Patent Grant
10946378
With the desire to move many diagnostic tests to the point of use, microfluidic devices have incredible potential for widespread use in healthcare, environmental monitoring, food safety, and other applications. In particular, the ability of microfluidic systems to process small volumes of liquid renders them well suited for many well suited for many bio-analytical applications.
Despite their many advantages, some significant technical hurdles have prevented the widespread adoption of microfluidic devices for many applications. For example, most microfluidics rely on bulky, expensive pumps to direct and control the fluid flow within the device. Such external pumps are typically required because precise control of fluid flow offers advantages for many applications. For example, by carefully controlling/optimizing fluid flow, one can increase the sensitivity of tests (e.g., immunoassays), transfer products from cell cultures for analysis, and minimize the effect of the depletion zones that limit target binding to immobilized recognition molecules in biosensors. However, the need for complex and/or expensive external instrumentation, such as pumps, dramatically limits the potential use of microfluidic tests for point-of-care diagnostics, food and water testing, and environmental monitoring, particularly in low resource environments. In order for these microfluidic devices to be simple to use, more affordable, and more reliable in operation, improved devices and methods for controlling fluid flow within microfluidic devices are needed.
Provided herein are microfluidic pumps. The pumps (including the hybrid pumps and compound pumps described herein) are simple to fabricate, inexpensive, and provide for facile and accurate control of fluid flow through attached microfluidic systems. Further, the pumps are passive (i.e., require no energy input), and can be designed to be disposable, biodegradable, and/or combustible.
The passive microfluidic pumps comprise a fluid inlet, an absorbent region, a resistive region fluidly connecting the fluid inlet and the absorbent region, and an evaporation barrier enclosing the resistive region, the absorbent region, or a combination thereof. The resistive region can comprise a first porous medium, and a fluidly non-conducting boundary defining a path for fluid flow through the first porous medium from the fluid inlet to the absorbent region. The absorbent region can comprise a fluidly non-conducting boundary defining a volume of a second porous medium sized to absorb a predetermined volume of fluid imbibed from the resistive region. The resistive region and the absorbent region can be configured to establish a capillary-driven fluid front advancing from the fluid inlet through the resistive region to the absorbent region when the fluid inlet is contacted with fluid.
The dimensions and properties of the resistive region and the absorbent region can be selected to provide a passive pump configured to produce a desired fluid flow rate profile (e.g. constant, step-increase, step-decrease, oscillating, gradually increasing or decreasing) when fluidly connected to a microfluidic device. For example, in certain embodiments, the resistance to fluid flow through the resistive region is greater (e.g., at least five times greater, at least ten times greater, or at least twenty times greater) than the resistance to fluid flow through the absorbent region. In these embodiments, the dimensions and properties of the resistive region can be modified to select the flow rate provided by the pump when the pump is fluidly connected to a microfluidic device. In certain embodiments, the resistive region is configured to provide a rate of fluid flow of from 1 nL/min to 100 μL/min as the capillary-driven fluid advances through the second porous medium from the resistive region. Likewise, the dimensions and properties of the absorbent region can be modified to select a predetermined volume of fluid to be pumped at the flow rate determined by the resistive region. For example, the absorbent region can be sized to absorb from 1 μL to 10 mL (e.g., 10 μL to 10 mL) of fluid imbibed from the resistive region. In certain embodiments, the resistive region can be configured to provide a rate of fluid flow effective to deliver the predetermined volume of fluid to the absorbent region in from 10 seconds to 7 days (e.g., from 0.1 minutes to 90 minutes).
If desired, the pumps described herein can further include a flow delay element to influence fluid flow though the pump. For example, the pump can further comprise a dissolvable solute disposed in the fluid inlet, the resistive region, or a combination thereof. The pump can also comprise a dissolvable membrane forming a barrier to fluid flow through elements of the pump.
The evaporation barrier can enclose the resistive region, the absorbent region, or a combination thereof. In some cases, the evaporation barrier can enclose the resistive region. In some cases, the evaporation barrier can enclose the absorbent region. In certain embodiments, the evaporation barrier can enclose both the resistive region and the absorbent region. In cases where the evaporation barrier encloses the absorbent region, the pump can further include a vent operatively coupled to the absorbent region (e.g., to allow for pressure equalization as the absorbent region fills with fluid).
In some embodiments, the passive microfluidic pump can further include a second (or more) absorbent region. Such pumps are referred to herein as “hybrid pumps.” Such pumps can be designed to induce more complex fluid flow rate profiles when fluidly connected to a microfluidic device. For example, in some embodiments, the pump can further comprise a second resistive region and a second absorbent region. The second absorbent region can be fluidly connected in parallel or in series to the first absorbent region.
For example, in some embodiments, the second absorbent region can be fluidly connected in parallel to the first absorbent region. In these embodiments, the second resistive region can comprise a third porous medium, and a fluidly non-conducting boundary defining a path for fluid flow through the third porous medium from the fluid inlet to the second absorbent region, and the second absorbent region can comprise a fluidly non-conducting boundary defining a volume of a fourth porous medium sized to absorb a predetermined volume of fluid imbibed from the second resistive region. In certain cases, the pump can further include flow delay element(s) to influence fluid flow though the pump. For example, in some embodiments, the pump can further comprise a dissolvable solute disposed in the second resistive region. In some embodiments, the pump can further comprise a dissolvable membrane forming a barrier to fluid flow from the fluid inlet into the second resistive region.
In some embodiments, the second absorbent region can be fluidly connected in series to the first absorbent region. In these embodiments, the second resistive region can comprise a third porous medium, and a fluidly non-conducting boundary defining a path for fluid flow through the third porous medium from the first absorbent region to the second absorbent region; and the second absorbent region can comprise a fluidly non-conducting boundary defining a volume of a fourth porous medium sized to absorb a predetermined volume of fluid imbibed from the second resistive region. In certain cases, the pump can further include flow delay element(s) to influence fluid flow though the pump. For example, in some embodiments, the pump can further comprise a dissolvable solute disposed in the second resistive region. In some embodiments, the pump can further comprise a dissolvable membrane forming a barrier to fluid flow from the first absorbent region to the second resistive region.
In some embodiments, the hybrid pump can include three or more absorbent regions. For example, the hybrid pump can include three or more absorbent regions fluidly connected in parallel via resistive regions. The hybrid pump can also include three or more absorbent regions fluidly connected in series via resistive regions. In some cases, the hybrid pump can include absorbent regions fluidly connected both in parallel and in series. For example, in some embodiments, the hybrid pump can comprise two or more absorbent regions fluidly connected in parallel via resistive regions, and two or more absorbent regions fluidly connected in series via resistive regions.
The porous medium making up regions of the pumps described herein can be formed from any suitable porous material. Suitable porous materials can be selected in view of a number of factors, including the identity of the fluid to be transported by the pump (e.g., an aqueous fluid or an organic fluid) and the desired fluid flow rate profile to be induced by the pump. For example, in the case of pumps configured to drive the flow of aqueous solutions, the porous materials can comprise a porous hydrophilic material. In certain embodiments, the porous materials can comprise a cellulosic substrate (e.g., paper, cellulose derivatives, woven cellulose materials, non-woven cellulose materials, or a combination thereof). In certain embodiments, the pump can be a paper-based pump (i.e., the porous materials can comprise paper). Examples of suitable papers include, but are not limited to, chromatography paper, card stock, filter paper, vellum paper, printing paper, wrapping paper, ledger paper, bank paper, bond paper, blotting paper, drawing paper, fish paper, tissue paper, paper towel, wax paper, and photography paper.
In some embodiments, the porous regions of the pumps described herein (e.g., the first porous medium and the second porous medium) can be formed within a single piece of substrate material. In other embodiments, the porous regions of the pumps described herein (e.g., the first porous medium and the second porous medium) comprise separate pieces of substrate material that are in fluid contact with one another (e.g., separate pieces of substrate material that are abutted to one another). In these embodiments, the separate pieces of substrate material have the same thickness or a different thickness. In one example, the piece of substrate material forming the second porous medium can be thicker than the piece of substrate material forming the first porous material (i.e., the porous medium forming the absorbent region can be thicker than the porous medium forming the resistive region). In some cases, the piece of substrate material forming the second porous medium and the piece of substrate material forming the first porous material are not coplanar. In certain cases, the absorbent region is non-planar. For example, if desired, the absorbent region can be folded or bent into a three dimensional shape to reduce the footprint of the absorbent region (and by extension, the overall footprint of the pump).
In one embodiment, the absorbent region can be detachably connected to the resistive region. In this way, the absorbent region can be removed (e.g., once filled with a fluid), and replaced with a fresh absorbent region (e.g., allowing the pump to imbibe another volume of fluid). If desired, detachable absorbent regions can be used, for example, to collect multiple fractions of fluid for subsequent analysis.
If desired, the pumps described herein can be integrally formed within larger microfluidic devices to provide for control of fluids within the microfluidic device. In other cases, the pumps described herein can be modular in construction, and configured to be readily attached to an external microfluidic device. In this way, the pumps described herein can be used in a ‘plug-and-play’ fashion to control fluid flow in a wide range of conventional microfluidic devices. In certain embodiments, the fluid inlet can be configured to fluidly connect with a microfluidic channel. Specifically, the fluid inlet can have a geometry and construction that facilitates attachment of the pump with a microfluidic device (e.g., an external microfluidic device). By way of example, the fluid inlet can comprise a fluidly conductive region defining a path for fluid flow to the first resistive region. The fluidly conductive region can comprise, for example, a porous medium forming a path for fluid flow to the first resistive region. The fluidly conductive region can also comprise an open air-filled channel and/or a conductive material (e.g., glass beads, fiberglass, and/or glass wool) which provides a path for fluid flow to the first resistive region.
Also provided herein are compound pumps comprising a plurality of fluidly connected pumps or hybrid pumps described herein. The plurality of the pumps can be fluidly connected in parallel, in series, or with pumps fluidly connected both in parallel and in series. In some embodiments, the plurality of the pumps can comprise two or more pumps fluidly connected in series. In some embodiments, the plurality of the pumps can comprise two or more pumps fluidly connected in parallel. In certain embodiments, the plurality of the pumps can comprise two or more pumps fluidly connected in series and two or more pumps fluidly connected in parallel.
The plurality of pumps can be fluidly connected in any suitable fashion. In certain embodiments, the plurality of the pumps are stacked in parallel planes. Optionally, compound pumps can further include flow delay element(s) to influence fluid flow though the compound pump (e.g., into at least one of the plurality of fluidly connected pumps). For example, in some embodiments, the pump can further comprise a dissolvable solute disposed in the fluid inlet of a pump in the compound pump, the resistive region of the pump in the compound pump, or a combination thereof. In some embodiments, the pump can further comprise a dissolvable membrane forming a barrier to fluid flow between two of the plurality of the pumps in the compound pump.
Also provided are microfluidic devices that include one or more of the passive pumps described herein. Example microfluidic devices can include a microfluidic channel fluidly connecting a fluid inlet to a fluid outlet, and a pump described herein (e.g., a pump, hybrid pump, and/or compound pump) fluidly connected to the fluid outlet of the microfluidic channel (e.g., such that the pump induces fluid flow through the microfluidic channel when the fluid inlet is contacted with fluid). In some cases, the fluid inlet of the pump can be in direct contact with the fluid outlet of the microfluidic channel. In certain embodiments, the pump can be configured to drive fluid flow through the microfluidic channel at a substantially continuous flow rate for a period of at least 0.1 minutes (e.g., at least 0.5 minutes, at least 1 minutes, at least 5 minutes, at least 10 minutes, at least 30 minutes, at least 60 minutes, or longer). In other embodiments, the pump can be configured to drive fluid flow through the microfluidic channel at a variable flow rate for a period of at least 10 minutes (e.g., at least 30 minutes, at least 60 minutes, or longer). The variable flow rate can comprise, for example, a stepwise increasing flow rate or a stepwise decreasing flow rate.
Also provided are methods of using the pumps (including the hybrid pumps and compound pumps) described herein. The pumps described herein can be used to induce fluid flow through an attached microfluidic device (e.g., to achieve a controlled flow rate for a set volume, and/or to achieve multiple predetermined flow rates through the device). Accordingly, also provided are methods for inducing fluid flow through a microfluidic device that comprise fluidly connecting a pump described herein to a fluid outlet of the microfluidic device; and contacting a fluid inlet of the microfluidic device with a fluid. In some embodiments, the pump can be directly connected to the fluid outlet of the microfluidic device. In certain embodiments, the pump can be configured to drive fluid flow through the microfluidic channel at a substantially continuous flow rate for a period of at least 0.1 minutes (e.g., at least 0.5 minutes, at least 1 minutes, at least 5 minutes, at least 10 minutes, at least 30 minutes, at least 60 minutes, or longer). In other embodiments, the pump can be configured to drive fluid flow through the microfluidic channel at a variable flow rate for a period of at least 10 minutes (e.g., at least 30 minutes, at least 60 minutes, or longer). The variable flow rate can comprise, for example, a stepwise increasing flow rate or a stepwise decreasing flow rate.
The pumps (including the hybrid pumps and compound pumps described herein) can also be used in process control applications. For example, pumps described herein can be used to determine the fluidic resistance of microfluidic channels, to measure the height of microfluidic channels, to quantify the properties (e.g. the permeability) of a porous material such as paper, and/or to quantify the properties (e.g., the viscosity) of an unknown fluid.
Given the modular nature of the pumps described herein, individual modular pumps can be readily assembled to form a compound pump to provide a predetermined fluid flow rate within a microfluidic channel. Accordingly, also provided are methods of assembling passive compound pumps configured to provide a predetermined fluid flow rate within a microfluidic channel. These methods can comprise fluidly connecting one or more pumps described herein (referred to in this context as a “pump subunit”) shaped to induce a particular fluid flow rate upon contact with a fluid to a fluid inlet to form the passive compound pump. Each pump subunit can comprise a resistive region comprising a first porous medium, and a fluidly non-conducting boundary defining a path for fluid flow through the first porous medium from the fluid inlet to the absorbent region, and an absorbent region comprising a fluidly non-conducting boundary defining a volume of a second porous medium sized to absorb a predetermined volume of fluid imbibed from the resistive region. Optionally, each pump subunit can be enclosed within an evaporation barrier.
In some embodiments, methods of assembling a passive compound pump can comprise fluidly connecting two or more pump subunits. In some embodiments, methods can comprise fluidly connecting two or more pump subunits in series. In some embodiments, methods can comprise fluidly connecting two or more pump subunits in parallel. In certain embodiments, methods can comprise fluidly connecting two or more pump subunits in series, and fluidly connecting two or more pump subunits in parallel. In certain embodiments, fluidly connecting the pump subunits can comprise stacking the pump subunits to form the fluid inlet. In these embodiments, the fluid inlet can comprise a fluidly conductive region extending through the pump subunits in the stack, and defining a path for fluid flow to the first resistive region of each of the pump subunits. The fluidly conductive region can comprise, for example, a porous medium forming a path for fluid flow. The fluidly conductive region can also comprise an open air-filled channel and/or a conductive material (e.g., fiberglass or glass wool) which provides a path for fluid flow. In some embodiments, methods can further comprise positioning a dissolvable membrane between pump subunits in the stack (e.g., transecting the fluid inlet) so as to form a barrier to fluid flow between pump subunits in the compound pump.
The methods and devices described herein may be understood more readily by reference to the following detailed description of specific aspects of the disclosed subject matter, figures and the examples included therein.
Before the present devices and methods are disclosed and described, it is to be understood that the aspects described below are not intended to be limited in scope by the specific devices and methods described herein, which are intended as illustrations. Various modifications of the devices and methods in addition to those shown and described herein are intended to fall within the scope of that described herein. Further, while only certain representative devices and method steps disclosed herein are specifically described, other combinations of the devices and method steps also are intended to fall within the scope of that described herein, even if not specifically recited. Thus, a combination of steps, elements, components, or constituents may be explicitly mentioned herein or less; however, other combinations of steps, elements, components, and constituents are included, even though not explicitly stated.
The term “comprising” and variations thereof as used herein is used synonymously with the term “including” and variations thereof and are open, non-limiting terms. Although the terms “comprising” and “including” have been used herein to describe various examples, the terms “consisting essentially of” and “consisting of” can be used in place of “comprising” and “including” to provide for more specific examples of the invention and are also disclosed. Other than in the examples, or where otherwise noted, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood to be construed in light of the number of significant digits and ordinary rounding approaches.
As used in the description and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a composition” includes mixtures of two or more such compositions, reference to “an agent” includes mixtures of two or more such agents, reference to “the component” includes mixtures of two or more such components, and the like.
“Optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.
“Multiple” or “plurality” as used herein, is defined as two or more than two.
It is understood that throughout this specification the identifiers “first” and “second” are used solely to aid in distinguishing the various components and steps of the disclosed subject matter. The identifiers “first” and “second” are not intended to imply any particular order, amount, preference, or importance to the components or steps modified by these terms.
Also, throughout this specification, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which the disclosed matter pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon.
Passive Pumps
Provided herein are microfluidic pumps. The pumps (including the hybrid pumps and compound pumps described herein) are simple to fabricate, inexpensive, and provide for facile and accurate control of fluid flow through attached microfluidic systems. Further, the pumps are passive (i.e., require no energy input), and can be designed to be disposable, biodegradable, and/or combustible.
An example passive microfluidic pump is schematically illustrated in
The dimensions and properties of the resistive region and the absorbent region can be selected to provide a passive pump configured to produce a desired fluid flow rate profile when fluidly connected to a microfluidic device. For example, in certain embodiments, the resistive region can be sized such that the resistance to fluid flow through the resistive region is greater than the resistance to fluid flow through the absorbent region. In some embodiments, the resistance to fluid flow through the resistive region can be at least five times greater (e.g., at least ten times greater, at least fifteen times greater, at least twenty times greater, at least twenty-five times greater, or at least fifty times greater) than the resistance to fluid flow through the absorbent region. In certain cases, the resistance to fluid flow through the resistive region can be from five times greater to one thousand times greater (e.g., from five times greater to five hundred times greater, from five times greater to one hundred times greater, from five times greater to fifty times greater, from five times greater to twenty-five times greater, from five times greater to twenty times greater, or from ten times greater to twenty times greater) than the resistance to fluid flow through the absorbent region.
In these embodiments, the dimensions and properties of the resistive region can be modified to select the flow rate provided by the pump when the pump is fluidly connected to a microfluidic device. In certain embodiments, the resistive region is configured to provide a rate of fluid flow of from 1 nL/min to 100 μL/min (e.g., from 100 nL/min to 100 μL/min, from 1 μL/min to 100 μL/min, or from 1 μL/min to 10 μL/min) as the capillary-driven fluid advances through the second porous medium from the resistive region. In certain embodiments, the resistive region can be configured to provide a rate of fluid flow effective to deliver the predetermined volume of fluid to the absorbent region in from 5 seconds to 7 days (e.g., from 0.1 minutes to 90 minutes).
In certain embodiments, the resistive region can have any suitable cross-sectional shape. For example, the resistive region can have a round, square, or rectangular cross-section. The cross-sectional area of the resistive region (e.g., defined by a width and height in the case of a rectangular cross-section) can be varied as desired. In some embodiments, the resistive region can have a cross-sectional area of at least 0.005 mm2 (e.g., at least 0.01 mm2, at least 0.05 mm2, at least 0.1 mm2, at least 0.5 mm2, at least 1.0 mm2, at least 1.5 mm2, at least 2.0 mm2, at least 2.5 mm2, at least 3.0 mm2, at least 3.5 mm2, at least 4.0 mm2, at least 4.5 mm2, at least 5.0 mm2, at least 5.5 mm2, at least 6.0 mm2, at least 6.5 mm2, at least 7.0 mm2, at least 7.5 mm2, at least 8.0 mm2, at least 8.5 mm2, at least 9.0 mm2, or at least 9.5 mm2). In some embodiments, the resistive region can have a cross-sectional area of 10.0 mm2 or less (e.g., 9.5 mm2 or less, 9.0 mm2 or less, 8.5 mm2 or less, 8.0 mm2 or less, 7.5 mm2 or less, 7.0 mm2 or less, 6.5 mm2 or less, 6.0 mm2 or less, 5.5 mm2 or less, 5.0 mm2 or less, 4.5 mm2 or less, 4.0 mm2 or less, 3.5 mm2 or less, 3.0 mm2 or less, 2.5 mm2 or less, 2.0 mm2 or less, 1.5 mm2 or less, 1.0 mm2 or less, 0.5 mm2 or less, 0.1 mm2 or less, 0.05 mm2 or less, or 0.01 mm2 or less). The resistive region can have a cross-sectional area ranging from any of the minimum values described above to any of the maximum values described above. For example, the resistive region can have a cross-sectional area of from 0.005 mm2 to 10.0 mm2 (e.g., from 0.1 mm2 to 10.0 mm2, or from 1.0 mm2 to 10.0 mm2).
The resistive region can stretch for a varying distance (defining the length of the resistive region), for example, between a fluid inlet and an absorbent region. In some embodiments, the resistive region can have a length of at least 0.1 cm (e.g., at least 0.2 cm, at least 0.3 cm, at least 0.4 cm, at least 0.5 cm, at least 0.6 cm, at least 0.7 cm, at least 0.8 cm, at least 0.9 cm, at least 1 cm, at least 2 cm, at least 2.5 cm, at least 3 cm, at least 4 cm, at least 5 cm, at least 10 cm, at least 15 cm, at least 20 cm, or longer). In some embodiments, the resistive region can have a length of 25 cm or less (e.g., 20 cm or less, 15 cm or less, 10 cm or less, 5 cm or less, 4 cm or less, 3 cm or less, 2.5 cm or less, 2 cm or less, 1 cm or less, 0.9 cm or less, 0.8 cm or less, 0.7 cm or less, 0.6 cm or less, 0.5 cm or less, 0.4 cm or less, 0.3 cm or less, or 0.2 cm or less). The resistive region can have a length that ranges from any of the minimum dimensions to any of the maximum dimensions described above. For example, the resistive region can have a length of from 0.1 cm to 25 cm (e.g., from 0.1 cm to 10 cm, or from 0.5 cm to 5 cm). The resistive region of the pump does not have to be straight. It could, for example, be serpentine.
Likewise, the dimensions and properties of the absorbent region can be modified to select a predetermined volume of fluid to be pumped at the flow rate determined by the resistive region. The absorbent region can be fabricated in any suitable shape. For example, the absorbent region can have a circular, fan-shaped, triangular, square, or rectangular footprint. It could also have cross sections that are not rectangular. In some embodiments, the absorbent region can be sized to absorb from 1 μL to 10 mL (e.g., 10 μL to 10 mL) of fluid imbibed from the resistive region.
In some embodiments, the absorbent region can be detachably connected to the resistive region. In this way, the absorbent region can be removed (e.g., once filled with a fluid), and replaced with a fresh absorbent region (e.g., allowing the pump to imbibe another volume of fluid). If desired, detachable absorbent regions can be used, for example, to collect multiple fractions of fluid for subsequent analysis. In some embodiments, the absorbent region(s) can include an assay reagent (e.g., a reagent to facilitate the detection of an analyte of interest in the fluid imbibed from the resistive region). In other embodiments, the absorbent region(s) does not include an assay reagent.
The porous medium making up regions of the pumps described herein can be formed from any suitable porous material. Suitable porous materials can be selected in view of a number of factors, including the identity of the fluid to be transported by the pump (e.g., an aqueous fluid or an organic fluid) and the desired fluid flow rate profile to be induced by the pump. For example, the porous material must be substantially insoluble in the fluid to be transported by the pump. Pore size and characteristics (e.g. hydrophobicity, resistance to fouling) can be selected as appropriate for the individual application. For example, the porous materials can be prefabricated and cut to achieve the desired shape, they can be printed with waxes or inks that create fluidly non-conducting boundaries, or they can be introduced into molds and polymerized in place.
Porous material can be envisioned as a matrix (i.e., a skeletal portion) permeated with interconnecting pores. Generally, porous materials can be characterized by three primary characteristics with respect to their performance in a passive pump described herein: effective porosity, capillary pressure, and permeability. These are either intrinsic to the given porous material or intrinsic to the relationship of that material with the imbibing fluid. A set of primary characteristics might be useful for a given application. A given porous material—with the set of primary characteristics—can then be shaped for desired functionality.
Effective Porosity:
The effective porosity (φ) is here defined as the percent of the volume that the fluid can fill. This value can be determined by measuring the volume of fluid required to saturate a given porous material. The ratio of the volume of the fluid added to the original, total spatial volume of the porous material is the effective porosity. In an ideal material, this equals the ratio of the void volume of the porous material to the total spatial volume and is independent of the fluid used.
Capillary Pressure:
The capillary pressure (Pc) generated at the wetted front as a fluid is imbibing through a porous material is a function of the mean pore size of the porous material (rm), the interfacial tension (γ), and the wetting angle (Θ) of the imbibing fluid. The former is independent of the fluid, and the latter two are dependent on the fluid. For capillary tubes of a given radius, the capillary pressure has been described with Equation 4.
Permeability:
The permeability is a measure of the ability of the porous material to allow the flow of fluid. This is related to the porosity of the material, but it is also dependent on the shape and connectivity of the pores. There is an intrinsic permeability for a given porous material, and, depending on the constitution of the material, there might be anisotropy in the permeability based on the direction of flow.
The matrix, the mean pore size, and the density of pores in a porous material can be varied to achieve the desired capillary pressures for a given fluid, porosity, and permeability. By way of example, cellulose papers typically have a porosity of ˜60% and a mean pore size of from 2 μm to 30 μm (depending on the particular cellulose paper). Cellulose papers can achieve permeabilities of from 10−12 m2 to 10−16 m2 and capillary pressures (for water imbibing into the paper) of from 1 kPa to 100 kPa.
A wide variety of porous materials are in principle suitable. Suitable porous materials are known in the art, and include, for example, porous polymer films, glass fibers, fritted glass, glass beads, aerogels, xerogels, open cell foams, and a variety of cellulosic substrates (e.g., paper, cellulose derivatives, woven cellulose materials, non-woven cellulose materials, and combinations thereof). In some embodiments, the porous materials can be flexible. For certain applications, it is desirable that the porous material can be folded, creased, or otherwise mechanically shaped to impart three-dimensional structure to the pump.
In some embodiments, the pump can be configured to drive the flow of aqueous solutions, and the porous materials can comprise a porous hydrophilic material. In certain embodiments, the porous materials can comprise a cellulosic substrate (e.g., paper, cellulose (e.g., cotton fibers), cellulose derivatives such as nitrocellulose or cellulose acetate, woven cellulose materials, non-woven cellulose materials, or a combination thereof).
In certain embodiments, the pump can be a paper-based pump (i.e., the porous materials can comprise paper). Paper is inexpensive, widely available, readily patterned, thin, lightweight, and can be disposed of with minimal environmental impact. Furthermore, a variety of grades of paper are available, permitting the selection of a paper substrate with the weight (i.e., grammage), thickness and/or rigidity and characteristics (i.e., porosity, hydrophobicity, and/or permeability), desired for the fabrication of a particular paper-based device. Suitable papers include, but are not limited to, chromatography paper, card stock, filter paper, vellum paper, printing paper, wrapping paper, ledger paper, bank paper, bond paper, blotting paper, drawing paper, fish paper, tissue paper, paper towel, wax paper, and photography paper.
In some embodiments, the porous regions of the pumps described herein (e.g., the first porous medium and the second porous medium) can be formed within a single piece of substrate material. In other embodiments, the porous regions of the pumps described herein (e.g., the first porous medium and the second porous medium) comprise separate pieces of substrate material that are in fluid contact with one another (e.g., separate pieces of substrate material that are abutted to one another). In these embodiments, the separate pieces of substrate material have the same thickness or a different thickness. In one example, the piece of substrate material forming the second porous medium can be thicker than the piece of substrate material forming the first porous material (i.e., the porous medium forming the absorbent region can be thicker than the porous medium forming the resistive region). In some cases, the piece of substrate material forming the second porous medium and the piece of substrate material forming the first porous material are not coplanar. In certain cases, the absorbent region is non-planar. For example, if desired, the absorbent region can be folded or bent into a three dimensional shape to reduce the footprint of the absorbent region (and by extension, the overall footprint of the pump).
The fluidly non-conducting boundaries within the pumps described herein can vary depending on, for example, the identity of the fluid to be transported by the pump and the methods by which the pump is manufactured. By way of example, in the case of a pump configured to drive the flow of aqueous solutions, the fluidly non-conducting boundary can comprise a hydrophobic material patterned on/within the porous material (e.g., impregnated within the porous material and/or coated on the porous material) so as to render portions of the porous material hydrophobic thereby inhibiting transport of the aqueous solution through the porous material. Examples of suitable hydrophobic materials include, for example, curable polymers, natural waxes, synthetic waxes, polymerized photoresists, alkyl ketene dimers, alkenyl succinic anhydrides, rosins, silicones, fluorinated reagents, fluoropolymers, polyolefin emulsions, resin and fatty acids, or combinations thereof.
By way of example, the fluidly non-conducting boundary can be formed by patterning the hydrophobic material (e.g., a wax) on a layer of porous material (e.g., paper). For example, an inkjet printer can be used to pattern a wax material on the porous material. Many types of wax-based solid ink are commercially available and are useful in such methods as the ink provides a visual indication of the position of the fluidly non-conducting boundary. However, it should be understood, that the wax material used to form the fluidly non-conducting boundary does not require an ink to be functional. Examples of wax materials that maybe used include polyethylene waxes, hydrocarbon amide waxes or ester waxes. Once the wax is patterned, the porous material can be heated (e.g., by placing the material on a hot plate with the wax side up at a temperature of 120° C.) and cooled to room temperature. This allows the wax material to substantially permeate the thickness of the porous material so as to form a fluidly non-conducting boundary within the porous material.
In other examples, the fluidly non-conducting boundary can comprise an air gap through which fluid cannot flow. In other examples, the fluidly non-conducting boundary can comprise a fluidly impermeable material (e.g., a polymeric membrane) abutting the porous material. In other embodiments, the porous material can be selectively modified (e.g., by covalent reaction) to form the fluidly non-conducting boundary. By way of example, in the case of a pump configured to drive the flow of aqueous solutions, regions of the porous material (e.g., regions within the paper) can be rendered hydrophobic (i.e., hydrophobically modified) by covalently modifying the porous material (e.g., the paper) with a hydrophobic agent, such as a hydrophobic silane,
Optionally, the pumps described herein can further include a flow delay element to influence fluid flow though the pump. Flow delay elements can be used to begin the desired flow rate at a time after the point that fluid actually reaches the inlet region of passive pump or to temporarily delay the continuation of the flow. This level of control may be desirable if, for example, additional time is needed for sample loading or reagent incubation. Examples of flow delay elements include dissolvable solutes disposed in the fluid inlet, the resistive region, or a combination thereof, and dissolvable membranes forming a barrier to fluid flow through elements of the pump.
In some embodiments, the pump can further comprise a dissolvable solute disposed in the fluid inlet, the resistive region, or a combination thereof. For example, a varying amount of a solute can be dried in the fluid inlet and/or resistive region of the pump to delay fluid transport. Upon imbibition of a fluid such into the fluid inlet and/or resistive region, the dried solute will be dissolved, increasing the viscosity of the solution in that region of the paper according to the solute concentration. Because resistance of a given segment of porous material is proportional to the viscosity of the liquid flowing through the porous material, dissolved solute can produce a significant increase in the resistance and decrease in the volumetric flow rate in the passive pump.
Since the resistive region is typically the controller of flow rate through the pump, the flow rate increases and the pump ‘turns on’ once the fluid in the resistive region no longer contains the concentrated solute. When the dissolved solute reaches the absorbent region of the passive pump, the cross sectional area of the wetted front increases, decreasing the length of the viscous plug. This decreases the overall resistance to fluid flow, increasing the flow rate toward the limit established by the resistance of the resistive region for the fluid without the solute.
A variety of suitable solutes can be used. Appropriate solutes can be selected, for example, based on various design considerations including the identity of fluid flowing into the pump. While the solute can be any solid that will dissolve in the imbibing fluid, solutes that are stable in dry form under conditions of storage are preferred. For example, in some embodiments, the solute can be an organic small molecule (e.g., a sugar such as sucrose) or a polymer (e.g., polyvinyl alcohol). Varying amounts of solute can be deposited, with the amount of solute depositing influencing the magnitude of the impact on fluid flow through the pump. The solute can be deposited in the fluid inlet, the resistive region, or a combination thereof by, for example, applying a solution of the solute to the fluid inlet, the resistive region, or a combination thereof, and allowing the solvent to evaporate, leaving behind the dried solute.
In some embodiments, the pump can comprise a dissolvable membrane forming a barrier to fluid flow through elements of the pump. For example, the pump can include a dissolvable polymeric membrane (e.g., a polyvinyl alcohol membrane) disposed across the fluid flow path within the pump. For example, the pump can include a dissolvable polymeric membrane covering the fluid inlet, disposed between the fluid inlet and the resistive region, or a combination thereof to form a temporary barrier to fluid flow through elements of the pump.
The pumps can further include an evaporation barrier (e.g., an impermeable polymer membrane) enclosing the resistive region, the absorbent region, or a combination thereof. In some cases, the evaporation barrier can enclose the resistive region. In some cases, the evaporation barrier can enclose the absorbent region. In certain embodiments, the evaporation barrier can enclose both the resistive region and the absorbent region. In cases where the evaporation barrier encloses the absorbent region, the pump can further include a vent operatively coupled to the absorbent region (e.g., to allow for pressure equalization as the absorbent region fills with fluid).
If desired, the pumps described herein can be integrally formed within larger microfluidic devices to provide for control of fluids within the microfluidic device. In other cases, the pumps described herein can be modular in construction, and configured to be readily attached to an external microfluidic device. In this way, the pumps described herein can be used in a ‘plug-and-play’ fashion to control fluid flow in a wide range of conventional microfluidic devices. In certain embodiments, the fluid inlet can be configured to fluidly connect with a microfluidic channel. Specifically, the fluid inlet can have a geometry and construction that facilitates attachment of the pump with a microfluidic device (e.g., an external microfluidic device). By way of example, the fluid inlet can comprise a fluidly conductive region defining a path for fluid flow to the first resistive region. The fluidly conductive region can comprise, for example, a porous medium forming a path for fluid flow to the first resistive region. The fluidly conductive region can also comprise an open air-filled channel and/or a conductive material (e.g., fiberglass or glass wool) which provides a path for fluid flow to the first resistive region.
Hybrid Pumps
In some embodiments, the passive microfluidic pump can further include a second (or more) absorbent region. Such pumps are referred to herein as “hybrid pumps.” Such pumps can be designed to induce more complex fluid flow rate profiles when fluidly connected to a microfluidic device. For example, in some embodiments, the pump can further comprise a second resistive region and a second absorbent region. The second absorbent region can be fluidly connected in parallel or in series to the first absorbent region.
An example hybrid pump (200) including a second resistive region (204) and a second absorbent region (206) fluidly connected in series is illustrated in
An example hybrid pump (300) including a second resistive region (304) and a second absorbent region (306) fluidly connected in parallel is illustrated in
In some embodiments, the hybrid pump can include three or more absorbent regions. For example, the hybrid pump can include three or more absorbent regions fluidly connected in parallel via resistive regions. The hybrid pump can also include three or more absorbent regions fluidly connected in series via resistive regions. In some cases, the hybrid pump can include absorbent regions fluidly connected both in parallel and in series. For example, in some embodiments, the hybrid pump can comprise two or more absorbent regions fluidly connected in parallel via resistive regions, and two or more absorbent regions fluidly connected in series via resistive regions.
Compound Pumps
Also provided herein are compound pumps comprising a plurality of fluidly connected pumps or hybrid pumps described herein. Such pumps can be designed to induce more complex fluid flow rate profiles (programmable flow rates) when fluidly connected to a microfluidic device. The plurality of the pumps can be fluidly connected in parallel, in series, or with pumps fluidly connected both in parallel and in series. In some embodiments, the plurality of the pumps can comprise two or more pumps fluidly connected in series. In some embodiments, the plurality of the pumps can comprise two or more pumps fluidly connected in parallel. In certain embodiments, the plurality of the pumps can comprise two or more pumps fluidly connected in series and two or more pumps fluidly connected in parallel.
The plurality of pumps can be fluidly connected in any suitable fashion. In certain embodiments, the plurality of the pumps are stacked in parallel planes. Optionally, compound pumps can further include flow delay element(s) to influence fluid flow though the compound pump (e.g., into at least one of the plurality of fluidly connected pumps). For example, in some embodiments, the pump can further comprise a dissolvable solute disposed in the fluid inlet of a pump in the compound pump, the resistive region of the pump in the compound pump, or a combination thereof. In some embodiments, the pump can further comprise a dissolvable membrane forming a barrier to fluid flow between two of the plurality of the pumps in the compound pump.
Microfluidic Devices
Also provided are microfluidic devices that include one or more of the passive pumps described herein. Example microfluidic devices can include a microfluidic channel fluidly connecting a fluid inlet to a fluid outlet, and a pump described herein (e.g., a pump, hybrid pump, and/or compound pump) fluidly connected to the fluid outlet of the microfluidic channel (e.g., such that the pump induces fluid flow through the microfluidic channel when the fluid inlet is contacted with fluid). In some cases, the fluid inlet of the pump can be in direct contact with the fluid outlet of the microfluidic channel.
In certain embodiments, the pump can be configured to drive fluid flow through the microfluidic channel at a substantially continuous flow rate for a period of at least 0.1 minutes (e.g., at least 0.5 minutes, at least 1 minutes, at least 5 minutes, at least 10 minutes, at least 30 minutes, at least 60 minutes, or longer). In other embodiments, the pump can be configured to drive fluid flow through the microfluidic channel at a variable flow rate for a period of at least 10 minutes (e.g., at least 30 minutes, at least 60 minutes, or longer). The variable flow rate can comprise, for example, a stepwise increasing flow rate or a stepwise decreasing flow rate.
Methods of Use
Also provided are methods of using the pumps (including the hybrid pumps and compound pumps) described herein. The pumps described herein can be used to induce fluid flow through an attached microfluidic device (e.g., to achieve a controlled flow rate for a set volume, and/or to achieve multiple predetermined flow rates through the device). Accordingly, also provided are methods for inducing fluid flow through a microfluidic device that comprise fluidly connecting a pump described herein to a fluid outlet of the microfluidic device; and contacting a fluid inlet of the microfluidic device with a fluid. In some embodiments, the pump can be directly connected to the fluid outlet of the microfluidic device.
In certain embodiments, the pump can be configured to drive fluid flow through the microfluidic channel at a substantially continuous flow rate for a period of at least 0.1 minutes (e.g., at least 0.5 minutes, at least 1 minutes, at least 5 minutes, at least 10 minutes, at least 30 minutes, at least 60 minutes, or longer). In other embodiments, the pump can be configured to drive fluid flow through the microfluidic channel at a variable flow rate for a period of at least 10 minutes (e.g., at least 30 minutes, at least 60 minutes, or longer). The variable flow rate can comprise, for example, a stepwise increasing flow rate or a stepwise decreasing flow rate.
The pumps (including the hybrid pumps and compound pumps described herein) can also be used in process control applications. For example, pumps described herein can be used to determine the fluidic resistance of microfluidic channels, to measure the height of microfluidic channels, to quantify the properties (e.g. the permeability) of a porous material such as paper, and/or to quantify the properties (e.g., the viscosity) of an unknown fluid.
Methods of Making Compound Pumps
Given the modular nature of the pumps described herein, individual modular pumps can be readily assembled to form a compound pump to provide a predetermined fluid flow rate within a microfluidic channel. Accordingly, also provided are methods of assembling passive compound pumps configured to provide a predetermined fluid flow rate within a microfluidic channel. These methods can comprise fluidly connecting one or more pumps described herein (referred to in this context as a “pump subunit”) shaped to induce a particular fluid flow rate upon contact with a fluid to a fluid inlet to form the passive compound pump. Each pump subunit can comprise a resistive region comprising a first porous medium, and a fluidly non-conducting boundary defining a path for fluid flow through the first porous medium from the fluid inlet to the absorbent region, and an absorbent region comprising a fluidly non-conducting boundary defining a volume of a second porous medium sized to absorb a predetermined volume of fluid imbibed from the resistive region. Optionally, each pump subunit can be enclosed within an evaporation barrier.
In some embodiments, methods of assembling a passive compound pump can comprise fluidly connecting two or more pump subunits. In some embodiments, methods can comprise fluidly connecting two or more pump subunits in series. In some embodiments, methods can comprise fluidly connecting two or more pump subunits in parallel. In certain embodiments, methods can comprise fluidly connecting two or more pump subunits in series, and fluidly connecting two or more pump subunits in parallel. In certain embodiments, fluidly connecting the pump subunits can comprise stacking the pump subunits to form the fluid inlet. In these embodiments, the fluid inlet can comprise a fluidly conductive region extending through the pump subunits in the stack, and defining a path for fluid flow to the first resistive region of each of the pump subunits. The fluidly conductive region can comprise, for example, a porous medium forming a path for fluid flow. The fluidly conductive region can also comprise an open air-filled channel and/or a conductive material (e.g., fiberglass or glass wool) which provides a path for fluid flow. In some embodiments, methods can further comprise positioning a dissolvable membrane between pump subunits in the stack (e.g., transecting the fluid inlet) so as to form a barrier to fluid flow between pump subunits in the compound pump.
By way of non-limiting illustration, examples of certain embodiments of the present disclosure are given below.
Materials and Methods
As discussed above, the absorbent region and resistive region of the passive pumps described herein are formed from porous materials. The porous materials can be shaped to provide the flow rates and volumes of fluid flow desired for a particular application. The fluid inlet can be composed of the same porous material or other materials, both porous and non-porous. These materials can be selected to facilitate fluid connection of the pump to an external fluid source (e.g., a microfluidic device). The fluid inlet can in principle be adapted to connect the pump to any fluid source from which or through which one wishes to control the fluid flow rate, including but not limited to microfluidic channels or tubing. Pumps including a plurality of absorbent regions (referred to herein as “hybrid pumps”) as well as compound pumps (multi-pump assemblies including a plurality of fluidly connected pumps and/or hybrid pumps) were also prepared. As demonstrated below, hybrid pumps and compound pumps can be used to pump fluid at a variety of pre-programmed flow rates that are more complex than a simple continuous flow at a single flow rate for a set time.
For proof-of-principle experiments, chromatography paper (e.g., Whatman #1 chromatography paper), filter papers, and commercially prepared nitrocellulose membranes were used as porous materials for the fabrication of pump components. While the examples below reference paper, it will be understood that other porous materials (as discussed above) can also be used to fabricate the pumps described herein. Laser cutting was performed on a VLS3.60 laser cutting platform from Universal Laser Systems; however, other methods of shaping porous materials are also suitable. For convenience, lamination of the porous material was performed using Scotch thermal laminating pouches (letter size and photo size) with a Scotch thermal laminator was used (2 roller, maximum width 9″). The laminator settings were changed (3 mil vs 5 mil) depending on the requirements for the thermal pouch used. The cutting plotter that was used was from Graphtec (Model # CE6000-40). Clear, biaxially-oriented polystyrene films (125 μm) were from Goodfellow, Inc. Thin, double-sided adhesives were used from 3M. Single-sided Scotch tape was from 3M. Other methods for lamination, cutting and attachments are also applicable.
The imbibing fluid used in these experiments was deionized water that had been spiked with blue food coloring (Acid Blue 9, Great Value Assorted Food Coloring) to aid in the visual contrast at the wetted front and/or at the lagging edge of the fluid. A wide variety of imbibing fluids can be used including clinical fluids, environmental water samples, cell culture medium, beverages, food homogenates, and aqueous or organic solvents containing a wide variety of solutes or particles. A wide variety of suitable papers, porous materials, coating materials, machinery, and imbibing fluids can be combined for use in other embodiments.
Modeled Flow Through Segments of Porous Material
While not a perfect analogy, fluid flow through pumps can be modeled in an analogous manner to circuits, where the volumetric flow rate (Q) through a given component is equal to the pressure difference (ΔP) across the component divided by its resistance to flow (Rt) (Equation 1). In the case of paper and many other porous materials, there exists a capillary pressure at the wetted front due to the surface tension of the fluid imbibing through the pores of the porous material. This capillary pressure acts on the fluid to pull it toward unwetted regions of the porous material (i.e., imbibition). The interaction between the fluid and matrix of the porous material behind the wetted front impedes flow. Therefore, as the length of the fully wetted segment increases, the resistance does as well. For a given capillary pressure and an increasing resistance, the flow rate decreases over time
As shown in
The total resistance of the paper up to the wetted front can be approximated by adding the resistance of each segment of the wetted paper in series. In addition, the volumetric capacity of the first segment that is not yet wetted can be approximated. The volumetric flow rate at a given position of the wetted front can be calculated by using the calculated pressure difference and resistance between the fluid source and the wetted front, as described with Equation 1 and shown in
Methods of Fabricating Passive Pumps
To minimize evaporation and still provide an escape for air as the fluid imbibes, certain modifications can be made to the assembly. For example, an air gap can be maintained around the boundary of the paper. The paper in the assembly, including the air gap, can be covered from the external atmosphere to minimize evaporation effects, with only a small vent in this seal to allow for pressure equilibration. Other methods of preventing evaporation from the absorbent and resistive regions can also be used. The need for venting can likewise depend on the specific device design and application.
During step 1, a halo of paper is defined around and spaced apart from the absorbent region and the resistive region to provide the air gap around the porous material that forms a fluidly non-conducting boundary. When the vent opening is cut, the portion of the halo that is coupled to the absorbent region is removed, which prevents the halo from being in fluid communication with the absorbent region of the pump. The air gap is in communication with the vent opening. As shown in
Methods of Measuring Flow Rate
Flow studies were performed by adding fluid (e.g., 45 μL) at the inlet region, and tracking the imbibition as a function of time. The fluid used was deionized water with Acid Blue 9 in this example. Time-lapse videos of imbibition into various shapes were captured with an iPhone, and a stopwatch was included in the video to serve as an absolute measure of time. Individual frames were analyzed using ImageJ (http://imagej.nih.gov/ij/) to measure the number of pixels from the center of the inlet region to the wetted front at different time points. The pixels were converted to millimeters by knowing the length of the associated shape. For each shape, the actual position was compared with the modeled position versus time. In another method, the flow rate profile was determined for a given pump by attaching the pump to a microfluidic channel and/or tubing and tracking the position of the lagging edge of the fluid upstream.
It will be readily understood by a skilled artisan that tracking the imbibition of the fluid through the porous medium can be accomplished using a variety of, for example, optical or electrochemical approaches, to include, without limitation, the use of a dye in the porous medium instead of in the fluid (as discussed above) and the use of electrodes within the porous medium that will transmit a signal upon interaction with the fluid.
Example Passive Pumps
Assemblies of shaped porous materials can be used as passive pumps for microfluidic devices. The passive pump requires no external power or tubing to connect it to the microfluidic device. If desired, passive pump assemblies can be fabricated on and/or integrated within a microfluidic device to provide for fluid control. Alternatively, the pump can be configured to attach to a separate microfluidic device. For example, the pump can be constructed in a modular fashion (e.g., as a single disposable unit) which can then be fluidly connected to a microfluidic device. In these cases, spent pumps can be replaced with fresh pumps, for example, if pumping over long periods (e.g., several days) is required or sequential samples are collected for further analysis over time. The pump can be fabricated to be disposable, biodegradable, and/or combustible. In addition, the pumps can be designed to occupy a very small footprint.
Depending on design, the pumps can provide flow rates in the nL/min to μL/min range and can be programmed to stop flow after a fixed volume of liquid has been pumped. These programmable pumps are low-cost and can be used in a ‘plug-and-play’ fashion with a wide range of conventional microfluidic devices. As an example,
The passive pumps can be connected to the outlet of the microfluidic channel. The negative capillary pressure of the fluid in the porous material can cause a pressure differential that drives fluid flow from the reservoir at the inlet of the microchannel, through the microchannel, and into the pump. The passive pumps can be formed out of any shaped porous material, such as paper, can include up to three defined regions: (a) a fluid inlet (e.g., an inlet region) to connect to the outlet of the microchannel, (b) a resistive region (e.g., a resistive neck), and (c) an absorbent region. The inlet region (a) is designed to provide for a reproducible connection to the outlet of a microfluidic channel. For a given porous material, the size of the resistive neck (b) controls the flow rate. The resistance of the neck can be increased by increasing the length of the neck and/or decreasing the cross-sectional area of the neck. For a neck with a rectangular cross-section, this can be done by decreasing the thickness of the neck, and/or decreasing the width of the neck. The void volume of the absorbent region (c) controls the volume that can be absorbed. The time that the pump functions corresponds to the volume that can be absorbed and the flow rate defined by the neck. In
Typically, the flow rate of these passive pumps can be programmed to be from below 1 nL/min to greater than 100 μL/min. To achieve the lowest flow rates using this basic pump design, the resistance of the neck can be increased to high levels. As long as the resistance of this neck is higher than the expected resistance of the microchannel, a specific pump design will generate the same flow rate in a variety of microchannels of different geometry. This effectively makes it a ‘plug and play’ pump for a known fluid. In these cases, the pump is analogous to an ideal current source.
To achieve maximum flow rates using the basic pump design, the resistance of the neck can be minimized. With a minimal resistive region between the microfluidic channel and the absorbent region, the volumetric flow rate of the passive pump could be dependent on the resistance of the microchannel.
The effect that the neck resistance has on the volumetric flow rate can be seen in
The effect that varying the area of the absorbent region has on the volumetric flow rate can be seen in
The assembly of
This example experimentally demonstrates how to introduce time delays into the flow rate profiles produced by the passive pump assembly. Such flow delays can be used to begin the desired flow rate at a time after the point that fluid actually reaches the inlet region of the passive pump or to temporarily delay the continuation of the flow. This level of control may be desirable if additional time is needed for sample loading or reagent incubation, for example. A varying amount of sucrose or polyvinyl alcohol (or functionally equivalent material) can be dried in the fluid inlet and/or resistive region of the pump to delay fluid transport. Upon imbibition of a fluid such as water into the fluid inlet and/or resistive region, the dried solute will be dissolved, increasing the viscosity of the solution in that region of the paper according to the solute concentration (Table 1). Different solutes can be selected, particularly when using fluids other than water; the use of sucrose dried in the resistive region of a pump is described in this example.
Because resistance of a given segment of wetted paper is proportional to the viscosity of the liquid (Equation 2), dissolved sucrose can produce a significant increase in the resistance and decrease in the volumetric flow rate in the passive pump.
Since the neck is designed to be the controller of the flow rate, the flow rate increases and the pump ‘turns on’ once the fluid in the neck no longer contains the concentrated sucrose. When the dissolved sucrose reaches the absorbent section of the passive pump, the cross sectional area of the wetted front increases, decreasing the length of the viscous plug. This decreases the overall resistance to fluid flow (Equation 2), increasing the flow rate toward the limit established by the resistance of the neck for the fluid without the sucrose.
For some applications, it can be desirable to pump at a given flow rate for a given time and then decrease the flow rate to another flow rate for a second given time. Multiple, sequential flow rates (either increasing or decreasing) are also desirable for some applications. Hybrid pumps that include a plurality of resistive regions and absorbent regions can be used to provide such flow rates. For example, multiple absorbent regions can be fluidly connected in series via resistive regions as shown in
Once the fluid front reaches the second resistive region (C), the flow rate will be decreased due to the increasing resistance from the second resistive region relative to the first absorbent region (B). Once the fluid reaches the second absorbent region (D), the flow rate will again be constant. This flow behavior will continue to occur for additional resistive region/absorbent region fluidly connected in series.
Hybrid pump assemblies can also include multiple absorbent regions fluidly connected in parallel via resistive regions.
Hybrid pumps can also be designed to pump at one flow rate for a period of time and then pump at a higher flow rate for a period of time. Pumps capable of producing such flow rates can include multiple absorbent regions fluidly connected in parallel via resistive regions.
Instead of making programmable flow rates with hybrid pumps that design multiple pumping areas on a continuous sheet of porous material, multiple laminated, coplanar resistive regions and absorbent regions (referred to herein as pump subunits) can be stacked to form a single compound pump. The individual pump subunits within each coplanar layer can be fluidly connected by a single fluid inlet spanning the height of the stacked subunits as shown in
To generate more complex flow rate profiles, one can stack these subunit pumps at the distal end of the microfluidic channel. This can be used to attach subunit pumps in a manner that might otherwise be impossible using a collection of pumps in the same plane due to physical limitations to space, either between the pump subunits or because of the need to integrate the entire pump into a particular microfluidic device. Solutes generating time delays can be integrated into the resistive region of the appropriate subunit pumps that are to actuate later in a flow process. Time delays can also be generated by inserting a layer of dissolvable material (e.g., a polyvinyl alcohol membrane) between two subunit pumps in a stack (e.g., within the fluid inlet between coplanar layers of the stacked pump assembly). In this approach, the introduction of fluid into components that are after the layer of dissolvable material in the fluid path would be delayed.
The volumetric flow rate versus time for each subunit pump is additive in this setup to give the changing volumetric flow rates in the microfluidic channel.
Pump assemblies can also be stacked in order to achieve maximum volumetric flow in minimal space.
Furthermore, as illustrated in
Pumps can be fabricated to include regions of varying thickness. Because the resistance of a porous material is inversely proportional to the area normal to the direction of flow, increasing the height of certain regions of the porous material might be advantageous. For example, it could be particularly useful for the height of the absorbent region of the pump to be higher than the height of the resistive region to make the pump even more constant when the wetted from is in the absorbent region.
The three-dimensional shape of the absorbent regions of pumps can be modified to decrease the footprint of a given pump without changing the transport properties of the pump. In this case, the porous material is chromatography paper, and there is a fluid-impermeable layer on both faces of the porous material. One situation where this might be useful is if the absorbent region is significantly larger than the other portions of the pump and/or the container that it is intended to fit into. In cases like this and others, the absorbent region can be folded onto itself to decrease its footprint (
Time delays can also be introduced using dissolvable membranes. In these cases, a dissolvable membrane can be positioned between adjacent portions of porous or non-porous material in a pump or compound pump (e.g., between the fluid inlet pads of two pumps in a compound pump). While the dissolvable membrane remains intact, it can serve as a barrier to fluid flow between these adjacent portions of a pump or compound pump (e.g., between the fluid inlet pads of two fluidly connected pumps in a compound pump). However, once the membrane is breached, fluid can then flow between the adjacent portions of a pump or compound pump.
Suitable dissolvable membranes for use with aqueous fluids can be formed from polyvinyl alcohol (PVA). PVA is a water-soluble polymer that can be cast into films/sheets. Disks can be fabricated out of these films and inserted between inlet regions of stacked pumps. When exposed to a solvent in which PVA is soluble (e.g., water), the film will begin to dissolve. Once the film breaches, the fluid can advance to dry regions of the stacked pumps. This effectively gives a time delay before certain pumps (those downstream of the delay) are turned on. This delay time can be controlled through means such as adjusting the thickness of the film.
Pumps can be prepared from porous materials that have various properties (e.g. capillary pressure, porosity, and permeability). These properties have an effect on the flow rate profile. If, for example, the footprint of the pump needed to be a fixed size, these properties might be chosen to achieve the desired flow rate profile for a given fluid/microchannel. In other examples, a material might be chosen to have a mean pore size that is larger than particles expected to be in the fluid to avoid clogging.
Using Passive Pump Assemblies in Process and Quality Control
The pumps (including the hybrid pumps and compound pumps described herein) can also be used in process control applications. For example, pumps described herein can be used to determine the fluidic resistance of microfluidic channels, to measure the height of microfluidic channels, to quantify the properties (e.g. the permeability) of a porous material such as paper, and/or to quantify the properties (e.g., the viscosity) of an unknown fluid.
The passive pumps described herein can be used in conjunction with a simple microfluidic device to determine the viscosity of an unknown fluid. The microfluidic device can include a microfluidic channel fluidly connecting a fluid inlet to a fluid outlet. The microfluidic channel can contain a pre-loaded fluid. The fluid inlet of a pump that has been well characterized for the imbibition of the pre-loaded fluid can be fluidly connected to the fluid outlet of the microfluidic device. An unknown fluid can be added to the fluid inlet of the microfluidic device, and the device could be actuated to bring the pre-loaded fluid in contact with the passive pump.
The passive pump will induce fluid flow into the microfluidic channel. The rate by which the pump causes fluid to flow will be inversely proportional to the total resistance to fluid flow (which is the sum of the resistance of the pump, the resistance of the plug of pre-loaded fluid, and the resistance of the unknown plug of fluid). To make the flow rate sensitive to the viscosity of the unknown fluid, the total resistance should be dominated by a region where the unknown fluid is flowing. This can be done by the proper design of the pump, pre-loaded fluid, and microfluidic channel. The resistance will be directly proportional to the viscosity of the unknown fluid. Accordingly, the rate of pumping and/or time of pumping can be measured and compared to a calibration curve to quantify the viscosity of the unknown fluid.
Microfluidic devices are generally fabricated to have a set of dimensions in an attempt to produce desirable fluid dynamics. However, while the fluid dynamics can be predicted with a computational model, it is generally difficult to characterize microfluidic devices to determine whether devices were fabricated to the original specified dimensions. Measuring the fluidic resistance of a microchannel is one way to determine its physical dimensions.
The passive pump can be used to measure the resistance of a microfluidic channel for cost-effective quality control. For a given pump, the time that the pump takes to fill is dependent on the resistance of the microfluidic device. The resistance of a microfluidic channel can be measured using the setup schematically illustrated in
One can test the microfluidic channel with a set of passive pumps that have various ranges of quantitation. The lower limit of quantitation of a given pump is dependent on the effective resistance/permeability of that porous material. If the pump's resistance is significantly greater than the microchannel, the pump will likely be unable to quantify the resistance—as the pump's resistance will dominate. If the resistance of the channel is significantly higher than the resistance of the wetted assembly, the channel's resistance would be the dominant controller of the volumetric flow rate. Thus the time that the passive pump takes to fill is directly dependent on the resistance of the microchannel (inset of
The flow of fluid in a porous material such as paper can be described with a first order model by knowing the 3D shape and three characteristic properties of the given material and fluid: the effective porosity (Por), capillary pressure (Pc), and permeability (K). The product of the capillary pressure and permeability can be determined by tracking fluid flow through a single segment. However, the individual properties are essential to describe the flow fully.
A set of microfluidic channels with known resistance can be used to quantify properties of porous materials in a rapid, simple measurement. Using the known resistances of microfluidic channels to generate several unique sets of imbibition data can provide solutions for the two unknowns (Pc and K) for the paper or other porous material. A microfluidic channel with a known resistance can be placed between the reservoir and the paper, adding a known resistance in series to the fluidic circuit. These unique sets of imbibition data can then be fit using a least squares approach to identify the Pc and K values that best describe the imbibition of that given fluid into the paper.
This method for determining microfluidic resistance could also be used in process control of paper substrates such as those intended to be used for paper-based microfluidics. A set of microfluidic channels with various resistances, spanning from much lower than the resistance of the paper to much higher resistance than the paper could be used to test different batches of paper. The collected imbibition data could then be used in the model to predict the Pc and K for the given fluid and paper and monitor the functional capacity of the paper.
The devices, systems, and methods of the appended claims are not limited in scope by the specific devices, systems, and methods described herein, which are intended as illustrations of a few aspects of the claims. Any devices, systems, and methods that are functionally equivalent are intended to fall within the scope of the claims. Various modifications of the devices, systems, and methods in addition to those shown and described herein are intended to fall within the scope of the appended claims. Further, while only certain representative devices, systems, and method steps disclosed herein are specifically described, other combinations of the devices, systems, and method steps also are intended to fall within the scope of the appended claims, even if not specifically recited. Thus, a combination of steps, elements, components, or constituents may be explicitly mentioned herein or less, however, other combinations of steps, elements, components, and constituents are included, even though not explicitly stated.
Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of skill in the art to which the disclosed invention belongs. Publications cited herein and the materials for which they are cited are specifically incorporated by reference.
This application claims benefit of U.S. Provisional Application No. 62/214,352 filed Sep. 4, 2015, is hereby incorporated herein by reference in its entirety.
This invention was made with Government Support under Grant No. UL1TR001111 awarded by the National Institutes of Health. The Government has certain rights in the invention.
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| Number | Date | Country | |
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| 20170065973 A1 | Mar 2017 | US |
| Number | Date | Country | |
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| 62214352 | Sep 2015 | US |
