of microvesicles in the heterogeneous mixture containing microvesicles administered to the subject.

[0020] In addition, the adjustment of the ratio of the heterogeneous mixture containing microvesicles to the microvesicle carrier liquid can be carried out during the administration of the heterogeneous mixture containing microvesicles to the subject, thereby allowing the concentration of microvesicles in the mixture administered to the subject to be adjusted during the process of administering the heterogeneous mixture containing microvesicles to the subject. As previously mentioned, storing the heterogeneous mixture containing microvesicles at a higher microvesicle concentration increases the stability of the microvesicles in the heterogeneous mixture containing microvesicles. The use of the mixing unit advantageously allows the heterogeneous mixture containing microbubbles stored in the holding unit to be stored at a high concentration and only diluted to the desired microvesicle concentration during the administration of the heterogeneous mixture containing (diluted) microvesicles to the subject. Diluting the heterogeneous mixture containing microvesicles during administration is one of the latest times to dilute the mixture, which maximizes the time that the heterogeneous mixture containing microvesicles can be held at a higher concentration in the holding unit before being administered to the subject.

[0021] Preferably, the holding unit comprises a holding container in which a movable piston member is arranged, wherein the holding container and the movable piston member enclose an internal volume for holding the heterogeneous mixture comprising microvesicles, and wherein the movable piston member is capable of moving in the holding container to increase or decrease the internal volume such that the heterogeneous mixture comprising microvesicles can be diluted by adding a microvesicle carrier liquid to the heterogeneous mixture comprising microvesicles in the holding unit and / or such that the heterogeneous mixture comprising microvesicles can be discharged from the holding unit, wherein the movable piston member is preferably arranged to be driven by a first drive mechanism which particularly comprises a linear drive. Thus, the holding container can directly administer the mixture held therein in a precisely controlled manner, such that this significantly reduces the risk of human error and the time span between the mixture leaving the system and entering the circulatory system of the subject, as described above.

[0022] In particular, the volume change of the internal volume due to the unit stroke length of the movable piston member multiplied by the ratio of the unit stroke length of the movable piston to the front surface area of the movable piston member multiplied by the unit stroke length of the movable piston ≤ 1. This ratio allows precise control of the amount and flow rate of the mixture being administered. In a preferred embodiment, the ratio < 1, preferably < 0.75, more preferably < 0.5, most preferably < 0.25, such that it allows very small amounts of the mixture to be delivered in a precise manner as the volume change of the internal volume caused by each stroke length displacement of the piston is reduced. For example, this can be achieved by arranging the piston member to have through holes therein and / or not having a fluid-tight seal between the piston member and the inner wall of the holding container, whereby the effective change in the internal volume is determined by the driving part of the piston member, such as a drive rod, which is capable of moving in and out of the holding container, thus effectively changing the internal volume of the holding container. Therefore, the volume change per unit stroke length is determined by the volume per unit length of the driving part.

[0023] In a preferred embodiment, the homogenization mechanism comprises a movable mixing element extending into the holding unit; and wherein the system comprises a homogenization drive mechanism for driving the movable mixing element, the homogenization drive mechanism particularly comprising a rotary drive. By moving the movable mixing element through the heterogeneous mixture, the mixture remains agitated and thereby homogenized, preventing separation between the microvesicle carrier liquid and the microvesicles produced. The homogenization mechanism is particularly arranged to continuously homogenize the heterogeneous mixture comprising microvesicles held in the holding unit.

[0024] Then preferably, the movable mixing element is included in a movable piston member, wherein the movable piston member is capable of moving within the holding container in a direction that is at least substantially parallel to the longitudinal axis of the holding container, preferably linearly, and wherein the movable mixing element is a rotary mixing element, the rotary mixing element preferably including a plurality of fins extending within the internal volume, and the movable mixing element is arranged to rotate with or relative to the movable piston member;

[0025] Wherein, in an embodiment, the movable piston member and the movable mixing element include a common shaft, wherein the common shaft is rotatably connected to the movable mixing element and translationally connected to the movable piston member.

[0026] On the one hand, this prevents the movable mixing element and the movable piston member from possibly colliding and thus being blocked. On the other hand, when the movable mixing element moves together with the movable piston member, the mixing element can remain in contact with the heterogeneous mixture, even when the internal volume of the holding unit decreases due to the administration of a portion of the heterogeneous mixture held therein.

[0027] Preferably, the homogenization drive mechanism further includes a releasable coupler for releasably coupling the movable piston member and / or the rotatable mixing element to the drive mechanism, wherein the releasable coupler includes one or more movable annular coupling members, the movable annular coupling members including protrusions arranged to engage recesses or grooves arranged on the movable piston member. This arrangement reduces the number of movable parts required to construct the releasable coupler.

[0028] Preferably, the movable coupling member is arranged to slide within a locking sleeve and is capable of moving between a coupled state and a released state, wherein when the movable coupling member slides from the released state to the coupled state, the protrusion moves inwardly towards the central axis of the locking sleeve. Preferably, the movable coupling member is arranged at or near one end of the locking sleeve.

[0029] This allows the protrusion to engage the recesses or grooves arranged on the movable piston member. The inwardly sliding coupling member moves the protrusion inwardly and away from the end of the locking sleeve, thereby firmly engaging the movable piston member and pulling the movable piston member towards the locking sleeve and / or the end stop, thereby providing a clearly defined connection state, i.e., an engaged state, of the releasable coupler and further increasing the security of the engagement.

[0030] Preferably, the movable coupling member includes a cam portion arranged to engage with the locking sleeve, wherein, when the movable coupling member moves towards the coupled state, the cam portion engages with a part of the locking sleeve, thereby pushing the cam portion, at least a part of the movable coupling member, and the protrusion inwardly towards the central axis of the locking sleeve. This allows the protrusion to move towards a recess or groove in the movable piston member to engage with the movable piston member.

[0031] Preferably, the releasable coupler further includes a cap disposed at an end of the locking sleeve, wherein the cap includes a hole that allows at least a part of the movable piston member and at least a part of the mixing element to pass through, and wherein the cap includes an inner surface arranged to engage with the movable coupling member, preferably with the cam portion of the movable clamping member, and wherein, when the coupling member moves towards the released state, the inner surface guides at least a part of the movable coupling member outwardly away from the central axis of the locking sleeve.

[0032] This provides positive guidance of the movable coupling member towards the coupled state and the released state, thereby ensuring that the movable piston member is firmly coupled or fully released respectively in the coupled state and the released state of the coupler. The cap is also used to abut against the movable piston member in the coupled state. In the coupled state, the movable coupling member pulls the movable piston towards the cap to provide a firm and rigid coupling between the piston member and the drive mechanism.

[0033] Preferably, the homogenization drive mechanism further includes a shaft connected to the homogenization drive mechanism, wherein the shaft is arranged to be connected to the rotatable mixing element as defined above when the movable piston member is connected to the releasable coupler.

[0034] Preferably, the shaft is located inside the locking sleeve. This concentric configuration allows for a compact construction, where the locking sleeve provides an enclosure for the rotating shaft, thereby protecting the shaft and the operator who operates the system.

[0035] In a preferred embodiment, the homogenization drive mechanism is arranged to rotate the movable mixing element alternately in the clockwise and counterclockwise directions. This prevents the fluid in the holding unit, more specifically the heterogeneous mixture containing microvesicles, from reaching a steady state, and instead ensures continuous turbulent motion of the liquid in the holding unit. This prevents sedimentation of the microvesicles in the heterogeneous mixture containing microvesicles in the holding unit.

[0036] Preferably, the system includes a base system and a disposable cartridge removably connected thereto, wherein the base system includes a releasable connection device for holding the disposable cartridge in a predefined position and a predefined orientation, and wherein the disposable cartridge includes at least one, preferably all, of a microvesicle generation unit, a device for receiving the generated microvesicles in a microvesicle carrier liquid, a holding unit, and at least a part of a homogenization mechanism.

[0037] By effectively separating the system between the disposable cartridge and the (reusable) base system (i.e., the base station), all consumables and disposable items, i.e., all materials required to provide and / or generate microvesicles, can be combined in a single cartridge, making the system easy to prepare for manufacturing microvesicles. Additionally, this also allows isolation, i.e., separation, of all reusable parts of the system (such as the controller and / or driver) from contact with the subject's (fluid), so that these parts are not contaminated due to direct fluid contact with the subject.

[0038] Preferably, the homogenization drive mechanism is arranged in the base system. This allows the drive mechanism to be reused instead of being discarded together with the disposable cartridge after use.

[0039] In a preferred embodiment and also suitable for a general system for providing microvesicles, a second fluid is included in a sealed reservoir, which is arranged or can be arranged in the system, particularly in a sealed reservoir receiving section for receiving and holding the sealed reservoir arranged in the disposable cartridge, and wherein, when the system is in an initial state, the sealed reservoir is arranged to be open, i.e., unsealed or the seal is broken, pierced, and / or ruptured, and

[0040] wherein the system, particularly the disposable cartridge, is arranged such that the second fluid in the open container can be in fluid communication with the microvesicle generation unit.

[0041] It is noted that the sealed reservoir can also be a separate container, and the cartridge includes a sealed reservoir receiving section for receiving and holding the sealed reservoir. This allows the correct amount of the second fluid to be directly positioned in the system, thereby preventing any possible errors or contamination compared to the case of manually filling an internal container. In particular, when the sealed reservoir is included in the cartridge, the correct amount of the second fluid and the sealed (i.e., sterile) second fluid are easily arranged in the system and are available for direct use by the microvesicle generation unit when opened.

[0042] Then it is also preferred that the sealed reservoir is arranged at least to be held within the system, in particular arranged to be received in a sealed reservoir receiving section for receiving and holding the sealed reservoir arranged within the cartridge, and wherein an opening tool, such as a cutting tool, a piercing tool, and / or a rupturing tool, is arranged, and the opening tool, such as a cutting tool, a piercing tool, and / or a rupturing tool, is moved relative to the sealed reservoir and / or the sealed reservoir receiving section, or the sealed reservoir and / or the sealed reservoir receiving section is moved relative to the opening tool, such as a cutting tool, a piercing tool, and / or a rupturing tool, to open the seal of the sealed reservoir for opening the sealed reservoir, and wherein, preferably, a reservoir fluid conduit is arranged in or together with the opening tool, and the reservoir fluid conduit is such that in an initial state, the open end of the conduit is arranged to be inserted into a second fluid to put the second fluid in fluid communication with the microvesicle generating unit.

[0043] Wherein the system includes an opening tool drive mechanism, in particular a linear drive mechanism, for driving the opening tool relative to the sealed reservoir or for driving the sealed reservoir relative to the opening tool. This allows the reservoir to be opened and access to the second fluid in a single, simple action. The sealed reservoir can also be constituted by a sealed container, and any component interacting with the sealed reservoir, in particular the sealed reservoir receiving section, is also arranged to receive the sealed container.

[0044] Preferably, the system includes a main pressure-regulated gaseous medium source arranged to be in fluid communication with the opened reservoir in a microvesicle generating state after the system is in an initial state to force the second fluid to flow to the microvesicle generating unit. Thereby, the second fluid can be supplied to the microvesicle generating unit at a predefined flow rate and pressure, and thus no (mechanical) pump is required. Preferably, the main pressure-regulated gaseous medium is air, and more preferably, the main pressure-regulated gaseous medium source is a pressurized container containing air.

[0045] Preferably, the system includes an auxiliary pressure-regulated gaseous medium source arranged to provide a stream of pressurized gaseous medium as the first fluid and / or wherein the second fluid is a continuous phase fluid, in particular a liquid comprising a stabilizing material, such as for example a surfactant, a polymer, a lipid, a protein, preferably a phospholipid. Suitable stabilizing materials are disclosed for example in paragraphs

[0033] to

[0067] of European patent EP 1784 228B1. Microvesicles are formed by introducing the first fluid, i.e. the pressurized gas, together with a stream of the second fluid into the microvesicle generating unit, whereby the pressurized gas is enclosed in a thin layer of the second fluid. In a particular embodiment, the main pressure-regulated gaseous medium source and the auxiliary pressure-regulated gaseous medium source are derived from the same source, and in another embodiment, the main pressure-regulated gaseous medium source and the auxiliary pressure-regulated gaseous medium source are derived from different sources. Preferably, the auxiliary pressure-regulated gaseous medium is a biocompatible gas, a gas precursor or a mixture thereof. Preferred gases are for example fluorinated gases, such as sulfur hexafluoride (SF6) and / or perfluorocarbon gases, such as octafluoropropane (C3F8) or decafluorobutane (C4F10). Alternatively, the auxiliary pressure-regulated gaseous medium is or comprises any of the following: air, nitrogen, carbon dioxide, hydrogen, nitrous oxide; noble gases and / or inert gases, such as helium, argon, xenon or krypton. Suitable biocompatible gases are disclosed for example in paragraphs

[0083] to

[0092] of European patent EP 1784 228B1. More preferably, the auxiliary pressure-regulated gaseous medium source is a pressurized container containing the corresponding auxiliary pressure-regulated gaseous medium given above.

[0046] In a preferred embodiment and also suitable for use in a general system for providing microvesicles, the basic system includes a main pressure-regulated gaseous medium source and / or an auxiliary pressure-regulated gaseous medium source and a main gaseous medium outlet and / or an auxiliary gaseous medium outlet;

[0047] wherein the disposable cartridge includes a main gaseous medium cartridge inlet and / or an auxiliary gaseous medium cartridge inlet, the main gaseous medium cartridge inlet and / or the auxiliary gaseous medium cartridge inlet being arranged to engage and cooperate with the main gaseous medium outlet and / or the auxiliary gaseous medium outlet to provide a fluid connection between the main pressure-regulated gaseous medium source and / or the auxiliary pressure-regulated gaseous medium source and the microvesicle generating unit and / or the sealed reservoir, preferably between the main pressure-regulated gaseous medium source and the sealed reservoir and between the auxiliary pressure-regulated gaseous medium source and the microvesicle generating unit;

[0048] Wherein, the main gaseous medium inlet and / or the auxiliary gaseous medium inlet are preferably arranged in a movable manner in the cartridge, and preferably include a biasing device for pressing the inlet towards the base system, as seen in the state where the cartridge is coupled to the base system; and / or

[0049] Wherein, the main gaseous medium outlet and / or the auxiliary gaseous medium outlet are preferably arranged in a movable manner in the base system, and preferably include a biasing device for pressing the outlet towards the cartridge, as seen in the state where the cartridge is coupled to the base system.

[0050] As described above, this enables the separation of the gas source, i.e., the reusable part of the system, from the disposable and / or consumable items. In the most preferred embodiment, as described above, the corresponding inlets are fixedly arranged in the cartridge, and the corresponding outlets are movable.

[0051] The biasing device may include a passive biasing mechanism, which includes, for example, an elastic element, such as a (compression) spring, and the biasing device may alternatively or additionally further include an active biasing mechanism, such as a pneumatic actuator having a pneumatic cylinder, the pneumatic cylinder including a movable piston rod, the movable piston rod being arranged to move the corresponding inlet and / or outlet towards and away from the base system and / or the cartridge respectively. In other words, the main gaseous medium outlet and / or the auxiliary gaseous medium outlet are arranged to be movable between a retracted position and an extended position, in the retracted position, the outlet retracts into the base system, and in the extended position, the outlet extends outwards towards the position of the disposable cartridge. This allows the fluid connection between the main pressure-regulating gaseous medium source and / or the auxiliary pressure-regulating gaseous medium source and the microvesicle generating unit to be disconnected, so that the pressurized gas can be released into the surrounding environment, and / or this allows the cartridge to be depressurized before disconnecting and / or unlocking the cartridge from the base system, so that the cartridge can be safely removed from the base system. In addition, the step of depressurizing the cartridge is an important step for safely administering the microvesicles to a subject, because this thereby prevents the following situation: when the subject is connected to the system by means of an infusion line to administer a heterogeneous mixture to the subject's circulatory system, the pressurized gas may accidentally come into fluid contact with the subject's circulatory system.

[0052] Preferably, the base system of the system or the general system further includes an outlet guard, which is arranged to be movable between a closed position and an open position. In the closed position, the outlet guard covers the main gaseous medium outlet and / or the auxiliary gaseous medium outlet. In the open position, the outlet guard exposes the outlet. The outlet guard protects the outlet and prevents the outlet from being contaminated. In addition, the outlet guard being in the closed position can be used as proof that the outlet is disconnected from the disposable cartridge and the disposable cartridge is decompressed.

[0053] Preferably, the main gaseous medium outlet and / or the auxiliary gaseous medium outlet are arranged to prevent the outlet guard from moving from the open position towards the closed position when the outlet is in the extended position, wherein the outlet guard is arranged to close only when the outlet is in the retracted position. This prevents the outlet guard from closing when the outlet is still in the extended position and may be in contact with the cartridge, thereby preventing the outlet guard from being recorded as closed when the outlet is still extended.

[0054] Preferably, in the closed position, the outlet guard is arranged to seal the main gaseous medium outlet and / or the auxiliary gaseous medium outlet. This allows the outlet to be pressurized when the outlet guard is closed, thereby allowing the pressurization function of the main gaseous medium source and / or the auxiliary gaseous medium source, or other functions related to the sealed outlet, to be tested. The sealing of the outlet also further prevents the outlet from being contaminated. To improve the sealing, preferably, the outlet guard includes a seal arranged to interact with the main gaseous medium outlet and / or the auxiliary gaseous medium outlet to seal the outlet.

[0055] Preferably, the system or the general system for providing microvesicles further includes a movable connector guard. Preferably, the movable connector guard is arranged at the connector for selectively covering and exposing the connector, wherein the movable cover is preferably driven by a connector guard actuator. The connector guard can cover the connector for connecting to the infusion line, thereby preventing the infusion line or any other object from being connected to the connector, wherein the infusion line can be connected to a subject. This provides a function of increasing the safety of the system by preventing the subject from being connected to the system when certain conditions such as safety conditions are not met.

[0056] Preferably, the movable connector guard includes a biasing device arranged to bias the connector guard towards the covering position to cover the connector. Therefore, the default position of the connector guard is the closed position. This further increases the safety-providing function of the connector guard.

[0057] Preferably, the connector guard actuator is arranged to move the connector guard to expose the connector when the pressure in the disposable cartridge is substantially equal to the ambient pressure. This is part of the safety function of the system. Pressurizing the cartridge when it is connected to a subject may be unsafe. Thus, the connector guard is arranged to expose the connector only when the pressure in the cartridge is below a threshold, preferably approximately equal to the ambient pressure.

[0058] Preferably, the connector guard actuator is arranged to move the connector guard to expose the connector when the primary gaseous medium outlet and / or the secondary gaseous medium outlet is disengaged from the primary gaseous medium inlet and / or the secondary gaseous medium inlet and / or when the primary gaseous medium outlet and / or the secondary gaseous medium outlet is in a retracted position. When the outlet is disengaged from the disposable cartridge, the disposable cartridge cannot be (re)pressurized. Thus, ensuring that the outlet is disconnected from the cartridge further ensures that a subject cannot be connected to the system when the cartridge is pressurized. Preferably, after the outlet has been previously disconnected from the cartridge, the outlet can be re-engaged with the cartridge - preferably thereby triggering the connector guard actuator to close the connector guard and optionally only after confirmation of the closed position of the connector guard - in order to repressurize the cartridge. The said disconnection and reconnection of the outlet, and preferably the accompanying opening and closing of the connector guard, can preferably be cycled infinitely. This advantageously allows potential reuse of the cartridge to blow the primary gaseous medium and / or the secondary gaseous medium through the cartridge in order to, among other things, clean the cartridge, and / or allows the use of an external microvesicle suspension (the use of which will be further explained below).

[0059] Preferably, the system or the general system further comprises a safety controller operatively connected to the connector guard actuator, wherein the safety controller further comprises one or more sensors arranged to record the pressure in the disposable cartridge and / or the state of the primary gaseous medium outlet and / or the secondary gaseous medium outlet, wherein the safety controller is arranged to command the connector guard actuator to open or close the movable connector guard at least based on the pressure in the disposable cartridge and / or the state of the primary gaseous medium outlet and / or the secondary gaseous medium outlet. In a preferred embodiment, the safety controller is configured to command the connector guard actuator to open the connector guard only when the pressure in the disposable cartridge is at least approximately equal to the ambient pressure and when the primary gaseous medium outlet and / or the secondary gaseous medium outlet is disconnected from the disposable cartridge. Preferably, the safety controller requires the primary gaseous medium outlet and / or the secondary gaseous medium outlet to be retracted and requires the outlet guard to be closed in order to allow the connector guard actuator to open the movable connector guard. Other safety conditions can also be programmed into the safety controller.

[0060] Preferably, the safety controller includes a programmable electronic microcontroller that is connected to the pressure sensing unit and the movable outlet guard and is programmed to command the connector guard actuator based on the pressure in the cartridge and the position of the movable outlet guard. However, the safety controller may additionally or alternatively include mechanical components and / or electronics. A mechanical interconnect may be constructed that connects the movable outlet guard, the pressure sensing unit, and the outlet guard, wherein the mechanical interconnect opens the connector guard only when the outlet guard is closed and the pressure in the cartridge is approximately equal to the ambient pressure.

[0061] In an alternative embodiment, the system is arranged to receive microvesicles generated in an external microvesicle suspension in a holding unit, the external microvesicle suspension comprising preformed microvesicles in a microvesicle carrier fluid. In this embodiment, the microvesicles are thus not generated in a disposable cartridge. This alternative embodiment advantageously allows the system to administer a wider range of microvesicles or other compounds.

[0062] In this embodiment, the external microvesicle suspension is included in a sealed reservoir that is arranged or can be arranged in the system, particularly in a sealed reservoir receiving section for receiving and holding the sealed container arranged in the disposable cartridge, and wherein the system, particularly the disposable cartridge, is arranged such that the external microvesicle suspension in the open container can be in fluid communication with the holding unit. Preferably, a reservoir fluid conduit is arranged to put the external microvesicle suspension in fluid communication with the holding unit.

[0063] In embodiments using an external microvesicle suspension, a microfluidic chip and an auxiliary pressure regulating gaseous medium for generating microvesicles are not required. However, these components do not need to be removed to use the external microvesicle suspension in combination with the disposable cartridge. Preferably, a reservoir containing the external microvesicle suspension, preferably various vials, is connected to a fluid connector on the cartridge via a reservoir fluid conduit. Preferably, the reservoir fluid conduit includes a tube and a connector arranged to connect the reservoir to a connector arranged on the cartridge, wherein the connector is in fluid communication with the holding unit.

[0064] Preferably, the connector is the same connector as that arranged for connecting an infusion line which is arranged to be in fluid communication with the circulatory system of the subject. Then, the external microvesicle suspension can be delivered to the holding unit by first making the fluid connection and then increasing the volume of the holding unit to create a negative pressure or a pressure lower than the pressure in the reservoir containing the external microvesicle suspension, and the negative pressure or lower pressure sucks the external microvesicle suspension into the holding unit. By connecting with the same connector that is also used to connect to an infusion line for administering a fluid, in particular a heterogeneous mixture containing microvesicles, to the subject, the microfluidic chip can be bypassed.

[0065] In the art, there are known vials that are supplied with a cap in a sealed state, the cap including a tool for opening the vial and forming a fluid connection with a fluid conduit, such as a tube, which can then be connected to a cartridge, more specifically to a cartridge connector which is preferably a Luer-type connector.

[0066] Preferably, the system or the general system includes a first optical scanner arranged to scan a visual code arranged on a sealed reservoir. This allows for (automatic) verification of the presence and type of the sealed reservoir arranged on the disposable cartridge. The visual code can be any visual code known in the art, such as a barcode and / or a QR code. Preferably, the first optical scanner is arranged on the base system. This allows for relatively expensive components to be reused rather than being discarded together with the disposable cartridge after use.

[0067] Preferably, the visual code is arranged on the bottom of the sealed reservoir. Preferably, the first optical scanner is arranged to scan the bottom of the sealed reservoir when the sealed reservoir is arranged on the disposable cartridge. This allows the sealed reservoir to be arranged at any angle in the sealed reservoir receiving section while keeping the visual code visible to the optical scanner.

[0068] Preferably, the base system includes a second optical scanner arranged to scan a visual code arranged on the disposable cartridge. The cartridge visual code can similarly be any visual code known in the art, such as a barcode and / or a QR code. Thus, the second optical scanner can be used to verify the presence and type of the disposable cartridge arranged on the base system.

[0069] Preferably, the system or the general system includes a locking mechanism having a release state and a locking state, wherein, in the release state, the disposable cartridge can be removed from the base system, and wherein, in the locking state, the disposable cartridge is fixedly held in the base system and is pressed towards the base station by the locking system with a preloading force, and wherein the locking system preferably includes a locking drive mechanism for driving the locking mechanism. This allows the cartridge to be firmly locked in place such that when starting, for example, a pressurized gas source, the cartridge is firmly and securely held in place and can withstand the resulting reaction forces.

[0070] Then, preferably, the locking mechanism includes a first movable clamping unit, in particular a rotatable clamping unit, which is arranged in the base station and arranged to engage a first clamping portion of the cartridge, which is preferably arranged at the lower section of the disposable cartridge, and the first movable clamping unit presses the clamping portion towards the base station in a first direction and presses the clamping portion in a second direction substantially parallel to the base station and preferably perpendicular to the first direction, and wherein the locking mechanism further includes a second movable clamping unit, which is arranged to engage the cartridge at a second clamping portion different from the first clamping position, which is preferably arranged at the upper section of the disposable cartridge, and the second movable clamping unit presses the second position in the first direction. This enables the cartridge to be fastened to the base system in a unique position and orientation.

[0071] Preferably, in the locking state, the locking mechanism, in particular the respective movable clamping units, is arranged to apply a preloading force to the following sections of the cartridge: the sections including the first gaseous medium inlet and / or the first gaseous medium outlet and / or the second gaseous medium inlet and / or the second gaseous medium outlet, preferably the movable first gaseous medium inlet and / or the first gaseous medium outlet and / or the second gaseous medium inlet and / or the second gaseous medium outlet. Thus, the preloading force is transmitted to, at least partially transmitted to, the connection between the respective inlets and outlets, such that an airtight engagement between the disposable cartridge and the base system is obtained.

[0072] Preferably, the locking mechanism is biased towards the locking state, more preferably such that in the absence of actuation by the locking drive mechanism, the locking mechanism moves or remains in the locking state. Then, accidental removal of the cartridge is prevented, even in the event of any failure of the locking drive mechanism.

[0073] Preferably, the locking mechanism includes a clamping mechanism, which includes a second movable clamping unit and a locking drive mechanism. Among them, the locking drive mechanism is arranged to move the clamping mechanism, and the clamping mechanism is arranged to move the clamping unit between a locked state and a released state. The clamping mechanism is arranged to move between the locked state and the released state through a dead point. Preferably, at the dead point, a force acting in a direction opposite to the movement direction of the clamping unit is not transmitted to the actuator. In other words, the dead point defines a threshold for moving the clamping unit from the locked state to the released state. Any force applied below the threshold will not move the clamping unit to the released state.

[0074] Since the clamping mechanism must move through the dead point between the locked state and the released state, the force pushing against the clamping unit in the locked state cannot move the clamping mechanism to the released state because this force is only used to force the mechanism towards the locked state.

[0075] Preferably, the clamping mechanism includes: a rotating member, which is rotatably arranged on the base system using a first pivot portion; a rotary clamping unit, which is rotatably arranged on the base system using a second pivot portion; and a connecting rod, which is connected to the rotating member through a first hinge portion positioned at a non-zero offset distance from the first pivot portion and is connected to the rotary clamping unit through a second hinge portion positioned at a non-zero distance from the second pivot portion. The rotation of the rotating member is transmitted to the clamping unit through the connecting rod, thereby rotating the clamping unit. When the clamping mechanism is in a position where the first pivot portion, the first hinge portion, and the second hinge portion are aligned, a dead point state occurs.

[0076] Preferably, a line drawn through the first pivot portion and the second pivot portion defines a dead point line separating the locked side and the released side. The first hinge portion is located on the locked side in the locked state, on the released side in the released state, and on the dead point line in the dead point state. Preferably, the locking drive mechanism is arranged to push against the rotating member to cause the rotating member to rotate. When moving between the locked state and the unlocked state, this mechanism provides a geometry with a dead point.

[0077] Preferably, the clamping unit includes a biasing device, which is arranged to transmit the clamping force applied by the clamping mechanism to the disposable cartridge.

[0078] When the clamping mechanism moves through the dead center, the clamping unit moves beyond its position in the locked state. In principle, this would cause the clamping unit to be pushed further into the disposable cartridge than intended, potentially damaging the cartridge. By arranging a biasing device to transfer the clamping force applied by the clamping mechanism to the disposable cartridge, this movement of the clamping unit is absorbed by the biasing device rather than being transferred to the disposable cartridge. This prevents the cartridge from being damaged when the clamping mechanism moves through the dead center.

[0079] Preferably, the clamping unit includes a separate clamp and a clamp rod, wherein the clamp and the clamp rod are arranged to be rotatable about a second pivot portion, wherein the clamp rod includes a second hinge portion, wherein the biasing device is arranged between the clamp and the clamp rod, and wherein the rotation of the clamp rod is transferred to the clamp only through the biasing device.

[0080] This arrangement allows for a compact construction of the clamping unit including the biasing device. As the clamp rod and the clamp rotate relative to each other, the biasing device is compressed. Preferably, the biasing force provided by the biasing device is selected to be high enough to firmly hold the disposable cartridge, since the biasing device is the only component that transfers the holding force from the clamping mechanism to the disposable cartridge. Preferably, when the clamping mechanism moves through the dead center state, the biasing force is low enough to prevent damage to the disposable cartridge when the biasing device is compressed.

[0081] In a preferred embodiment of this system or a general system, the base system and the disposable cartridge include mating recesses and protrusions for aligning the disposable cartridge in the base system, preferably wherein the mating recesses and protrusions are arranged such that the cartridge has only a single unique fitting orientation by which the cartridge can be positioned and coupled in the base system. This enables further reduction of any human error that may occur during the process and thus further contributes to improving the effectiveness of the drug delivery method.

[0082] Preferably, the microvesicle generating unit includes a microfluidic chip, in particular a microfluidic flow focusing chip, the microfluidic chip including a first chip inlet for receiving a first fluid and a second chip inlet for receiving a second fluid, wherein channels extending from the first chip inlet and the second chip inlet converge at a junction, and a microvesicle forming channel extends from the junction towards a chip outlet for discharging the generated microvesicles from the microfluidic chip towards the outlet side of the microvesicle generating unit. Such a microfluidic flow focusing chip is capable of generating a continuous flow of generated microvesicles having a predefined size and / or size distribution in a generating state. It will be understood that this mechanism is also applicable to a general system without, for example, a homogenization unit.

[0083] Preferably, the system further includes a heat transfer element arranged to heat and / or cool the microfluidic chip. This allows the temperature at which the microvesicles are produced to be controlled, such that improved control over the size and / or size distribution of the microvesicles is obtained.

[0084] In a preferred embodiment, the heat transfer element is arranged in the base system and is arranged to abut, at least in the connected state in which the disposable cartridge is connected to the base system, a section of the cartridge including the microvesicle generation unit, in particular the microfluidic chip, and in particular to directly abut the microvesicle generation unit, in particular the microfluidic chip. This contact allows good heat transfer from the heat transfer element to the microvesicle generation unit, in particular the microfluidic chip, such that the temperature of the microvesicle generation unit, in particular the microfluidic chip, can be precisely controlled.

[0085] Preferably, the heat transfer element is arranged in the base system in a manner such that it can move along a direction towards and away from the disposable cartridge, and wherein the heat transfer element is biased towards the disposable cartridge by a heat transfer element biasing mechanism. Thus, proper contact between the heat transfer element and the disposable cartridge, in particular the microvesicle generation unit, and more particularly the microfluidic chip, is ensured.

[0086] Preferably, the heat transfer element is further arranged in the base system in a manner such that it can move along a direction having a component orthogonal to the direction towards and away from the disposable cartridge, and wherein the heat transfer element is preferably additionally arranged in the base system in a manner such that it can rotate about all three perpendicular directions, wherein the base system and the heat transfer element are arranged to limit translational movement along the two said directions to a displacement smaller than the displacement allowed in the direction towards and away from the disposable cartridge, and wherein the base system and the heat transfer element are additionally arranged to limit rotational movement of the heat transfer element about each of the three perpendicular axes to less than 10°, preferably less than 5°, more preferably less than 2°, and most preferably approximately 1.5°.

[0087] These additional degrees of freedom allow the heat transfer element to adapt to a slightly deformed disposable cartridge and / or microfluidic chip to ensure optimal contact with the disposable cartridge, in particular the microfluidic chip.

[0088] Preferably, the heat transfer element includes a heat transfer element shaft that extends through a guiding section and cooperates with the guiding section to guide the heat transfer element, wherein at least one diameter dimension of the heat transfer element shaft is smaller than the corresponding diameter dimension of the guiding section, and wherein the diameter difference between the heat transfer element shaft and the guiding section allows at least one degree of rotation and / or at least one degree of translation along at least one direction perpendicular to the main axis. This allows for a simple construction of the heat transfer element and the guiding section.

[0089] In a preferred embodiment, the microfluidic chip is disposed in a disposable cartridge such that limited movement between the chip and the cartridge is permitted in a state unconnected to the base station, and / or wherein, in a connected and / or locked state, the chip is forced against the cartridge, or the cartridge is forced against the chip, to obtain a fluid-tight fluid connection between the fluid circuit of the cartridge and the microfluidic chip, the fluid circuit being arranged to guide a first fluid and a second fluid through the cartridge. Preferably, the chip includes a plurality of chip inlets and / or chip outlets, wherein the inlets and / or outlets are in fluid connection with the fluid circuit of the cartridge, wherein a flexible sealing member, particularly an O-ring preferably made of an elastomeric or rubber material, is disposed between the chip and the cartridge, and wherein, when the chip is forced against the cartridge, or the cartridge is forced against the chip, the flexible sealing member is pressed between the chip and the cartridge to obtain a fluid-tight hydraulic coupling. This allows for a simple and robust (fluid-tight) coupling between the chip and the cartridge, such that microvesicles are generated under constant conditions, resulting in substantially equal sizes and / or size distributions. It should be noted that this function can also be performed without heating the microfluidic chip. In this embodiment, the heat transfer element simply serves as a biasing device to correctly position the microfluidic chip in the disposable cartridge. It is also preferred that an internal filter member is disposed at the fluid-tight fluid coupling between the fluid circuit of the cartridge and the microfluidic chip. The internal filter member preferably has an orifice, i.e., an opening, the size of which is approximately 0.25 times to 2 times, more preferably approximately 0.5 times to 1.5 times, the size of the smallest channel disposed in the microfluidic chip. This reduces the chance of the channels being blocked by any particles present in the system, thereby increasing the reliability of the process of generating microvesicles. Additionally, the safety of the system is further improved because residues are captured by the filter. Thus, a corresponding internal filter can be applied in a hydraulic coupler arranged to guide a second fluid, particularly a second liquid, and / or can be applied in a corresponding gas coupler arranged to guide a first fluid, particularly a pressurized gas. Alternatively or additionally, the internal filter can also be incorporated (e.g., directly formed) in the microfluidic chip itself.

[0090] Preferably, any corresponding drive mechanism in the above corresponding drive mechanisms includes a drive unit, such as an electric motor, a pneumatic motor, or a hydraulic motor, or a combination thereof, and wherein the drive unit of the corresponding drive mechanism is arranged in the base system and is releasably and operatively coupled to the part of the corresponding drive mechanism arranged in the disposable cartridge. As described above, this enables the system to be effectively separated between the disposable cartridge and the (reusable) base system (i.e., the base station). Preferably, the corresponding drive unit includes a pneumatic motor powered by a primary pressure-regulated gaseous medium source. The use of a pneumatic drive enables an MRI-safe device to be obtained.

[0091] In a preferred embodiment, the system or the general system, in particular the disposable cartridge, includes an auxiliary sealed reservoir that contains a microvesicle carrier liquid, in particular a salt solution, wherein, in the initialization phase, the auxiliary sealed reservoir is arranged to be opened and arranged to be in fluid communication with the holding unit. This enables all consumables to be aggregated in a single disposable cartridge, making the system easy to prepare for drug delivery treatment and minimizing any human error as much as possible.

[0092] Then, preferably, the auxiliary sealed reservoir includes a movable sealing element that is arranged to be held in a sealed position before use, wherein the movable sealing element seals the auxiliary sealed reservoir, and in the initialization phase, the movable sealing element moves to an open position, whereby the auxiliary reservoir is in fluid communication with the holding unit. The use of a sealed reservoir enables the corresponding liquid to remain sterile for a longer period of time and prevents liquid evaporation, thereby ensuring effective drug delivery over an extended period of time.

[0093] In an embodiment, the auxiliary sealed reservoir is arranged to be opened by increasing the internal pressure in the auxiliary sealed reservoir to a pre-defined minimum pressure. This enables the reservoir to be easily unsealed without relying on piercing, rupturing, or otherwise removing a fixed seal opening.

[0094] Alternatively or additionally, the auxiliary sealed reservoir is arranged to be opened when the cartridge is coupled and / or locked in the base system. To this end, the base system can be provided with a fixedly arranged raised member that is arranged to abut the movable sealing member and push the movable sealing member from the sealed position when the cartridge is coupled and / or locked, in which sealed position, the movable sealing member covers the opening (i.e., the inlet / outlet) of the auxiliary sealed reservoir.

[0095] In a preferred embodiment, the movable sealing element is capable of moving between three positions, including a sealing position, an open position, and a filling position, at which filling position the auxiliary sealed reservoir is opened to receive fluid from a source external to the disposable cartridge. So far, the basic system may be arranged with a fixedly arranged projection member arranged to abut against the movable sealing member and push the movable sealing member from the sealing position when the cartridge is coupled and / or locked, at which sealing position the movable sealing member covers the opening (i.e., inlet / outlet) of the auxiliary sealed reservoir.

[0096] The additional filling position allows for filling of the auxiliary sealed reservoir of the disposable cartridge, for example during the production of the disposable cartridge. By moving the movable sealing element to the sealing position after sealing, the auxiliary reservoir is sealed.

[0097] Preferably, the movable sealing element is movably arranged in a sealing element retaining channel in the cartridge, wherein the movable sealing element and the sealing element retaining channel interact to form a valve for opening and sealing the auxiliary sealed reservoir, and wherein the diameter of the movable sealing element is preferably smaller than the diameter of the sealing element retaining channel at least at one point. It should be noted that other ways of forming the fluid passage are also possible, for example by providing a through-hole in the movable sealing element, which provides a fluid passage from the opening of the auxiliary sealed reservoir and to the opening in the sealing element retaining channel of the holding unit. In this embodiment, it is not required that the diameter of the movable sealing element is smaller than the diameter of the sealing element retaining channel at any point.

[0098] Preferably, the movable sealing element includes at least three seals, in particular O-rings, arranged around its circumference, wherein the third seal is positioned close to the end of the movable sealing element pointing into the cartridge, the first seal is positioned close to the end of the movable sealing element pointing out of the cartridge, and the second seal is positioned between the first seal and the third seal. Preferably, the movable sealing element includes an axial hole extending through the length of the movable sealing element. Preferably, at least between the second seal and the first seal, the diameter of the movable sealing element is smaller than the diameter of the sealing element retaining channel.

[0099] Preferably, the sealing element retaining channel includes an open end and a closed end, and at least two openings in the channel wall, at least the first opening providing a fluid connection between the sealing element retaining channel and the auxiliary sealed reservoir, and at least the second opening providing a fluid connection between the sealing element retaining channel and the holding unit, wherein the first opening and the second opening are arranged at different distances from the closed end of the sealing element retaining channel. Preferably, the valve is arranged to be movable between the filling position, the sealing position and the open position.

[0100] Preferably, at the filling position, the movable sealing element is in a position where the third seal is positioned on the open end side of the seal element holding channel, wherein a passage is formed that passes from the outside of the cartridge through an opening in the movable sealing element, towards the first opening, and towards the auxiliary sealed reservoir. Preferably, at the sealing position, the movable sealing element is in a position where the third seal and the second seal are positioned on opposite sides of the first opening, thereby sealing the auxiliary sealed reservoir. Preferably, at the open position, the movable sealing element is in a position where the second seal is positioned on the closed end side of the seal element holding channel relative to the first opening and the first seal is positioned on the open end side of the seal element holding channel relative to the second opening. In other words, at the open position of the valve, the second seal and the first seal are located on opposite sides of both the first opening and the second opening, thereby forming a fluid connection from the first opening to the second opening through the gap between the movable sealing element and the wall of the seal element holding channel, allowing fluid to flow between the auxiliary sealed reservoir and the holding unit.

[0101] The described embodiments allow for an efficient workflow in filling, sealing, and unsealing the auxiliary sealed reservoir. During production, the movable sealing element is in the filling position, and then the movable sealing element can be pushed inwardly towards the sealing position. A seal can be applied to the movable sealing element to prevent the movable sealing element from being accidentally pushed inwardly towards the open position during operation. Preferably, the movable sealing element cannot easily move from the sealing position to the filling position, for example by not allowing the movable sealing element to protrude significantly from the disposable cartridge at the sealing position and thus not being able to easily move from the sealing position to the filling position, preventing the movable sealing element from being grasped and pulled out. This prevents the auxiliary sealed reservoir from accidentally opening towards the filling position, which could potentially empty the auxiliary reservoir and / or contaminate the contents of the auxiliary sealed reservoir. Other measures for holding the movable sealing element in the sealing position at least to some extent during storage of the disposable cartridge can be envisioned, such as locking devices - including, for example, snap mechanisms or other known locking geometries and / or mechanisms - and / or removable or breakable seals. Devices for holding the movable sealing element in other positions, such as the filling position or the open position, can also be envisioned, such as snap mechanisms or other holding mechanisms known in the art that can hold the movable sealing element in multiple different positions.

[0102] Preferably, the auxiliary sealed reservoir is arranged such that the movable sealing element after opening is restricted from moving back to the sealed position in the connected and / or locked state, such that the auxiliary (un)sealed reservoir remains open. This allows, for example, the auxiliary reservoir to be used as a waste container for collecting any residual liquid remaining in the cartridge after the generation and administration of the microvesicles. Thus, after removal of the cartridge, the liquid can be easily drained from the cartridge and separately processed. This enables improved separation of any waste. Alternatively or additionally, the sealed reservoir is arranged to remain open after opening in the connected and / or locked state, such that the opened sealed reservoir serves as a waste container as described above.

[0103] Preferably, an optional movable sealing element biasing mechanism is provided for urging the movable sealing element to the sealed position to close the auxiliary sealed reservoir when the cartridge is in the unconnected and / or released state. Thus, any waste collected in the auxiliary reservoir is confined within the reservoir and prevented from spilling accidentally.

[0104] As previously described, the concentration of the heterogeneous mixture containing microvesicles administered to or infused in a subject can be adjusted in a mixing unit in which a flow of a microvesicle carrier fluid, preferably saline, is combined with a flow of the heterogeneous mixture containing microvesicles from a holding unit. Preferably, the mixing unit is arranged to be in fluid connection with the auxiliary sealed reservoir and the holding unit and the connector. Then, the ratio of the heterogeneous mixture containing microvesicles from the holding unit to the microvesicle carrier fluid from the auxiliary sealed reservoir in the mixture can be adjusted by adjusting the flow rates from both the holding unit and the auxiliary sealed reservoir.

[0105] Preferably, the system further includes an operative controller for controlling the various drivers, actuators, heat transfer elements, and valves that operate the system. The operative controller can also be arranged to receive and process sensor data inputs, which can be fed back in a loop as controls for the respective drivers, actuators, heat transfer elements, and valves. The operative controller can also include the aforementioned safety controller, or the safety controller can include the operative controller. For example, the two controllers can be included in a single control unit. Alternatively, the operative controller and the safety controller are both separate components, and the safety controller and the operative controller can then be operatively connected to allow communication between the two controllers. However, it is not necessary for the safety controller and the operative controller to communicate or otherwise cooperate.

[0106] Preferably, the system or the general system further comprises a sensing unit, the sensing unit comprising a first light source and a first light sensor, the system further comprising a monitoring fluid line, wherein, in the case where a heterogeneous mixture containing microvesicles is present in the monitoring fluid line, light from the first light source passes through the monitoring fluid line and is directed to the first light sensor, and the sensing unit is preferably arranged to determine the concentration of microvesicles in the heterogeneous mixture containing microvesicles based on the intensity of the light received by the first light sensor. Optical measurement of the presence or concentration of microvesicles prevents the degradation of microvesicles associated with, for example, ultrasonic measurement.

[0107] Preferably, the presence or concentration of microvesicles in the heterogeneous mixture containing microvesicles is measured by measuring the transmittance of the heterogeneous mixture containing microvesicles. The presence of liquid in the monitoring fluid line, more particularly brine containing microvesicles, most particularly the presence of a heterogeneous mixture containing microvesicles causes the refractive index of the monitoring fluid line and the fluid therein to cause the light beam received from the first light source to pass through the monitoring fluid line and the liquid therein and be transmitted towards the first light sensor. This allows for an accurate measurement of the concentration of microvesicles in the heterogeneous mixture containing microvesicles without the need to arrange additional components within the fluid flow in the cartridge. The concentration measurement can be used as an input to the aforementioned operational controller and can be used, for example, to adjust the ratio, where the heterogeneous mixture containing microvesicles is diluted with a microvesicle carrier fluid in the mixing unit.

[0108] Preferably, the basic system further comprises a second light sensor, wherein the light from the first light source reflected by the monitoring fluid line is directed to the second light sensor, and the sensing unit is arranged to determine the presence of gas in the monitoring fluid line based on the light received by the second light sensor.

[0109] The absence of liquid in the fluid line, particularly the monitoring fluid line, and the resulting presence of gas, or the presence of (large) air cavities in the fluid in the monitoring fluid line, changes the refractive index of the monitoring fluid line such that the light received from the direction of the first light source is reflected by the monitoring fluid line in the direction of the second light sensor. Thus, if the second light sensor records light, it can be detected that there is no liquid in the monitoring fluid line.

[0110] Preferably, the first light source, the first light sensor and the second light sensor are arranged in the basic system, while the monitoring fluid line is arranged in a disposable cartridge. This allows these relatively expensive components to be reused repeatedly rather than discarded together with the disposable cartridge after use.

[0111] Preferably, the disposable cartridge includes one or more reflective surfaces for reflecting light received from the first light source towards the monitoring fluid line, and preferably includes one or more reflective surfaces for reflecting light transmitted through the monitoring fluid line towards the first light sensor and for reflecting light reflected by the monitoring fluid line towards the second light sensor. This allows the light source and the light sensors to be arranged in the base system to point outwards, which allows for a simple construction. Arranging the light source and the light sensors to be substantially flush with the outer surface of the base system also advantageously allows for easier cleaning of the base system. Additionally, the substantially flush arrangement allows for a smooth surface for engaging with the disposable cartridge, thereby reducing the complexity of the base system and the disposable cartridge.

[0112] Alternative embodiments are also contemplated, which include two or more protrusions arranged on the base system and protruding into the disposable cartridge, whereby when the disposable cartridge is connected to the base system, the monitoring fluid line passes between the protrusions. Then, the light source and the light sensors can be directed directly towards the monitoring fluid line without the need for at least a portion of the aforementioned reflective surfaces.

[0113] Preferably, a second light source is also arranged in the base system, thereby providing the same benefits as those mentioned above regarding the positioning of the first light source and the light sensors. In the aforementioned contemplated alternative embodiments, the second light source can also be positioned on the protrusions.

[0114] Preferably, the sensing unit includes a second light source, wherein the sensing unit is arranged to determine the alignment of the monitoring fluid line based on the light received by the second light sensor from the first light source and the light received by the first light sensor from the second light source.

[0115] This provides an additional signal to determine the correct positioning of the disposable cartridge. Additionally, this provides a self-test mode to ensure the correct operation of the light source and the light sensors.

[0116] Preferably, the system or the general system is arranged to detect the pressure in a fluid line, i.e., a fluid circuit, in a pressure detection unit arranged downstream of the microvesicle generation unit. Thus, it is preferred that the pressure detection unit includes a pressure detection point arranged in the system, in particular in a disposable cartridge, the pressure detection point including a bellows-type member that expands under an increased fluid pressure in the disposable cartridge, wherein the pressure detection unit includes a displacement sensor and / or a force sensor arranged at a corresponding position, in particular at a corresponding position on the basic system, wherein the displacement sensor and / or the force sensor is arranged to detect the expansion of the bellows-type member. In other words, the basic system includes a force sensor arranged to measure a force proportional to the fluid pressure in the disposable cartridge. Preferably, an operational controller is arranged to receive a detection signal from the pressure detection unit. This allows monitoring of the hydraulic conditions in the fluid circuit, in particular allowing monitoring of whether microvesicle generation occurs under substantially constant pressure conditions to obtain microvesicles having a substantially constant size and / or size distribution.

[0117] Preferably, the pressure detection unit includes a force transmission member arranged to transmit a force from the disposable cartridge to the force sensor. This allows the force sensor to be arranged in a more convenient position in the basic system. Additionally, the force transmission member includes a flat tip having a predefined surface area, the flat tip being arranged to interact with the pressure detection point. Thus, the force transmitted by the force transmission member is the product of the area of the flat tip and the pressure applied to the flat tip by the pressure detection point.

[0118] Preferably, the force transmission member is connected to the basic system by one or more elastic members, the one or more elastic members being arranged to allow the force transmission member to move in a substantially linear manner relative to the basic system. The elastic members allow the installation of the force transmission member without parts sliding past each other. Sliding parts inevitably involve at least some friction, which causes at least some hysteresis and thus inaccurate measured pressure. The elastic members allow a hysteresis-free installation of the force transmission member in the basic system, thus allowing for more precise measurements.

[0119] Preferably, one or more resilient members include linear guiding flexures. The linear guiding flexures are generally annular, whereby the force transmission member is disposed in the center of the linear guiding flexure, and the edges of the flexure are connected to the base system. Each of the linear guiding flexures is composed of an annularly folded resilient member that extends from the edge of the flexure to the force transmission member. This folding allows the length of the resilient member to be increased without increasing the footprint of the linear guiding flexure. The rotationally symmetric annular arrangement of these resilient members essentially only allows linear movement of the force transmission member. The increased length of the resilient members allows the force transmission member to have a relatively large range of motion within the flexure because the spring constant of the resilient member decreases as the length of the resilient member increases.

[0120] Preferably, the force transmission member includes a biasing device, wherein the biasing device is arranged to transmit the force applied to the force transmission member to the force sensor. The biasing device serves as a buffer between the force applied to the force transmission member and the force transmitted to the force sensor. This allows the biasing device to absorb accidental shocks to the force transmission member, thereby preventing damage to the force sensor.

[0121] Preferably, the biasing device is arranged in a preloaded state, wherein the biasing device is arranged to compress once the force applied to the biasing device exceeds the preloading force. Preferably, the preloading force is set high enough to allow the full range of forces applied to the force transmission member under normal operation to be fully transmitted to the force sensor. In other words, the preloading force is set to be higher than the maximum force experienced by the force transmission member due to the pressure in the disposable cartridge under normal operating conditions. If the threshold preloading force is exceeded, for example due to an accidental shock to the force transmission member during the installation of the cartridge, the excess force is at least partially absorbed by the biasing device, thereby preventing damage to the force sensor.

[0122] Preferably, the compression of the biasing device compresses the force transmission member, wherein the force transmission member is arranged to contact a rigid end stop when the biasing device compresses. Any force applied to the force transmission member that is higher than the threshold preloading force in the biasing device is then transmitted to the rigid end stop rather than the force sensor. This allows for more effective prevention of damage to the force sensor because continuous excessive forces are also diverted away from the force sensor and into the rigid end stop.

[0123] Preferably, the force transmission member includes a cavity and a plunger, wherein the biasing device is at least partially disposed in the cavity, and wherein the plunger is at least partially disposed in the cavity and held by the cavity, wherein the plunger is arranged to slide into the cavity, thereby compressing the biasing device, wherein the plunger is arranged to contact the force sensor, and wherein the force applied to the force transmission member is transmitted to the force sensor through the force transmission member, the biasing device, and the plunger.

[0124] This allows for a compact construction of the force transfer member. Additionally, the biasing device is held within the cavity by the plunger, which is also held within the cavity. The holding of the biasing device by the plunger allows for a preloading force to be applied to the plunger, thereby allowing the aforementioned force threshold. Additionally, the force transfer member, biasing device, and plunger are independent and do not require external support to hold, for example, the biasing device.

[0125] In a second aspect, the invention relates to a disposable cartridge for a system according to the foregoing embodiments.

[0126] In a third aspect, the invention relates to a base system for a system according to the foregoing embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0127] The invention is further illustrated by the following drawings, which show preferred embodiments of the invention and are not intended to limit the scope of the invention in any way, in which:

[0128] - Figure 1 A 3D perspective view schematically shows an embodiment of a system for generating microvesicles, particularly microbubbles, having a predefined size and / or size distribution.

[0129] - Figure 2 A front 3D perspective view schematically shows an embodiment of a disposable cartridge, particularly a disposable cartridge included in the Figure 1 system shown.

[0130] - Figure 3 A 3D perspective view schematically shows the back side of an embodiment of a disposable cartridge.

[0131] - Figure 4 A cross-sectional view schematically shows an embodiment of a disposable cartridge.

[0132] - Figure 5 A first functional layout of fluid channels included in an embodiment of a disposable cartridge is schematically shown.

[0133] - Figure 6 A second functional layout of fluid channels included in an embodiment of a disposable cartridge is schematically shown.

[0134] - Figure 7 A front 3D perspective view schematically shows an embodiment of a base system, particularly a base system included in the Figure 1 system shown, wherein the base system is partially cut away.

[0135] - Figure 8 A releasable coupler is schematically shown in more detail in a front, partially transparent view.

[0136] - Figures 9A to 9C Schematically shows an alternative embodiment of a sealing mechanism for an auxiliary sealed reservoir as arranged in an embodiment of a disposable cartridge.

[0137] - Figures 10A to 10C Shows an embodiment of a sealing mechanism for an auxiliary sealed reservoir as arranged in an embodiment of a disposable cartridge.

[0138] - Figure 11 Shows a schematic diagram of a heat transfer member.

[0139] - Figures 12A to 12C Shows a releasable coupler for coupling a movable piston member and a mixing member to a homogenization drive unit.

[0140] - Figure 13A 、 Figure 13B Shows a schematic diagram of a clamping mechanism.

[0141] - Figure 14 Shows a more detailed view of the clamping mechanism.

[0142] - Figure 15 Shows a schematic diagram of a sensing unit.

[0143] - Figure 16 Shows a schematic diagram of a portion of a sensing unit arranged on a base system.

[0144] - Figures 17A to 17C Shows a schematic diagram of a portion of a sensing unit arranged in a disposable cartridge.

[0145] - Figure 18 Shows an embodiment of a disposable cartridge using an external microvesicle suspension.

[0146] - Figure 19A 、 Figure 19B Shows a cartridge connector guard.

[0147] - Figure 20A 、 Figure 20B Shows a portion constituting a pressure detection unit.

[0148] - Figure 21A 、 Figure 21B Shows a movable outlet guard on a base unit.

[0149] - Figure 22 Shows a schematic diagram of a mixing unit. Detailed Description

[0150] Figure 1A 3D perspective view schematically shows an embodiment of a system 1 for generating microvesicles having a predefined size and / or size distribution. It should be noted that the current example is arranged to generate microvesicles having a predefined size and / or size distribution, and in a more general sense, the current example is also suitable for generating microvesicles having a predefined size and / or size distribution. System 1 is shown as including a base system hereinafter referred to as base station 200 and a disposable cartridge 100, and the disposable cartridge 100 is arranged in a cartridge receiving section 210 of the base station. It can be seen that the cartridge 100 includes a handle 111 in its front cover 110, and the handle 111 is used to improve the grasping and manipulation of the cartridge 100, and the cartridge 100 includes an external sealing member 101 (see Figure 2 ), and the external sealing member 101 is used to seal the connector 102 ( Figure 4 ) and a part of the rear cover 120 ( Figure 3 ) of the cartridge 100. It should be noted that although the external sealing member 101 is shown as a single external sealing member 101, the external sealing member 101 may also include a plurality of individual external sealing members (not shown).

[0151] System 1 includes an input control unit 300, and the input control unit 300 allows a user to set corresponding parameters and system controls for operating the system 1. The input control unit 300 may include buttons, switches, knobs, etc. for setting corresponding parameters and / or may include a display unit 301 for displaying corresponding parameters and / or system status. The display unit 301 may also include a touch-sensitive display for displaying a graphical interface unit on the touch-sensitive display. A movable support cart 400 may also be arranged, and the support cart 400 includes a set of wheels 401 and a cart support member 402, and the cart support member 402 is used to hold the base system 200, the cartridge 100 and the input control unit 300 at an ergonomic working height. A workbench 403 may also be provided on the cart support member 402 for providing a small workbench for the operator. In a housing section 410 of the movable support cart, a pressurized gas source in the form of a pressurized gas container may be provided. By combining the pressurized gas source with a battery unit (not shown), the system can operate wirelessly (i.e., as a self-supporting system), so that the system is easy to move and can be used in places without power supply.

[0152] In Figures 2 to 6The cassette 100 in various embodiments is shown in more detail below. The rear cover 120 is shown as including a protrusion 121 and a recess 122, the protrusion 121 and the recess 122 being arranged on opposite sides of the lower side portion 107 of the cassette 100 relative to each other. The front cover 110 and the rear cover 120 are part of the housing 103 of the cassette 100. The cassette receiving section 210 of the base station 200 includes corresponding mating shapes for the protrusion 121 and the recess 122, namely correspondingly formed recesses and correspondingly formed protrusions, such that the cassette 100 can be received by the base station 200 in the cassette receiving section 210 in only a unique position and orientation to correctly align different features or subsystems of the cassette 100 with corresponding features or subsystems of the base station 200. In particular, the rear cover 120 is arranged to abut against the back plate 211 of the receiving section 210. It can be seen that the housing 103 includes lower holes 123 and 124 arranged through its lower side portion 107. As discussed below, these lower holes 123, 124 are arranged for coupling corresponding drive mechanisms that drive various subsystems arranged in the disposable cassette 100.

[0153] It can be seen that various holes, namely openings 125, 126, 127, 128, gas inlets 131, 132 and other features (which will be discussed in more detail below) have been arranged in / through the rear cover 120 of the housing 103. These holes 125, 126, gas inlets 131, 132 and other features allow various (partial) subsystems arranged in the disposable cassette 100 to cooperate with various (partial) subsystems arranged in the base station 200.

[0154] First, the main gas inlet 131 and the auxiliary gas inlet 132 are provided for coupling the internal fluid system of the cassette 100 to a source of a main pressure-regulated gaseous medium originating from the base station 200. In the current example, the inlets 131, 132 are fixedly arranged in the cassette 100 and are arranged to engage nozzles 231, 232 arranged in the base station 200. The nozzles 231, 232 are capable of moving in a direction towards and away from the disposable cassette 100 (as Figure 1as seen in the connection state shown), and the nozzles 231, 232 include biasing means for pressing the nozzles 231, 232 towards the cartridge 100. The inlets 131, 132 are thus arranged to abut against the mating gas outlets, namely the nozzles 231, 232, and to form a gas-tight connection with the mating gas outlets, namely the nozzles 231, 232, which are arranged in the base station 200 and can be fluidly connected to a corresponding pressure-regulated gaseous medium source. Preferably, a sterile filter element with an aperture of 0.22 μm or less is arranged between the inlets 131, 132 and the outlets 231, 232 to prevent any contaminants from entering the cartridge. The sterile filter element can be arranged in the cartridge 100, the base station 200, or both the cartridge 100 and the base station 200. It should be noted that, Figure 7 the second rotary clamping member 206 in Figure 7 is arranged to press the cartridge including the gas inlets 131, 132 towards the nozzles 231, 232, such that a corresponding biasing means such as a spring, an elastic element or a pneumatic cylinder is compressed, thereby generating the preload required to obtain a gas-tight engagement.

[0155] The various holes 125, 126, 127, 128 in the current example are for different purposes. However, it should be noted that the functions described below are not intrinsically related to the holes 125, 126, 127, 128, as alternatives to the holes in the housing 103 are conceivable. A first through-hole 125 is arranged in the rear cover 120 to allow the holding unit heat transfer element 241 arranged in the base station 200 to project through the rear cover 120 and abut against the storage container 141 of the holding unit 140 through the active heating / cooling surface 242 of the holding unit heat transfer element 241, which will be discussed in more detail below. The holding unit heat transfer element 241 allows for the rapid heating and / or cooling of the contents of the holding container of the holding unit 140, namely the storage container 141, which is a heterogeneous mixture including the generated microvesicles and the microvesicle carrier liquid. The holding unit 140 is also shown to include a movable piston member 142, the movable piston member 142 including a slidable seal 146 that abuts against the inner wall of the holding container 141. The movable piston member 142 and the holding container 141 enclose an internal volume 143 for holding the heterogeneous mixture containing microvesicles, and wherein the movable piston member 142 is capable of moving in the holding container 141 to increase or decrease the internal volume 143, such that the heterogeneous mixture containing microvesicles can be diluted by adding the microvesicle carrier liquid to the heterogeneous mixture including the generated microvesicles in the holding container 141, and / or such that the heterogeneous mixture containing microvesicles can be discharged from the holding container 141. In the current example, the movable piston member 142 is arranged to be driven in the up-down direction II.

[0156] The homogenizing mechanism 160 is arranged together with the movable piston member 142 and includes a rotatable mixing element 161 which extends from the movable piston member 142 into the holding unit 140, in particular into the internal volume 143. The rotatable mixing element 161 includes a plurality of fins which extend inside the internal volume 143 and is arranged to rotate relative to the movable piston member 142 since the rotatable mixing element 161 and the movable piston member 142 are connected by means of a rotary bearing 166. To allow driving of the movable piston member 142 and the rotatable mixing element 161, a common shaft 162 is provided which has a releasable coupling 163 at its bottom. The common shaft 162 is thus connected to the rotatable mixing element 161 at least in a rotatable manner and to the movable piston member 142 in a translatable manner.

[0157] Also as Figure 8 shown, the releasable coupling 163 is arranged to be received in a mating coupling sleeve 263 of a rotary and translational drive mechanism 260 which is arranged in the base station 200. For this purpose, the releasable coupling 163 includes a plurality of recesses or pits 164 arranged in the outer wall of the releasable coupling 163. The mating coupling sleeve 263 includes a plurality of movable projections, in particular spherical members, which are arranged to move in a radially outward direction relative to the central axis IV of the mating coupling sleeve 263 so that the sleeve 263 moves over the releasable coupling 163, after which the movable projections 264 are arranged to move inwards in order to be received in the plurality of recesses or pits 164. The movable projections can then be locked in place, for example by setting a locking ring 265 around the movable projections 264 to restrict the outward radial movement, so as to obtain the connection between the common shaft 162 and the rotary and translational drive mechanism 260. The rotary and translational drive mechanism 260 is arranged to rotatably drive the mating coupling sleeve 263 and thus the rotatable mixing element 161 about the central axis IV, and is arranged to translationally drive the mating coupling sleeve 263 and thus the movable piston member 142 together with the rotatable mixing element 161 along the vertical translation direction II. The sleeve 263 is arranged to project through the second lower hole 124 in order to be connected to the common shaft 162.

[0158] Since the inlet / outlet 145 of the holding unit 140 can be fluidly connected to the connector 102, which in the current example is a luer type connector to which an infusion line can be coupled, the heterogeneous mixture included in the internal volume 143 can be directly administered to a subject undergoing treatment. By moving the movable piston member 142 upward along direction II, the internal volume 143 is reduced, such that the heterogeneous mixture held in the internal volume is pushed toward the connector and toward the subject through the inlet / outlet 145.

[0159] The current example also includes a second through hole 126 covered by an outer sealing member 101, and the second through hole 126 is arranged to receive a movable pushing member 251( Figure 7 ). The movable pushing member 251 is arranged to push a sealed reservoir, i.e., the container 150( Figure 4 ) toward the sealed opening spike 151 in an initial state. The container 150 is an inverted sealed vial in the current example, and the sealed opening spike 151 is arranged to pierce the seal 152, and the sealed reservoir is closed by the seal 152. In the current example, the sealed reservoir 150 is held in the elastic suspension member 156, thereby preventing accidental opening of the container 150 because a pre-defined pressing force is required to move the sealed container 150 from the elastic suspension member 156. The movable pushing member 251 arranged to linearly move in the up and down direction II is also arranged to push the sealed reservoir 150 such that the tip 153 of the spike 151 is arranged to terminate in the upper region 154, i.e., near the bottom of the vial. A pair of inlets / outlets are arranged together with the spike 151. A first inlet / outlet is arranged in or near the tip 153, thereby allowing pressurized gas to be introduced into the reservoir 150. A second inlet / outlet is arranged near the bottom 155 of the spike 151, thereby allowing a second fluid held in the reservoir 150, which is a liposome solution in this example, to be pushed from the reservoir to the microvesicle generating unit 1600, which will be discussed below.

[0160] A sensing unit 270 is provided on the base station 200. In the current example, the sensing unit 270 is arranged to protrude through the sensing holes 127, 128 so as to monitor the fluid passing through the monitoring fluid pipeline 170 arranged between the holes 127, 128. The sensing unit 270 is arranged to detect the translucency of the fluid, particularly the translucency of the fluid from the holding unit 140 passing through the monitoring fluid pipeline, and thereby detect whether a heterogeneous mixture including microvesicles passes through the pipeline or whether a single-phase liquid or gas passes through the pipeline. At this point, the operational controller can, for example, detect a malfunction of the system 1 or that the fluid is not yet suitable for introduction into the circulatory system of the subject. Thus, the sensing unit 270 is also capable of detecting the presence of gas in the fluid pipeline or the presence of (large) cavitation in the fluid, such that they can be prevented from being introduced into the circulatory system of the subject, as also described above.

[0161] The disposable cartridge 100 further includes an auxiliary sealed reservoir 180 that houses a microvesicle carrier fluid, particularly a salt solution. During the initialization phase, the auxiliary sealed reservoir is arranged to be opened and arranged to be in fluid communication with the holding unit 140. It can be seen that the auxiliary sealed reservoir 180 includes a movable sealing element 181 that is arranged to be held in a sealed position before use, where the movable sealing element 181 seals the auxiliary sealed reservoir 180, and when in the initialization phase, the movable sealing element 181 moves to an open position, whereby the auxiliary reservoir 180 can be in fluid communication with the holding unit 140.

[0162] It can be seen that the auxiliary sealed reservoir 180 includes a second movable piston member 185 that includes a slidable sealing element 183 arranged between the inner wall of the reservoir 180 and the second movable piston member 185. The second movable piston member 184 is arranged to be movable in the vertical direction II. Thus, by using a corresponding auxiliary sealed reservoir drive mechanism 280 to push the second movable piston member 185 upward to define a second internal volume 182, the auxiliary sealed reservoir drive mechanism 280 includes a push rod 281 that is arranged to protrude from the lower hole 123 and contact and push the second movable piston member 185. The second internal volume 182 decreases, thereby increasing the pressure until it exceeds a specific pressure threshold. The movable sealing element 181 moves upward and remains in the upward position, even when the pressure decreases again. When the movable sealing element 181 thus disengages from the auxiliary sealed reservoir outlet 184, the liquid held in the auxiliary sealed reservoir freely enters the internal channel system 109 of the cartridge 100.

[0163] The disposable box-shaped part 100 includes a pair of hooking elements 104, 105 located at the corresponding side parts of the rear covering part 120, and the pair of hooking elements 104, 105 are arranged to be engaged by rotating the clamping members 204, 205, and the clamping members 204, 205 are arranged at corresponding positions in the base station 200. The pair of hooking elements 104, 105 forming the first clamping part are pressed towards the base station along the first clamping direction V by the rotary clamping members 204, 205 and are pressed along the second clamping direction VI, and the second clamping direction VI is substantially parallel to the base station 200, especially the receiving section 210, and is directed downward and preferably perpendicular to the first direction V. The second rotary clamping mechanism 206 is arranged at the top of the receiving section 210 and is arranged to engage with the upper side part 106 of the front covering part 110 of the box-shaped part 100 to press the upper side part 106 along the first clamping direction V.

[0164] Figure 5 The first functional layout of the fluid channel system 109, that is, the fluid circuit, that is, the pneumatic and hydraulic circuits, included in the embodiment of the disposable box-shaped part 100 is schematically shown. As described above, by moving the second movable piston member 185 upward, the seal of the auxiliary sealed reservoir 180 is opened, and if the fourth valve 194 is opened and the second valve 192 and the third valve 193 are closed, the microvesicle carrier liquid, such as a salt solution, is pushed towards the holding container 141. The pressure in the corresponding fluid pipeline is measured at the pressure detection point 129, and the pressure detection point 129 mainly includes a bellows-type member that expands under pressure. By arranging the displacement and / or force sensor 229 at the corresponding position in the base station, this can be recorded by both the safety controller and the operation controller of the base station.

[0165] It can be seen that the microvesicle generation unit 1600 including the microfluidic chip 1610 includes a first microfluidic chip inlet 1630 and a second microfluidic chip inlet 1620. The first microfluidic chip inlet 1630 is connected to the first gas inlet 131 to supply a first fluid to the microfluidic chip 1610. The second microfluidic chip inlet 1620 is selectively fluidly connected to the second inlet / outlet of the spike 151 by using the first valve 191. The first inlet / outlet of the spike 151 (which has opened the sealed reservoir as described above) is fluidly connected to the second gas inlet 132. When the first valve 191 is opened, the second gas inlet 132 supplies a pressurized gas to push the second fluid through the second inlet / outlet of the spike 151 toward the microfluidic chip 1610. The respective flows of the first fluid and the second fluid are mixed in the microfluidic chip 1610 to generate microvesicles in a manner known to those skilled in the art. The generated microvesicles leave the microfluidic chip 1610 through the microfluidic chip outlet 1640. And if the second valve 192 is opened and the third valve 193 and the fourth valve 194 are closed, the generated microvesicles are guided toward the inlet / outlet 145 of the holding unit 140 into the holding container 141 and through the inlet / outlet 145 of the holding unit 140 into the holding container 141. The holding container 141 includes the microvesicle carrier fluid derived from the auxiliary sealed reservoir 180 as described above. As described above, the microvesicles are mixed with the carrier fluid to form a heterogeneous mixture. The excess (gas) pressure in the holding container 141 can be discharged through the pressure relief valve 195. The valves 191-195 can be actuated by using valve actuators 291-295 located at corresponding positions in the base station 200. The microfluidic chip 1610 is arranged to be heated by a (movable as described above) heat transfer element 261, and the heat transfer element 261 is arranged at a corresponding position in the base station 200.

[0166] The microfluidic chip 1610 is preferably held in a cartridge in such a way that in the unconnected state of the cartridge, the microfluidic chip can have a limited movement relative to the disposable cartridge 100. To obtain a fluid-tight seal, at least for the pressure delivered by the gas source (i.e., generally 6 bar or less), an O-ring (not shown) made of an elastomeric or rubber material is arranged between the chip 1610 and the cartridge 100. When the cartridge 100 is coupled and locked into the base station 200, the chip is forced toward the cartridge by using the heat transfer element 261, which is biased in the direction toward the cartridge by a biasing mechanism. The O-ring, i.e., the flexible seal member, is thereby pressed between the chip 1610 and the cartridge 100 to obtain a fluid-tight hydraulic coupling. As described above, an internal filter member (not shown) is arranged at the fluid-tight hydraulic coupling between the fluid circuit of the cartridge 100, i.e., the fluid channel system 109, and the microfluidic chip 1610.

[0167] After the microvesicles have been generated and stored in the holding container 141, the pressure is released from the cartridge (the pressurized gas source can be, for example, turned off, disconnected, or any pressurized gas in the cartridge can be released into the environment so that the cartridge is no longer pressurized), and the second valve 192 and the fourth valve 194 are closed and the third valve 193 is open. In this state, by moving the movable piston member 142 upward, the heterogeneous mixture held in the holding container 141 is pressed toward the connector and the connected infusion line so that, under the action of continuous homogenization by driving the rotatable mixing element 161, the heterogeneous mixture can be directly administered to the subject. When the cartridge 100 is removed from the base station 200, any remaining pressurized gas at the inlets 131, 132 will automatically escape.

[0168] Figure 5 An embodiment of the mixing unit 197 is also shown, which is arranged to combine a stream 1972 of a microvesicle carrier fluid, preferably saline, from the auxiliary reservoir 180 and a stream 1971 of a fluid from the holding unit 140, preferably a heterogeneous and preferably homogenized mixture containing microvesicles or an external microvesicle suspension, into a combined stream 1973 of fluid. The combined stream 1973 then flows toward the connector 102 and the subject connected to said connector. The geometry of the mixing unit affects the mixing of the two fluids, and the mixing unit includes a junction of fluid channels through which the streams 1971 and 1972 flow. Preferably, a T-shaped junction is used in which the streams 1971 and 1972 flow toward each other in opposite and preferably substantially parallel directions, and a T-shaped junction is used in which the combined stream exits in a vertical direction (schematically shown in Figure 22 ).

[0169] Adopt Figure 5 An alternative embodiment of the system using the cartridge shown, in particular a base station (not shown), includes a manually operated mode switch by which a pressure release valve, in particular a 3 / 2-way valve, is manually opened to release any remaining pressurized gas in the fluid circuit of the disposable cartridge. After the pressure is released, the disposable cartridge can be removed from the base station or the generated microvesicles can be administered to the subject, as described above.

[0170] Figure 6 A second functional layout of the fluid channel system 1109 of the cartridge 100, i.e., the fluid circuit, i.e., the pneumatic and hydraulic circuits, is schematically shown. The second layout differs from the first layout only in that a pressure release valve 1110 fluidly connected to the first gas inlet and the second gas inlet is added, and the pressure release valve 1110 is capable of releasing any remaining pressurized gas at the inlets 131, 132 before the cartridge 100 is removed from the base station.

[0171] Figures 9A to 9C Schematically shows an alternative embodiment of an auxiliary sealing mechanism as arranged in an embodiment of a disposable cartridge 100, the auxiliary sealing mechanism including an alternative movable sealing element 1810 for assisting in sealing the reservoir 180. In Figure 9A , the base station 200 and the cartridge 100 are in an unconnected state, but are positioned relative to each other to enter a connected state. It can be seen that the base station 200, particularly the back plate 211 of the cartridge receiving portion 210, includes an auxiliary sealing mechanism raised member 212 extending from the back plate 211 in a direction towards the cartridge 100. The cartridge 100, particularly the rear cover 120, includes mating openings 1201 arranged to receive the auxiliary sealing mechanism raised member 212. The mating openings 1201 extend into an alternative movable sealing element retaining channel 1813, in which the alternative movable sealing element 1810 is slidably arranged. The alternative movable sealing element 1810 includes a blocking section 1812 arranged to close, i.e., seal, the auxiliary sealed reservoir outlet 184. An auxiliary sealing biasing mechanism 1815 is arranged to urge the alternative movable sealing element 1810 to a closed position, in which the blocking section 1812 closes the outlet 184.

[0172] As in Figure 9B and Figure 9C best seen, when connecting the cartridge 100 and the base station 200, the auxiliary sealing mechanism raised member 212 abuts the outer end 1811 of the alternative movable sealing element 1810 to push the alternative movable sealing element 1810 against the biasing direction, such that the blocking section 1812 moves from the closed position to the open position, thereby allowing the fluid held in the second internal volume 182 to be pushed from the second internal volume 182 through the alternative movable sealing element retaining channel 1813 of the cartridge 100 into the corresponding channel 1814. Thereby allowing the microvesicle carrier fluid held in the second internal volume 182 to be pushed to the holding container 141, as described above.

[0173] Figures 10A to 10C Shows another alternative embodiment of the auxiliary sealing mechanism, the auxiliary sealing mechanism including an alternative movable sealing element 1810, the movable sealing element 1810 including a through hole 1816. The illustrated embodiment allows the auxiliary sealing element 1810 to have three different positions in the sealing element retaining channel 1813. The auxiliary sealing element 1810 includes three seals, namely a first seal 1817, a second seal 1818 and a third seal 1819, all three seals preferably being O-ring seals. In Figure 10AA first position is shown, which is a filling position. In the filling position, all three seals 1817 - 1819 are on one side of the outlet 184 of the auxiliary sealed reservoir, on the side closest to the opening of the seal element holding passage 1813a. Thus, a passage is formed from the outside of the cartridge, through the through - holes 1816 in the auxiliary seal element, towards the outlet 184 of the auxiliary sealed reservoir. In the filling position, fluid can be added to the auxiliary sealed reservoir 182 to fill the auxiliary sealed reservoir 182. In Figure 10B a second position is shown, which is a sealing or closing position. The same sealing principle as that Figure 9A shown is used, where the second seal 1818 and the third seal 1819 are positioned on opposite sides of the outlet 184 of the auxiliary sealed reservoir, thereby sealing the outlet 184 of the auxiliary sealed reservoir. In Figure 10C a third position is shown, which is an unsealed or open position, and again the same principle as that in Figure 9C is applied. The first seal 1817 and the second seal 1818 are positioned on opposite sides of the outlet 184 of the auxiliary sealed reservoir. Since at least between the first seal 1817 and the second seal 1818, the diameter of the movable seal element 1810 is smaller than the diameter of the seal element holding passage 1813, a passage is formed as follows: the passage leads from the outlet 184 of the auxiliary sealed reservoir, through the seal element holding passage 1813 and around the movable seal element 1810 towards the passage 1814 in the cartridge 100.

[0174] Figure 11 The heat transfer element assembly 261 is shown in more detail. The heat transfer element 261 includes a heating / cooling surface 261 and a heat transfer element shaft portion 243, and the heat transfer element shaft portion 243 is arranged in a slidable manner in the guiding section 244. The biasing element 245 provides a biasing force to push the heat transfer element 261 outward towards the position of the disposable cartridge. The shaft portion 243 includes a cylindrical member having a circular cross - section with a diameter of d2, and the guiding section 244 includes a tubular section having a circular cross - section with a diameter of d1. The diameter d2 is smaller than the diameter d1, which allows a certain degree of play between the heat transfer element shaft 243 and the guiding section 244. This play allows the heat transfer element shaft 243 to rotate and translate limitedly about two axes perpendicular or orthogonal to the central axis of the heat transfer element shaft 243. These additional degrees of freedom allow the heating / cooling surface to move its position to optimally contact the disposable cartridge, especially the microfluidic chip. One of the degrees of freedom of the heat transfer element is represented by the angle α p which pPreferably about 1.5°. Preferably, a similar degree of play is allowed in the orthogonal direction. A certain degree of rotation about an axis parallel to the central axis of the heat transfer element shaft 243 is also possible.

[0175] Figures 12A to 12C An alternative embodiment of the releasable connector 163 is shown. The connector 163 includes an outer locking sleeve 2650 that encloses an inner locking sleeve 2653, and the inner locking sleeve 2653 encloses the hybrid drive shaft 1621. The connector 163 additionally includes a plurality of movable coupling members 2610 that are partially held between the inner locking sleeve 2653 and the outer locking sleeve 2650 and move with the inner locking sleeve 2653. The movable coupling members 2610 include cam portions 2611 and protrusions 2640 that are arranged to interact with corresponding grooves 1640 on the piston member 142. A cover 2651 is additionally arranged at the end of the outer locking sleeve 2650, and when the piston member 142 is coupled to the connector 163, the piston member 142 is pulled against the cover 2651. There is a gap between the end of the outer locking sleeve 2650 and the opposite lower side portion 2652 of the cover. When the releasable connector 163 is in the open position, the gap provides a space for the movable locking members 2610 to move into. In Figure 12A , the cam portions 2611 of the movable locking members 2610 are shown to be located in the gap. The connector includes a coupled state ( Figure 12C ) and a released state ( Figure 12A , Figure 12B ). In the released state, the inner locking sleeve 2653 moves towards the cover 2651, causing the coupling members 2610 to move with the inner locking sleeve 2653. The cam portions 2611 are guided through the lower side portion 2652 of the cover into the gap between the lower side portion and the end of the outer locking sleeve 2650. The cam portions 2611 and the protrusions 2640 thus move outward from the central axis of either locking sleeve. The coupling portion 1422 of the piston member 142 can then be inserted into the connector 163 through the hole 2654 in the cover 2651. To couple the piston member 142 to the connector 163, the inner locking sleeve 2653 and the coupling members 2610 move away from the cover 2651 in the direction D L , as Figure 12B , Figure 12CAs shown. Then, the cam portion 2611 engages the end of the outer locking sleeve 2650 and is pushed inward, causing the top portion and the protrusion 2640 of the coupling member 2610 to move inward and away from the cover 2651. Thus, the protrusion 2640 can engage the groove 1640 on the coupling portion 1421 of the piston member 142, pulling the piston member 142 towards the cover 2651 and holding the piston member 142. A biasing device 2655 - preferably including a spring - is arranged below the inner sleeve 2653, and the inner sleeve 2653 is supported by a ridge on the inner surface of the outer sleeve 2650 at its lower side portion. The biasing device 2655 biases the inner sleeve 2653 upward towards the open position to improve the process of disconnecting the piston member 142 from the releasable coupler 163. An additional biasing device 2656 is arranged around the movable coupling member 2610 at the lower portion of the movable coupling member 2610. The biasing device preferably includes a ring, such as an O-ring. The biasing device 2656 pulls the lower portion of the movable coupling member 2610 inward, which generates an outward biasing force at the top portion of the movable coupling member 2610. This provides an additional force that pushes the movable coupling member 2610 towards the open state when the releasable coupler is opened and when the inner sleeve 2653 and the movable coupling member 2610 move upward.

[0176] The mixing element 161 includes a drive rod 1611 which is arranged to be inserted through the hole 1422 in the piston member 142 and is held in the hole 1422 in the piston member 142 in a rotatable manner (meaning allowing rotational movement). When the piston member 142 is connected to the coupler 163, the drive rod 1611 is connected to the mixing drive shaft 1621 to allow the mixing drive shaft 1621 to transmit rotational movement to the mixing element 161. The drive rod 1611 includes a plurality of flexible protrusions 1612 to allow the drive rod to snap into the narrower portion of the hole 1422 in the piston member 142, thereby holding the mixing element 161 in the piston member 142.

[0177] Figure 13A , Figure 13B A schematic overview of an embodiment of the rotatable clamping mechanism 206 is shown. The rotatable clamping mechanism is shown in Figure 13A in the closed position, and in Figure 13Bis shown in the open position. The clamping mechanism 206 includes a rotary clamp 2061 which is rotatably connected to a base station 200 (not shown) by a second pivot portion 2066. An L-shaped rotary member 2062 is rotatably connected to the base station 200 (not shown) by a first pivot portion 2065, and a connecting rod 2063 connects the rotary member 2062 and the clamp 2061. The connecting rod 2063 is connected to a first hinge portion 2067 and a second hinge portion 2068, and the first hinge portion 2067 and the second hinge portion 2068 are respectively offset from the first pivot portion 2065 and the second pivot portion 2066. The rotation of the rotary member 2062 is transmitted to the clamp 2061 through the connecting rod 2063, so that the clamp 2061 rotates in a direction opposite to the rotation direction of the rotary member 2062. As Figure 13A shown, the line drawn between the first pivot portion 2065 and the second hinge portion 2068 defines a dead point line L d . When the first hinge portion 2067 is located on the dead point line L d , a dead point occurs. In this dead point state, the force acting on the clamp 2061 is transmitted by the clamp in a direction pointing to the center of the first pivot portion 2065. Therefore, this transmitted force has no moment arm around the first pivot portion 2065, thus preventing this force from rotating the rotary member 2062 to release the clamp. In Figure 13A the shown closed state, the center of the hinge portion 2067 is located outside the dead point line L d at a distance represented by D d . The clamp 2061 includes two parts, namely a main clamp 2061 and a clamp rod 2061a, and the main clamp 2061 and the clamp rod 2061a are rotatably connected by a second pivot portion 2066. The connecting rod 2063 is connected to the clamp rod 2061a at the second hinge portion 2068. A biasing device - preferably a flexible member such as a spring 2069 - is arranged between the clamp rod 2061a and the main clamp 2061, so that the rotation of the clamp rod 2061a is transmitted to the main clamp 2061 only through the biasing device 2069. This allows the clamping mechanism 206 to rotate through the dead point without forcing the main clamp 2061 to further enter the box-shaped member 100 beyond the position where the clamp 2061 is in the closed position. The rotation of the clamp rod 2061a beyond its position in the closed position is absorbed by the biasing device 2069, thus preventing an excessive force from being applied by the main clamp 2061 to the box-shaped member 100.

[0178] Figure 14A cross-section of an embodiment of a rotatable clamping mechanism 206 in a locked state is shown. The locking drive mechanism includes an actuator 2064 arranged to push against a rotating member 2062 to rotate the rotating member 2062, and thereby rotate the clamp 2061 between a locked state and a released state. The actuator 2064 extends to move the rotating member 2062 towards the locked state. In the locked state, the clamping mechanism 206 moves through a dead point, which means that the force acting on the clamp is transmitted to pull the actuator 2064. Since the actuator cannot extend beyond the position it is in the locked state, as the clamping mechanism 206 moves towards the end stop in the locked position, the force cannot cause the clamp 2061 to rotate from the locked state to the released state.

[0179] Figure 15 A schematic side view of a preferred embodiment of the sensing unit 270, more specifically the part arranged in the base system 200, is shown. The sensing unit 270 includes two interacting parts 270b and 270c, which are arranged at corresponding positions on the base system 200 and the disposable cartridge 100 respectively. The base unit part of the sensing unit 270b includes a first light source 271 such as an LED, and two light sensors 272, 273. Preferably, the base unit part of the sensing unit additionally includes a second light source 274. The light sources 271, 274 and the light sensors 272, 273 are oriented to emit light towards the position of the disposable cartridge 100 or receive light from the position of the disposable cartridge 100.

[0180] Figure 16 A view of the base system part of the sensing unit 270b seen in the direction towards the base system 200 is shown. The two light sources 271, 274 are arranged to project light from the base system 200 towards the position of the disposable cartridge 100. The two light sensors 272, 273 are similarly arranged towards the outside of the base system to receive light from the direction of the disposable cartridge 100.

[0181] Figure 17A A view of the cartridge part of the sensing unit 270c seen in the direction towards the disposable cartridge 100 is shown. The cartridge part of the sensing unit 270c includes four reflective surfaces 275 - 278 arranged around the monitoring fluid line 170. The reflective surfaces 275 - 278 can include any reflective material, such as a mirror or a reflective plastic part. The reflective surfaces 275 - 278 can be made of the same material as the material forming the housing of the disposable cartridge 100. The reflective surfaces 275 and 278 are oriented to correspond to the positions of the light sources 271, 274 when the cartridge is mounted on the base system 200. The reflective surfaces 275 and 278 are arranged at an angle to reflect the received light towards the monitoring fluid line 170. InFigure 17A In Figure 17A , the reflective surface 275 reflects the light received from the light source 271 towards the monitoring fluid pipeline 170 in the form of a light beam B1, and the light beam B1 is reflected by the monitoring fluid pipeline 170. This reflection occurs when there is no liquid in the monitoring fluid pipeline 170, or when there is a local absence of liquid due to cavitation in the monitoring fluid pipeline 170 at the point where the light beam B1 is projected onto the monitoring fluid pipeline 170, thereby generating a refractive index that causes the light beam B1 to be reflected towards the reflective surface 276. The reflective surface 276 corresponds to the position of the light sensor 272 and is arranged to reflect the received light beam B1 towards the light sensor 272.

[0182] Figure 17B It shows the following situation: The light beam B1 reflected by the reflective surface 275 towards the monitoring fluid pipeline 170 passes through the monitoring fluid pipeline 170 and is transmitted towards the reflective surface 277. The reflective surface 277 is oriented at an angle to reflect the light beam B1 towards the light sensor 273. This situation occurs when there is fluid in the monitoring fluid pipeline 170 because the change in refractive index causes the light beam B1 to be transmitted by the monitoring fluid pipeline 170 and the fluid inside.

[0183] Figure 17C It shows the self - test mode of the sensing unit 270. In the case where there is no fluid in the monitoring fluid pipeline 170, both light sources 271 and 274 emit light. The reflective surface 275 reflects the light received from the light source 271 towards the monitoring fluid pipeline 170 in the form of a light beam B1, and the reflective surface 278 reflects the light received from the light source 274 towards the monitoring fluid pipeline 170 in the form of a light beam B2. There is a lack of fluid in the monitoring fluid pipeline 170, while the monitoring fluid pipeline 170 contains a gas such as air, which generates the following refractive index: This refractive index causes the two light beams B1 and B2 to be reflected to the reflective surfaces 276 and 277 respectively. The self - test mode is used to verify the correct alignment of the cartridge 100 on the base system 200.

[0184] Figure 18 It shows an embodiment of the disposable cartridge 100, in which a vial (sealed reservoir) 1501 containing a pre - prepared microvesicle suspension (external microvesicle suspension) is used. The vial (sealed reservoir) 1501 is installed in a holder 1506 on the disposable cartridge 100 and is connected to a connector 1505, and the connector 1505 can be the same connector 102 for connecting the cartridge 100 to a subject. This connection is achieved by means of a reservoir fluid conduit, preferably a flexible tube 1503, and a tube connector 1504. A cap 1502 is arranged on the vial 1501, and the cap 1502 includes a spike and a vent hole (not shown), and the spike and the discharge port are used to open the vial 1501 and allow the external microvesicle suspension to flow out of the vial 1501. The shown embodiment does not includeFigure 4 The parts 150 - 156 shown. The parts are for holding, opening, and delivering fluid from a sealed reservoir that contains a second fluid, which is a lipid - containing liquid from which microvesicles can be produced. For models of disposable cartridges that use a pre - formed microvesicle suspension, also known as an external microvesicle suspension, these parts can be removed, but this is not necessary. A visual code scanner, such as a barcode scanner or a QR code scanner 1507, is arranged on the base system 200 and is preferably protruded such that the QR code scanner 1507 can see the lower side of the vial 150 / 1501 mounted on the cartridge 100. The QR code scanner 1507 is arranged to scan a visible machine - readable code, such as a barcode or a QR code, on the vial 150 / 1501, preferably on the lower side of the vial 150 / 1501. The scanner 1507 is also compatible with, for example Figure 4 the embodiment of the cartridge arranged to produce microvesicles as shown. Figure 18 The position of the QR code scanner 1507 in is for illustrative purposes only and is not intended to limit the position of the QR code scanner to the position shown.

[0185] Figure 19A , Figure 19B shows the operation of the removable connector guard 1021, which is arranged to selectively cover or expose the connectors 102, 1505. In Figure 19A the closed, covered position, the removable connector guard 1021 covers the connectors 102, 1505, thereby preventing another connector from connecting to the connectors 102, 1505. It is not important that the entire connectors 102, 1505 are covered by the connector guard 1021. Preferably, at least a part of the connectors 102, 1505 is covered to prevent another connector from connecting to the connectors 102, 1505. In Figure 19B the open, uncovered position shown, the connectors 102, 1505 are unobstructed to allow another connector to connect to the connectors 102, 1505.

[0186] Figure 20A , Figure 20B shows the components that make up the cartridge pressure detection unit. Figure 20A shows in more detail the pressure detection point 129 on the cartridge 100, which is also shown in Figure 5 . The pressure detection point 129 includes a pressure sensor 1291, such as a bellows - type member 1291, which transfers the following force F p : The force is proportional to the fluid pressure in the various fluid lines in the cartridge and more specifically to the fluid pressure in the pressure detection point fluid chamber 1290. Figure 20BThe pressure sensing unit 229 is shown in more detail. Figure 7 The pressure sensing unit 229 includes a force transmitting member 2292 that transmits a force F applied to a flat tip 2291 of the force transmitting member 2292. p Transmitted to force sensor 2293. Force F p It is the product of the pressure in the pressure detection point 129 and the contact area of ​​the flat tip 2291. The force transfer member 2292 is installed in the base system 200 and is connected to the base system 200 by means of elastic members 2297, preferably linear guide flexures 2297. These linear guide flexures 2297 allow linear movement of the force transfer member 2292 without friction and the resulting hysteresis. The linear guide flexures 2297 are generally annular and are connected to the base system 200 at their outer edges 2297a. The flexure 2297 is also composed of a plurality of folding members 2297b. The fact that these folding members are folded allows the folding members 2297b to be longer without increasing the total footprint of the linear guide flexure 2297. At the end of the force transfer member 2292 in contact with the force sensor 2293, a cylindrical cavity 2294 is arranged, and the cavity 2294 includes a biasing device 2295 and a plunger 2296. Force F p The force is transmitted by the force transmitting member 2292 to the biasing device 2295, then to the plunger 2296, and finally to the force sensor 2293. The biasing device 2295 is preferably a coil spring. The biasing device is preloaded to allow forces up to a predetermined threshold to be transmitted to the force sensor 2293, exceeding which the biasing device is compressed and the plunger 2296 moves into the cavity 2294. Figure 20B 2 shows a possible arrangement of a rigid stop 2298, which is arranged to stop the force transfer member after moving a set distance and absorb any force above the force threshold, thereby preventing the force above the threshold from being applied to the force sensor 2293. Preferably, the rigid stop is alternatively provided in the base system 200 at a position corresponding to the lower side of the flat tip 2291 of the force transfer member 2292, so that the lower side of the flat tip 2291 impacts the rigid stop. This position of the rigid stop increases the rigidity of the following component: the component transfers the force impacting on the flat tip 2291 to the rigid stop, because only the flat tip 2291 transfers the force, rather than the larger part of the force transfer member 2292.

[0187] Figure 21A , Figure 21BShows a cross-section of the basic system 200, in particular a cross-section along a plane that laterally cuts through the nozzle (outlet) 231, valve actuators 291 and 293, and heat transfer element 261. The nozzles (outlets) 231 and 232 are arranged in the basic system in a movable manner, and in Figure 21A , the nozzles 231 and 232 are shown in the retracted position, and in Figure 21B , the nozzles 231 and 232 are shown in the extended position. In the Figure 21B shown retracted position, the nozzles 231 and 232 are covered by an outlet guard 233, which is also arranged in the basic system 200 in a slidable manner. The outlet guard 233 additionally includes a seal 234, in particular an O-ring, which forms a seal with the tips of the nozzles 231, 232 when the nozzles press against the seal 234. To achieve this sealing state, the nozzles 231, 232 first retract towards the retracted position, then the outlet guard 233 closes, and then the nozzles 231, 232 partially extend, thus pressing against the seal 234 to seal the openings of the nozzles 231, 232. In Figure 21B , the outlet guard 233 is in the uncovered, open position. The nozzles 231, 232 can then be moved to the extended position. Preferably, when the nozzles 231, 232, in particular nozzle 231, move from the extended position to the retracted position, the airflow towards the nozzles is cut off.

[0188] Figure 22 Shows a schematic overview of a mixing unit 197, which is arranged to combine a flow 1972 of a microvesicle carrier fluid, preferably saline, from an auxiliary reservoir 180 and a flow 1971 of a fluid from a holding unit 140, preferably a heterogeneous mixture containing microvesicles or an external microvesicle suspension, preferably a heterogeneous mixture containing microvesicles or an external microvesicle suspension homogenized in the holding unit 140, into a combined fluid flow 1973. The combined flow 1973 then flows towards a connector 102 and a subject connected to the connector. The geometry of the mixing unit affects the mixing of the two fluids, and the mixing unit includes a junction of fluid channels through which the flows 1971 and 1972 flow. Preferably, a T-shaped junction is used, in which the flows 1971 and 1972 flow towards each other in directly opposite directions - thus parallel directions - and a T-shaped junction is used where the combined flow exits in a perpendicular direction. By separately changing the speeds of the second movable piston member 185 and the movable piston member 142, the flow rate of the flow 1972 from the auxiliary reservoir and the flow rate of the flow 1971 from the holding unit 140 can be changed, thereby allowing a change in the ratio of the two flows.

[0189] For illustrative purposes, the following embodiments are further provided:

[0190] 1. A system for generating microvesicles, in particular microbubbles, having a predefined size and / or size distribution, the system comprising:

[0191] - a microvesicle generation unit for generating microvesicles having a predefined size and / or size distribution, wherein the microvesicle generation unit comprises an inlet side and an outlet side, the inlet side being arranged to receive a first fluid through a first inlet and a second fluid through a second inlet, the first fluid and the second fluid being mixed by the microvesicle generation unit to generate the microvesicles, and the outlet side being arranged downstream and arranged to discharge the generated microvesicles;

[0192] - a device for receiving the generated microvesicles in a microvesicle carrier fluid to obtain a heterogeneous mixture containing microvesicles;

[0193] - a holding unit for holding the heterogeneous mixture containing microvesicles, the heterogeneous mixture containing microvesicles comprising the generated microvesicles and the microvesicle carrier fluid, in particular a salt solution;

[0194] - a homogenization mechanism arranged to homogenize the heterogeneous mixture containing microvesicles held in the holding unit.

[0195] 2. The system according to embodiment 1, wherein the holding unit comprises a device for discharging the heterogeneous mixture containing microvesicles from the holding unit for administering the heterogeneous mixture containing microvesicles to a subject, preferably, wherein the holding unit is in fluid communication with a connector, wherein the connector is preferably of the Luer type and is arranged to couple an infusion line arranged to be in fluid communication with the circulatory system of the subject.

[0196] 3. The system according to any one of the preceding embodiments, wherein the holding unit comprises a holding container in which a movable piston member is arranged, wherein the holding container and the movable piston member enclose an internal volume for holding the heterogeneous mixture containing microvesicles, and wherein the movable piston member is capable of moving in the holding container to increase or decrease the internal volume such that the heterogeneous mixture containing microvesicles can be diluted by adding the microvesicle carrier fluid to the heterogeneous mixture containing microvesicles in the holding unit, or such that the heterogeneous mixture containing microvesicles can be discharged from the holding unit, in particular from the holding container, wherein the movable piston member is preferably arranged to be driven by a first drive mechanism, the first drive mechanism particularly comprising a linear drive.

[0197] 4. The system according to Embodiment 3, wherein the volume change of the internal volume due to the unit stroke length of the movable piston member, multiplied by the ratio between the unit stroke length of the movable piston and the product of the front surface area of the movable piston member and the unit stroke length of the movable piston, is ≤ 1, and this ratio allows for precise control of the amount and flow rate of the mixture to be applied.

[0198] 5. The system according to any one of the foregoing embodiments, wherein the homogenization mechanism includes a movable mixing element extending into the holding unit; and

[0199] wherein the system includes a homogenization drive mechanism for driving the movable mixing element, and the homogenization drive mechanism particularly includes a rotary drive.

[0200] 6. The system according to at least Embodiments 3 and 5, wherein the movable mixing element is included in the movable piston member, wherein the movable piston member is capable of linearly moving inside the holding container, and wherein the movable mixing element is a rotary mixing element, the rotary mixing element preferably includes a plurality of fins extending inside the internal volume, and the movable mixing element is arranged to rotate together with the movable piston member or relative to the movable piston member;

[0201] wherein, preferably, the movable piston member and the movable mixing element include a common shaft, and the common shaft is rotatably connected to the movable mixing element and translationally connected to the movable piston member.

[0202] 7. The system according to any one of the foregoing embodiments, including a basic system and a disposable cartridge detachably connected thereto, wherein the basic system includes a releasable connecting device for holding the disposable cartridge in a predefined position and orientation, and wherein the disposable cartridge includes at least a part of the microvesicle generating unit, the device for receiving the generated microvesicles in a microvesicle carrier liquid, the holding unit, and the homogenization mechanism.

[0203] 8. A system according to any of the preceding embodiments, wherein the second fluid is contained in a sealed reservoir, which is arranged or can be arranged in the system, in particular in a sealed container receiving section, the sealed container receiving section being used to receive and hold the sealed container arranged in the disposable box-like member, and wherein, when the system is in an initialized state, the sealed reservoir is arranged to be opened, and

[0204] Therein, the system, in particular the disposable box-like piece, is arranged so that the second fluid in the opened container can be in fluid communication with the microvesicle generating unit.

[0205] 9. A system according to embodiment 8, wherein the sealed reservoir is arranged to be, at least arranged to be maintained in the system, in particular arranged to be received in a sealed container receiving section, the sealed container receiving section is used to receive and maintain the sealed container arranged in the box-pack, and wherein an opening tool, such as a cutting tool, a piercing tool and / or a rupture tool is arranged, and the opening tool, such as the cutting tool, the piercing tool and / or the rupture tool moves relative to the sealed reservoir and / or the sealed container receiving section, or the sealed reservoir and / or the sealed container receiving section moves relative to the opening tool, such as the cutting tool, the piercing tool and / or the rupture tool, to open the seal of the sealed reservoir for opening the sealed reservoir, and wherein, preferably, a reservoir fluid conduit is arranged in the opening tool or together with the opening tool, wherein the reservoir fluid conduit is such that in the initialization state, the open end of the conduit is arranged to be inserted into the second fluid so that the second fluid is in fluid communication with the microvesicle generating unit,

[0206] The system comprises an opening tool drive mechanism, in particular a linear drive mechanism, which is used to drive the opening tool relative to the sealed container, or the opening tool drive mechanism is used to drive the sealed container relative to the opening tool.

[0207] 10. A system according to any one of embodiments 8 to 9 above, wherein the system includes a main pressure-regulating gaseous medium source, in particular a pressurized air source, and the main pressure-regulating gaseous medium source is arranged to be connected to the opened reservoir fluid when the system is in the microcapsule production state after the initialization state, so as to force the second fluid to flow to the microcapsule production unit.

[0208] 11. The system according to any one of the foregoing embodiments, wherein the system includes an auxiliary pressure-regulated gaseous medium source arranged to provide a flow of pressurized gaseous medium as the first fluid, and / or wherein the second fluid is a continuous-phase liquid.

[0209] 12. The system according to at least embodiments 7 and 10 or at least embodiments 7 and 11, wherein the base system includes the main pressure-regulated gaseous medium source and / or the auxiliary pressure-regulated gaseous medium source and a main gaseous medium outlet and / or an auxiliary gaseous medium outlet;

[0210] wherein the disposable cartridge includes a main gaseous medium cartridge inlet and / or an auxiliary gaseous medium cartridge inlet arranged to engage and cooperate with the main gaseous medium outlet and / or the auxiliary gaseous medium outlet to provide a fluid connection between the main pressure-regulated gaseous medium source and / or the auxiliary pressure-regulated gaseous medium source and the microvesicle generation unit;

[0211] wherein the main gaseous medium inlet and / or the auxiliary gaseous medium inlet is preferably arranged movably in the cartridge and preferably includes a biasing device for urging the inlet towards the base system when in a state in which the cartridge is coupled to the base system, and / or

[0212] wherein the main gaseous medium outlet and / or the auxiliary gaseous medium outlet is preferably arranged movably in the base system and preferably includes a biasing device for urging the outlet towards the cartridge, as seen in a state in which the cartridge is coupled to the base system.

[0213] 13. The system according to at least embodiment 7, wherein the system includes a locking mechanism having a release state and a locked state, wherein in the release state, the disposable cartridge can be removed from the base system, and wherein in the locked state, the disposable cartridge is fixedly held in the base system and urged towards the base station by a locking system with a preloading force, wherein the locking system preferably includes a locking drive mechanism for driving the locking mechanism.

[0214] 14. The system according to embodiment 13, wherein the locking mechanism comprises a first movable clamping unit, in particular a rotatable clamping unit, which is arranged in the base station and is arranged to engage with a first clamping part of the cartridge, the first clamping part being preferably arranged at a lower section of the disposable cartridge, and the first movable clamping unit presses the clamping part towards the base station in a first direction and presses the clamping part in a second direction which is substantially parallel to the base station and preferably perpendicular to the first direction, and wherein the locking mechanism further comprises a second movable clamping unit which is arranged to engage the cartridge at a second clamping part which is different from the first clamping position, the second clamping part being preferably arranged at an upper section of the disposable cartridge, and the second movable clamping unit presses the second position in the first direction.

[0215] 15. The system according to at least embodiments 13 and 14, wherein in the locked state, the locking mechanism, in particular the respective movable clamping units, is arranged to apply the preloading force to the following sections of the cartridge: the sections include the first gaseous medium inlet and / or the second gaseous medium inlet, preferably the movable first gaseous medium inlet and / or second gaseous medium inlet.

[0216] 16. The system according to at least embodiment 7, wherein the base system and the disposable cartridge include mating recesses and protrusions for aligning the disposable cartridge in the base system, preferably, wherein the mating recesses and protrusions are arranged such that the cartridge has only a single unique fitting mode by which the cartridge can be placed and connected in the base system.

[0217] 17. The system according to any one of the foregoing embodiments, wherein the microvesicle generating unit comprises a microfluidic chip, in particular a microfluidic flow focusing chip, the microfluidic chip comprising a first chip inlet for receiving the first fluid and a second chip inlet for receiving the second fluid, wherein the channels extending from the first chip inlet and the second chip inlet converge at a junction: a microvesicle forming channel extends from the junction towards a chip outlet for discharging the generated microvesicles from the microfluidic chip towards the outlet side of the microvesicle generating unit.

[0218] 18. The system according to embodiment 17, wherein the system further comprises a heat transfer element arranged to heat and / or cool the microfluidic chip.

[0219] 19. The system according to at least embodiments 7 and 18, wherein the heat transfer element is arranged in the base system and is arranged to abut at least the section of the cartridge including the microfluidic chip, in particular directly abut the microfluidic chip, in the connection state in which the disposable cartridge is connected to the base system.

[0220] 20. The system according to embodiment 19, wherein the heat transfer element is arranged in the base system in a manner capable of moving in a direction towards and away from the disposable cartridge, and wherein the heat transfer element is forced in the direction towards the disposable cartridge by a heat transfer element biasing mechanism.

[0221] 21. The system according to at least embodiment 7, wherein the respective drive mechanism includes a drive unit, such as an electric motor, a pneumatic motor or a hydraulic motor, and wherein the drive unit of the respective drive mechanism is arranged in the base system and is releasably and operatively coupled to the part of the respective drive mechanism arranged in the disposable cartridge.

[0222] 22. The system according to any one of the foregoing embodiments, wherein the system, in particular the disposable cartridge, includes an auxiliary sealed reservoir containing a salt solution, wherein, in the initialization phase, the auxiliary sealed reservoir is arranged to be opened and arranged to be in fluid communication with the holding unit, or wherein the auxiliary sealed reservoir is arranged to be opened when the disposable cartridge is coupled and / or locked in the base system.

[0223] 23. The system according to embodiment 22, wherein the auxiliary sealed reservoir includes a movable sealing element arranged to be held in a sealed position before use, wherein the movable sealing element seals the auxiliary sealed reservoir, and in the initialization phase, the movable sealing element moves to an open position, and / or wherein the base system can be provided with a fixedly arranged projection member arranged to abut the movable sealing element when the cartridge is coupled and / or locked and push the movable sealing element from the opening of the auxiliary sealed reservoir, so that the auxiliary reservoir is in fluid communication with the holding unit, in particular the holding container.

[0224] 24. The system according to embodiment 22 or 23, wherein the auxiliary sealed reservoir is arranged to be opened by increasing the internal pressure in the auxiliary sealed reservoir to a pre-defined minimum pressure.

[0225] 25. A disposable box-shaped member for use in a system according to at least Embodiment 7.

[0226] 26. A basic system for use in a system according to at least Embodiment 7.

[0227] The present invention is not limited to the embodiments shown, but also extends to other embodiments falling within the scope of the appended claims.

Claims

1. A system for providing microvesicles, in particular microbubbles, having a predefined size and / or size distribution, the system comprising: - a device for receiving microvesicles in a microvesicle carrier liquid to obtain a heterogeneous mixture comprising microvesicles; - a holding unit for holding the heterogeneous mixture comprising microvesicles, the heterogeneous mixture comprising microvesicles and the microvesicle carrier liquid, in particular a salt solution; - a homogenization mechanism arranged to homogenize the heterogeneous mixture comprising microvesicles held in the holding unit; - an auxiliary reservoir containing a microvesicle carrier liquid, in particular a salt solution, wherein the auxiliary reservoir is arranged in fluid connection with the holding unit.

2. The system according to claim 1, further comprising a microvesicle generating unit configured to generate microvesicles having a predefined size and / or size distribution, wherein, The microvesicle generating unit includes an inlet side and an outlet side, the inlet side being arranged to receive a first fluid through a first inlet and a second fluid through a second inlet, the first fluid and the second fluid being mixed by the microvesicle generating unit to generate the microvesicles, and the outlet side being arranged downstream and arranged to discharge the generated microvesicles.

3. The system according to claim 1 or 2, wherein, The holding unit includes a device for discharging the heterogeneous mixture comprising microvesicles from the holding unit for administering the heterogeneous mixture comprising microvesicles to a subject, preferably, wherein the holding unit is in fluid communication with a connector, wherein the connector is preferably of the Luer type, the connector being arranged to couple an infusion line, the infusion line being arranged to be in fluid communication with the circulatory system of the subject.

4. The system according to claim 3, further comprising a mixing unit in fluid communication with at least the holding unit and the connector via an outlet, wherein, The mixing unit further includes an inlet for receiving a microvesicle carrier liquid, in particular saline, wherein the mixing unit is arranged to combine the heterogeneous mixture comprising microvesicles from the holding unit and the microvesicle carrier liquid at the outlet for supply to the connector.

5. The system according to claim 4, wherein, The system is arranged to regulate the ratio of the heterogeneous mixture comprising microvesicles flowing into the mixing unit to the microvesicle carrier liquid.

6. The system according to any one of the preceding claims, wherein, The holding unit includes a holding container in which a movable piston member is arranged, wherein the holding container and the movable piston member enclose an internal volume for holding the heterogeneous mixture comprising microvesicles, and wherein the movable piston member is capable of moving in the holding container to increase or decrease the internal volume such that the heterogeneous mixture comprising microvesicles can be diluted by adding the microvesicle carrier liquid to the heterogeneous mixture comprising microvesicles in the holding unit, or such that the heterogeneous mixture comprising microvesicles can be discharged from the holding unit, in particular the holding container, wherein the movable piston member is preferably arranged to be driven by a first drive mechanism, the first drive mechanism particularly including a linear drive.

7. The system according to any one of the preceding claims, wherein, The homogenization mechanism includes a movable mixing element extending into the holding unit; and wherein the system includes a homogenization drive mechanism for driving the movable mixing element, the homogenization drive mechanism particularly including a rotary drive.

8. The system according to claim 7, wherein The homogenization drive mechanism is arranged to rotate the movable mixing element alternately in a clockwise direction and a counterclockwise direction.

9. The system according to at least claims 6 and 7 or 8, wherein, The movable mixing element is included in the movable piston member, wherein the movable piston member is capable of linearly moving inside the holding container, and wherein the movable mixing element is a rotary mixing element, the rotary mixing element preferably includes a plurality of fins extending inside the internal volume, and the movable mixing element is arranged to rotate together with the movable piston member or to rotate relative to the movable piston member.

10. The system according to claim 9, wherein, The homogenization drive mechanism further includes a releasable coupler for releasably coupling the movable piston member and / or the rotatable mixing element to the drive mechanism, wherein the releasable coupler includes one or more movable annular coupling members, the movable annular coupling members include protrusions arranged to engage recesses or grooves arranged on the movable piston member.

11. The system according to claim 10, wherein, The movable coupling member is arranged to slide in the locking sleeve and is capable of moving between a coupling state and a release state, wherein when the movable coupling member slides from the release state to the coupling state, the protrusion moves inwardly towards the central axis of the locking sleeve.

12. The system according to claim 11, wherein, The releasable coupler further includes a cap arranged at an end of the locking sleeve, wherein the cap includes a hole allowing at least a part of the movable piston member and at least a part of the mixing element to pass through, wherein the cap includes an inner surface arranged to engage the movable coupling member, preferably to engage a cam portion of the movable clamping member, wherein when the coupling member moves towards the release state, the inner surface guides at least a part of the movable coupling member away from the central axis of the locking sleeve outwardly.

13. The system according to any one of the preceding claims 10 to 12, further comprising a shaft connected to the homogenization drive mechanism, wherein, The shaft is arranged to be coupled to the rotatable mixing element as defined in claim 7 when the movable piston member is connected to the releasable coupler.

14. The system according to any one of the preceding claims 11 to 13, wherein, The shaft is arranged inside the locking sleeve.

15. The system according to any one of the preceding claims, comprising a base system and a disposable cartridge removably connected thereto, wherein, The base system includes a releasable connecting device for holding the disposable cartridge in a predefined position and a predefined orientation, wherein the disposable cartridge includes at least a part of the device for receiving the generated microvesicles in the microvesicle carrier liquid, the holding unit, and the homogenization mechanism.

16. The system according to at least claims 2 and 15, wherein, The disposable cartridge further includes the microvesicle generating unit.

17. The system according to any one of the preceding claims 2 to 16, wherein, The second fluid is included in a sealed reservoir, which is arranged or can be arranged in the system, in particular in a sealed reservoir receiving section, for receiving and holding the sealed reservoir arranged in the disposable cartridge, and wherein, when the system is in an initial state, the sealed reservoir is arranged to be opened, and wherein the system, in particular the disposable cartridge, is arranged such that the second fluid in the opened reservoir can be in fluid communication with the microvesicle generating unit.

18. The system according to claim 17, wherein, The sealed reservoir is arranged, at least arranged to be held within the system, in particular arranged to be received in a sealed reservoir receiving section for receiving and holding the sealed reservoir arranged within the cartridge, and wherein an opening tool, such as a cutting tool, a piercing tool and / or a rupturing tool, is arranged, and the opening tool, such as the cutting tool, the piercing tool and / or the rupturing tool, moves relative to the sealed reservoir and / or the sealed reservoir receiving section, or the sealed reservoir and / or the sealed reservoir receiving section moves relative to the opening tool, such as the cutting tool, the piercing tool and / or the rupturing tool, to open the seal of the sealed reservoir for opening the sealed reservoir, and wherein, preferably, a reservoir fluid conduit is arranged in the opening tool or together with the opening tool, and wherein the reservoir fluid conduit is such that in the initial state, the open end of the conduit is arranged to be inserted into the second fluid to put the second fluid in fluid communication with the microvesicle generating unit, and wherein the system includes an opening tool drive mechanism, in particular a linear drive mechanism, for driving the opening tool relative to the sealed reservoir or for driving the sealed reservoir relative to the opening tool.

19. The system according to any one of the preceding claims, wherein, The system is arranged to receive microvesicles generated in an external microvesicle suspension in the holding unit, the external microvesicle suspension including prefabricated microvesicles in a microvesicle carrier liquid.

20. The system according to claim 19, wherein, The external microvesicle suspension is included in a sealed reservoir, which is arranged or can be arranged in the system, in particular in a sealed reservoir receiving section, for receiving and holding the sealed reservoir arranged in the disposable cartridge, and wherein the system, in particular the disposable cartridge, is arranged such that the external microvesicle suspension in the opened reservoir can be in fluid communication with the holding unit, and wherein, preferably, a reservoir fluid conduit is arranged to put the external microvesicle suspension in fluid communication with the holding unit.

21. The system according to claim 20, wherein, The reservoir fluid conduit includes a tube arranged to connect the reservoir to a connector disposed on the cartridge, wherein the connector is in fluid communication with the holding unit.

22. The system according to claim 21, wherein The connector is the same connector as the connector arranged for connecting an infusion line, which is arranged to be in fluid communication with the circulatory system of the subject.

23. The system according to any one of the preceding claims 17 to 22, wherein, The system includes a first optical scanner arranged to scan a visual code disposed on the sealed reservoir.

24. The system according to claim 23, wherein The visual code is disposed on the bottom of the sealed reservoir.

25. The system according to any one of the preceding claims 15 to 24, wherein, The base system includes a second optical scanner arranged to scan a visual code disposed on the disposable cartridge.

26. The system according to at least claim 15 and any one of the preceding claims 23 to 25, wherein, The first optical scanner is disposed on the base system.

27. The system according to any one of the preceding claims 2 to 18 and 23 to 26, wherein, The system includes a main pressure-regulated gaseous medium source, particularly a pressurized air source, arranged to be in fluid communication with the opened reservoir in the microbubble generation state after the system is in the initialization state, to force a second fluid to flow to the microbubble generation unit.

28. The system according to any one of the preceding claims 2 to 27, wherein, The system includes an auxiliary pressure-regulated gaseous medium source arranged to provide a flow of pressurized gaseous medium as the first fluid, and / or wherein the second fluid is a continuous phase liquid.

29. The system according to at least claim 15 and any one of claims 16 to 28, wherein, The base system includes the main pressure-regulated gaseous medium source and / or the auxiliary pressure-regulated gaseous medium source, as well as a main gaseous medium outlet and / or an auxiliary gaseous medium outlet; - wherein the disposable cartridge includes a main gaseous medium cartridge inlet and / or an auxiliary gaseous medium cartridge inlet, the main gaseous medium cartridge inlet and / or the auxiliary gaseous medium cartridge inlet being arranged to engage and cooperate with the main gaseous medium outlet and / or the auxiliary gaseous medium outlet to provide a fluid connection between the main pressure-regulated gaseous medium source and the sealed reservoir and / or between the auxiliary pressure-regulated gaseous medium source and the microbubble generation unit; - wherein the main gaseous medium inlet and / or the auxiliary gaseous medium inlet is preferably arranged movably in the cartridge and preferably includes a biasing device for pressing the inlet towards the base system in a state where the cartridge is coupled to the base system, and / or - wherein the main gaseous medium outlet and / or the auxiliary gaseous medium outlet is preferably arranged movably in the base system and preferably includes a biasing device for pressing the outlet towards the cartridge, as seen in a state where the cartridge is coupled to the base system.

30. The system according to at least claims 15 and 29, wherein, The base system further includes an outlet guard arranged to be movable between a closed position and an open position, in the closed position, the outlet guard covers the main gaseous medium outlet and / or the auxiliary gaseous medium outlet, and in the open position, the outlet guard exposes the outlet.

31. The system according to any one of the preceding claims 29 to 30, wherein, The main gaseous medium outlet and / or the auxiliary gaseous medium outlet are arranged to be movable between a retracted position and an extended position. In the retracted position, the outlet is retracted into the base system, and in the extended position, the outlet projects outwardly towards the position of the disposable cartridge.

32. The system according to any one of the preceding claims 30 to 31, wherein, The main gaseous medium outlet and / or the auxiliary gaseous medium outlet are arranged to prevent the outlet protector from moving from the open position towards the closed position when the outlet is in the extended position, wherein the outlet protector is arranged to close only when the outlet is in the retracted position.

33. The system according to any one of the preceding claims 30 to 32, wherein, In the closed position, the outlet protector is arranged to seal the main gaseous medium outlet and / or the auxiliary gaseous medium outlet.

34. The system according to claim 33, wherein, The outlet protector includes a seal which is arranged to interact with the main gaseous medium outlet and / or the auxiliary gaseous medium outlet to seal the outlet.

35. The system according to any one of the preceding claims 3 to 34, wherein, A movable connector protector is arranged at the connector for selectively covering and uncovering the connector, wherein the movable cover is preferably driven by a connector protector actuator.

36. The system according to claim 35, wherein, The movable connector protector includes a biasing device which is arranged to bias the connector protector towards the covering position to cover the connector.

37. The system according to any one of the preceding claims 35 to 36, wherein, The connector protector actuator is arranged to move the connector protector to uncover the connector when the pressure in the disposable cartridge is substantially equal to the ambient pressure.

38. The system according to any one of the preceding claims 35 to 37, wherein, The connector protector actuator is arranged to move the connector protector to uncover the connector when the main gaseous medium outlet and / or the auxiliary gaseous medium outlet are disengaged from the main gaseous medium inlet and / or the auxiliary gaseous medium inlet and / or when the main gaseous medium outlet and / or the auxiliary gaseous medium outlet are in the retracted position.

39. The system according to any one of the preceding claims 35 to 38, further comprising a safety controller operatively connected to the connector guard actuator, wherein, The safety controller further includes one or more sensors which are arranged to record the pressure in the disposable cartridge and / or the state of the main gaseous medium outlet and / or the auxiliary gaseous medium outlet, wherein the safety controller is arranged to command the connector protector actuator to open or close the movable connector protector based on at least the pressure in the disposable cartridge and / or the state of the main gaseous medium outlet and / or the auxiliary gaseous medium outlet.

40. The system according to at least claim 15, wherein, The system includes a locking mechanism having a released state and a locked state, wherein in the released state, the disposable cartridge can be removed from the base system, and wherein in the locked state, the disposable cartridge is fixedly held in the base system and is pressed towards the base system by a locking system with a preloading force, wherein the locking system preferably includes a locking drive mechanism for driving the locking mechanism.

41. The system according to claim 40, wherein, The locking mechanism includes a first movable clamping unit, in particular a rotatable clamping unit, which is arranged in the base system and arranged to engage with a first clamping part of the cartridge, the first clamping part being preferably arranged at a lower section of the disposable cartridge, and the first movable clamping unit presses the clamping part towards the base system in a first direction and presses the clamping part in a second direction substantially parallel to the base system and preferably perpendicular to the first direction, and wherein the locking mechanism further includes a second movable clamping unit, which is arranged to engage the cartridge at a second clamping part different from the first clamping position, the second clamping part being preferably arranged at an upper section of the disposable cartridge, and the second movable clamping unit presses the second position in the first direction.

42. The system according to claim 41, wherein, In the locked state, the locking mechanism, in particular the respective movable clamping unit, is arranged to apply the preloading force to the following sections of the cartridge: the sections include the first gaseous medium inlet and / or the second gaseous medium inlet, preferably the movable first gaseous medium inlet and / or the second gaseous medium inlet.

43. The system according to any one of the preceding claims 40 to 42, wherein, The locking mechanism includes a clamping mechanism, the clamping mechanism includes the second movable clamping unit and a locking drive mechanism, wherein the locking drive mechanism is arranged to move the clamping mechanism, wherein the clamping mechanism is arranged to move the clamping unit between the locked state and the released state, and wherein the clamping mechanism is arranged to move through a dead point between the locked state and the released state.

44. The system according to claim 43, wherein, The clamping mechanism includes: a rotating member, which is rotatably arranged on the base system using a first pivot part; a rotary clamping unit, which is rotatably arranged on the base system using a second pivot part; and a connecting rod, which is connected to the rotating member through a first hinge part positioned at a non-zero offset distance from the first pivot part and connected to the rotary clamping unit through a second hinge part positioned at a non-zero distance from the second pivot part, wherein the rotation of the rotating member is transmitted to the clamping unit through the connecting rod, thereby rotating the clamping unit, and wherein a dead point state occurs when the clamping mechanism is in a position where the first pivot part, the first hinge part and the second hinge part are aligned.

45. The system according to claim 44, wherein, The clamping unit includes a biasing device arranged to transmit the clamping force applied by the clamping mechanism to the disposable cartridge.

46. The system according to claim 45, wherein, The clamping unit includes a separate fixture and a fixture rod, wherein the fixture and the fixture rod are arranged to be rotatable around the second pivot part, wherein the fixture rod includes the second hinge part, wherein the biasing device is arranged between the fixture and the fixture rod, and wherein the rotation of the fixture rod is transmitted to the fixture only through the biasing device.

47. The system according to at least claim 15, wherein The base system and the disposable cartridge include mating recesses and protrusions for aligning the disposable cartridge in the base system. Preferably, the mating recesses and protrusions are arranged such that the cartridge has only a single unique fitting orientation by which the cartridge can be positioned and connected in the base system.

48. The system according to at least claim 2, wherein, The microvesicle generating unit includes a microfluidic chip, in particular a microfluidic flow focusing chip, which includes a first chip inlet for receiving the first fluid and a second chip inlet for receiving the second fluid. Channels extending from the first and second chip inlets converge at a junction from which a microvesicle forming channel extends towards a chip outlet for discharging the generated microvesicles from the microfluidic chip towards the outlet side of the microvesicle generating unit.

49. The system according to claim 48, wherein, The system further includes a heat transfer element arranged to heat and / or cool the microfluidic chip.

50. The system according to at least claims 15 and 49, wherein, The heat transfer element is arranged in the base system and is arranged to abut, at least in a connected state in which the disposable cartridge is connected to the base system, a section of the cartridge including the microfluidic chip, in particular directly abutting the microfluidic chip.

51. The system according to claim 50, wherein, The heat transfer element is arranged in the base system so as to be movable in a direction towards and away from the disposable cartridge, and wherein the heat transfer element is biased in the direction towards the disposable cartridge by a heat transfer element biasing mechanism.

52. The system according to claim 51, wherein, The heat transfer element is further arranged in the base system so as to be movable in a direction having a component orthogonal to the direction towards and away from the disposable cartridge, and wherein the heat transfer element is preferably additionally arranged in the base system so as to be rotatable about all three perpendicular directions. The base system and the heat transfer element are arranged to limit translational movement along the two directions to displacements smaller than the displacements allowed in the direction towards and away from the disposable cartridge. The base system and the heat transfer element are additionally arranged to limit rotational movement of the heat transfer element about each of the three perpendicular axes to less than 10°, preferably less than 5°, more preferably less than 2°, and most preferably approximately 1.5°.

53. The system according to at least claim 15, wherein The corresponding drive mechanism includes a drive unit, such as an electric motor, a pneumatic motor or a hydraulic motor, and wherein the drive unit of the corresponding drive mechanism is arranged in the base system and is releasably and operatively coupled to a part of the corresponding drive mechanism arranged in the disposable cartridge.

54. The system according to any one of the preceding claims, wherein, The system, in particular the disposable cartridge, comprises an auxiliary sealed reservoir containing a salt solution, wherein, in the initialization phase, the auxiliary sealed reservoir is arranged to be opened and arranged to be in fluid communication with the holding unit, or wherein the auxiliary sealed reservoir is arranged to be opened when the disposable cartridge is coupled and / or locked in the base system.

55. The system according to claim 54, wherein, The auxiliary sealed reservoir includes a movable sealing element which is arranged to be held in a sealed position before use, wherein the movable sealing element seals the auxiliary sealed reservoir, and in the initialization phase, the movable sealing element moves to an open position, and / or wherein the base system can be arranged with a fixedly arranged raised member which is arranged to abut the movable sealing element and push the movable sealing element from the opening of the auxiliary sealed reservoir when the cartridge is coupled and / or locked, so that the auxiliary reservoir is in fluid communication with the holding unit, in particular the holding container.

56. The system according to any one of the preceding claims 54 to 55, wherein, The auxiliary sealed reservoir is arranged to be opened by increasing the internal pressure in the auxiliary sealed reservoir to a pre-defined minimum pressure.

57. The system according to any one of the preceding claims 55 to 56, wherein, The movable sealing element is movable between three positions, the three positions including a sealed position, an open position and a filling position, in the filling position, the auxiliary sealed reservoir is opened to receive fluid from a source external to the disposable cartridge.

58. The system according to claim 57, wherein, The movable sealing element is movably arranged in a sealing element holding channel in the cartridge, wherein the movable sealing element and the sealing element holding channel interact to form a valve for opening and sealing the auxiliary sealed reservoir, wherein the diameter of the movable sealing element is at least at one point smaller than the diameter of the sealing element holding channel.

59. The system according to claim 58, wherein, The movable sealing element includes at least three seals, in particular O-rings, arranged around the circumference of the movable sealing element, wherein a third seal is positioned close to the end of the cylindrical member pointing into the cartridge, a first seal is positioned close to the end of the cylindrical member pointing out of the cartridge, and a second seal is positioned between the first seal and the third seal, wherein the cylindrical member preferably includes an axial hole which extends through the length of the cylindrical member.

60. The system according to claim 59, wherein, The sealing element holding channel includes an open end and a closed end, and at least two openings in the channel wall, at least the first opening providing a fluid connection between the sealing element holding channel and the auxiliary sealed reservoir, and at least the second opening providing a fluid connection between the sealing element holding channel and the holding unit, wherein the first opening and the second opening are arranged at different distances from the closed end of the sealing element holding channel.

61. The system according to claim 60, wherein: - At the filling position, the movable sealing element is in a position where the third seal is positioned on the open end side of the seal element holding channel, wherein a passage is formed from the outside of the cartridge through an opening in the movable sealing element, towards the first opening, and towards the auxiliary sealed reservoir; and - At the sealing position, the movable sealing element is in a position where the third seal and the second seal are positioned on opposite sides of the first opening, thereby sealing the auxiliary sealed reservoir; and - At the open position, the movable sealing element is in a position where the second seal is positioned on the closed end side of the seal element holding channel relative to the first opening, and the first seal is positioned on the open end side of the seal element holding channel relative to the second opening.

62. The system according to any one of the foregoing claims further comprises a sensing unit, the sensing unit comprising a first light source and a first light sensor, and the system further comprises a monitored fluid pipeline, wherein, In the case where the heterogeneous mixture containing microvesicles is present in the monitoring fluid line, light from the first light source passes through the monitoring fluid line and is directed to the first light sensor, wherein the sensing unit is arranged to determine the concentration of microvesicles in the heterogeneous mixture containing microvesicles based on the intensity of the light received by the first light sensor.

63. The system according to claim 62, wherein, The concentration of microvesicles in the heterogeneous mixture containing microvesicles is measured by measuring the transmittance of the heterogeneous mixture containing microvesicles.

64. The system according to any one of the preceding claims 62 to 63, wherein, The system further includes a second light sensor, wherein light from the first light source reflected by the monitoring fluid line is directed to the second light sensor, wherein the sensing unit is arranged to determine the presence of gas in the monitoring fluid line based on the light received by the second light sensor.

65. The system according to claim 64, wherein, The sensing unit includes a second light source, wherein the sensing unit is arranged to determine the alignment of the monitoring fluid line based on the light received by the second light sensor from the first light source and the light received by the first light sensor from the second light source.

66. The system according to any one of the preceding claims 62 to 66, wherein, The first light source, the first light sensor, and the second light sensor are arranged in the base system.

67. The system according to any one of the preceding claims 65 to 66, wherein, The second light source is arranged in the base system.

68. The system according to at least claim 15, further comprising a pressure detection unit arranged to measure the pressure in the disposable cartridge.

69. The system according to claim 68, wherein, The disposable cartridge includes a pressure detection point arranged to transmit a force proportional to the pressure in the cartridge to the pressure detection unit.

70. The system according to claim 69, wherein, The pressure detection point includes a bellows-type member that expands under an increased fluid pressure in the disposable cartridge.

71. The system according to any one of the preceding claims 68 to 70, wherein, The base system includes a force sensor arranged to measure a force proportional to the fluid pressure in the disposable cartridge.

72. The system according to any one of the preceding claims 68 to 71, wherein, The pressure detection unit includes a force transfer member arranged to transfer a force from the disposable cartridge to the force sensor.

73. The system according to claim 72, wherein, The force transfer member is connected to the base system by one or more resilient members arranged to permit substantially linear movement of the force transfer member relative to the base system.

74. The system according to claim 73, wherein, The one or more resilient members include linear guiding flexures.

75. The system according to any one of the preceding claims 72 to 74, wherein The force transfer member includes a biasing device arranged to transfer a force applied to the force transfer member to the force sensor.

76. The system according to claim 75, wherein, The biasing device is arranged in a preloaded state and is arranged to compress once a force applied to the biasing device exceeds the preload force.

77. The system according to claim 76, wherein, Compression of the biasing device compresses the force transfer member which is arranged to contact a rigid end stop when the biasing device compresses.

78. The system according to any one of the preceding claims 75 to 77, wherein, The force transfer member includes a chamber and a plunger, wherein the biasing device is at least partially arranged in the chamber and wherein the plunger is at least partially arranged in and held by the chamber, wherein the plunger is arranged to slide into the chamber thereby compressing the biasing device, wherein the plunger is arranged to contact the force sensor and wherein a force applied to the force transfer member is transferred to the force sensor through the force transfer member, the biasing device and the plunger.

79. A disposable cartridge for use in a system according to at least claim 15.

80. A base system for use in a system according to at least claim 15.

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