Delivery devices with dosage measurement

Abstract

The present disclosure provides a device for injectable delivery of microparticles to a patient, the device being fluidly connectable to a source of an injectable medium, The delivery device includes: a receptacle connectable to receive an initial dosage of microparticles; an array of signal emitters positioned adjacent to the receptacle and configured to direct a signal at the microparticles held within the receptacle of the delivery device; an array of signal detectors positioned adjacent to the receptacle and configured to detect the signal from the array of signal emitters that has interacted with the microparticles; and, a control system connected to the array of signal detectors and configured to determine a delivered dosage of microparticles based on the detected signal. In some embodiments the delivery device further comprises one or more valves connected to be actuated by the control system, and positioned along a flow path for the injectable medium to stop the flow of microparticles once a target dosage has been delivered.

Description

DELIVERY DEVICES WITH DOSAGE MEASUREMENTCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from U.S. Provisional Patent Application No. 63 / 708,125 filed October 16, 2024, which is entitled DELIVERY DEVICES WITH DOSAGE MEASUREMENT. For purposes of the United States of America, this application claims the benefit under 35 U.S.C. §119 of U.S. Provisional Patent Application No. 63 / 708,125 filed October 16, 2024, which is hereby incorporated herein by reference for all purposes.FIELD

[0002] The present disclosure relates to devices for delivering microparticles to a patient.BACKGROUND

[0003] The following paragraphs are not an admission that anything discussed in them is prior art or part of the knowledge of persons skilled in the art.

[0004] Microparticles are employed by interventional radiologists for the selective occlusion of blood vessels in the treatment of, for example, hypervascular tumors such as leiomyoma uteri, and vascular anomalies such as vascular malformations. Such microparticles are injected into the vasculature of the tumour in a patient.

[0005] Selective internal radiation therapy (SIRT) may be used to treat primary or metastatic hepatic malignancies. In SIRT, yttrium-90 (90Y) radiolabeled microparticles are injected into a hepatic artery of a patient, preferentially localizing in the hepatic tumours due to their increased vascularization. The radioactive yttrium-90 labeled microparticles decay and deliver radiation to the surrounding tissue.

[0006] W02020082168 describes a delivery device for loading with microparticles for intravenous delivery to a patient. The device is fluidly couplable to a transport medium and a displacement medium. The device includes: a first fluid inlet fluidly couplable to the transport medium, a fluid outlet, a fluid mixer fluidly coupling the first fluid inlet to the fluid outlet. The device also includes a receptacle configured to hold microparticles, the receptacle fluidly coupled to the fluid mixer. The device further includes a second fluid inlet fluidly couplable to the displacement medium and fluidly coupled to the receptacle, the receptacle fluidly coupling the second fluid inlet to the fluid mixer.INTRODUCTION

[0007] The following introduction is intended to introduce the reader to this specification but not to define any invention. One or more inventions may reside in a combination or subcombination of the apparatus elements or method steps described below or in other parts of this document. The inventors do not waive or disclaim their rights to any invention or inventions disclosed in this specification merely by not describing such other invention or inventions in the claims.

[0008] Microparticles are injected intravenously into a patient with an injection medium, such as an aqueous intravenous solution. However, when the microparticles have a substantially higher density than the injection medium (such as glass microparticles in an aqueous solution) the microparticles may settle together making it difficult to inject the microparticles into the patient. It may be especially difficult to administer the microparticles at a slow and consistent rate.

[0009] BTG (a subsidiary of Boston Scientific) attempts to address this problem with their TheraSphere™ yttrium-90 glass microparticles product by flowing the injection medium up through the bottom of the settled microparticles to generate in the delivery device a fluidized bed of microparticles in a constant volume reservoir. Fluidized microparticles are carried along with the injection medium to the patient. Since the microparticles are significantly more dense than the injection medium, this approach may result in an injection medium with an undesirably high concentration of microparticles being delivered over a short period time.

[0010] There remains a need for improved delivery devices that, in operation, can be used to intravenously administer microparticles to a patient.

[0011] In a device that includes two parallel flow paths, where microparticles are housed in a substantially vertical receptacle located in one of the flow paths before delivery to the patient, the microparticles would act as a fluid restrictor. Applying a single fluid pressure against both the flow path with the microparticles and the flow path without the microparticles would result in fluid preferentially flowing through the flow path without the microparticles.

[0012] In devices according to the present disclosure, a flow restrictor is included in the flow path without the microparticles. The flow restrictor modulates the pressure between the two parallel flow paths to result in sufficient pressure in the flow path with the microparticles so that the microparticles are displaced into the fluid mixer at a desired rate. Devices according to the present disclosure may be fluidly connectable to a single source of injectable medium, suchas a syringe, which may apply a single fluid pressure to the device. The single source of injectable medium may provide the injectable medium to the device at a fluid pressure from about 10 to about 100 psi. The fluid pressure may be a low fluid pressure, such as from about 10 to about 30 psi; a medium fluid pressure, such as about 30 to about 80 psi, for example from about 30 to about 60 psi; or a high pressure, such as from about 80 to about 100 psi.

[0013] In one aspect, the present disclosure provides a device for loading with microparticles for injectable delivery to a patient. The device is fluidly connectable to a source of an injectable medium. The device includes a first fluid inlet fluidly connectable to the source of the injectable medium, a first fluid outlet, and a fluid mixer fluidly coupling the first fluid inlet to the first fluid outlet. The device also includes a second fluid outlet and a second fluid inlet that, when fluidly coupled together, result in the device having a displacement-medium flow path fluidly coupling the first fluid inlet to the fluid mixer. The displacement-medium flow path includes a receptacle for holding the microparticles. The device also includes a transportmedium flow path distinct from the displacement-medium flow path. The transport-medium flow path fluidly coupling the first fluid inlet to the fluid mixer. The transport-medium flow path includes a transport-medium flow restrictor upstream of the fluid mixer.

[0014] In another aspect, the present disclosure provides a device housing microparticles for injectable delivery to a patient using an injectable medium, or for loading with microparticles for injectable delivery to a patient using an injectable medium. The device includes: a fluid inlet fluidly connectable to a source of the injectable medium; two parallel fluid flow paths, each flow path is (a) fluidly connected or fluidly connectable to the fluid inlet and (b) fluidly connected or fluidly connectable to the fluid mixer; a fluid mixer fluidly connecting the first and the second fluid flow paths; and a fluid outlet downstream of the fluid mixer. The first fluid flow path includes a receptacle for holding the microparticles. The two parallel fluid flow paths are configured to flow the injectable medium at different flow rates when the injectable medium is provided at the same fluid pressure and when the device lacks microparticles in the receptacle.

[0015] In still another aspect, the present disclosure provides a device for injectable delivery of microparticles to a patient. The delivery device is fluidly connected to a source of an injectable medium. The delivery device includes: a fluid inlet fluidly connected to the source of the injectable medium; a fluid outlet; a fluid mixer fluidly coupling the fluid inlet to the fluid outlet; a displacement-medium flow path fluidly coupling the fluid inlet to the fluid mixer; anda transport-medium flow path distinct from the displacement-medium flow path, the transportmedium flow path fluidly coupling the fluid inlet to the fluid mixer. The displacement-medium flow path includes a receptacle housing the microparticles. The transport-medium flow path includes a flow restrictor upstream of the fluid mixer. During operation, the injectable medium is split between the displacement-medium flow path and the transport-medium flow path, the injectable medium flowing through the displacement-medium flow path fluidly drives microparticles from the receptacle into the fluid mixer, mixing with the injectable medium flowing from the transport-medium flow path, and delivering the microparticles to the patient via the fluid outlet.

[0016] In still another aspect, the present disclosure provides a device for injectable delivery of microparticles to a patient, the device being fluidly connectable to a source of an injectable medium. The delivery device includes: a receptacle connectable to receive an initial dosage of microparticles; an array of signal emitters positioned adjacent to the receptacle and configured to direct a signal at the microparticles held within the receptacle of the delivery device; an array of signal detectors positioned adjacent to the receptacle and configured to detect the signal from the array of signal emitters that has interacted with the microparticles; and, a control system connected to the array of signal detectors and configured to determine a delivered dosage of microparticles based on the detected signal. In some embodiments the delivery device further comprises one or more valves connected to be actuated by the control system, and positioned along a flow path for the injectable medium to stop the flow of microparticles once a target dosage has been delivered.In still another aspect, the present disclosure provides a device for injectable delivery of microparticles to a patient, the device being fluidly connectable to a source of an injectable medium. The delivery device includes: a receptacle connectable to receive an initial dosage of microparticles; an array of signal emitters positioned adjacent to the receptacle and configured to direct a signal at the microparticles held within the receptacle of the delivery device; an array of signal detectors positioned adjacent to the receptacle and configured to detect the signal from the array of signal emitters that has interacted with the microparticles; an outflow sensor comprising a signal sensing pair or an array of signal emitters and signal detectors positioned adjacent to a portion of an outlet flow path; and, a control system connected to the array of signal detectors positioned adjacent to the receptacle and configured to determine a delivered dosage of microparticles based on the detected signal, wherein the control system isfurther connected to the signal detectors of the signal sensing pair or array of signal detectors positioned adjacent to the portion of the outlet flow path and configured to detect the presence of microparticles based on the attenuation of a detected signal. In some embodiments the delivery device further comprises one or more valves connected to be actuated by the control system, and positioned along a flow path for the injectable medium to stop the flow of microparticles once a target dosage has been delivered.BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0017] Examples according to the present disclosure will now be described, by way of example only, with reference to the attached Figures. To easily identify the discussion of any particular element or act, the most significant digit or digits in a reference number refer to the figure number in which that element is first introduced.

[0018] FIG. 1 is an illustration of an exemplary device according to the present disclosure.

[0019] FIG. 2 is a cross-sectional illustration of an exemplary flow restrictor according to the present disclosure.

[0020] FIG. 3 is a cross-sectional illustration of an exemplary unitary combination of a flow restrictor and fluid mixer according to the present disclosure.

[0021] FIG. 4A is an illustration of an exemplary device according to the present disclosure.

[0022] FIG. 4B is an illustration of a three-quarter view of the exemplary device illustrated in FIG. 4A.

[0023] FIGs. 5, 5A, 5B, and 5C are illustrations of exemplary delivery devices having a dosage measurement system according to the present disclosure.

[0024] FIG. 6 shows a portion of a prototype embodiment of a delivery device having a dosage measurement system according to the present disclosure.

[0025] FIGs. 6A, 6B and 6C show additional details of the prototype embodiment of FIG. 6.

[0026] FIGs. 7, 7A, 7B and 7C show additional views of the prototype embodiment of FIG. 6.

[0027] FIG. 8 shows an example graphical user interface for a delivery device having a dosage measurement system according to the present disclosure.

[0028] FIG. 9 is an illustration of an exemplary delivery device having a dosage measurement system and a multi-catheter manifold according to the present disclosure.

[0029] FIG. 10 is an illustration of another exemplary delivery device having a dosage measurement system according to the present disclosureGLOSSARY OF VARIOUS TERMS

[0030] A "flow path" refers to the route through which a fluid moves, such as from one location in the device to another location in the device. For example, a device may include a flow path from an inlet to an outlet; or a flow path from a fluid splitter to a fluid mixer. One flow path may be a part of another flow path, for example a flow path from an inlet to an outlet may also include a flow path from a fluid splitter to a fluid mixer. A flow path may be defined by the component or components that allow the fluid to flow therethrough, such as tubing, receptacles, fluid mixers, microparticle traps, and / or flow-rate reducers.

[0031] " Downstream" refers to a relative position in a flow path based on the direction that the injectable medium flows during operation of the device. In a flow path with two components, the downstream component is closer to the outlet of the device. "Upstream" refers to a relative position in a flow path based on the direction that the injectable medium flows during operation of the device. In a flow path with two components, the upstream component is closer to the inlet of the device.

[0032] " Fluid splitter" refers to component or combination of components that allow a fluid in one flow path to flow into two or more different flow paths. For example, a fluid splitter may be a 3-way connector, such as a Y-set connector, where fluid flowing into the trunk of the Y is split into two flow paths flowing out of the branches of the Y.

[0033] "Fluidly coupling" or “fluidly connecting” refers to joining two other components in fluid communication. The specification may state that a component or combination of components “fluidly couples” or "fluidly connects" the other components. Two components that are capable of being joined in fluid communication may be referred to as “fluidly couplable” or “fluidly connectable”.

[0034] "Injectable medium" refers to a liquid suitable for injection into a patient. The liquid may be an intravenous solution, such as a saline solution or a medical contrast having an osmolality less than or equal to 350 mgl / mL.

[0035] "Loading fluid" refers to a liquid suitable for filling the device before microparticles are loaded therein. The loading fluid may be the same fluid as the injectable medium.

[0036] In the context of the present disclosure, the term “microparticle” refers to a particle that has a diameter that is less than 1200 pm and that has a density greater than the density of the injectable medium. For a mixture of particles, the mixture has an average diameter for all microparticles that is less than 1200 pm. In some examples, the average diameter may be less than 600 pm. In particular examples, a mixture of microparticles may have an average diameter of all microparticles that is from about 25 pm to about 150 pm.

[0037] "Receptacle" refers to a component or combination of components sized and shaped to house the microparticles when the microparticles are loaded into the device and the device is in a delivery orientation. The receptacle may be, for example, an elongate housing such as tubing. The receptacle may include an elongate housing having an inner diameter that is about 5 to 110 times larger than the average diameter of the microparticles.

[0038] In the context of the present disclosure, a "microparticle trap" refers to a component or combination of components that prevent the microparticles from entering the fluid mixer when no external fluid pressure is being applied to the device and the device is positioned in a delivery orientation. The microparticle trap may include a bend in the flow path, such as a bend that is from about 90° to about 180°. The microparticle trap may form a portion of the receptacle.

[0039] "Unitary" refers to two or more components of the device being part of a single, undivided unit, such as being made as a single piece during manufacturing.

[0040] In the context of the present disclosure, a "flow restrictor" refers to a component or combination of components that hinders the flow of a fluid medium passing through the component or combination of components. Hindering the flow of a fluid generates an upstream static pressure that is higher than the static pressure in the flow restrictor. A flow path that includes a flow restrictor may divert a portion of fluid away from the flow path.

[0041] Examples of a flow restrictor include: a portion of the flow path having a smaller inner diameter than the portion of the flow path immediately upstream of the flow restrictor; one or more obstructions to the fluid flowing through the flow path, such as a filter or a torturous flow path; or a portion of the flow path that induces turbulent flow, such as a portion of the flow path with rough sidewalls.

[0042] In the context of the present disclosure, a “fluid mixer” should be understood to refer to any combination of components that mixes the injectable mediums flowing from two or more flow paths to the fluid outlet. In some embodiments, a fluid mixer may be a 3-wayconnector, such as a T-connector, where fluid flows from two flow paths into the two arms of the T, and is dispensed as a mixture from the trunk of the T. In some embodiments, a fluid mixer may comprise a 4-way connector, where fluid flows from three flow paths into the fluid mixer, and a mixture of the three fluid flows is dispensed toward the fluid outlet.

[0043] In the context of the present disclosure, “dilution point” refers to an area where fluids from two (or more) flow paths mix together (e.g. in a fluid mixer), and past which the mixture of fluids will be dispensed to the outlet.

[0044] In the context of the present disclosure, "parallel" flow paths refers to flow paths where incoming fluid is split and travels down separate flow paths. Fluid flowing in one fluid flow path would not later flow through the other parallel fluid flow path or paths. In parallel flow paths, with all other conditions being equal, restricting the flow of fluid through one of the parallel flow paths results in the fluid preferentially flowing through the other parallel flow path or flow paths. For example, in otherwise identical flow paths, adding a flow restrictor to one path may result in fluid flowing through the unrestricted flow path at a rate that is greater than the rate of the fluid flowing through the restricted flow path.DETAILED DESCRIPTION

[0045] In one aspect, the present disclosure provides a device (A) housing microparticles for injectable delivery to a patient using an injectable medium, or (B) for loading with microparticles for injectable delivery to a patient using an injectable medium. The device includes: a fluid inlet fluidly connectable to a source of the injectable medium; two parallel fluid flow paths, each flow path being (a) fluidly connected or fluidly connectable to the fluid inlet and (b) fluidly connected or fluidly connectable to the fluid mixer; a fluid mixer fluidly connecting the first and the second fluid flow paths; and a fluid outlet downstream of the fluid mixer.

[0046] The first fluid flow path includes a receptacle for holding the microparticles. The two parallel fluid flow paths are configured to flow the injectable medium at different flow rates when the injectable medium is provided at the same fluid pressure and when the device lacks microparticles in the receptacle.

[0047] In some examples, the receptacle may be sized to hold about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1 gram, about 1.1 grams, about 1.2 grams, about1.3 grams, about 1.4 grams, about 1.5 grams, about 2 grams, about 3 grams, about 4 grams, about 5 grams, about 6 grams, about 7 grams, about 8 grams, about 9 grams, or about 10 g of the microparticles before any of the microparticles are delivered to the patient. In some examples, the receptacle may hold from about 50 mg to about 200 mg of the microparticles before any of the microparticles are delivered to the patient. In other examples, the receptacle may hold from about 200 mg to about 500 mg, about 500 mg to about 1000 mg, or about 1000 mg to about 2000 mg of the microparticles before any of the microparticles are delivered to the patient.

[0048] In another aspect, the present disclosure provides a device for loading with microparticles for injectable delivery to a patient. The device is fluidly connectable to a source of an injectable medium. The device includes a first fluid inlet fluidly connectable to the source of the injectable medium, a first fluid outlet, and a fluid mixer fluidly coupling the first fluid inlet to the first fluid outlet. The device also includes a second fluid outlet and a second fluid inlet that is fluidly couplable to the second fluid outlet. When fluidly coupled together, the second fluid outlet and the second fluid inlet result in the device having a displacementmedium flow path that fluidly connects the first fluid inlet to the fluid mixer. The displacement-medium flow path includes a receptacle for holding the microparticles. The device also includes a transport-medium flow path distinct from the displacement-medium flow path. The transport-medium flow path fluidly coupling the first fluid inlet to the fluid mixer. The transport-medium flow path includes a transport-medium flow restrictor upstream of the fluid mixer.

[0049] In the context of the present disclosure, "displacement medium" refers to the portion of the injectable medium flowing through the flow path that includes, or is configured to include, the microparticles. In operation, when a device according to the present disclosure includes microparticles, the displacement medium helps move microparticles from the receptacle to the fluid mixer, where it is mixed with transport medium and delivered to the patient via the outlet. A "displacement-medium flow path" refers to the fluid flow path for the displacement medium.

[0050] In the context of the present disclosure, "transport medium" refers to the portion of the injectable medium flowing through the flow path that lacks the microparticles. In operation, when a device according to the present disclosure includes microparticles, displacement medium carrying microparticles from the receptacle is mixed with the transport medium in the fluid mixer, and the resulting combination is delivered to the patient via the outlet.

[0051] A "transport-medium flow path" refers to a fluid flow path for the transport medium. A "transport-medium" flow restrictor refers to a flow restrictor positioned in the transport medium flow path.

[0052] The first fluid flow path discussed above may be referred to as the displacementmedium flow path. The second fluid flow path discussed above may be referred to as the transport-medium flow path. It should be understood that features discussed below with respect to the transport-medium flow path, such as the transport-medium flow restrictor, are equally applicable to the second fluid flow path of the device above. Similarly, it should be understood that features discussed below with respect to the displacement-medium flow path, such as the displacement-medium flow restrictor, are equally applicable to the first fluid flow path of the device above.

[0053] The transport-medium flow restrictor may include a restricting passage that has an inner diameter that is about 20% to about 30% of the inner diameter of the flow path immediately upstream of the flow restrictor.

[0054] The transport-medium flow restrictor may include a restricting passage having an inner diameter that is from about 0.012 inches to about 0.018 inches when the microparticles have an average diameter from about 25 pm to about 150 pm. For example, the inner diameter may be about 0.015 inches when the microparticles have an average diameter of about 29 pm; the inner diameter may be about 0.013 inches when the microparticles have an average diameter of about 51 pm; the inner diameter may be about 0.015 inches when the microparticles have an average diameter of about 104 pm; or the inner diameter may be about 0.017 inches when the microparticles have an average diameter of about 145 pm. Microparticles with an average diameter from about 28 to about 30 pm may be used to treat or visualize a hepatocellular carcinoma, such as by delivery of radioactive microparticles or radiopaque microparticles, respectively. Microparticles with an average diameter from about 150 to about 300 pm may be used for middle meningeal artery embolization, such as to treat a chronic subdural hematoma.

[0055] The device may also include a microparticle trap fluidly connecting the receptacle to the fluid mixer. For example, the microparticle trap may include a bend in the tubing that makes up the displacement-medium flow path. The bend may be from about 90° to about 180°.

[0056] The displacement-medium flow path may also include a displacement medium flow restrictor downstream of the receptacle and upstream of the fluid mixer. When the device includes a microparticle trap, the displacement medium flow restrictor is downstream of themicroparticle trap. The magnitude of the flow restriction caused by the displacement medium flow restrictor may be selected to be less than the magnitude of the flow restriction caused by the transport medium flow restrictor. In such a device, when the device lacks microparticles and when the injectable medium is provided at the same fluid pressure, the flow rate through the displacement-medium flow path is greater than the flow rate through the transport-medium flow path.

[0057] As microparticles are delivered from a device according to the present disclosure, and the number of microparticles in the receptacle falls, the magnitude of the flow restriction caused by the microparticles is reduced.

[0058] In a device according to the present disclosure that has a flow rate through the displacement-medium flow path that is greater than the flow rate through the transport-medium flow path when the device lacks microparticles and when the injectable medium is provided at the same fluid pressure, as the number of microparticles approaches zero, the greater flow rate through the displacement-medium flow path helps displace the remaining microparticles into the mixer and out of the device.

[0059] The displacement medium flow restrictor may include a restricting passage having an inner diameter that is about 40% to about 80% of the inner diameter of the displacementmedium flow path immediately upstream of the flow restrictor.

[0060] The displacement medium flow restrictor may include a restricting passage having an inner diameter that is from about 0.027 inches to about 0.043 inches when the microparticles have an average diameter from about 25 pm to about 150 pm. For example the inner diameter may be about 0.030 inches when the microparticles have an average diameter of about 29 pm; the inner diameter may be about 0.029 inches when the microparticles have an average diameter of about 51 pm; the inner diameter may be about 0.030 inches when the microparticles have an average diameter of about 104 pm; or the inner diameter may be about 0.030 or about 0.041 inches when the microparticles have an average diameter of about 145 pm.

[0061] The displacement medium flow restrictor and the transport-medium flow restrictor may both include restricting passages, and the ratio of the cross-sectional area of the displacement medium flow restrictor to the cross-sectional area of the transport-medium flow restrictor may be from about 3 : 1 to about 7: 1.

[0062] Different combinations of microparticle sizes, receptacle dimensions, flow path dimensions and flow restrictors can provide different flow restrictions through the different flow paths and can result in the microparticles being deliverable at different average concentrations. For example, all other conditions being kept constant:• increasing the transport medium flow path restrictor diameter results in delivery at a lower average concentration;• decreasing the transport medium flow path restrictor diameter results in delivery at a higher average concentration;• increasing the displacement medium flow path restrictor diameter results in delivery at a higher average concentration;• decreasing the displacement medium flow path restrictor diameter results in delivery at a lower average concentration;• increasing the average microparticle diameter results in delivery at a higher average concentration;• decreasing the average microparticle diameter results in delivery at a lower average concentration;• increasing the receptacle diameter results in delivery at a higher average concentration;• decreasing the receptacle diameter results in delivery at a lower average concentration;• increasing the volume of microparticles within the receptacle results in delivery at a lower average concentration; and• decreasing the volume of microparticles within the receptacle results in delivery at a higher average concentration.

[0063] The second fluid outlet may be fluidly couplable to the second fluid inlet via a microparticle-supply conduit engageable with the device. The microparticle-supply conduit may include: an inlet fluidly couplable to the second fluid outlet of the device, an outlet fluidly couplable to the second fluid inlet of the device, a valve between the inlet and the outlet, and a primary container for holding the microparticles. The primary container is in fluid communication with one port of the valve. The valve may be a 3 -way valve.

[0064] The microparticles may be housed in the primary container during transportation, and the microparticle-supply circuit may be provided separately from a device according to the present disclosure. The microparticle-supply conduit may be used to load the microparticles into the device, such as before the device is used to deliver the microparticles to the patient.The inlet and the outlet of the microparticle-supply conduit may be fluidly connected to the second fluid outlet and the second fluid inlet, respectively, and the microparticles housed in the primary container may be allowed to flow down into the receptacle by positioning the device in a loading orientation. The loading orientation of the device may be an angle of about 15° to about 20° off vertical. The microparticles may be prompted to flow into the receptacle by injecting an amount of fluid into the primary container.

[0065] The device may also include a loading fluid inlet upstream of the transport-medium flow path and the displacement-medium flow path. The loading fluid inlet may be in fluid communication with the first fluid inlet. The loading fluid inlet allows for fluid, such as injectable medium, to be drawn into a syringe that is fluidly coupled to the fluid inlet of the device. The loading fluid drawn into the syringe may be used to prime the device before the microparticles are loaded into the receptacle.

[0066] The displacement-medium flow path may be parallel to the transport-medium flow path.

[0067] It should be understood that features discussed above with respect to the transportmedium flow path, such as the transport-medium flow restrictor, are equally applicable to the transport-medium flow path of the device below. Similarly, it should be understood that features discussed above with respect to the displacement-medium flow path, such as the displacement-medium flow restrictor, are equally applicable to the displacement-medium flow path of the device below.

[0068] In still another aspect, the present disclosure provides a device for injectable delivery of microparticles to a patient. In this aspect, the delivery device is set up for delivery of the microparticles out of the device, such as to the patient. The delivery device is fluidly connected to a source of an injectable medium. The delivery device includes: a fluid inlet fluidly connected to the source of the injectable medium; a fluid outlet; a fluid mixer fluidly coupling the fluid inlet to the fluid outlet; a displacement-medium flow path fluidly coupling the fluid inlet to the fluid mixer; and a transport-medium flow path distinct from the displacementmedium flow path, the transport-medium flow path fluidly coupling the fluid inlet to the fluid mixer. The displacement-medium flow path includes a receptacle housing the microparticles. The transport-medium flow path includes a flow restrictor upstream of the fluid mixer. During operation, the injectable medium is split between the displacement-medium flow path and the transport-medium flow path, the injectable medium flowing through the displacement-mediumflow path fluidly drives microparticles from the receptacle into the fluid mixer, mixing with the injectable medium flowing from the transport-medium flow path, and delivering the microparticles to the patient via the fluid outlet.

[0069] Specific combinations (Examples 1 to 6) of different features disclosed above are shown in Tables 1 to 3. Examples 1 to 6 of Tables 1 to 3 relate to six specific devices.

[0070] Table 1 - Microparticle sizes and microparticle receptacle

[0071] Table 2 - Displacement-medium flow path

[0072] Table 3 - Transport-medium flow path

[0073] One particular example of a device according to the present disclosure is illustrated in FIG. 1. Device 100 is fluidly connected to a source of injectable medium 102, illustrated as a syringe, via first fluid inlet 104. The device 100 also includes a first fluid outlet 106. The fluid inlet 104 and the fluid outlet 106 are fluidly coupled by a fluid mixer 108, with an outlet flow path 107 leading from the fluid mixer 108 to the fluid outlet 106. The device 100 also includes a second fluid outlet 110 and a second fluid inlet 112. Inlet 110 and outlet 112 are fluidly connectable through a microparticle-supply conduit (not shown). When inlet 110 and outlet 112 are fluidly connected, such as by a microparticle-supply circuit (not shown), the device 100 includes a displacement-medium flow path 114. When inlet 110 and outlet 112 are not fluidly connected, the device 100 may be considered to have a flow path that is (a) fluidly connectable to the fluid inlet and (b) fluidly connectable to the fluid mixer.

[0074] The device 100 also includes a fluid splitter 116, which splits the incoming fluid between the displacement-medium flow path 114 and a transport-medium flow path 118. The transport-medium flow path 118 includes a transport-medium flow restrictor 120. The displacement-medium flow path 114 includes a receptacle 122 for housing the microparticles, a displacement-medium flow restrictor 124, and a microparticle trap 126. The flow restrictor 124 is located in one arm of the fluid mixer 108, and is unitary with the mixer 108. The device 100 also includes a loading fluid inlet 128, which is in fluid communication with the source of injectable medium 102.

[0075] During operation, inlet 110 and outlet 112 are fluidly connected and receptacle 122 houses the microparticles. Injectable medium from 102 is injected into the inlet 104 by the syringe and flows into the fluid splitter 116. The injectable medium is split between the displacement-medium flow path 114 and the transport-medium flow path 118. Injectable medium flowing through the displacement-medium flow path 114 moves microparticles towards the fluid mixer 108. Injectable medium flowing through the transport-medium flow path 118 mixes with the displacement medium and the microparticles from the flow path 114.The resulting mixture travels from the fluid mixer 108 and out of the device via the outlet flow path 107 to the fluid outlet 106.

[0076] Microparticles in the receptacle 112 may act as a fluid flow restrictor. In a device without the transport-medium flow restrictor 120, a sufficient number of microparticles packed into the receptacle 122 may result in sufficient flow restriction in the flow path 114 that fluid preferentially travels through the transport-medium flow path 118 and no microparticles are delivered from the device. The transport-medium flow restrictor 120 rebalances the relative fluid pressures between the two flow paths 114 and 118, which allows the displacement medium to move microparticles towards the fluid mixer 108.

[0077] An illustration of an exemplary transport-medium flow restrictor 120 is illustrated in FIG. 2. The flow restrictor 120 includes a fluid inlet 202, a fluid outlet 204, and a constricting passage 206.

[0078] An illustration of an exemplary unitary combination of flow restrictor 124 and flow mixer 108 is illustrated in FIG. 3. The combination 300 is illustrated as a T-connector, with a first inlet arm 302 fluidly connecting to the transport-medium flow path 118, and a second inlet arm 304 fluidly connecting to the displacement-medium flow path 114. The combination 300 includes a constricting passage 306. Injectable medium from the two flow paths, 114 and 118, mix and travel out the outlet arm 308.

[0079] Another particular example of a device according to the present disclosure is illustrated in FIG. 4A. The device of FIG. 4A is illustrated in three-quarter view in FIG. 4B. Device 400 is fluidly connectable to a source of injectable medium (not shown) via a first fluid inlet 104. The device 400 also includes a first fluid outlet 106 and a fluid mixer 108. The device 400 also includes a fluid splitter 116 (not shown in FIG. 4A but visible in FIG. 4B). The fluid splitter 116 splits the incoming fluid between a displacement-medium flow path 114 and a transport-medium flow path 118.

[0080] The transport-medium flow path 118 includes a transport-medium flow restrictor 120. The transport-medium flow path 118 fluidly connects the first fluid inlet 104 to the fluid mixer 108.

[0081] The displacement-medium flow path 114 includes a receptacle 122, a displacementmedium flow restrictor 124, and a microparticle trap 126. The device 400 includes a 3-way valve 402 in the displacement-medium flow path 114. The 3-way valve 402 allows microparticles to be loaded into the receptacle 122 via a fluid inlet 404. The 3-way valve 402allows the displacement-medium flow path 114 to fluidly connect the first fluid inlet 104 to the fluid mixer 108 when the valve is in an operating position.

[0082] During operation, the receptacle 122 houses the microparticles. Injectable medium is injected into the first fluid inlet 104 and is split by the fluid splitter 116 between the displacement-medium flow path 114 and the transport-medium flow path 118. Injectable medium flowing through the displacement-medium flow path 114 travels through the 3-way valve 402, into the receptacle 122, and moves microparticles towards the fluid mixer 108. Injectable medium flowing through the transport-medium flow path 118 mixes with the displacement medium and the microparticles from the flow path 114. The resulting mixture travels from the fluid mixer 108 and out of the device via the first fluid outlet 106.

[0083] Microparticles in the receptacle 112 may act as a fluid flow restrictor. In a device without the transport-medium flow restrictor 120, a sufficient number of microparticles packed into the receptacle 122 may result in sufficient flow restriction in the flow path 114 that fluid preferentially travels through the transport-medium flow path 118 and no microparticles are delivered from the device. The transport-medium flow restrictor 120 rebalances the relative fluid pressures between the two flow paths 114 and 118, which allows the displacement medium to move microparticles towards the fluid mixer 108.

[0084] Examples

[0085] The specific combinations of features identified in Example 1 were tested using 600 mg of microparticles with an average size of 29 pm. Example 2 was tested using 200 mg of microparticles with an average size of 29 pm. Example 3 was tested using 1250 mg of microparticles with an average size of 51 pm. Example 4 was tested using 1250 mg of microparticles with an average size of 104 pm. Example 5 was tested using 1250 mg of microparticles with an average size of 145 pm. Examples 1-5 were tested using 0.9% saline solution as the injectable medium. The results are shown in Table 4. Examples 1 and 2 were tested using the device illustrated in FIG. 4A and FIG. 4B. Examples 3, 4 and 5 were tested using the device illustrated in FIG. 1 using saline delivered at a constant rate of 20 mL / min.

[0086] Table 4

[0087] Multiple Dose Delivery

[0088] In some situations, it may be desirable to deliver microparticles to multiple targets within a patient. Traditional existing methods for multi-target treatment requires multiple delivery devices to inject precise amounts of radiation to each target, and it would be difficult or impossible for a user to ensure the required level of precision by, e.g. stopping and starting motion of a syringe. The present disclosure provides delivery devices with integrated dosage measurement systems, which allow for splitting the microparticles of an initial dosage loaded in a single delivery device into a plurality of target doses which can be delivered in precise amounts, so that a single delivery device can be used to target multiple tumours / segments. In some embodiments, the delivery device comprises one or more automated valves (such as for example pinch valves) that are controlled to stop delivery of microparticles one a target dosage has been delivered. For example, if a treatment regime calls for 2 GBq to be delivered to a first target, 1.5 GBq to be delivered to a second target, and 2.5 GBq to a third target, a delivery device with a dosage measurement system according to the present disclosure could be loaded with microparticles having an overall dosage of 6 GBq, and operated to deliver the required portions of the microparticles to each target, as described further below.

[0089] One particular example of a device according to the present disclosure is illustrated in FIG. 5. The device shown in FIG. 5 comprises all of the same or similar features of device 100 illustrated in FIG. 1, which will not be described again to avoid repetition. The device of FIG. 5 further includes a dosage measurement system 500 comprising an array of signal emitters 502 and an array of signal detectors 504 arranged adjacent to the receptacle 122, and a control system 510 connected to drive the signal emitters 502 and configured to determine a delivered dosage of microparticles based on signals from the signal detectors 504, as described further below. As one of skill in the art will appreciate, the dosage measurement system 500 shown in FIG. 5 could also be incorporated into other types of delivery devices. For example, a dosage measurement system of the type shown in FIG. 5, or the other embodiments discussed below,could also be incorporated into the device 400 illustrated in FIG. 4A and FIG. 4B, or in other delivery devices.

[0090] The control system 510 is connected to the array of signal emitters 502 and the array of signal detectors 504 and configured to monitor a volume of microparticles within the receptacle 122 in real time as the microparticles are being delivered to a target location by measuring the intensity of light that has interacted with microparticles held in the receptacle 122. In some embodiments, at least a portion of the wall of the receptacle 122 is transparent along at least a substantial length of the receptacle 122, and the signal emitters 502 and signal detectors 504 are arranged along the length of the receptacle 122 and along the length of at least a substantial portion of the fluid mixer 108 (e.g. up until at least the outlet of the fluid mixer 108). In some embodiments, in addition to the signal emitters 502 and signal detectors 504 adjacent to the receptacle 122, the dosage management system also comprises an outflow sensor configured to detect the presence of microparticles flowing through the outlet flow path 107 leading out of the fluid mixer 108. In some such embodiments, the signal emitters 502 and signal detectors 504 are only along the straight (vertical) portion of the receptacle 122, and the control system 510 is configured to determine the location of the trailing edge of the column of microparticles in the receptacle 122 based on the signals from the signal detectors 504, and to determine a time at which the leading edge of the column of microparticles passes the outflow sensor and record the location of the trailing edge at that time to determine a starting volume when a dose starts being delivered, and monitor the trailing edge to determine when the correct dosage has been delivered, as discussed further below. The outflow sensor may, for example comprise one or more signal emitters and one or more signal detectors (not shown in FIG. 5, see FIG. 5C and FIG. 9) positioned adjacent to the outlet of the fluid mixer 108, as discussed further below.

[0091] The signal intensity measurements by the signal detectors 504 may be taken at regular intervals of time or continuously. The signal emitters 502 may emit a signal in intermittent pulses, or continuously, while the device is in operation. In some embodiments, the signals are emitted simultaneously by all of the signal emitters 502. In some embodiments, the signals are emitted by groups of one or more signal emitters 502 along the length of the receptacle 122 and at least a portion of the fluid mixer 108, as described further below with reference to FIGs 6B and 6C. The groups of one or more signal emitters 502 may be activated selectively or sequentially. In some embodiments, the signal emitters 502 comprise light emitters, such as forexample infrared LEDs, and the signal detectors comprise light detectors, such as for example photodiodes. In other embodiments, the signal emitters 502 may comprise other types of electromagnetic radiation emitters such as sources of visible light, ultraviolet light, or X-rays (although as one skilled in the art will appreciate, if the signal emitters 502 are configured to emit visible light, the signal detectors 504 would need to be shielded from ambient light). In some embodiments, the control system 510 is configured to sample the signal detectors 504 at a frequency of at least 10 Hz. In some embodiments, the control system 510 is configured to drive the signal emitters 502 to emit a signal at a frequency of at least 60 Hz.

[0092] In the illustrated embodiment of FIG. 5, the dosage measurement system 500 also includes an automated valve 512 coupled to the transport-medium flow path 118, and another automated valve 514 on the displacement-medium flow path 114 connected to be actuated by the control system 510. The valves 512, 514 are configured to, when closed, shut off fluid communication through the flow paths 118, 114 and thereby stop flow of injectable medium containing microparticles through the first fluid outlet 106. In some embodiments, the control system 510 is configured to automatically close the valves 512, 514 after a delivered dosage has reached to a target dose. FIG. 5 A shows another embodiment wherein the dosage measurement system 500A only includes an automated valve 514 on the displacement-medium flow path 114, and omits the automated valve 512 on the transport-medium flow path 118. FIG. 5B shows another embodiment wherein the dosage measurement system 500B includes another automated valve 516 on the outlet flow path 107 leading from the fluid mixer 108 to the first fluid outlet 106. In some embodiments, valve(s) 512, 514 and / or 516 may comprise a pinch valve configured to pinch a flexible tubing containing the flow of microparticles contained in injectable medium (as opposed to a valve wherein the fluid flows through the valve body itself), such that there is no possibility of microparticles getting caught in internal features of the valve. In other embodiments, all automated valves may be omitted, and the control system may comprise a display device configured to display the delivered dosage to an operator of the delivery device and / or to transmit the delivered dosage to another device (e.g. a personal computer, a smartphone, a tablet, or other computing device). For example, FIG. 5C shows another embodiment wherein the dosage measurement system 500C does not include any automated valves. In the FIG. 5C embodiment, the dosage measurement system 500C also comprises an outflow sensor configured to detect the presence of microparticles flowing through the outlet flow path 107 leading out of the fluid mixer 108, and the controller 510 isconfigured to determine the position of the trailing edge of the column of microparticles at the time when the leading edge of the column of microparticles is detected by the outflow sensor. In the illustrated example, the outflow sensor comprises a signal emitter 503 and a signal detector 505 positioned adjacent to the outlet flow path 107. In some embodiments, the signal emitter 503 and signal detector 505 of the outflow sensor may be provided in the form of an inline optical flow sensor, such as for example an OPB350 series liquid sensor manufactured by TT Electronics.

[0093] FIG. 6 shows a portion of a prototype device 600 that includes a dosage measurement system according to an example embodiment of the present disclosure. Device 600 comprises a cartridge 610 configured to hold tubing and other elements forming the receptacle 122, fluid mixer 108 and portions of flow paths 114 and 118, as well as a portion of the tubing leading to the first fluid outlet 106. In the example of the prototype device shown in FIG. 6, the signal emitters 502 emit infrared light (a filter was utilized to take the photograph from which FIG. 6 is derived such that the infrared light is depicted as a visible light for demonstration purposes), while a volume of injectable medium containing microparticles is held in the receptacle 122, and the control system is configured to detect a top 122-T and bottom 122-B of a column of microparticles within the receptacle 122 based on light detected by the signal detectors 504. The positions of the microparticle column top 122-T and bottom 122-B are then used to determine a volume of microparticles remaining within the receptacle, and from that, a delivered dosage of microparticles that has already been administered to the patient.

[0094] With reference to FIGs. 6A-6C and additional views of the prototype device 600 shown in FIGs 7-7C, in an example embodiment, the signal emitters 502 and signal detectors 504 are mounted on a printed circuit board assembly (PCBA) 506, and held within an optical baffle 508 configured to hold the signal emitters 502 and signal detectors 504 (which are in the form of infrared LEDs and photodetectors in some embodiments) in precise positions in relation to the receptacle 122 when the PCBA 506 is installed on the cartridge 610. In some embodiments, the emitters 502 and detectors 504 are arranged in a plurality of sensing pairs, with one emitter 502 and one detector 504 in each pair, and the exact geometry of the sensing pairs and optical baffle 508 varies based on their position along the length of the receptacle. In the illustrated example, the signal emitters 502 direct infrared light at the receptacle 122 holding a volume of injectable medium with microparticles (not shown), and the infrared light is reflecting off of the microparticles in the injectable medium back towards the signaldetectors 504, as indicated by the dotted arrows in FIG. 6A, but in other embodiments the signal emitters 502 and signal detectors 504 can be differently arranged. For example, in some embodiments, the signal emitter 502 and signal detector 504 of each sensing pair are located on opposite sides of the receptacle 122, and configured such that the presence of microparticles in the receptacle 122 blocks the signal, such that a lower strength signal is detected when microparticles are present.

[0095] In a prototype embodiment, the emitters 502 and detectors 504 comprise 48 LED / PD sensing pairs positioned adjacent to the receptacle each positioned to illuminate a segment of the receptacle and to capture the reflected light. The signal from each sensing pair, which is proportional to the reflected light intensity, is amplified and converted to a digital value for software processing by an Analog-to-Digital Converter (ADC). Each sensor pair is individually calibrated with offset and full scale values. In a reflective arrangement as illustrated in FIG. 6A, the offset calibration represents the signal with a water-filled column as a baseline 0% value and is subtracted from all readings. The full scale value represents the signal when the sensing pair’s segment of the column is entirely filled with microparticles and is used as the 100% value in the signal processing step. Alternatively, in a transmissive arrangement with emitters and detectors arranged on opposite sides of the receptacle, the signal from a water-filled column is used to determine the 100% calibration value, and the signal from a microsphere-filled column is used to determine the 0% calibration value. In total there are thus 96 calibration parameters in the prototype embodiment: an offset and full scale value for each sensing pair. In some embodiments, the offset and full scale calibration values are initially determined with reference columns (i.e., full of water for the offset value, or full of microparticles for the full scale value in reflective arrangements), and are stored in non-volatile memory in the control system 510. In some embodiments, before each microsphere delivery operation, the control system 510 is re-calibrated by first updating the offset calibration value after the column is fully primed but before microparticles have been loaded, and then once the microsphere dose has been added to the column and it is fully settled, the full scale value is updated to match the current reading for sensing pairs which are believed to be filled with microparticles. The sensing pairs which are not known to be filled with microparticles have their full scale calibration values adjusted based on the average change in the known-filled sensing pairs. This process effectively re-calibrates each sensing pair to correctly read between 10 and 100% signal as the adjacent portion of the receptacle 122 transitions from empty to full to maximize system accuracy.

[0096] In some embodiments, the control system 510 is configured to operate the emitters 502 and detectors 504 in three repeated steps: Data Collection, where a signal level is captured for each LED / Photodiode pair; Rough Edge Finding, where an initial column edge position is determined using a signal thresholding scheme; and then Fine Edge Finding, where a more precise edge location is calculated based on exact signal level from one or more sensing pairs determined in the Rough Edge Finding step.

[0097] In the Data Collection step, in order to reduce interference from adjacent sensing pairs, in some embodiments data collection occurs in 4 phases within which every 4th sensing pair is activated (LED on, PD signal collected) with the others inactive (LED off, PD signal ignored). The 4 phases are incremented through in a single data collection step, activating each sensing pair once. Powerline noise is reduced by integrating the signal received over the duration of a powerline cycle (16.6ms in 60Hz regions), so each of the 4 phases lasts for this duration. In some embodiments, data collection occurs in 2 phases where first one pair near the column edge is activated, then the next pair higher in the column. These sampling pairs are selected at the start of each data collection cycle based on where the column edge is currently measured to be. The selected pairs either stay the same, or increment up or down in single increments each data collection period to track the column edge. In each phase only the single signal emitter (LED) which is part of the active pair is illuminated. Once signal levels have been captured for each sensing pair, they are converted to a value between 0% and 100% based on predetermined calibration values. These output values are used for the next processing steps.

[0098] In the Rough Edge Finding step, as illustrated in FIG. 6B, to determine the location of the trailing edge of a column of microparticles in the receptacle, the processed sensing pair signal values are compared to a constant threshold value, starting with the signal value from the trailing-most sensing pair (i.e. the sensing pair closest to the trailing end / top of the receptacle). If this value doesn’t exceed the threshold, the signal value from the next sending pair is checked, iterating toward the leading end of the receptacle, until one of the signal values exceeds the threshold. When one of the signal values exceeds the threshold, that sensing pair is captured and identified as the “rough edge” pair, and because each sensing pair is at a known location, the rough location of the trailing edge is determined accordingly. This same processis followed for the other end of the sensor array, except in the opposite direction starting with the leading-most sensing pair value and iterating toward the trailing edge.

[0099] In the Fine Edge Finding step, as illustrated in FIG. 6C, the positions of the leading and trailing edges of the column determined in the rough edge finding step are refined utilizing the signal from the prior sensing pair. For the trailing edge, the signal level from the sensor pair adjacent to the “rough edge” pair in the direction toward the trailing end, is utilized. The value returned by this prior pair is converted into an incremental length assuming the signal level is proportional to the position of the edge within that sensing pair operating length. This adjustment length is added to the position found in rough edge finding to determine the final edge location. This process is repeated for the leading edge of the column utilizing the signal level from the prior sensing pair adjacent to the “rough edge” pair in the direction toward the leading end.

[0100] In some embodiments, the control system 510 is configured to determine only the trailing edge of the column, and record the precise position of the trailing edge when the leading edge is detected passing through the outlet flow path 107 (e.g. by an outflow sensor) just downstream from the fluid mixer 108, as described further below.

[0101] One particular example of a prototype graphical user interface for interacting with a dosage measurement system of a delivery device according to the present disclosure is illustrated in FIG. 8. The graphical user interface 800 has a section that shows different types of input values entered by the operator prior to beginning administration of the microparticles, such as, for example, the total mass of injectable medium, the total initial dosage of the microparticles, the amount of time prior to administration required to allow the microparticles to settle in the receptacle 122, and the target dose of microparticles to be administered at a given site of injection. The graphical user interface 800 also has a section that shows one or more indications reflecting live monitoring of dose administration while in operation, such as, for example, the dose of microparticles administered to the subject, and that which remains to be administered. The graphical user interface 800 further has a section that has operator controls for manually opening or closing valves on the transport-medium flow path 118 or displacement-medium flow path 114.

[0102] One particular example of a device 900 configured for connection to multiple catheters according to the present disclosure is illustrated in FIG. 9. Device 900 is substantially the same as the device shown in FIG. 5B, except that the device 900 comprises a plurality of fluid outlets106-1, 106-2, 106-3 for connecting to a plurality of catheters, and a multi-outlet valve 902 on the flow path leading from the fluid mixer 108 to the plurality of fluid outlets 106-1, 106-2, 106-3.

[0103] One particular example of a device according to the present disclosure is illustrated in in FIG. 10. The delivery device shown in FIG. 10 is substantially the same as the device 100 of FIG. 1, except that the device of FIG. 10 comprises an additional fluid splitter 115 upstream of fluid splitter 116 that splits a portion of the incoming injectable medium into a supplemental transport-medium flow path 117 that is fluidly coupled to the fluid mixer 108, and the fluid mixer 108 comprises a 4-way connector having a primary branch 108 A and a secondary branch 108B, with three inlets (two on the main body of the mixer 108 which are connected to the receptacle 122 and the transport-medium flow path 118, and one on the primary branch 108 A which is connected to the supplemental transport-medium flow path 117) and one outlet (on the secondary branch 108B, which is connected to the outlet flow path 107). In some embodiments, the delivery device may include an automated valve 1014 or a manual valve (not shown) on the supplemental transport-medium flow path 117. The delivery device shown in FIG. 10 has a dosage measurement system 1000 which is similar to system 500C of FIG. 5C, except that instead of an outflow sensor comprising a signal sensing pair as in FIG. 5C, in system 1000 the outflow sensor comprises an array of signal emitters 1002 and an array of signal detectors 1004, and the system 1000 also comprises an automated valve 1012 configured to selectively close the displacement-medium flow path 114 and the transport-medium flow path 118, and another automated valve 1014 configured to selectively close the supplemental transportmedium flow path 117. The portion of the outlet flow path 107 proximal to the fluid mixer 108 is substantially comprised of a transparent wall along which the array of signal emitters 1002 and the array of signal detectors 1004 are arranged. The control system 510 is connected to the output flow sensor and configured to detect in real time the presence of microparticles within the outlet flow path 107 as the microparticles begin to be delivered to a target location. The control system 510 is configured to detect a leading edge of a column of microparticles as the microparticles flow from the receptacle 122 into the outlet flow path 107 based on light detected by the signal detectors 1004, and to record the position of the trailing edge of the column at that time. In some embodiments, the outflow sensor’s trigger level is calibrated when the outlet flow path 107 is known to be full of fluid with no microparticles present. This baseline reading allows calculation of a lower trigger threshold, below which the controlsystem 510 will determine that the signal is being attenuated by microparticles which therefore must be present in the flow.

[0104] In operation, prior to administering an initial dose of a multidose regimen, a precise amount of microparticles will be loaded into the receptacle 122, and the will form a column in the receptacle with a trailing edge at height which is measurable by the control system 510 and a leading edge within the microparticle trap 126, but there is some “dead space” between the leading edge and the dilution point past which microparticles begin to flow into the outlet flow path 107. When administering an initial dose, the control system 510 is configured to close the automated valve 1014 while the automated valve 1012 remains open, such that fluid flows through the displacement-medium flow path 114 and carries microparticles from the receptacle 122 to the fluid mixer 108, where the microparticles mix with fluid flowing through the transport-medium flow path 118. The resulting mixture flows through the primary branch 108 A and the secondary branch 108B to be administered to the patient via the outlet flow path 107. Once administration of the microparticles begins, the leading edge of the column of microparticles is detected by the outflow sensor, and the control system 510 records a dosage starting location of the trailing edge at that time, which is utilized to determine a starting volume of the column of microparticles. The trailing edge position is then monitored by the control system 510 and once a desired volume for the initial dose of microparticles has been administered, the control system 510 closes valve 1012, opens valve 1014, and records a dosage ending location of the trailing edge, which is used to correct for microparticle slippage as described further below. After the current dose and prior to a subsequent dose, the control system 510 with the automated valve 1014 open and the automated valve 1012 closed, fluid flows through the supplemental transport-medium flow path 117 to flush out any microparticles from the initial dose remaining in the outlet flow line 107 and the primary branch 108 A and secondary branch 108B of the fluid mixer 108. This volume of transport medium will ensure that any remaining microparticles beyond the dilution point in the fluid mixer 108 is administered as part of the initial dose, and so as to avoid over-delivery of microparticles in a subsequent dose.

[0105] When administering multiple doses of microparticles, microparticle momentum in a prior dose can cause microparticles to pass a dilution point within the fluid mixer 108, which would typically be used in calculating a volume of microparticles remaining in the receptacle. If left uncorrected, this encroachment may cause over-delivery of microparticles in asubsequent dose as the microparticles past the dilution point are unaccounted for. Thus, in some embodiments, the control system 510 is configured to measure a column span (i.e., the distance between the trailing edge of the column and the dilution point) at the moment a prior dose completes and measure the columns span again at the start of each subsequent dose, as triggered by the output flow sensor, and to compare it to the column span of the immediately preceding dose. The difference between the two measured spans is determined by the control system 510 to be due to microparticle slippage and corresponds to microparticles which will be delivered before the span begins changing and tracking the actual microsphere span length. The control system 510 is configured to measure the slippage amount after each non-first dose in order to correct for microparticle slippage.

[0106] In the preceding description, for purposes of explanation, numerous details are set forth in order to provide a thorough understanding of the examples. However, it will be apparent to one skilled in the art that these specific details are not required. Accordingly, what has been described is merely illustrative of the application of the described examples and numerous modifications and variations are possible in light of the above teachings. Other technical features may be readily apparent to one skilled in the art from the figures, descriptions, and claims.

[0107] Since the above description provides examples, it will be appreciated that modifications and variations can be effected to the particular examples by those of skill in the art. Accordingly, the scope of the claims should not be limited by the particular examples set forth herein, but should be construed in a manner consistent with the specification as a whole.

Claims

CLAIMSWhat is claimed is:

1. A device for injectable delivery of microparticles to a patient, the device being fluidly connectable to a source of an injectable medium, the delivery device comprising: a receptacle connectable to receive an initial dosage of microparticles; an array of signal emitters positioned adjacent to the receptacle and configured to direct a signal at the microparticles held within the receptacle of the delivery device; an array of signal detectors positioned adjacent to the receptacle and configured to detect the signal from the array of signal emitters that has interacted with the microparticles; and a control system connected to the array of signal detectors and configured to determine a delivered dosage of microparticles based on the detected signal.

2. The device of claim 1, wherein at least a portion of a wall of the receptacle is transparent along a length of the receptacle.

3. The device of claim 1 or 2, wherein the array of signal emitters comprises an array of light emitters, and the array of signal detectors comprise an array of light detectors.

4. The device of claim 3 wherein the array of light emitters emit infrared light.

5. The device of any one of claims 1 to 4, wherein the array of signal emitters and the array of signal detectors are arranged in a plurality of sensing pairs, each sensing pair comprising one signal emitter and one signal detector arranged adjacent to a corresponding segment of the receptacle.

6. The device of claim 5, wherein the plurality of sensing pairs are arranged in a plurality of interleaved phases, and the control system is configured to activate the plurality of sensing pairs in sequential phases, such that adjacent sensing pairs are not activated at the same time.

7. The device of claim 5 or claim 6, wherein each sensing pair is calibrated by determining a baseline signal based on a detected signal when the receptacle contains no microparticles, anddetermining a full scale signal based on a detected signal when the receptacle is completely filled with microparticles.

8. The device of any one of claims 5 to 7, wherein the control system is configured to determine a leading edge and a trailing edge of a column of microparticles by comparing the signals from the sensing pairs to a threshold.

9. The device of claim 8, wherein the control system is configured to: determine the leading edge starting with comparing the signal from a sensing pair closest to a leading end of the receptacle to the threshold, then moving to comparing the signal from a next sensing pair in a direction towards a trailing end of the receptacle to the threshold, until the compared signal exceeds the threshold, and establish a rough position of the leading edge based on a position of the sensing pair whose signal first exceeded the threshold, and determine the trailing edge starting with comparing the signal from a sensing pair closest to the trailing end of the receptacle to the threshold, then moving to comparing the signal from a next sensing pair in a direction towards the leading end of the receptacle to the threshold, until the compared signal exceeds the threshold, and establish a rough position of the trailing edge based on a position of the sensing pair whose signal first exceeded the threshold.

10. The device of claim 9, wherein the control system is configured to refine the rough position of the leading edge based on a detected signal level from the sensing pair next closer to the leading end of the receptacle from the sensing pair whose signal first exceeded the threshold, and refine the rough position of the trailing edge based on a detected signal level from the sensing pair next closer to the trailing end of the receptacle from the sensing pair whose signal first exceeded the threshold.

11. The device according to any one of claims 1 to 10, further comprising at least one signal emitter positioned adjacent to an outlet flow path and configured to direct a signal at the outlet flow path, and at least one signal detector positioned adjacent to the outlet flow path and configured to detect the signal from the at least one signal emitter, wherein the control system is connected to the at least one signal detector and configured to determine the presence of microparticles in the outlet flow path based on the detected signal.

12. The device of claim 11, wherein at least a portion of a wall of the outlet flow path is transparent.

13. The device of claims 11 or 12, wherein the at least one signal emitter comprises one or more light emitters, and the at least one signal detector comprises one or more light detectors.

14. The device of claim 13 wherein the one or more light emitters emit infrared light.

15. The device of any one of claims 11 to 14, wherein the at least one signal emitter and the at least one signal detector are calibrated by determining a baseline signal based on a detected outflow signal when the outlet flow path contains no microparticles.

16. The device of any one of claims 1 to 15, further comprising a multi -catheter manifold at the end of a fluid outlet configured to deliver the injectable medium containing the microparticles to a plurality of catheters.

17. The device of any one of claims 1 to 16, further comprising at least one automated valve connected to be actuated by the control system positioned along a flow path for the injectable medium.

18. The device of claim 17, wherein the at least one automated valve is positioned upstream of the receptacle.

19. The device of claim 17, wherein the at least one automated valve is positioned downstream of the receptacle.

20. The device of any one of claims 17 to 19, wherein the at least one automated valve comprises one or more pinch valves.

21. The device of any one of claims 17 to 20, further comprising a graphical user interface comprising operator controls for manually opening or closing the at least one automated valve.

22. The device of any one of claims 17 to 21, wherein the control system is configured to automatically close the at least one automated valve after the delivered dosage has reached a target dose.

23. The device of any one of claims 1 to 22, further comprising a display device connected to the control system and configured to display the delivered dosage of microparticles to an operator of the delivery device.

24. A method of measuring a dosage of microparticles contained in an injectable medium as the injectable medium is being administered through a delivery device, the method comprising: providing an initial dosage of microparticles in a receptacle of the delivery device; emitting a plurality of signals through a wall of the receptacle as the injectable medium and microparticles are flowing through the receptacle of the delivery device; detecting the signal that has interacted with the microparticles in the injectable medium; and determining a delivered dosage of microparticles administered through the delivery device based on the detected signal.

25. The method of claim 24, wherein the initial dosage comprises a plurality of target doses for delivery to a plurality of target locations, and the method further comprises automatically stopping delivery of microparticles when the delivered dosage reaches a first target dose of the plurality of target doses.

26. The method of claim 24 or 25, wherein at least a portion of the wall of the receptacle is transparent wall along a length of the receptacle, and wherein emitting the plurality of signals comprise emitting light from a plurality of light emitters positioned in an array along the length of the receptacle.

Images