US20100282766A1 - Low-Dead Volume Microfluidic Component and Method - Google Patents

Low-Dead Volume Microfluidic Component and Method Download PDF

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Publication number
US20100282766A1
US20100282766A1 US12/436,360 US43636009A US2010282766A1 US 20100282766 A1 US20100282766 A1 US 20100282766A1 US 43636009 A US43636009 A US 43636009A US 2010282766 A1 US2010282766 A1 US 2010282766A1
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volume
variable
dead
fluid chamber
dead volume
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Heiko Arndt
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CeQur SA
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CeQur SA
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Priority to US12/436,360 priority Critical patent/US20100282766A1/en
Priority to US12/436,365 priority patent/US8230744B2/en
Assigned to CEQUR APS reassignment CEQUR APS ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ARNDT, HEIKO
Priority to EP17192248.7A priority patent/EP3287161A1/en
Priority to PCT/IB2010/001211 priority patent/WO2010128399A2/en
Priority to EP10728883A priority patent/EP2427235A2/en
Assigned to CEQUR SA reassignment CEQUR SA ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CEQUR APS
Publication of US20100282766A1 publication Critical patent/US20100282766A1/en
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/142Pressure infusion, e.g. using pumps
    • A61M5/145Pressure infusion, e.g. using pumps using pressurised reservoirs, e.g. pressurised by means of pistons
    • A61M5/148Pressure infusion, e.g. using pumps using pressurised reservoirs, e.g. pressurised by means of pistons flexible, e.g. independent bags
    • A61M5/152Pressure infusion, e.g. using pumps using pressurised reservoirs, e.g. pressurised by means of pistons flexible, e.g. independent bags pressurised by contraction of elastic reservoirs
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/142Pressure infusion, e.g. using pumps
    • A61M5/14244Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body
    • FMECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F04POSITIVE - DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS FOR LIQUIDS OR ELASTIC FLUIDS
    • F04BPOSITIVE-DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS
    • F04B19/00Machines or pumps having pertinent characteristics not provided for in, or of interest apart from, groups F04B1/00 - F04B17/00
    • F04B19/006Micropumps
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M2005/1401Functional features
    • A61M2005/1405Patient controlled analgesia [PCA]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/142Pressure infusion, e.g. using pumps
    • A61M5/14244Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body
    • A61M5/14248Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body of the skin patch type
    • A61M2005/14252Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body of the skin patch type with needle insertion means
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2206/00Characteristics of a physical parameter; associated device therefor
    • A61M2206/10Flow characteristics
    • A61M2206/20Flow characteristics having means for promoting or enhancing the flow, actively or passively
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/141Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor with capillaries for restricting fluid flow
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T137/00Fluid handling
    • Y10T137/0318Processes

Definitions

  • This invention relates generally to a system and method of reducing dead volume in a microfluidic circuit and, more specifically, to a system and method of reducing the dead volume in a component utilized within microfluidic circuits.
  • Microfluidic circuits are utilized in various personal medical devices (e.g., insulin infusion devices) to control delivery of medications or other fluids.
  • the volumetric flow rates within these circuits are very low, due to low dosing schedules, and to allow for accurate control of the medication being delivered.
  • the low flow rates can prevent the circuit from being quickly filled prior to utilizing the device, which can pose a significant inconvenience to the user. Additionally, any excess volume within the circuit results in medication that remains undelivered once a pressure source for the medication is terminated.
  • Lengthy fill times and undelivered medication are related to total volume within a microfluidic system.
  • Each component e.g., reservoirs or other chambers, valves, conduits or channels, pressure sensors, flow restrictors, etc.
  • This capacity is defined, in part, by the internal dimensions, function, and configuration of the component, including moving components within the flowpath. Manufacturing methods and tolerances may affect the capacity, as well. While a particular component may only require a relatively small portion of the total internal volume to perform its function (this volume may be referred to as the “working volume”), access required for manufacturing the component may prevent minimizing the total volume. This excess volume (or “dead volume”) over that of the working volume increases the total volume of the flow component and, subsequently, of the fluidic circuit of the delivery system.
  • the invention relates to a method for reducing a dead volume of a microfluidic circuit having a reservoir, an outlet, and a microfluidic flowpath fluidly connecting the reservoir and the outlet, the method including providing a variable-volume fluid chamber located between the reservoir and the outlet for performing a function and in fluidic communication with the microfluidic flowpath.
  • the variable-volume fluid chamber includes a total volume having a working volume and a dead volume, wherein the working volume is a volume necessary for the variable-volume fluid chamber to perform the function and the dead volume is a volume unnecessary for the variable-volume fluid chamber to perform the function.
  • the method includes configuring the variable-volume fluid chamber to reduce the dead volume, such that the working volume is substantially the same as the total volume. In an embodiment, the configuring step results in the total volume being substantially the same as the working volume.
  • variable-volume fluid chamber includes a base surface, an inlet, and a separate outlet.
  • the configuring step includes providing a flexible membrane, wherein the base surface and the membrane define a first volume when the membrane is proximate the base surface, and the base surface and the membrane define a second volume when the membrane is displaced by a fluid pressure away from the base surface.
  • the membrane can be biased towards the base surface.
  • the invention relates to a low-dead volume variable-volume fluid chamber manufactured in accordance with the method of the above embodiment. In an embodiment of the above aspect, the working volume is about 5% of the total volume.
  • FIG. 1 is a schematic diagram and related time/volume tables of an exemplary infusion device microfluidic circuit
  • FIG. 2 is a schematic diagram of another exemplary infusion device microfluidic circuit in accordance with one embodiment of the invention.
  • FIG. 3 is a schematic diagram of a theoretical microfluidic circuit flow component
  • FIGS. 4A and 4B are schematic sectional views of an exemplary variable-volume chamber and a low-dead volume version of the same variable-volume chamber in accordance with one embodiment of the invention.
  • a microfluidic circuit 10 for delivering a fluid medication to a patient, as depicted in FIG. 1 .
  • the fluid delivery or flow components of this circuit 10 include, in series, an elastomer reservoir or bladder 12 , a first channel 14 , a flow component 16 , a second channel 18 , and an outlet 20 .
  • the flow component 16 may function, e.g., as a storage chamber for doses of medicament to be delivered on an infrequent basis to a human user or patient 24 .
  • the reservoir 12 is filled with medication via a one-way inlet valve 22 .
  • the microfluidic circuit 10 is utilized in an insulin infusion delivery device used to deliver insulin to the patient 24 via a subcutaneous cannula in fluidic communication with the outlet 20 .
  • the lower table included in FIG. 1 depicts information relevant to a low-dead volume version of the microfluidic circuit 10 .
  • the upper table depicts information relevant to a baseline version of the microfluidic circuit 10 upon which no volume reduction modifications have been made.
  • the total volume of each flow component is depicted in FIG. 1 in Row A of both the upper and lower tables.
  • the elastomer reservoir 12 supplies the downstream microfluidic circuit flow components with insulin until the elastomer no longer exerts sufficient pressure to overcome the flow resistance in the circuit 10 . At that point, in this example, 87.39 ⁇ l of insulin remains in the reservoir 12 . See Row D.
  • Row B in both the upper and lower tables depicts the flow rate Q through the various components.
  • the flow rate Q is defined, at least in part, by flow restrictors and other components present within the circuit.
  • Row C in both the upper and lower tables depicts the amount of time required for insulin to completely fill each dry flow component once flow from the reservoir 12 is initiated, as the sum of which is the total start-up time for the entire microfluidic circuit 10 to fill.
  • This total start-up time reflects the time required to deliver a first dose of insulin to the user 24 .
  • the difference in volume between a standard flow component 16 (21.22 ⁇ l) and a low-dead volume flow component 16 (8.34 ⁇ l) contributes directly to the significant reduction in total start-up time of the circuit 10 .
  • the fill time for the standard flow component 16 is over twice that of the low-dead volume fill time, while the total fill time of the standard circuit is over 1 hour and 15 minutes greater than the microfluidic circuit using a low-dead volume component. This significant delay inherent in the baseline version of the circuit 10 is both an inconvenience and could be a risk to the user's health.
  • Row D in both the upper and lower tables depicts the amount of insulin that is effectively trapped within the microfluidic circuit 10 once the elastomer reservoir 12 can no longer induce flow at the outlet 20 . Note that a significant portion of the trapped insulin, other than that remaining in the reservoir 12 , is contained within the flow component 16 . Accordingly, use of a low-dead volume flow component, for example, a variable-volume chamber, is advantageous to reduce the total amount of lost insulin within the microfluidic circuit 10 .
  • FIG. 2 is a schematic diagram of an exemplary infusion device microfluidic circuit 100 that benefits from the low-dead volume technology described herein.
  • Other infusion device microfluidic circuits benefit as well, such as those described, for example, in U.S. Patent Application Publication No. 2005/0165384 A1, published Jul. 28, 2005, the disclosure of which is hereby incorporated by reference herein in its entirety.
  • Microfluidic circuits having other configurations or utilizing any number of other components also may benefit from inclusion of the low-dead volume variable-volume fluid chamber described herein.
  • the microfluidic circuit 100 includes a reservoir 102 that is, in this case, comprised of an elastomer bladder.
  • a fill port 104 is used to introduce insulin to the microfluidic circuit 100 .
  • introducing insulin via the fill port 104 fills both the reservoir 102 and a variable-volume bolus reservoir 106 .
  • Check valves 108 in the circuit 100 prevent backflow of insulin in a number of locations.
  • a basal flowpath 112 delivers a constant dose of insulin to a user; the bolus flowpath 114 delivers a bolus dose of insulin to the user as needed or desired by the user, upon actuation of a bolus button 118 .
  • the basal flowpath 112 includes a pressure sensor 116 or other flow sensor in communication with the flowpath 112 .
  • the user presses the bolus button 118 that drives a single stroke (delivering a single dose) of a bolus displacement chamber 120 and opens two valves 122 .
  • the valves 122 are in series providing failsafe redundancy for safety purposes.
  • Flow restrictors 124 limit the rate of fluid flow through the flowpaths 112 , 114 .
  • the parallel flowpaths 112 , 114 join at a common channel 126 , upstream of an internal chamber or a cannula void 128 .
  • the cannula void 128 is formed in a cannula base 130 , that provides a fluidic connection to a cannula 132 .
  • the cannula 132 extends below the skin 134 of the user, thus delivering the insulin subcutaneously.
  • reducing the dead volume in the variable-volume bolus reservoir 106 decreases the dead volume throughout the entire microfluidic circuit 100 .
  • FIG. 3 depicts a theoretical flow component 200 . While most flow components utilized in a microfluidic circuit serve specific purposes, each generally share several common elements, as depicted in FIG. 3 .
  • the flow component includes a housing or some other inner physical boundary that is in contact with the fluid passing therethrough. In FIG. 3 , this inner physical boundary 202 is depicted as a hollow cube.
  • the flow component includes an inlet, through which fluid flows into the component.
  • the inlet 204 penetrates a wall of the physical boundary 202 defined by corners bearing the letter “A”; the dimensions of the inlet 204 are defined by a height h, and a width w, although the inlet 204 could be circular or any other shape.
  • the flow component includes an outlet, through which fluid flows out of the component.
  • the outlet 206 penetrates a wall of the physical boundary 202 defined by the corners bearing the letter “B”; the dimensions of the outlet 206 are defined by a height h, and a width w, in this case, matching the dimensions of the inlet 204 , although the outlet 206 could be any shape or size and disposed at any location along the boundary 202 .
  • the inner physical boundary of a flow component defines three volumes: a total volume V, a working volume W, and a dead volume D.
  • the total volume V is the volume bounded by the inner physical boundary; accordingly, in FIG. 3 , the total volume V is defined by the walls of the cube (i.e., the inner physical boundary 202 ).
  • the working volume W is the minimum volume required to perform the function of the flow component, including connecting fluidicly the inlet and the outlet.
  • the theoretical flow component 200 functions as a constant-volume chamber through which fluid passes (where the entire cube must be filled with fluid via the inlet 204 prior to any fluid exiting the cube via the outlet 206 ).
  • the working volume W is the volume defined around a straight line 208 from a center C i of the inlet 204 to a center C o of the outlet 206 , the straight line having a length L.
  • the actual volume of this working volume W may be defined, in part, by the total length of straight line L and the height h and width w of the inlet 204 and the outlet 206 , assuming the working volume has outer dimensions substantially similar to height h and width w. Therefore the working volume W may be defined approximately by equation (i) below.
  • the dead volume D is the volume of the flow component 200 unnecessary to perform the function, and may be defined as the difference between the total volume V and the working volume W (in this case, the remainder of the volume contained within the inner physical boundary 202 , not including the working volume W), as shown in equation (ii) below.
  • the dead volume-reduction example described herein may effectively configure the flow component to reduce the dead volume, such that the working volume is substantially the same as the total volume or as close to the total volume as reasonably achievable, under the circumstances.
  • a number of factors may be considered.
  • the function and operational performance of the flow component should not be affected adversely by the dead volume-reduction configuration change.
  • the dead volume-reduction change should consider the potential impact on pressure losses associated with the flow component. Care should be taken when reducing dead volume of a flow component, to ensure the component can still be manufactured at acceptable cost.
  • An example of the use of dead volume-reduction configuration change to reduce the dead volume of a flow component is described below.
  • FIG. 4A is a schematic sectional view of a variable-volume chamber 500 .
  • the chamber 500 is formed within a solid housing 502 and has a rigid base surface 504 , as well as an inlet 506 , and an outlet 508 .
  • a rigid top surface 516 defines the upper surface of the chamber 500 .
  • the entire volume of an internal chamber 500 a below a line 510 a must be filled before any fluid may pass out of the outlet 508 .
  • FIG. 4B Depicted in FIG. 4B is a variable-volume chamber 500 ′ according to one embodiment of the present invention with reduced dead volume.
  • membrane 510 ′ is biased or disposed against the rigid base 504 of the internal chamber 500 a ′ to define a first small volume approaching zero, as depicted here.
  • the membrane 510 a ′ expands 512 ′.
  • the pressure contained within expansion volume 514 ′ is immediately exerted against the membrane 510 a ′ and the fluid contained within the internal chamber 500 a ′.
  • Pressure within the expansion volume 514 ′ may be relieved by a suitable vent, not shown. Due to the initial location of the membrane 510 a ′, once filling begins, pressure is essentially immediately exerted against the fluid, without requiring filling of an excessive dead volume of the internal chamber 500 a′.
  • variable-volume chamber 500 depicted in FIG. 4A includes a total volume V of 230 ⁇ l. Of this amount, 218.5 ⁇ l was determined to be dead volume D and was subsequently reduced by membrane 510 a ′, leaving a working volume W of 11.5 ⁇ l. For this embodiment, then, reducing the dead volume D results in a working volume W that is about 5% of the total volume V for the variable-volume chamber 500 ′ of FIG. 6B , thus achieving a 95% reduction in the volume of the variable-volume chamber 500 . Other reductions are also contemplated.
  • the basal circuit 112 includes a pressure sensor 116 and a cannula void 128 .
  • the bolus circuit 114 includes a variable-volume chamber 106 and two valves 122 .
  • the total volume of all conduits in the microcircuit 100 is about 7 ⁇ l, of which nearly none is dead volume.
  • Other flow components in an exemplary microcircuit may include at least a cannula void 128 , valves 122 , and a pressure sensor 116 .
  • a microcircuit 100 such as that depicted in FIG. 2
  • the difference in volume of a standard microcircuit (having a baseline-volume fluid chamber) versus the volume of a low-dead volume circuit (having a low-dead volume variable-volume chamber) is depicted.
  • TABLE 2 depicts other relevant properties of a low-dead volume variable-volume chamber, in an exemplary microcircuit, as that component is described in the Example.
  • the total volume V and dead volume D of a standard flow component is provided.
  • Other flow components in an exemplary microcircuit, as depicted in TABLE 2 may include at least a cannula void 128 , valves 122 , and a pressure sensor 116 .
  • the cannula void 128 flow component is set aside separately, because its flow rate is different than the other flow components.
  • Flow rates Q through each component are also provided.
  • the flow rates Q are used to calculate the fill time for each component. Initially, the fill time for the exemplary fluid chamber is calculated before any dead-volume reduction structure is utilized. In that case, total volume V is divided by the flow rate Q to obtain the fill time for that component. Next, the fill time for the variable-volume chamber is calculated after the dead-volume reduction structure is utilized. In that case, working volume W is divided by the flow rate Q to obtain the fill time for the low-dead volume variable-volume chamber. It should be noted that the working volume is, as defined above, the minimum volume required to perform the function of the flow component.
  • variable-volume chamber Since the function of the chamber is to hold liquid medicine, it has been assumed here for the purposes of illustration of the concept that a minimum of 11.5 ⁇ l is required for the functional working volume. Indeed, the working volume and dead volume of the variable-volume chamber may change as the chamber is made to hold different amounts of liquid medicine.
  • the various materials utilized in the flow components described herein, as well as the microfluidic circuits in which those flow components are utilized may be metal, glass, and/or any type of polymer suitable for sterilization and useful for delivering insulin or other medicaments subcutaneously.
  • Polyurethane, polypropylene, PVC, PVDC, EVA, and others are contemplated for use.
  • medical-grade plastics may be utilized for the cannula itself, as well as other components that contact or otherwise penetrate the body of the patient. Needles made from medical-grade stainless steel are also desirable, to prevent failure associated with use. Accordingly, the components utilized to reduce the dead volume within the various components should be the same as, similar to, or at least compatible with the existing materials utilized.

Abstract

A method is described for reducing a dead volume of a microfluidic circuit that includes, in one embodiment, a reservoir, an outlet, and a microfluidic flowpath fluidly connecting the reservoir and the outlet. The method includes providing a variable-volume fluid chamber between the reservoir and the outlet for performing a function and in fluidic communication with the microfluidic flowpath, wherein the variable-volume fluid chamber includes a total volume including a working volume and a dead volume. The working volume is a volume necessary for the variable-volume fluid chamber to perform the function and the dead volume is a volume unnecessary for the variable-volume fluid chamber to perform the function. The method includes configuring the variable-volume fluid chamber to reduce the dead volume, such that the working volume of the component is substantially the same as the total volume.

Description

    FIELD OF THE INVENTION
  • This invention relates generally to a system and method of reducing dead volume in a microfluidic circuit and, more specifically, to a system and method of reducing the dead volume in a component utilized within microfluidic circuits.
  • BACKGROUND
  • Microfluidic circuits are utilized in various personal medical devices (e.g., insulin infusion devices) to control delivery of medications or other fluids. In general, the volumetric flow rates within these circuits are very low, due to low dosing schedules, and to allow for accurate control of the medication being delivered. The low flow rates, however, can prevent the circuit from being quickly filled prior to utilizing the device, which can pose a significant inconvenience to the user. Additionally, any excess volume within the circuit results in medication that remains undelivered once a pressure source for the medication is terminated.
  • Lengthy fill times and undelivered medication are related to total volume within a microfluidic system. Each component (e.g., reservoirs or other chambers, valves, conduits or channels, pressure sensors, flow restrictors, etc.) of a system has an internal capacity for a volume of fluid. This capacity is defined, in part, by the internal dimensions, function, and configuration of the component, including moving components within the flowpath. Manufacturing methods and tolerances may affect the capacity, as well. While a particular component may only require a relatively small portion of the total internal volume to perform its function (this volume may be referred to as the “working volume”), access required for manufacturing the component may prevent minimizing the total volume. This excess volume (or “dead volume”) over that of the working volume increases the total volume of the flow component and, subsequently, of the fluidic circuit of the delivery system.
  • SUMMARY OF THE INVENTION
  • In one aspect, the invention relates to a method for reducing a dead volume of a microfluidic circuit having a reservoir, an outlet, and a microfluidic flowpath fluidly connecting the reservoir and the outlet, the method including providing a variable-volume fluid chamber located between the reservoir and the outlet for performing a function and in fluidic communication with the microfluidic flowpath. The variable-volume fluid chamber includes a total volume having a working volume and a dead volume, wherein the working volume is a volume necessary for the variable-volume fluid chamber to perform the function and the dead volume is a volume unnecessary for the variable-volume fluid chamber to perform the function. The method includes configuring the variable-volume fluid chamber to reduce the dead volume, such that the working volume is substantially the same as the total volume. In an embodiment, the configuring step results in the total volume being substantially the same as the working volume.
  • In yet another embodiment, the variable-volume fluid chamber includes a base surface, an inlet, and a separate outlet. The configuring step includes providing a flexible membrane, wherein the base surface and the membrane define a first volume when the membrane is proximate the base surface, and the base surface and the membrane define a second volume when the membrane is displaced by a fluid pressure away from the base surface. The membrane can be biased towards the base surface. In another aspect, the invention relates to a low-dead volume variable-volume fluid chamber manufactured in accordance with the method of the above embodiment. In an embodiment of the above aspect, the working volume is about 5% of the total volume.
  • BRIEF DESCRIPTION OF THE FIGURES
  • Other features and advantages of the present invention, as well as the invention itself, can be more fully understood from the following description of the various embodiments, when read together with the accompanying drawings, in which:
  • FIG. 1 is a schematic diagram and related time/volume tables of an exemplary infusion device microfluidic circuit;
  • FIG. 2 is a schematic diagram of another exemplary infusion device microfluidic circuit in accordance with one embodiment of the invention;
  • FIG. 3 is a schematic diagram of a theoretical microfluidic circuit flow component; and
  • FIGS. 4A and 4B are schematic sectional views of an exemplary variable-volume chamber and a low-dead volume version of the same variable-volume chamber in accordance with one embodiment of the invention.
  • DETAILED DESCRIPTION
  • Consider one embodiment of a microfluidic circuit 10 for delivering a fluid medication to a patient, as depicted in FIG. 1. The fluid delivery or flow components of this circuit 10 include, in series, an elastomer reservoir or bladder 12, a first channel 14, a flow component 16, a second channel 18, and an outlet 20. The flow component 16 may function, e.g., as a storage chamber for doses of medicament to be delivered on an infrequent basis to a human user or patient 24. The reservoir 12 is filled with medication via a one-way inlet valve 22. In this example, the microfluidic circuit 10 is utilized in an insulin infusion delivery device used to deliver insulin to the patient 24 via a subcutaneous cannula in fluidic communication with the outlet 20. The lower table included in FIG. 1 depicts information relevant to a low-dead volume version of the microfluidic circuit 10. The upper table depicts information relevant to a baseline version of the microfluidic circuit 10 upon which no volume reduction modifications have been made. The total volume of each flow component is depicted in FIG. 1 in Row A of both the upper and lower tables. The elastomer reservoir 12 supplies the downstream microfluidic circuit flow components with insulin until the elastomer no longer exerts sufficient pressure to overcome the flow resistance in the circuit 10. At that point, in this example, 87.39 μl of insulin remains in the reservoir 12. See Row D.
  • Row B in both the upper and lower tables depicts the flow rate Q through the various components. The flow rate Q is defined, at least in part, by flow restrictors and other components present within the circuit. Row C in both the upper and lower tables depicts the amount of time required for insulin to completely fill each dry flow component once flow from the reservoir 12 is initiated, as the sum of which is the total start-up time for the entire microfluidic circuit 10 to fill. This total start-up time reflects the time required to deliver a first dose of insulin to the user 24. Notably, the difference in volume between a standard flow component 16 (21.22 μl) and a low-dead volume flow component 16 (8.34 μl) contributes directly to the significant reduction in total start-up time of the circuit 10. Note that the fill time for the standard flow component 16 is over twice that of the low-dead volume fill time, while the total fill time of the standard circuit is over 1 hour and 15 minutes greater than the microfluidic circuit using a low-dead volume component. This significant delay inherent in the baseline version of the circuit 10 is both an inconvenience and could be a risk to the user's health.
  • Row D in both the upper and lower tables depicts the amount of insulin that is effectively trapped within the microfluidic circuit 10 once the elastomer reservoir 12 can no longer induce flow at the outlet 20. Note that a significant portion of the trapped insulin, other than that remaining in the reservoir 12, is contained within the flow component 16. Accordingly, use of a low-dead volume flow component, for example, a variable-volume chamber, is advantageous to reduce the total amount of lost insulin within the microfluidic circuit 10.
  • FIG. 2 is a schematic diagram of an exemplary infusion device microfluidic circuit 100 that benefits from the low-dead volume technology described herein. Other infusion device microfluidic circuits benefit as well, such as those described, for example, in U.S. Patent Application Publication No. 2005/0165384 A1, published Jul. 28, 2005, the disclosure of which is hereby incorporated by reference herein in its entirety. Microfluidic circuits having other configurations or utilizing any number of other components also may benefit from inclusion of the low-dead volume variable-volume fluid chamber described herein. The microfluidic circuit 100 includes a reservoir 102 that is, in this case, comprised of an elastomer bladder. A fill port 104 is used to introduce insulin to the microfluidic circuit 100. In this microfluidic circuit 100, introducing insulin via the fill port 104 fills both the reservoir 102 and a variable-volume bolus reservoir 106. Check valves 108 in the circuit 100 prevent backflow of insulin in a number of locations.
  • During use, insulin is forced from the reservoir 102 due to contraction of the elastomer bladder, through a filter 110, and into two parallel flowpaths: a basal flowpath 112 and a bolus flowpath 114. The basal flowpath 112 delivers a constant dose of insulin to a user; the bolus flowpath 114 delivers a bolus dose of insulin to the user as needed or desired by the user, upon actuation of a bolus button 118. The basal flowpath 112 includes a pressure sensor 116 or other flow sensor in communication with the flowpath 112. To deliver a bolus via the bolus flowpath 114, the user presses the bolus button 118 that drives a single stroke (delivering a single dose) of a bolus displacement chamber 120 and opens two valves 122. The valves 122 are in series providing failsafe redundancy for safety purposes. Flow restrictors 124 limit the rate of fluid flow through the flowpaths 112, 114. The parallel flowpaths 112, 114 join at a common channel 126, upstream of an internal chamber or a cannula void 128. The cannula void 128 is formed in a cannula base 130, that provides a fluidic connection to a cannula 132. The cannula 132 extends below the skin 134 of the user, thus delivering the insulin subcutaneously. In the depicted microfluidic circuit 100, reducing the dead volume in the variable-volume bolus reservoir 106 decreases the dead volume throughout the entire microfluidic circuit 100.
  • FIG. 3 depicts a theoretical flow component 200. While most flow components utilized in a microfluidic circuit serve specific purposes, each generally share several common elements, as depicted in FIG. 3. First, the flow component includes a housing or some other inner physical boundary that is in contact with the fluid passing therethrough. In FIG. 3, this inner physical boundary 202 is depicted as a hollow cube. Second, the flow component includes an inlet, through which fluid flows into the component. In FIG. 3, the inlet 204 penetrates a wall of the physical boundary 202 defined by corners bearing the letter “A”; the dimensions of the inlet 204 are defined by a height h, and a width w, although the inlet 204 could be circular or any other shape. Third, the flow component includes an outlet, through which fluid flows out of the component. In FIG. 3, the outlet 206 penetrates a wall of the physical boundary 202 defined by the corners bearing the letter “B”; the dimensions of the outlet 206 are defined by a height h, and a width w, in this case, matching the dimensions of the inlet 204, although the outlet 206 could be any shape or size and disposed at any location along the boundary 202.
  • The inner physical boundary of a flow component defines three volumes: a total volume V, a working volume W, and a dead volume D. The total volume V is the volume bounded by the inner physical boundary; accordingly, in FIG. 3, the total volume V is defined by the walls of the cube (i.e., the inner physical boundary 202). The working volume W is the minimum volume required to perform the function of the flow component, including connecting fluidicly the inlet and the outlet. In FIG. 3, assume that the theoretical flow component 200 functions as a constant-volume chamber through which fluid passes (where the entire cube must be filled with fluid via the inlet 204 prior to any fluid exiting the cube via the outlet 206). The working volume W is the volume defined around a straight line 208 from a center Ci of the inlet 204 to a center Co of the outlet 206, the straight line having a length L. The actual volume of this working volume W may be defined, in part, by the total length of straight line L and the height h and width w of the inlet 204 and the outlet 206, assuming the working volume has outer dimensions substantially similar to height h and width w. Therefore the working volume W may be defined approximately by equation (i) below.

  • W=h×w×L   (i)
  • The dead volume D is the volume of the flow component 200 unnecessary to perform the function, and may be defined as the difference between the total volume V and the working volume W (in this case, the remainder of the volume contained within the inner physical boundary 202, not including the working volume W), as shown in equation (ii) below.

  • D=V−W   (ii)
  • By reducing the dead volume D of a flow component, the dead volume of a microfluidic circuit may be decreased, approaching, ideally, a condition where the total volume of the low-dead volume component VLD equals the working volume W of a standard-dead volume flow component, i.e., VLD=W.
  • Different implementations may be utilized to decrease the dead volume of a flow component. In general, however, the dead volume-reduction example described herein may effectively configure the flow component to reduce the dead volume, such that the working volume is substantially the same as the total volume or as close to the total volume as reasonably achievable, under the circumstances. Regardless of the configuration change implemented, a number of factors may be considered. For example, the function and operational performance of the flow component should not be affected adversely by the dead volume-reduction configuration change. The dead volume-reduction change should consider the potential impact on pressure losses associated with the flow component. Care should be taken when reducing dead volume of a flow component, to ensure the component can still be manufactured at acceptable cost. An example of the use of dead volume-reduction configuration change to reduce the dead volume of a flow component is described below.
  • EXAMPLE
  • FIG. 4A is a schematic sectional view of a variable-volume chamber 500. The chamber 500 is formed within a solid housing 502 and has a rigid base surface 504, as well as an inlet 506, and an outlet 508. A rigid top surface 516 defines the upper surface of the chamber 500. As can be seen in FIG. 4A, the entire volume of an internal chamber 500 a below a line 510 a must be filled before any fluid may pass out of the outlet 508.
  • Depicted in FIG. 4B is a variable-volume chamber 500′ according to one embodiment of the present invention with reduced dead volume. In this case, membrane 510′ is biased or disposed against the rigid base 504 of the internal chamber 500 a′ to define a first small volume approaching zero, as depicted here. As fluid enters the internal chamber 500 a′, the membrane 510 a′ expands 512′. The pressure contained within expansion volume 514′ is immediately exerted against the membrane 510 a′ and the fluid contained within the internal chamber 500 a′. Pressure within the expansion volume 514′ may be relieved by a suitable vent, not shown. Due to the initial location of the membrane 510 a′, once filling begins, pressure is essentially immediately exerted against the fluid, without requiring filling of an excessive dead volume of the internal chamber 500 a′.
  • In one embodiment, the variable-volume chamber 500 depicted in FIG. 4A includes a total volume V of 230 μl. Of this amount, 218.5 μl was determined to be dead volume D and was subsequently reduced by membrane 510 a′, leaving a working volume W of 11.5 μl. For this embodiment, then, reducing the dead volume D results in a working volume W that is about 5% of the total volume V for the variable-volume chamber 500′ of FIG. 6B, thus achieving a 95% reduction in the volume of the variable-volume chamber 500. Other reductions are also contemplated.
  • Application of the low-dead volume technique described herein can significantly reduce dead volume of a microcircuit 100 such as that depicted in FIG. 2. As depicted in FIG. 2, the basal circuit 112 includes a pressure sensor 116 and a cannula void 128. The bolus circuit 114 includes a variable-volume chamber 106 and two valves 122. The total volume of all conduits in the microcircuit 100 is about 7 μl, of which nearly none is dead volume. TABLE 1, below, depicts relevant properties of a low-dead volume variable-volume chamber, in an exemplary microcircuit, as that component is described in the Example. Other flow components in an exemplary microcircuit, as depicted in TABLE 1, may include at least a cannula void 128, valves 122, and a pressure sensor 116. Assuming a microcircuit 100, such as that depicted in FIG. 2, the difference in volume of a standard microcircuit (having a baseline-volume fluid chamber) versus the volume of a low-dead volume circuit (having a low-dead volume variable-volume chamber) is depicted.
  • TABLE 1
    Reduction in Dead Volume for Microcircuit Utilizing Low-Dead
    Volume Variable-Volume Chamber
    Improvement
    Component V (μl) D (μl) W (μl) (% Reduction In V)
    Bolus Reservoir 230 218.5 11.5 95
    106
    Other Flow 25.26 0 25.26 0
    Components
    All Conduits 7 0 7 0
    Total 262.26 218.5 43.76 83.3
  • TABLE 2, below, depicts other relevant properties of a low-dead volume variable-volume chamber, in an exemplary microcircuit, as that component is described in the Example. The total volume V and dead volume D of a standard flow component is provided. Other flow components in an exemplary microcircuit, as depicted in TABLE 2, may include at least a cannula void 128, valves 122, and a pressure sensor 116. In TABLE 2, the cannula void 128 flow component is set aside separately, because its flow rate is different than the other flow components. After utilizing the low-dead volume structure described herein, dead volume D of the variable-volume chamber was essentially eliminated, to achieve the significantly smaller, essentially idealized, working volume W. Also provided is the cumulative volume for all conduits within the microcircuit.
  • Flow rates Q through each component are also provided. The flow rates Q are used to calculate the fill time for each component. Initially, the fill time for the exemplary fluid chamber is calculated before any dead-volume reduction structure is utilized. In that case, total volume V is divided by the flow rate Q to obtain the fill time for that component. Next, the fill time for the variable-volume chamber is calculated after the dead-volume reduction structure is utilized. In that case, working volume W is divided by the flow rate Q to obtain the fill time for the low-dead volume variable-volume chamber. It should be noted that the working volume is, as defined above, the minimum volume required to perform the function of the flow component. Since the function of the chamber is to hold liquid medicine, it has been assumed here for the purposes of illustration of the concept that a minimum of 11.5 μl is required for the functional working volume. Indeed, the working volume and dead volume of the variable-volume chamber may change as the chamber is made to hold different amounts of liquid medicine.
  • Reduction in fill times from that of the standard baseline component to that of the low-dead volume component are also provided. As noted above, while the reduction in fill time for the Example is quite large, this reduction varies depending on the working volume W selected and results in a significant reduction in fill time for the complete circuit.
  • TABLE 2
    Reduction in Fill Time for Microcircuit Utilizing Low-Dead Volume Variable-
    Volume Chamber
    Flow Fill Fill Fill Time Improvement
    W Rate Time V Time W Reduc. (%
    Component V (μl) D (μl) (μl) Q (μl/hr) at Q (hr) at Q (hr) (hr) Reduc.)
    Cannula Void 1.74 0 1.74 5 0.348 0.348 0 0
    128
    Bolus 230 218.5 11.5 10 23 1.15 21.85 95
    Reservoir 106
    Other Flow 23.52 0 23.52 10 2.352 2.352 0 0
    Components
    All Conduits 7 0 7 185 0.038 0.038 0 0
    Total 262.26 218.5 43.76 N/A 25.738 3.888 21.85 84.9
  • The various materials utilized in the flow components described herein, as well as the microfluidic circuits in which those flow components are utilized, may be metal, glass, and/or any type of polymer suitable for sterilization and useful for delivering insulin or other medicaments subcutaneously. Polyurethane, polypropylene, PVC, PVDC, EVA, and others are contemplated for use. More specifically, medical-grade plastics may be utilized for the cannula itself, as well as other components that contact or otherwise penetrate the body of the patient. Needles made from medical-grade stainless steel are also desirable, to prevent failure associated with use. Accordingly, the components utilized to reduce the dead volume within the various components should be the same as, similar to, or at least compatible with the existing materials utilized.
  • While there have been described herein what are to be considered exemplary and preferred embodiments of the present invention, other modifications of the invention will become apparent to those skilled in the art from the teachings herein. The particular methods of manufacture and geometries disclosed herein are exemplary in nature and are not to be considered limiting. It is therefore desired to be secured in the appended claims all such modifications as fall within the spirit and scope of the invention. Accordingly, what is desired to be secured by Letters Patent is the invention as defined and differentiated in the following claims, and all equivalents.

Claims (5)

1. A method for reducing a dead volume of a microfluidic circuit comprising a reservoir, an outlet, and a microfluidic flowpath fluidly connecting the reservoir and the outlet, the method comprising:
providing a variable-volume fluid chamber located between the reservoir and the outlet for performing a function and in fluidic communication with the microfluidic flowpath,
wherein the variable-volume fluid chamber comprises a total volume comprising a working volume and a dead volume, wherein the working volume comprises a volume necessary for the variable-volume fluid chamber to perform the function and the dead volume comprises a volume unnecessary for the variable-volume fluid chamber to perform the function; and
configuring the variable-volume fluid chamber to reduce the dead volume, such that the working volume is substantially the same as the total volume.
2. The method of claim 1, wherein the configuring step results in the total volume being substantially the same as the working volume.
3. The method of claim 1, wherein the variable-volume fluid chamber comprises a base surface, an inlet, and a separate outlet, and wherein the configuring step comprises:
providing a flexible membrane wherein the base surface and the membrane define a first volume when the membrane is proximate the base surface, wherein the base surface and the membrane define a second volume when the membrane is displaced by a fluid pressure away from the base surface, and wherein the membrane is biased towards the base surface.
4. A low-dead volume variable-volume fluid chamber manufactured in accordance with the method of claim 3.
5. The low-dead volume variable-volume fluid chamber of claim 4, wherein the working volume comprises about 5% of the total volume.
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CN106716097A (en) * 2014-09-25 2017-05-24 英福康有限责任公司 Device and method for calibrating film chamber for leak detection
WO2018122174A1 (en) * 2016-12-28 2018-07-05 Cequr Sa Microfluidic flow restrictor and system
US10258741B2 (en) 2016-12-28 2019-04-16 Cequr Sa Microfluidic flow restrictor and system

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