Fluid delivery system for providing a flow of microvesicle containing liquid to a subject

Abstract

Fluid delivery system for providing a flow of microvesicle containing liquid to a subject, wherein the system comprises a first fluid conduit arranged to contain microvesicle containing liquid, wherein said first fluid conduit comprises an inlet arranged to receive microvesicle containing liquid at an input flow rate and an outlet arranged to provide microvesicle containing liquid at an output flow rate to said subject, wherein the system comprises a first pumping mechanism in fluid communication with the first fluid conduit arranged to induce a varying flow rate component in said first fluid conduit for at least partially preventing decantation of the microvesicles in the microvesicle containing liquid present in the first fluid conduit.

Description

FLUID DELIVERY SYSTEM FOR PROVIDING A FLOW OF MICRO VESICLECONTAINING LIQUID TO A SUBJECTThe present invention relates to a fluid delivery system and method for providing a flow of microvesicle containing liquid to a subject.Focused Ultrasound (FUS) in combination with microvesicles has emerged as a potential new means of effective drug delivery to the brain. Recent research has shown that, under burst-type energy exposure with the presence of microvesicles (e.g. nano / microdroplets, microcapsules, microbubbles), this modality can transiently permeate the blood-brain barrier (BBB).Microvesicles are heterogeneous membrane-bound objects having a core, such as a fluid (i.e. gas or liquid), that is enclosed by the outer membrane. Compositions used for generating such microvesicles are described in, for instance, European Patent EP 1784 288 Bl.For an effective drug delivery, it is important that said microvesicles, typically microbubbles, have a predefined size and / or size distribution, wherein the distribution is preferably as narrow as possible. Existing systems for generating microvesicles typically lead to a too wide size distribution of the generated microbubbles. Additionally, in current systems, the microvesicles are typically produced in a dedicated system from which a microvesicles suspension, i.e. a heterogeneous mixture comprising the generated microvesicles and a microvesicles carrier liquid, results. Syringes are thereafter typically manually filled and connected to an infusion line for introducing the microvesicles in the circulatory (blood) system of a subject.It is a goal of the present invention, next to other goals, to provide a fluid delivery system for delivering a flow of microvesicle containing liquid to a subject in an efficient and reliable manner, wherein preferably the above mentioned problem is at least partially alleviated.This goal, amongst other goals, is met by a fluid delivery system according to appended claim 1. More specifically, this goal, amongst other goals, is met by a fluid delivery system for providing a flow of microvesicle containing liquid to a subject, wherein the system comprises a first fluid conduit arranged to contain microvesicle containing liquid, wherein said first fluid conduit comprises an inlet arranged to receive microvesicle containing liquid at an input flow rate and an outlet arranged to provide microvesicle containing liquid at an output flow rate to said subject, wherein the system comprises a first pumping mechanism in fluid communication with the first fluid conduit arranged to induce a varying flow rate component in said first fluid conduit for atleast partially preventing decantation of the microvesicles in the microvesicle containing liquid present in the first fluid conduit.It is highly desirable that the suspended microvesicles are homogeneously distributed through the carrier liquid, especially for administration to a subject. In existing systems, especially during administration, it was found that the distribution of microvesicles in the carrier liquid becomes less homogeneous in locations as microvesicles float upwards in the carrier liquid (decantation) or sink downwards in the carrier liquid (sedimentation). In other words, microvesicles may fall out of suspension. By providing a mechanism for preventing, or at least reducing, decantation and / or sedimentation in the fluid conduit, the quality of the microvesicles to be administered is improved, as well as the homogeneity of the distribution of microvesicles through the carrier liquid (the micro vesicle containing liquid). Preferably, a pumping mechanism is provided to this end, although any mechanism may be used.Inducing a varying flow rate component in the microvesicle containing liquid present in the system agitates the liquid, which helps to maintain the microvesicles in suspension in the liquid, and prevents decantation. Decantation in this context refers to the microvesicles falling out of suspension and potentially accumulating in certain parts of the system, preventing the microvesicles from being effectively administered. In this text, the phenomenon of microvesicles falling out of suspension, which includes the aforementioned phenomena of decantation and sedimentation, is also referred to as simply ‘decantation’.It is noted that the ‘inlet’ as referred to above does not necessarily refer to a physical inlet component arranged on an end of for example a tube. Instead, the ‘inlet’ should be understood as to be a part of a fluid conduit which demarcates the upstream end of the first fluid conduit. Thus, the first fluid conduit should also be understood as to refer to a section of a larger fluid conduit, not a single, separate, physical component. As such, an inlet may not be required, for instance in a closed system, an example of which will also be discussed below. The system may also comprise more than one inlet. For instance one inlet for microvesicle containing fluid and another inlet for additional fluid.Typically, the fluid containing the microvesicles is saline or another suitable liquid. The micro vesicles or microbubbles have a size in the range of 0.1-20 pm, preferably 1-10 pm, most preferably 2-5 pm, or a size distribution according to the following specifications: the mode, median or mean in diameter of between 2 and 5 pm and a geometric standard deviation (GSD) < 1.25, most preferably a GSD <1.1. Preferably, the micro vesicle containing liquid is generated usinga system for generating microvesicles as described in pending international application PCT / NL2023 / 050580 in the name of the same applicant.Preferably, the first pumping mechanism is arranged to induce a cyclically varying flow rate component. A cyclic variation is relatively easy to induce, and the magnitude of a cyclically varying flow rate component is relatively easy to adjust to prevent damage to the microvesicles on one hand, and to ensure sufficient agitation of the microvesicle containing liquid to prevent decantation. Preferably, the varying flow rate oscillates at a frequency of at least 0.001 Hz, preferably at least 1Hz, more preferably at least 3Hz, or at least any of the values between 0.001- 10Hz, and at most 100Hz, preferably at most 20Hz, more preferably at most 7Hz, or at most any of the values between 7-100Hz. It was found that these frequency ranges were most effective. In particular, the frequency range of l-10Hz, more in particular approximately 5Hz, was found to be effective.Preferably, the first pumping mechanism is arranged to induce a varying flow rate component in said first fluid conduit having an average flow rate of zero over a period of time. By ensuring that the average flow rate of the varying flow rate component is zero it is ensured that the varying flow rate component does not result in a net fluid output at the output, which is then administered to the subject.Preferably, the system further comprises a mechanism, for instance a second pumping mechanism, arranged to induce an outflow flow rate component in the first fluid conduit. The first pumping mechanism, or generally a mechanism, may be arranged to induce the outflow flow rate component. This outflow flow rate component is however preferably being induced separately by the second pumping mechanism allows for a more accurate control of the outflow flow rate component.The outflow flow rate component may be a constant flow rate, for instance by gradually increasing a pressure. The varying flow component is then superimposed on this outflow flow rate to prevent sedimentation. As said, a single mechanism or device may be responsible for generating this flow rate pattern, preferably however, separate mechanisms are provided. In the context of this description, any property of the first or second pumping mechanism may thus also be attributed to a general mechanism or the other of the first and second pumping mechanism.Preferably, the second pumping mechanism is arranged to induce an outflow flow rate component, wherein the average of the outflow flow rate component over a period of time is equal to theaverage output flow rate over the period of time. The average output flow rate over the period of time being equal to the average outflow rate over the period of time allows for accurate control of the output flow rate.Preferably, the outflow flow rate component equals the input flow rate. This thus means that substantially all the fluid flowing into the first fluid conduit through the inlet originates from the outflow flow rate component. This allows a single fluid source to be used to provide the outflow flow rate, simplifying the system and allowing for more accurate control of the outflow flow rate and thus more accurate control over the output flow rate at the output. However, said single fluid source does not necessarily refer to a singular volume containing fluid, as it may also refer to multiple separate fluid containing volumes arranged in fluid communication to each otherPreferably, the system comprises a primary reservoir arranged in fluid communication with the inlet of the first fluid conduit, wherein the primary reservoir comprises an internal volume that is arranged to contain liquid for supply to the first fluid conduit. In certain embodiments, the primary reservoir may comprise a plurality of individual reservoirs arranged in fluid communication with each other. Thus, in said embodiments, the internal volume may comprise a plurality of individual internal volumes arranged in fluid communication with each other.The primary reservoir further preferably comprises a vent valve to vent fluid pressure from the internal volume, wherein the primary reservoir further comprises a fill valve arranged to receive microvesicle containing liquid in the internal volume, wherein the vent valve and the fill valve are arranged to selectively seal. This allows filling and emptying of the system. The primary reservoir preferably further comprises a filling / emptying valve arranged to fill or empty the internal volume. The primary reservoir may be partially filled with microvesicle containing liquid, and partially with a gas. Said gas may be a gas chosen to increase the stability of the microvesicles present in the microvesicle containing liquid. Preferably, said gas is a biocompatible gas, gas precursor or a mixture thereof. Preferred gasses are for instance: fluorinated gasses, such as sulfurhexafluoride (SF6) and / or perfluorocarbon gases, such as octafluoropropane (C3F8) or decafluorobutane (C4F10). Alternatively, the gas is, or comprises, air, nitrogen, carbon dioxide, hydrogen, nitrous oxide; noble and / or inert gasses, such as helium, argon, xenon or krypton. Suitable biocompatible gasses are for instance disclosed in pars.

[0083] -

[0092] of European patent EP 1784 228 Bl.Preferably, the internal volume is arranged to contain microvesicle containing liquid for supply to the first fluid conduit. This primary reservoir thus provides a supply of liquid, preferably microvesicle containing liquid, for provision to the first fluid conduit.Preferably, the primary reservoir comprises the second pumping mechanism, wherein the second pumping mechanism is preferably arranged to induce the outflow flow rate component of liquid from the primary reservoir to the inlet of the first fluid conduit. This allows for precise control over the outflow flow rate component, and thus over the output flow rate.Preferably, the second pumping mechanism comprises a movable member arranged to selectively increase or decrease the internal volume of the primary reservoir. Preferably, the movable member comprises a longitudinal member extending through a sidewall of the primary reservoir from the internal volume of the primary reservoir to outside of the internal volume of the primary reservoir, wherein the movable member is arranged to move into the internal volume to bring a larger proportion of the volume of the movable member inside the internal volume to decrease the internal volume. This allows for precise control over the variance of the internal volume, and thus over the outflow flow rate component. In certain embodiments and as mentioned above, a single mechanism may comprise, or perform the functions of, the first pumping mechanism and the second pumping mechanism.Preferably, the system comprises a mixing mechanism arranged to mix microvesicle containing fluid. This allows for an additional means to agitate the microvesicle containing liquid and prevent decantation. More preferably, the primary reservoir comprises the mixing mechanism. Arranging the mixing mechanism in the primary reservoir improves the agitation of the microvesicle containing liquid in the primary reservoir, preventing decantation of the microvesicle containing liquid in the primary reservoir.Preferably, the mixing mechanism comprises a movable mixing element arranged in the internal volume of the primary reservoir. Preferably, the movable mixing element is arranged to rotate. Preferably, the movable member comprises the mixing mechanism. This allows for a compact construction of the movable member and the mixing mechanism, and optionally allows the mixing element to be rotated by rotating the movable member.Preferably, the movable mixing element is arranged to alternatingly rotate clockwise and counterclockwise. This prevents the fluid in the reservoir from reaching a steady state, and thus further prevents decantation of the micro vesicles.Preferably, the system in use only has a single opening at the outlet, and is otherwise closed. This means that a change of the overall internal fluid volume of the system is related to the output flowrate. This allows for precise control of the output flow rate, and prevents contaminants from entering the microvesicle containing liquid in the system.Preferably, the system further comprises a fluid damper arranged in fluid communication with the first fluid conduit, upstream of the outlet, and downstream of the first pumping mechanism. Without such fluid damper, the varying flow rate component is substantially entirely transferred through the outlet to the subject, which may have negative consequences. Providing a fluid damper between the first pumping mechanism and the outlet reduces the peak fluid pressures in the microvesicle containing liquid, and thus reduces the pressure variations transmitted to the subject, as well as preventing damage to the microvesicles from excessive pressure variations and / or excessive peak negative and / or positive pressures.Additionally or alternatively, the system preferably comprises a fluid damper arranged in fluid communication with the first fluid conduit, downstream of the inlet, and upstream of the first pumping mechanism. Providing a fluid damper between the inlet and the first pumping mechanism may additionally reduce peak negative and / or pressures and the magnitude of the pressure variations. The one or more fluid dampers may additionally be used to adjust the overall profile of the varying flow rate component.Preferably, the system further comprises a valve arranged upstream to the first pumping mechanism, wherein the valve is arranged to selectively open or close to respectively open or close the fluid communication between the inlet and at least part of the first fluid conduit. Without such valve, the varying flow rate component may propagate away from the outlet, for example into the primary reservoir, instead of towards the outlet. Thus, arranging the valve upstream of the first pumping mechanism, preferably between the primary reservoir and the first pumping mechanism, ensures that the varying flow rate component propagates through the first fluid conduit, and other optional conduits, to improve the agitation of the micro vesicle containing liquid to prevent decantation.More preferably, the valve is arranged to close before or during operation of the first pumping mechanism. Preferably, the valve is arranged to open before or during operation of the second pumping mechanism. By closing the valve, the outflow flow is prevented from entering the first fluid conduit, and thus it is prevented that a net outflow of microvesicle containing liquid is provided at the outlet. Thus, by closing the valve, the above mentioned benefits may be achieved, and by opening the valve a net output flow of liquid may be provided at the outlet. In operation, preferably, the first pumping mechanism and the second pumping mechanism operatealternatingly, with the valve opening and closing accordingly. In an embodiment, the valve in the open position comprises an internal valve volume arranged in fluid communication with the first fluid conduit, wherein the valve further comprises a closing member that moves into the internal valve volume to close the valve, thereby decreasing the internal valve volume. In a further embodiment, cycling the valve between the closed and the open position induces the varying flow rate component in the first fluid conduit.Preferably, the first fluid conduit comprises a T-split arranged downstream of the first pumping mechanism and upstream of the outlet, wherein the system further comprises a second fluid conduit arranged for conducting fluid away from the T-split. This allows for an increased total flow rate in the first fluid conduit, at least between the first pumping mechanism and the T-split, and preferably between the inlet and the T-split. The increased total flow rate may further prevent decantation of the microvesicle containing liquid. In addition, it might be the case that a certain minimum total flow rate is required in the first fluid conduit, for example to prevent decantation and / or if the second pumping mechanism has a lower limit for the flow rate it may generate. At the same time, this minimum flow rate may be too high for administration to the subject through the outlet. Thus, providing the T-split and the second fluid conduit allows for a reduction of the output flow rate component relative to the total flow rate in the first fluid conduit, upstream of the T-split.Typically, in pre-clinical applications, the liquid flow to be administrated is lower than needed in clinical applications. To be able to use the same system for generating microvesicle containing fluid, i.e., a system having the same outflow rate, the T-split allows branching off, or diversion, of a fluid flow to provide a lower output flow rate than the outflow flow rate delivered at the input. The remaining, branched off or diverted, fluid may for instance be reused, as will be explained in greater detail below. It will be appreciated that the concept of the T-split or branching off a fluid flow may also be used in systems not provided with the first pumping mechanism. The T-split is then arranged downstream of the inlet, upstream of the outlet. As mentioned above, also the increased flow in the section upstream the T-split aids in prevention of decantation.Preferably, the second fluid conduit is arranged in fluid communication with the first fluid conduit, wherein the second fluid conduit is arranged to conduct a second conduit flow at a second conduit flow rate (also referred to as the backflow flow rate component), wherein the average second conduit flow rate over a period of time is equal to the average input flow rate over the period of time minus the average output flow rate over the period of time.Preferably, the system further comprises a secondary reservoir arranged in fluid communication with the second fluid conduit. This reservoir may thus receive the second fluid conduit flow rate.Preferably, the secondary reservoir comprises a second movable member arranged to selectively increase or decrease the internal volume of the secondary reservoir. Preferably, this second movable member is arranged to induce the second conduit flow rate by moving the second movable member to increase the internal volume of the secondary reservoir at a rate that equals the second conduit flow rate. This allows control over the second fluid conduit flow rate (the backflow flow rate), providing an alternative or supplemental way to control the average output flow rate, in addition to the second pumping mechanism.Preferably, the second fluid conduit couples to the primary reservoir and is arranged for conducting fluid away from the T-split back to said primary reservoir. This allows for the micro vesicle containing liquid conducted by the second fluid conduit to be recirculated to the primary reservoir, establishing a ‘loop flow’.Preferably, the first pumping mechanism comprises a selectively variable volume arranged in fluid communication with the first fluid conduit, and is arranged to induce the varying flow rate component of microvesicle containing liquid by varying the volume of the variable volume at a rate corresponding to the varying flow rate component.Preferably the selectively variable volume comprises a section of flexible tubing arranged in fluid communication with the first fluid conduit, wherein the first pumping mechanism further comprises a movable pushing member arranged to deflect at least part of the section of flexible tubing to vary the volume of the variable volume at a rate equal to the varying flow rate component. This arrangement is similar to a peristaltic pump with one roller, which is relatively simple to construct. Alternatively, the first pumping mechanism comprises a peristaltic pump, wherein the two or more rollers of the peristaltic pump that deflect the tubing comprise movable pushing members. The peristaltic pump may be alternatingly run in a forward and in a reverse direction to induce the varying flow rate component. The peristaltic pump may be run asymmetrically - i.e. longer and / or faster in one direction than the other - to allow or induce a net throughflow, for example the aforementioned loop flow.Additionally or alternatively, the first pumping mechanism preferably comprises a movable membrane arranged to selectively vary the variable volume. This allows for an accurate variation of the variable volume, and thus allows for an accurate way to induce the varying flow ratecomponent. In addition, the amplitude of the movement of the movable membrane may be adjusted to adjust the profile of the varying flow rate component. In a preferred embodiment, the first pumping mechanism comprises a piezoelectric actuator arranged to selectively vary the variable volume. More specifically, preferably, the piezoelectric actuator is arranged to move the movable membrane to selectively vary the variable volume to induce the varying flow rate component. Piezoelectric actuators are relatively simple and are capable of moving at sufficiently high frequencies. In addition, piezoelectric actuators are suitable for use in the vicinity of magnetic resonance imaging devices, or other devices in the vicinity of which it is not desirable to use ferromagnetic components.Additionally or alternatively, preferably the first pumping mechanism is arranged in series with the first fluid conduit, and is arranged to induce the varying flow rate component of microvesicle containing liquid in the first fluid conduit by varying the flow rate of microvesicle containing liquid through the first pumping mechanism. Preferably, this embodiment of the first pumping mechanism comprises a positive displacement pump. This allows the first pumping mechanism to also induce a unidirectional flow rate component, in addition to the bidirectional varying flow rate component. This unidirectional flow rate component may for example induce the aforementioned loop flow through the first fluid conduit, the second fluid conduit, the primary reservoir, and again into the first fluid conduit.Another aspect relates to a method for providing a flow of microvesicle containing liquid to a subject, in particular using a system as mentioned above, comprising the steps of: providing a first fluid conduit arranged to contain microvesicle containing liquid, wherein said first fluid conduit comprises an inlet arranged to receive microvesicle containing liquid at an input flow rate and an outlet arranged to provide microvesicle containing liquid at an output flow rate to said subject; inducing a varying flow rate component in said first fluid conduit for at least partially preventing decantation of the microvesicles in the microvesicle containing liquid present in the first fluid conduit.As described above, the varying flow rate component, preferably cyclically varying flow rate, aids in preventing sedimentation or decantation of the micro vesicles. The varying flow rate component, which may be induced by the first pumping mechanism or any other mechanism as described above, may have a net zero flow. In order to output any liquid, another component may be added to flow. Thus, preferably the method additionally comprises the step of inducing an outflow flow ratecomponent in the first fluid conduit, wherein the average of the outflow flow rate component over a period of time is preferably equal to the average output flow rate over the period of time.The present invention is further illustrated by the following figures, which show a preferred embodiment of the system according to the invention, and are not intended to limit the scope of the invention in any way, wherein: figures 1 - 4 show different embodiments of the system; figure 5 shows a schematic overview of the flow components; figures 6-11 and 14 show different embodiments of the system; and figures 12 and 13 illustrate the fluid flow rate in a conduit of the system.Figure 1 shows a first embodiment of a system 1 for fluid delivery. A first fluid conduit 11 is connected to a subject S at the outlet 10, and to a primary reservoir 30 at an inlet 14. A first pumping mechanism 2 comprises a section of flexible tubing 21a, which in the shown embodiment forms part of the first fluid conduit 11, and a movable pushing member 21, which rotates clockwise or counterclockwise relative to direction Rpl to cyclically press on the flexible tubing 21a to induce the varying flow component. A peristaltic pump with a single roller can be used for this purpose. An optional fluid damper 50 is disposed in fluid communication with the first fluid conduit 11.The primary reservoir 30 is connected to the inlet 14 and comprises an internal volume 31. A second pumping mechanism 3 comprises a movable member 40, comprising a longitudinal member 41, extending through a gasket 35 arranged in a sidewall of the primary reservoir 30. The gasket 35 comprises an X-ring seal. Alternatively, an O-ring seal or a V-ring seal may be used. A syringe may be used as a primary reservoir 30. The internal volume 31 contains liquid F, which is preferably microvesicle containing liquid. However, it may be the case that not the entire internal volume 30 is filled with liquid F. The ‘empty’ volume is indicated as headspace H. This headspace H may contain a gas such as atmospheric air, or another gas, as described above. It should be noted that not all of the following figures show liquid F and headspace H, however the aforementioned applies similarly to these figures.In the shown embodiment, the movable member does not comprise a piston that seals with the cylindrical sidewall of the syringe, as is usual in syringes used in the art. Instead, the internal volume 31 is increased or decreased by respectively retracting a longitudinal body 41 from the internal volume 31 or extending the longitudinal body into the internal volume 31, both along direction Dp2. A rotating mixing member 42, rotating in direction Rm, is additionally disposed onthe longitudinal body 41. The primary reservoir 30 may further comprise a filling / emptying valve 33 which can be used to fill or empty the primary reservoir 30. To release pressure build up during filling, or to prevent a vacuum during emptying, a vent valve 32 may additionally be provided on the primary reservoir 30. Both the vent valve 32 and the filling / emptying valve 33 may be sealed during use of the system for providing microvesicle containing liquid to the subject S. The vent valve 32 and / or the filling / emptying valve 33 may additionally be used to replace the gas present in the headspace H.Figure 2 shows a second embodiment of the system 1. In this embodiment, the first pumping mechanism 2 comprises a movable membrane 25 which is arranged to move in direction Dpi to increase or decrease a varying volume 24 arranged in fluid communication with the first fluid conduit 11. On either side of the fluid connection of the varying volume 24 with the first fluid conduit 11 an optional fluid damper 50 is arranged. In the shown embodiment, the first pumping mechanism is placed roughly equidistant to the inlet 14 and the outlet 10. This improves the distribution of the fluid displacement caused by the first pumping mechanism 2 through the first fluid conduit 11 , improving the effect of the varying flow component.Figure 3 a shows a third embodiment of the system 1, similar to the second embodiment shown in figure 2. In the third embodiment, the first pumping mechanism is arranged closer to the inlet 14 than to the outlet 10. To improve the distribution of the fluid displacement caused by the first pumping mechanism 2 in the first fluid conduit 11 , a valve 34 is arranged in the first fluid conduit 11 between the first pumping mechanism 2 and the inlet 14. The valve 34 may selectively open or close, to respectively allow or prevent fluid communication between the primary reservoir 30 and the first fluid conduit 11. During operation of the first pumping mechanism 2, the valve 34 may be closed to ensure that the fluid displacement caused by the first pumping mechanism is directed into the first fluid conduit 11 towards the outlet 10, instead of into the primary reservoir 30. An optional fluid damper 50 is disposed downstream of the first pumping mechanism 2.Figure 3b shows a second version of the third embodiment of the system 1, wherein the primary reservoir 30’ comprises two individual reservoirs 30a, 30b arranged in fluid communication with the inlet 14. In the shown embodiment, the second pumping mechanism comprises two second pumping mechanisms 3a, 3b which are respectively arranged to selectively increase or decrease individual internal volumes 31a, 31b of the respective individual reservoirs 30a, 30b by moving in respectively directions Dp2a and Dp2b. Pumping mechanisms 3a, 3b comprise plungers 40a, 40b which comprise seals 43a, 43b to seal with the sidewalls of the individual reservoirs 30a, 30b.In the shown embodiment, individual reservoir 30a may contain microvesicle containing liquid, while individual reservoir 30b contains another liquid, such as saline, but possibly also another liquid or fluid such as a gas, which may be mixed together at, or upstream of, the inlet 14. Valves 34a, 34b may selectively open or close the fluid communication between respectively internal volume 31a and 31b. Plunger 40a comprises a mixing member 42, which is arranged to rotate clockwise or counterclockwise in direction Rm, optionally alternating between the clockwise and counterclockwise direction. The individual reservoirs 30a, 30b connect before the inlet 14.Figure 4 shows a fourth embodiment of the system 1. In the fourth embodiment, a simpler primary reservoir 30 is employed, for example in the form of a conventional syringe. The second pumping mechanism 3 comprises the movable piston member 40a commonly used in syringes. The piston member 40a comprises a seal 43 to seal with the primary reservoir 30. In an embodiment, the primary reservoir may be filled simply with saline, or another liquid substantially without microvesicles, while the first fluid conduit 11 is filled with the microvesicle containing liquid.Using the second pumping mechanism 3 to induce the output flow will then dilute the microvesicle containing liquid in the first fluid conduit 11.Figure 5 shows a schematic overview of the flow components present in the first fluid conduit 11 during use of the system to provide a microvesicle containing liquid. The primary reservoir 30 and first pumping mechanism 2 are indicated near the inlet 14 of the first fluid conduit 14, but not shown. Fv represents the varying flow rate component in the first fluid conduit 11 , upstream of a T-split 13 (if used, see for instance figure 6 for an embodiment with a T-split) and downstream of the inlet 14 and the first pumping mechanism 2. Fin represents the input flow rate into the inlet 14.In embodiments without the T-split 13, the average outlet flow rate Fout over a period of time equals the average input flow rate Fin over that period of time, which is equal to the average outflow flow rate from the primary reservoir 30 in that period of time. In addition, in embodiment without the T-split 13, the varying flow rate component Fv propagates as Fv” into the outlet 10. Preferably, the average flow rate of the varying flow rate component Fv over said period of time is zero.In embodiments with the T-split 13, a backflow flow rate component (also referred to as the second fluid conduit flow rate component) Fback enters the second fluid conduit 12. In such embodiments, the unidirectional flow rate component entering the inlet 14 may be split in a primary first conduit flow rate component Fl and a secondary conduit flow rate component F2. The average of Fl over a period of time is equal to the average of the outlet flow rate Fout over that period of time, whilethe average of F2 over a period of time is equal to the average of the backflow flow rate component Fback over that period of time.In embodiments wherein the second fluid conduit 12 is in fluid communication with the primary reservoir 30, or otherwise in fluid communication with the inlet 14, a part of the varying flow rate component Fv propagates into the second fluid conduit 12 as Fv’. In addition, as the second fluid conduit 12 provides a looping flow path through the primary reservoir, the backflow flow rate component Fback flows through the primary reservoir 30 back into the first fluid conduit 11 as the secondary first conduit flow rate component F2. The average outflow flow rate component over a period of time, which is the net outflow from the primary reservoir, is then equal to the average of Fl over the period of time as well as the average of Fout over the period of time. The total flow rate Fin provided at the input 14 is equal to the outflow flow rate component plus the backflow flow rate component Fback, which is equal to F2, plus the varying flow rate component originating from the second fluid conduit 12, Fv’.In embodiments wherein the second fluid conduit 12 is not in fluid communication with the primary reservoir 30, or otherwise in fluid communication with the inlet 14, the varying flow rate component Fv may not propagate into the second fluid conduit 12. In addition, as there is no loop flow as in embodiments wherein the second fluid conduit 12 is in fluid communication with the primary reservoir 30, or otherwise in fluid communication with the inlet 14, the average outflow flow rate component over a period of time, which is the net outflow from the primary reservoir 30, is then equal to the average of Fl over the period of time, which is the average of Fout over the period of time, plus the average of Fback over the period of time, which is the average of F2 over the period of time.Figure 6 shows a fifth embodiment of the system 1 , wherein the first fluid conduit 11 comprises a T-split 13 arranged upstream of the outlet 10, and downstream of the primary reservoir 30. The second fluid conduit 12 connects to the T-split 13 at one end, and to the primary reservoir 30 at another end. The outflow flow rate of liquid from the primary reservoir 30 towards the outlet 10 is provided by the second pumping mechanism 3, while the first pumping mechanism 2 comprises a pump 22, such as a positive displacement pump 22, arranged to induce the varying flow rate component, as well as a ‘circular’ flow (F2 and Fback) through the first fluid conduit 11, the second fluid conduit 12, and the primary reservoir 30. The pump 22 is arranged to transduce any other flows, such as the input flow rate component. In this embodiment, the average outflow rate over a period of time is equal to the average output flow rate at output 10 over that period of time.The overall layout of the primary fluid reservoir 30 and associated components 31, 32, 33, 40, 41, 42 may be similar to the embodiments shown in figures 1, 2, 3.Figure 7 shows a sixth embodiment of the system 1 , with a simpler arrangement of the primary reservoir 30 and the second pumping mechanism 3. The second pumping mechanism 3 comprises a plunger which seals with the sidewall of the primary reservoir 30 at seal 43. Similarly to the fifth embodiment shown in figure 6, the second fluid conduit 12 being arranged in fluid communication with the primary reservoir 30 allows for a loop flow of fluid through the primary reservoir 30, the first fluid conduit 11 and the second fluid conduit 12.Figure 8 shows a seventh embodiment of the system 1, wherein the second fluid conduit 12 is not arranged in fluid communication with the primary reservoir 30, but instead with a secondary reservoir 60. In addition, the seventh embodiment is shown without a first pumping mechanism. The secondary reservoir 60 comprises a third pumping mechanism 4, which is arranged to induce the backflow flow component Fback. The third pumping mechanism 4 comprises a movable plunger 61 which seals with the secondary reservoir 60 at seal 63. Moving the plunger 61 along direction Dp3 increases or decreases the secondary internal volume 64 to induce Fback. The average outflow rate over a period of time from the primary reservoir 30 equals the average output flow rate Fout at outlet 10 plus the average of Fback over the period of time.Figure 9 shows an eighth embodiment of the system 1, wherein the primary reservoir 30’ comprises multiple individual reservoirs 30a, 30b, 30c arranged in fluid communication to form a single internal volume, composed of volumes 31a, 31b and 31c, wherein the volume 31c is the volume of the fluid conduit 30c arranged between individual reservoirs 30a and 30b. In the shown embodiment, one individual reservoir 30a may comprise the second pumping mechanism 3. Additionally, the individual reservoir 30a may contain liquid without microvesicles, such as a saline solution, while another individual reservoir 30b may contain microvesicle containing liquid. Thus, operation of the second pumping mechanism 3 to induce the outflow flow component of liquid from the reservoir 30’ into the inlet 14 may dilute the microvesicle containing liquid. In some applications, this may be acceptable. The first pumping mechanism 2 may be arranged to induce the varying flow rate component Fv and the loop flow rate component comprising flow components F2 and Fback.Figure 10 shows a ninth embodiment of the system 1, wherein the primary reservoir 30’ also comprises multiple individual reservoirs 30a, 30b, 30c arranged in fluid communication to form a single internal volume, composed of volumes 31a, 31b and 31c, wherein the volume 31c is thevolume of the fluid conduit 30c arranged between individual reservoirs 30a and 30b.The first pumping mechanism 2 is arranged in direct fluid communication with an individual reservoir 30b, and thus forms part of the primary reservoir 30’. The individual reservoir 30b additionally comprises a mixing means 42. Also in this embodiment, the individual reservoir 30a may contain saline instead of the microvesicle containing liquid. The first pumping mechanism 2 induces a varying flow rate component Fv in the individual reservoir 30b, which then propagates through at least the first fluid conduit 11.Figure 11 shows a tenth embodiment of the system 1 , similar to the ninth embodiment. This embodiment comprises the first pumping mechanism 2 arranged in fluid communication with an individual reservoir 30b through two fluid conduits 22a, 22b. Thus, the first pumping mechanism may induce a loop flow component through the individual reservoir 30b and conduits 22a and 22b. In addition, the first pumping mechanism 2 may induce a varying flow component through said individual reservoir 30b and conduits 22a and 22b.Figure 14 shows an eleventh embodiment of the system 1, which is similar to the arrangement of the eighth embodiment shown in figure 9. The primary reservoir 30’ comprises multiple individual reservoirs 30a, 30b, 30c arranged in fluid communication to form a single internal volume, composed of volumes 31a, 31b and 31c, wherein the volume 31c is the volume of the fluid conduit 30c arranged between individual reservoirs 30a and 30b. An auxiliary conduit 30d, comprising an internal volume 3 Id, is additionally connected to the fluid conduits that make up the primary reservoir 30’, through three-way valves 60a, 60b. In this embodiment, the reservoir 30b comprises an external container 30b which holds for example a suspension of microvesicles. The valves 60a, b may be adjusted to place the external container 30b in fluid communication with, among others, the first pumping mechanism 2, and the second pumping mechanism 3 and reservoir 30a, as well as conduits 11, 12. By activating the first pumping mechanism 2 and / or second pumping mechanism 3, the reservoir 30a, as well as conduits 11, 12 may be filled (for example) with the microvesicles held in the container 30b. The container 30b may then be bypassed by adjusting the valves to uncouple the container 30b and conduct flow through the auxiliary conduit 30d. In this application of the auxiliary conduit 30d, the reservoir 30a and part of the other fluid conduits and / or reservoirs 30c, 11, 12 are initially filled with saline, and microvesicles are mixed into the saline to form a mixture when the external container conduit 30b is placed in fluid communication with the first pumping mechanism 2 and / or second pumping mechanism 3, the reservoir 30a, as well as conduits 11, 12 as described.The first pumping mechanism 2 may be arranged to induce the varying flow rate component Fv and the loop flow rate component comprising flow components F2 and Fback. The first pumping mechanism 2 may alternatingly run in a first direction R1 and in a second, opposite direction R2 to induce the varying flow rate component. In particular, the first pumping mechanism may comprise a peristaltic pump 28 and may alternatingly run in one direction R1 and in an opposite direction R2 to induce the varying flow rate component. By rotating the pump 28 faster and / or for a longer duration in direction R1 than in direction R2, a net throughflow is induced through the pump 28, including the loop flow rate components F2 and Fback. In addition, the primary first conduit flow rate component Fl is transduced through the pump 28.It will be appreciated that the respective components and arrangements of the described embodiments are not necessarily exclusive to the respective embodiments, and may be combined to form other embodiments.Figure 12 shows a graph of a selection of flow rate components in the first fluid conduit 11. The unidirectional, primary first conduit flow rate component Fl is constant, and is provided by the second pumping mechanism 3. The bidirectional, varying flow rate component Fv is provided by the first pumping mechanism 2. In embodiments without the T-split 13 and the second fluid conduit 12, the instantaneous output flow rate Fout at the output is equal to Fl plus Fv.Figure 13 shows a graph of the total fluid volumes provided by a selection of flow rates in the first fluid conduit 11 over a period of time, for embodiments of the system 1 without the T-split 13 and second fluid conduit 12. The average flow rate of the varying flow rate component Fv is zero. The total volume of fluid provided at the outlet 10 is equal to the total volume provided by the unidirectional flow rate Fl plus the bidirectional varying flow rate Fv.It should be noted that figures 12 and 13 imply an oscillation frequency of Fv that is different from the preferred frequency described above. Similarly, the ‘Flow’ and ‘Volume to subject’ implied on the Y axis do not reflect preferred values. Thus, figures 12 and 13 merely serve to indicate the relative behavior of Fl and Fv.The present invention is not limited to the embodiment shown, but extends also to other embodiments falling within the scope of the appended claims.The present invention is further illustrated by the following embodiments:1. Fluid delivery system for providing a flow of microvesicle containing liquid to a subject, wherein the system comprises a first fluid conduit arranged to contain microvesicle containingliquid, wherein said first fluid conduit comprises an inlet arranged to receive microvesicle containing liquid at an input flow rate and an outlet arranged to provide microvesicle containing liquid at an output flow rate to said subject, wherein the system comprises a first pumping mechanism in fluid communication with the first fluid conduit arranged to induce a varying flow rate component in said first fluid conduit for at least partially preventing decantation of the microvesicles in the microvesicle containing liquid present in the first fluid conduit.2. Fluid delivery system according to embodiment 1 , wherein the first pumping mechanism is arranged to induce a cyclically varying flow rate component.3. Fluid delivery system according to embodiment 1 or 2, wherein the first pumping mechanism is arranged to induce a varying flow rate component in said first fluid conduit having an average flow rate of zero over a period of time.4. Fluid delivery system according to embodiment 1, 2 or 3, further comprising a second pumping mechanism arranged to induce an outflow flow rate component in the first fluid conduit.5. Fluid delivery system according to embodiment 4, wherein the second pumping mechanism is arranged to induce an outflow flow rate component, wherein the average of the outflow flow rate component over a period of time is equal to the average output flow rate over the period of time.6. Fluid delivery system according to embodiment 4 or 5, wherein the outflow flow rate component equals the input flow rate.7. Fluid delivery system according to any of the preceding embodiments, further comprising a primary reservoir arranged in fluid communication with the inlet of the first fluid conduit, wherein the primary reservoir comprises an internal volume that is arranged to contain liquid for supply to the first fluid conduit.8. Fluid delivery system according to at least embodiments 4 and 7, wherein the primary reservoir comprises the second pumping mechanism, wherein the second pumping mechanism is arranged to induce the outflow flow rate component of liquid from the primary reservoir to the inlet of the first fluid conduit.9. Fluid delivery system according to embodiment 8, wherein the second pumping mechanism comprises a movable member arranged to selectively increase or decrease the internal volume of the primary reservoir.10. Fluid delivery system according to any of the preceding embodiments, further comprising a fluid damper arranged in fluid communication with the first fluid conduit, upstream of the outlet, and downstream of the first pumping mechanism.11. Fluid delivery system according to any of the preceding embodiments, further comprising a fluid damper arranged in fluid communication with the first fluid conduit, downstream of the inlet, and upstream of the first pumping mechanism.12. Fluid delivery system according to any of the preceding embodiments, further comprising a valve arranged upstream to the first pumping mechanism, wherein the valve is arranged to selectively open or close to respectively open or close the fluid communication between the inlet and at least part of the first fluid conduit.13. Fluid delivery system according to embodiment 12, wherein the valve is arranged to close before or during operation of the first pumping mechanism.14. Fluid delivery system according to any of the preceding embodiments 1 - 13, wherein the first fluid conduit comprises a T-split arranged downstream of the first pumping mechanism and upstream of the outlet, wherein the system further comprises a second fluid conduit arranged for conducting fluid away from the T-split.15. Fluid delivery system according to embodiment 14, further comprising a secondary reservoir arranged in fluid communication with the second fluid conduit.16. Fluid delivery system according to embodiment 15, wherein the secondary reservoir comprises a second movable member arranged to selectively increase or decrease the internal volume of the secondary reservoir.17. Fluid delivery system according to at least embodiments 7 and 14, wherein the second fluid conduit couples to the primary reservoir and is arranged for conducting fluid away from the T-split back to said primary reservoir.18. Fluid delivery system according to any of the preceding embodiments, wherein the first pumping mechanism comprises a selectively variable volume arranged in fluid communication with the first fluid conduit, and is arranged to induce the varying flow rate component of microvesicle containing liquid by varying the volume of the variable volume at a rate corresponding to the varying flow rate component.19. Fluid delivery system according to embodiment 18, wherein the first pumping mechanism comprises a movable membrane arranged to selectively vary the variable volume.20. Fluid delivery system according to embodiment 18 or 19, wherein the selectively variable volume comprises a section of flexible tubing arranged in fluid communication with the first fluid conduit, wherein the first pumping mechanism further comprises a movable pushing member arranged to deflect at least part of the section of flexible tubing to vary the volume of the variable volume at a rate equal to the varying flow rate component.21. Fluid delivery system according to any of the preceding embodiments, wherein the first pumping mechanism is arranged in series with the first fluid conduit, and is arranged to induce the varying flow rate component of microvesicle containing liquid in the first fluid conduit by varying the flow rate of microvesicle containing liquid through the first pumping mechanism.22. Method for providing a flow of microvesicle containing liquid to a subject, comprising the steps of: providing a first fluid conduit arranged to contain microvesicle containing liquid, wherein said first fluid conduit comprises an inlet arranged to receive microvesicle containing liquid at an input flow rate and an outlet arranged to provide microvesicle containing liquid at an output flow rate to said subject; inducing a varying flow rate component in said first fluid conduit for at least partially preventing decantation of the microvesicles in the microvesicle containing liquid present in the first fluid conduit.23. Method according to embodiment 22, further comprising the step of inducing an outflow flow rate component in the first fluid conduit, wherein the average of the outflow flow rate component over a period of time is equal to the average output flow rate over the period of time.

Claims

Claims1. Fluid delivery system for providing a flow of microvesicle containing liquid to a subject, wherein the system comprises a first fluid conduit arranged to contain microvesicle containing liquid, wherein said first fluid conduit comprises an inlet arranged to receive microvesicle containing liquid at an input flow rate and an outlet arranged to provide microvesicle containing liquid at an output flow rate to said subject, wherein the system comprises a first pumping mechanism in fluid communication with the first fluid conduit arranged to induce a varying flow rate component in said first fluid conduit for at least partially preventing decantation of the microvesicles in the microvesicle containing liquid present in the first fluid conduit.

2. Fluid delivery system according to claim 1 , wherein the first pumping mechanism comprises a selectively variable volume arranged in fluid communication with the first fluid conduit, and is arranged to induce the varying flow rate component of microvesicle containing liquid by varying the volume of the variable volume at a rate corresponding to the varying flow rate component.

3. Fluid delivery system according claim 2, wherein the first pumping mechanism comprises a movable membrane arranged to selectively vary the variable volume.

4. Fluid delivery system according to claim 2 or 3, wherein the selectively variable volume comprises a section of flexible tubing arranged in fluid communication with the first fluid conduit, wherein the first pumping mechanism further comprises a movable pushing member arranged to deflect at least part of the section of flexible tubing to vary the volume of the variable volume at a rate equal to the varying flow rate component.

5. Fluid delivery system according to claim 4, wherein the first pumping mechanism comprises a peristaltic pump, wherein the two or more rollers of the peristaltic pump that deflect the tubing comprise movable pushing members.

6. Fluid delivery system according to any of the preceding claims, wherein the first pumping mechanism is arranged to induce a cyclically varying flow rate component.

7. Fluid delivery system according to any of the preceding claims, wherein the first pumping mechanism is arranged to induce a varying flow rate component in said first fluid conduit having an average flow rate of zero over a period of time.

8. Fluid delivery system according to any of the preceding claims, further comprising a second pumping mechanism arranged to induce an outflow flow rate component in the first fluid conduit.

9. Fluid delivery system according to claim 8, wherein the second pumping mechanism is arranged to induce an outflow flow rate component, wherein the average of the outflow flow rate component over a period of time is equal to the average output flow rate over the period of time.

10. Fluid delivery system according to claim 8 or 9, wherein the outflow flow rate component equals the input flow rate.

11. Fluid delivery system according to any of the preceding claims, further comprising a primary reservoir arranged in fluid communication with the inlet of the first fluid conduit, wherein the primary reservoir comprises an internal volume that is arranged to contain liquid for supply to the first fluid conduit.

12. Fluid delivery system according to at least claims 8 and 11, wherein the primary reservoir comprises the second pumping mechanism, wherein the second pumping mechanism is arranged to induce the outflow flow rate component of liquid from the primary reservoir to the inlet of the first fluid conduit.

13. Fluid delivery system according to claim 12, wherein the second pumping mechanism comprises a movable member arranged to selectively increase or decrease the internal volume of the primary reservoir.

14. Fluid delivery system according to any of the preceding claims, further comprising a fluid damper arranged in fluid communication with the first fluid conduit, upstream of the outlet, and downstream of the first pumping mechanism.

15. Fluid delivery system according to any of the preceding claims, further comprising a fluid damper arranged in fluid communication with the first fluid conduit, downstream of the inlet, and upstream of the first pumping mechanism.

16. Fluid delivery system according to any of the preceding claims, further comprising a valve arranged upstream to the first pumping mechanism, wherein the valve is arranged to selectively open or close to respectively open or close the fluid communication between the inlet and at least part of the first fluid conduit.

17. Fluid delivery system according to claim 16, wherein the valve is arranged to close before or during operation of the first pumping mechanism.

18. Fluid delivery system according to any of the preceding claims 1 - 17, wherein the first fluid conduit comprises a T-split arranged downstream of the first pumping mechanism and upstream of the outlet, wherein the system further comprises a second fluid conduit arranged for conducting fluid away from the T-split.

19. Fluid delivery system according to claim 18, further comprising a secondary reservoir arranged in fluid communication with the second fluid conduit.

20. Fluid delivery system according to claim 19, wherein the secondary reservoir comprises a second movable member arranged to selectively increase or decrease the internal volume of the secondary reservoir.

21. Fluid delivery system according to at least claims 11 and 18, wherein the second fluid conduit couples to the primary reservoir and is arranged for conducting fluid away from the T-split back to said primary reservoir.

22. Fluid delivery system according to any of the preceding claims, wherein the first pumping mechanism is arranged in series with the first fluid conduit, and is arranged to induce the varying flow rate component of microvesicle containing liquid in the first fluid conduit by varying the flow rate of microvesicle containing liquid through the first pumping mechanism.

23. Method for providing a flow of microvesicle containing liquid to a subject, comprising the steps of:providing a first fluid conduit arranged to contain microvesicle containing liquid, wherein said first fluid conduit comprises an inlet arranged to receive microvesicle containing liquid at an input flow rate and an outlet arranged to provide microvesicle containing liquid at an output flow rate to said subject; - inducing a varying flow rate component in said first fluid conduit for at least partially preventing decantation of the microvesicles in the microvesicle containing liquid present in the first fluid conduit.

24. Method according to claim 23, further comprising the step of inducing an outflow flow rate component in the first fluid conduit, wherein the average of the outflow flow rate component over a period of time is equal to the average output flow rate over the period of time.

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